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Kamate M, Teranishi H, Umeda R, Shikano K, Kitaoka S, Hanada T, Hikida T, Kawano K, Hanada R. Dietary texture-driven masticatory activity and its impact on stress tolerance. J Oral Biosci 2025; 67:100628. [PMID: 39923995 DOI: 10.1016/j.job.2025.100628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/06/2025] [Accepted: 01/26/2025] [Indexed: 02/11/2025]
Abstract
OBJECTIVES Although previous studies suggest that dietary texture-driven masticatory activity is correlated with stress tolerance, the underlying mechanisms, including neurotransmitter dynamics, remain unclear. This study investigated the effects of dietary texture-driven masticatory activity on stress tolerance in mice. METHODS Behavioral responses to stress were assessed using the repeated social defeat stress (R-SDS) and social interaction test (SIT) model. Neurotransmitter levels in stress-related brain regions were analyzed in mice fed a solid diet (promoting masticatory activity) or a powdered diet (decreasing masticatory activity). RESULTS Mice fed the powdered diet exhibited reduced stress tolerance compared with those fed the solid diet. Following the R-SDS, the powdered diet group displayed elevated gamma-aminobutyric acid (GABA) and norepinephrine levels in the prefrontal cortex. Before stress treatment, glutamic acid levels increased and those of choline decreased in the amygdala, whereas dopamine levels decreased in the powdered diet group after the R-SDS. In the locus coeruleus, mice on the powdered diet showed decreased glutamic acid and adenosine levels, alongside increased GABA levels. Serotonin levels decreased in the powdered diet group after the R-SDS, with no changes observed after the SIT. In the ventral hippocampus, GABA levels increased in the powdered diet group but decreased after the SIT. CONCLUSIONS This study demonstrates a correlation between masticatory activity and stress tolerance, evidenced by both behavioral and neurotransmitter changes. These findings suggest that reduced masticatory activity due to dietary texture contributes to decreased stress resilience.
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Affiliation(s)
- Mie Kamate
- Department of Neurophysiology, Faculty of Medicine, Oita University, Oita, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Oita University, Oita, Japan
| | - Hitoshi Teranishi
- Department of Neurophysiology, Faculty of Medicine, Oita University, Oita, Japan
| | - Ryohei Umeda
- Department of Neurophysiology, Faculty of Medicine, Oita University, Oita, Japan; Department of Advanced Medical Science, Faculty of Medicine, Oita University, Oita, Japan
| | - Kenshiro Shikano
- Department of Neurophysiology, Faculty of Medicine, Oita University, Oita, Japan
| | - Shiho Kitaoka
- Department of Pharmacology, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Toshikatsu Hanada
- Department of Cell Biology, Faculty of Medicine, Oita University, Oita, Japan
| | - Takatoshi Hikida
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Kenji Kawano
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Oita University, Oita, Japan
| | - Reiko Hanada
- Department of Neurophysiology, Faculty of Medicine, Oita University, Oita, Japan.
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Garofalo S, Mormino A, Mazzarella L, Cocozza G, Rinaldi A, Di Pietro E, Di Castro MA, De Felice E, Maggi L, Chece G, Andolina D, Ventura R, Ielpo D, Piacentini R, Catalano M, Stefanini L, Limatola C. Platelets tune fear memory in mice. Cell Rep 2025; 44:115261. [PMID: 39903668 DOI: 10.1016/j.celrep.2025.115261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/13/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025] Open
Abstract
Several lines of evidence have shown that platelet-derived factors are key molecules in brain-body communication in pathological conditions. Here, we identify platelets as key actors in the modulation of fear behaviors in mice through the control of inhibitory neurotransmission and plasticity in the hippocampus. Interfering with platelet number or activation reduces hippocampal serotonin (5-HT) and modulates fear learning and memory in mice, and this effect is reversed by serotonin replacement by serotonin precursor (5-HTP)/benserazide. In addition, we unravel that natural killer (NK) cells participate in this mechanism, regulating interleukin-13 (IL-13) levels in the gut, with effects on serotonin production by enterochromaffin cells and uptake by platelets. Both NK cells and platelet depletion reduce the activation of hippocampal inhibitory neurons and increase the long-term potentiation of synaptic transmission. Understanding the role of platelets in the modulation of neuro-immune interactions offers additional tools for the definition of the molecular and cellular elements involved in the growing field of brain-body communication.
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Affiliation(s)
- Stefano Garofalo
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
| | - Alessandro Mormino
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Letizia Mazzarella
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Germana Cocozza
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Arianna Rinaldi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Erika Di Pietro
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | | | - Eleonora De Felice
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Laura Maggi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Giuseppina Chece
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Diego Andolina
- Department of Psychology and Center for Research in Neurobiology 'D. Bovet', Sapienza University of Rome, Rome, Italy
| | - Rossella Ventura
- Department of Psychology and Center for Research in Neurobiology 'D. Bovet', Sapienza University of Rome, Rome, Italy
| | - Donald Ielpo
- Department of Psychology and Center for Research in Neurobiology 'D. Bovet', Sapienza University of Rome, Rome, Italy
| | - Roberto Piacentini
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; IRCCS Fondazione Policlinico Universitario A. Gemelli, Largo A. Gemelli 1, Roma, Italy
| | - Myriam Catalano
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Lucia Stefanini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristina Limatola
- Laboratory affiliated with Istituto Pasteur, Department of Physiology and Pharmacology, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy.
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Wang T, Homberg JR, Boreggio L, Samina MCF, Castro RCR, Kolk SM, Alenina N, Bader M, Dai J, Wöhr M. Socio-affective communication in Tph2-deficient rat pups: communal nesting aggravates growth retardation despite ameliorating maternal affiliation deficits. Mol Autism 2024; 15:50. [PMID: 39614401 PMCID: PMC11606121 DOI: 10.1186/s13229-024-00629-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/30/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND A lack of serotonin (also known as 5-hydroxytryptamine, 5-HT) in the brain due to deficiency of the rate-limiting enzyme in 5-HT synthesis, tryptophan hydroxylase 2 (TPH2), was recently reported to result in impaired maternal affiliation across species, including mice, rats, and monkeys. In rodents, this was reflected in a lack of preference for maternal odors and reduced levels of isolation-induced ultrasonic vocalizations (USV), possibly contributing to a severe growth retardation phenotype. METHODS Here, we tested whether growth retardation, maternal affiliation deficits, and/or impairments in socio-affective communication caused by Tph2 deficiency can be rescued through early social enrichment in rats. To this aim, we compared male and female Tph2-/- knockout and Tph2+/- heterozygous rat pups to Tph2+/+ wildtype littermate controls, with litters being randomly assigned to standard nesting (SN; one mother with her litter) or communal nesting (CN; two mothers with their two litters). RESULTS Our results show that Tph2 deficiency causes severe growth retardation, together with moderate impairments in somatosensory reflexes and thermoregulatory capabilities, partially aggravated by CN. Tph2 deficiency further led to deficits in socio-affective communication, as evidenced by reduced emission of isolation-induced USV, associated with changes in acoustic features, clustering of subtypes, and temporal organization. Although CN did not rescue the impairments in socio-affective communication, CN ameliorated the maternal affiliation deficit caused by Tph2 deficiency in the homing test. To close the communicative loop between mother and pup, we assessed maternal preference and showed that mothers display a preference for Tph2+/+ controls over Tph2-/- pups, particularly under CN conditions. This is consistent with the aggravated growth phenotype in Tph2-/- pups exposed to the more competitive CN environment. CONCLUSION Together, this indicates that CN aggravates growth retardation despite ameliorating maternal affiliation deficits in Tph2-deficient rat pups, possibly due to reduced and acoustically altered isolation-induced USV, hindering efficient socio-affective communication between mother and pup.
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Affiliation(s)
- Tianhua Wang
- Faculty of Psychology, Experimental and Biological Psychology, Philipps-Universität Marburg, Behavioral Neuroscience, 35032, Marburg, Germany
- Philipps-Universität Marburg, Center for Mind, Brain, and Behavior (CMBB), 35032, Marburg, Germany
| | - Judith R Homberg
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, 6525 EN, Nijmegen, The Netherlands
| | - Laura Boreggio
- Molecular Biology of Peptide Hormones, Max-Delbrück-Centrum Für Molekulare Medizin (MDC), 13125, Berlin, Germany
| | - Marta C F Samina
- Radboud University, Donders Institute for Brain, Cognition, and Behaviour, 6525 AJ, Nijmegen, The Netherlands
| | - Rogério C R Castro
- Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, 6525 EN, Nijmegen, The Netherlands
| | - Sharon M Kolk
- Radboud University, Donders Institute for Brain, Cognition, and Behaviour, 6525 AJ, Nijmegen, The Netherlands
| | - Natalia Alenina
- Molecular Biology of Peptide Hormones, Max-Delbrück-Centrum Für Molekulare Medizin (MDC), 13125, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, 10785, Berlin, Germany
| | - Michael Bader
- Molecular Biology of Peptide Hormones, Max-Delbrück-Centrum Für Molekulare Medizin (MDC), 13125, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, 10785, Berlin, Germany
- Charité University Medicine Berlin, 10117, Berlin, Germany
- Institute for Biology, University of Lübeck, 23562, Lübeck, Germany
| | - Jinye Dai
- Department of Pharmacological Sciences and Department of Neuroscience, Mount Sinai, Icahn School of Medicine, Friedman Brain Institute, New York, 10029, USA
| | - Markus Wöhr
- Faculty of Psychology, Experimental and Biological Psychology, Philipps-Universität Marburg, Behavioral Neuroscience, 35032, Marburg, Germany.
- Philipps-Universität Marburg, Center for Mind, Brain, and Behavior (CMBB), 35032, Marburg, Germany.
- Faculty of Psychology and Educational Sciences, Research Unit Brain and Cognition, Laboratory of Biological Psychology, Social and Affective Neuroscience Research Group, KU Leuven, Tiensestraat 102 - Bus 3714, 3000, Louvain, Belgium.
- KU Leuven, Leuven Brain Institute, 3000, Louvain, Belgium.
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Imai M, Kawakami F, Uematsu T, Matsumoto T, Kawashima R, Kurosaki Y, Tamaki S, Maehana S, Ichikawa T, Hanaki H, Kitazato H, Kubo M. SARS-CoV-2 propagation to the TPH2-positive neurons in the ventral tegmental area induces cell death via GSK3β-dependent accumulation of phosphorylated tau. PLoS One 2024; 19:e0312834. [PMID: 39475992 PMCID: PMC11524480 DOI: 10.1371/journal.pone.0312834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 10/14/2024] [Indexed: 11/02/2024] Open
Abstract
COVID-19, an infectious disease caused by SARS-CoV-2, was declared a pandemic by the WHO in 2020. Psychiatric symptoms including sleep disturbance, memory impairment, and depression are associated with SARS-CoV-2 infection. These symptoms are causes long-term mental and physical distress in recovering patients; however, the underlying mechanism is unclear. In this study, we determined the effects of SARS-CoV-2 infection on brain tissue using k18hACE2 mice. Using brain tissue from 18hACE2 mice infected with SARS-CoV-2 through intranasal administration, SARS-CoV-2 spike protein and RNA were analyzed by immunohistochemical staining and in-situ hybridization. Immunohistochemical analysis revealed that Tryptophan hydroxylase 2 (TPH2)-positive cells and SARS-CoV-2 spike protein were co-localized in the ventral tegmental area of SARS-CoV-2-infected mice. We observed decreased TPH2 expression and increased accumulation of phosphorylated tau protein and Phospho-Histone H2A.X (γH2AX) expression in the ventral tegmental region. In addition, activation of glycogen synthase kinase 3β (GSK3β) was induced by SARS-CoV-2 infection. Overall, our results suggest that SARS-CoV-2 infection of TPH2-positive cells in the ventral tegmental area induces neuronal cell death through increased accumulation of phosphorylated tau. Attenuation of the GSK3β pathway and decreased serotonin synthesis through suppression of TPH2 expression may contribute to the development of neurological symptoms.
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Affiliation(s)
- Motoki Imai
- Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Fumitaka Kawakami
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Health Administration, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Takayuki Uematsu
- Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama, Japan
| | - Toshihide Matsumoto
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Pathology, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Rei Kawashima
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Yoshifumi Kurosaki
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Clinical Chemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Shun Tamaki
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Shotaro Maehana
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
| | - Takafumi Ichikawa
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Biochemistry, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Hideaki Hanaki
- Infection Control Research Center, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-Ku, Tokyo, Japan
| | - Hidero Kitazato
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
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Zaniewska M, Alenina N, Fröhler S, Chen W, Bader M. Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT 2C receptor in the mouse brain. Pharmacol Rep 2023; 75:1502-1521. [PMID: 37923824 PMCID: PMC10661786 DOI: 10.1007/s43440-023-00545-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/29/2023] [Accepted: 10/11/2023] [Indexed: 11/06/2023]
Abstract
BACKGROUND Serotonin (5-HT) 5-HT2C receptor mRNA editing (at five sites, A-E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence-often accompanied by depressive symptoms. METHODS We used deep sequencing to investigate 5-HT2C receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived "high ethanol-drinking" mice displayed reduced Tph2 expression, elevated 5-HT2C receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2-/- mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT2C receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT2C receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation.
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Affiliation(s)
- Magdalena Zaniewska
- Department of Pharmacology, Laboratory of Pharmacology and Brain Biostructure, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343, Kraków, Poland.
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Sebastian Fröhler
- Laboratory for New Sequencing Technology, Max-Delbrück-Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Wei Chen
- Laboratory for New Sequencing Technology, Max-Delbrück-Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Department of Systems Biology, School of Life Science, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin, Germany
- Institute for Biology, University of Lübeck, Lübeck, Germany
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Herrera K, Maldonado-Ruiz R, Camacho-Morales A, de la Garza AL, Castro H. Maternal methyl donor supplementation regulates the effects of cafeteria diet on behavioral changes and nutritional status in male offspring. Food Nutr Res 2023; 67:9828. [PMID: 37920679 PMCID: PMC10619398 DOI: 10.29219/fnr.v67.9828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 11/04/2023] Open
Abstract
Background Nutritional status and maternal feeding during the perinatal and postnatal periods can program the offspring to develop long-term health alterations. Epidemiologic studies have demonstrated an association between maternal obesity and intellectual disability/cognitive deficits like autism spectrum disorders (ASDs) in offspring. Experimental findings have consistently been indicating that maternal supplementation with methyl donors, attenuated the social alterations and repetitive behavior in offspring. Objective This study aims to analyze the effect of maternal cafeteria diet and methyl donor-supplemented diets on social, anxiety-like, and repetitive behavior in male offspring, besides evaluating weight gain and food intake in both dams and male offspring. Design C57BL/6 female mice were randomized into four dietary formulas: control Chow (CT), cafeteria (CAF), control + methyl donor (CT+M), and cafeteria + methyl donor (CAF+M) during the pre-gestational, gestational, and lactation period. Behavioral phenotyping in the offspring was performed by 2-month-old using Three-Chamber Test, Open Field Test, and Marble Burying Test. Results We found that offspring prenatally exposed to CAF diet displayed less social interaction index when compared with subjects exposed to Chow diet (CT group). Notably, offspring exposed to CAF+M diet recovered social interaction when compared to the CAF group. Discussion These findings suggest that maternal CAF diet is efficient in promoting reduced social interaction in murine models. In our study, we hypothesized that a maternal methyl donor supplementation could improve the behavioral alterations expected in maternal CAF diet offspring. Conclusions The CAF diet also contributed to a social deficit and anxiety-like behavior in the offspring. On the other hand, a maternal methyl donor-supplemented CAF diet normalized the social interaction in the offspring although it led to an increase in anxiety-like behaviors. These findings suggest that a methyl donor supplementation could protect against aberrant social behavior probably targeting key genes related to neurotransmitter pathways.
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Affiliation(s)
- Katya Herrera
- Universidad Autonoma de Nuevo León, Facultad de Salud Pública y Nutrición, Centro de Investigación en Nutrición y Salud Pública. Monterrey, Nuevo León, México
| | - Roger Maldonado-Ruiz
- Universidad Autonoma de Nuevo Leon, Unidad de Neurometabolismo, Centro de Investigación y Desarrollo en Ciencias de la Salud. Monterrey, Nuevo León, México
| | - Alberto Camacho-Morales
- Universidad Autonoma de Nuevo Leon, Unidad de Neurometabolismo, Centro de Investigación y Desarrollo en Ciencias de la Salud. Monterrey, Nuevo León, México
- Universidad Autonoma de Nuevo Leon, Facultad de Medicina, Departamento de Bioquímica. Monterrey, Nuevo León, México
| | - Ana Laura de la Garza
- Universidad Autonoma de Nuevo Leon, Unidad de Nutrición, Centro de Investigación y Desarrollo en Ciencias de la Salud. Monterrey, Nuevo León, México
| | - Heriberto Castro
- Universidad Autonoma de Nuevo León, Facultad de Salud Pública y Nutrición, Centro de Investigación en Nutrición y Salud Pública. Monterrey, Nuevo León, México
- Universidad Autonoma de Nuevo Leon, Unidad de Nutrición, Centro de Investigación y Desarrollo en Ciencias de la Salud. Monterrey, Nuevo León, México
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Peng S, He CY, Zhang Q, Wang M, Sheng X, Gao J, Ge L, Zhang Z, Wang H, Hu XZ. Acquisition and extinction of active avoidance compulsive-like behavior in mice. J Psychiatr Res 2023; 168:91-99. [PMID: 39492237 DOI: 10.1016/j.jpsychires.2023.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/19/2023] [Accepted: 10/12/2023] [Indexed: 11/05/2024]
Abstract
Approximately 90% of adults have ever experienced obsessions, yet less than 3% of them develop OCD. It is hypothesized that excessive fear of negative events contributes to OCD onset and development, which is related to the individual differences in psychopathology and neurophysiology associated with OCD among those who experience obsessions. To explore the hypothesis, this study examined if a fear-inducing aversive footshock could induce compulsive-like lever-pressing behavior in mice, the effects of extinction treatments on the compulsive-like behavior, and how the expression of tryptophan hydroxylase 2 (TPH2) in the amygdala would be regulated. This study successfully established a novel active avoidance OCD model in mice (model mice), manifesting compulsive-like lever-pressing with a smaller range of exploring in response to fear-inducing footshock. The compulsive-like behavior could be alleviated. The TPH2 in the left amygdala was down-regulated in model mice but up-regulated after food treatment and fluoxetine treatment. Food was the most effective treatment for reducing compulsive-like behavior and up-regulating the TPH2 levels in the left amygdala, followed by fluoxetine, sham, and sound. Our findings elucidate the fundamental processes of the acquisition and extinction of an active avoidance compulsive-like behavior in mice and provide insight into potential interventions to improve the prognosis of the compulsive-like behavior. This study provides evidence that the acquisition and extinction of active avoidance compulsive-like behavior in mice is associated with neuroplasticity relevant to protein regulation affected by brain-environment interactions.
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Affiliation(s)
- Shiyong Peng
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Chen-Yang He
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China; The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Qiuyu Zhang
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Mengting Wang
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Xiaohang Sheng
- Henan Key Laboratory of Immunology and Targeted Drugs, Department of Immunology, Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Jingjing Gao
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Lihao Ge
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Zhongjian Zhang
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Hui Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, Department of Immunology, Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China
| | - Xian-Zhang Hu
- Institute of Psychiatry and Neuroscience (IPN), Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China; The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, Henan Province, PR China.
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Wang J, Ding L, Yu X, Wu F, Zhang J, Chen P, Qian S, Wang M. Tryptophan improves antioxidant capability and meat quality by reducing responses to stress in nervous Hu sheep. Meat Sci 2023; 204:109267. [PMID: 37392733 DOI: 10.1016/j.meatsci.2023.109267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/14/2023] [Accepted: 06/21/2023] [Indexed: 07/03/2023]
Abstract
In sheep, the effect of tryptophan (Trp) on behavioural traits that are associated with temperament and any effects on production traits is unknown. The hypothesis of this study is that the supplementation of Trp would improve temperament by enhancing serotonin production, which is beneficial to meat production subsequently in sheep. Twelve ewes that had the lowest and 12 ewes that had the highest behavioural responses to human contact were selected into the calm and the nervous groups respectively. Then, the ewes from each group were equally assigned into two treatments that were treated with the basal diet and the diet with extra 90 mg/kg/d Trp for 30 d. The temperament traits, the growth performance, the biochemicals that are related to health the slaughter performance and meat quality were measured at the end of feeding experiment. The findings in this study suggested the Hu sheep with calm temperament would experience less stress during production, resulting in less oxidative stress, better growth performance, slaughter traits and carcass traits, compared to the nervous sheep. Meanwhile, the dietary supplementation of Trp reduced stress responses by enhancing production of 5-HT in sheep from the nervous group which is beneficial to improve the production traits that mentioned above.
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Affiliation(s)
- Jiasheng Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Luoyang Ding
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; School of Agriculture and Environment, The University of Western Australia, Perth 6009, WA, Australia; State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi 832000, Xinjiang, China
| | - Xiang Yu
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Feifan Wu
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Jinying Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Peigen Chen
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Shuhan Qian
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Mengzhi Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi 832000, Xinjiang, China.
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9
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Strekalova T, Moskvin O, Jain AY, Gorbunov N, Gorlova A, Sadovnik D, Umriukhin A, Cespuglio R, Yu WS, Tse ACK, Kalueff AV, Lesch KP, Lim LW. Molecular signature of excessive female aggression: study of stressed mice with genetic inactivation of neuronal serotonin synthesis. J Neural Transm (Vienna) 2023; 130:1113-1132. [PMID: 37542675 PMCID: PMC10460733 DOI: 10.1007/s00702-023-02677-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 07/21/2023] [Indexed: 08/07/2023]
Abstract
Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2+/- mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2+/- mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.
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Affiliation(s)
- Tatyana Strekalova
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Oleg Moskvin
- Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
- Singapore Medical School, BluMaiden Biosciences, Singapore, Singapore
| | - Aayushi Y Jain
- Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Nikita Gorbunov
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Anna Gorlova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
| | - Daria Sadovnik
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
| | - Aleksei Umriukhin
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
| | - Raymond Cespuglio
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov Moscow State Medical University, Moscow, Russia
- Neuroscience Research Center of Lyon, Beliv Plateau, Claude-Bernard Lyon-1 University, Bron, France
| | - Wing Shan Yu
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Anna Chung Kwan Tse
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Allan V Kalueff
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
| | - Lee Wei Lim
- Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
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10
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Vázquez-León P, Miranda-Páez A, Valencia-Flores K, Sánchez-Castillo H. Defensive and Emotional Behavior Modulation by Serotonin in the Periaqueductal Gray. Cell Mol Neurobiol 2023; 43:1453-1468. [PMID: 35902460 PMCID: PMC11412428 DOI: 10.1007/s10571-022-01262-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/13/2022] [Indexed: 11/26/2022]
Abstract
Serotonin 5-hydroxytryptamine (5-HT) is a key neurotransmitter for the modulation and/or regulation of numerous physiological processes and psychiatric disorders (e.g., behaviors related to anxiety, pain, aggressiveness, etc.). The periaqueductal gray matter (PAG) is considered an integrating center for active and passive defensive behaviors, and electrical stimulation of this area has been shown to evoke behavioral responses of panic, fight-flight, freezing, among others. The serotonergic activity in PAG is influenced by the activation of other brain areas such as the medial hypothalamus, paraventricular nucleus of the hypothalamus, amygdala, dorsal raphe nucleus, and ventrolateral orbital cortex. In addition, activation of other receptors within PAG (i.e., CB1, Oxytocin, µ-opioid receptor (MOR), and γ-aminobutyric acid (GABAA)) promotes serotonin release. Therefore, this review aims to document evidence suggesting that the PAG-evoked behavioral responses of anxiety, panic, fear, analgesia, and aggression are influenced by the activation of 5-HT1A and 5-HT2A/C receptors and their participation in the treatment of various mental disorders.
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Affiliation(s)
- Priscila Vázquez-León
- Neuropsychopharmacology Laboratory, Psychology School. 1er Piso Edif. B. Cub B001, National Autonomous University of Mexico, Avenida Universidad 3000, Colonia Copilco Universidad. Alcaldía de Coyoacan, Mexico City, Mexico
| | - Abraham Miranda-Páez
- Department of Physiology, National School of Biological Sciences, National Polytechnic Institute, Wilfrido Massieu esq. Manuel Stampa S/N Col. Nueva Industrial Vallejo, Gustavo A. Madero, Mexico City, CP:07738, Mexico
| | - Kenji Valencia-Flores
- Neuropsychopharmacology Laboratory, Psychology School. 1er Piso Edif. B. Cub B001, National Autonomous University of Mexico, Avenida Universidad 3000, Colonia Copilco Universidad. Alcaldía de Coyoacan, Mexico City, Mexico
| | - Hugo Sánchez-Castillo
- Neuropsychopharmacology Laboratory, Psychology School. 1er Piso Edif. B. Cub B001, National Autonomous University of Mexico, Avenida Universidad 3000, Colonia Copilco Universidad. Alcaldía de Coyoacan, Mexico City, Mexico.
- Research Unit of Psychobiology and Neurosciences (UIPyN), Psychology School, UNAM, CDMX Mexico, CP 04510, Mexico.
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11
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Sakala K, Katus U, Kiive E, Veidebaum T, Harro J. Is low platelet MAO activity associated with antisocial behavior? evidence from representative samples of longitudinally observed birth cohorts. Brain Res 2023; 1804:148249. [PMID: 36682705 DOI: 10.1016/j.brainres.2023.148249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/09/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023]
Abstract
Lower platelet monoamine oxidase (MAO) activity has been associated with problem behaviors, including criminal behavior, but not all studies agree. We have examined platelet MAO activity and antisocial behavior involving police contact in a longitudinal birth cohort study. The sample included both birth cohorts (original n = 1238) of the Estonian Children Personality Behavior and Health Study. Platelet MAO activity was measured at ages 15, 18 and 25 radioenzymatically with β-phenylethylamine as the substrate. Police contacts were self-reported in an interview and drug use in a questionnaire filled in during a laboratory visit. In cross-sectional analyses, males with the record of antisocial behavior had lower platelet MAO activity. In longitudinal mixed-effect regression models, this association was found to be independent of smoking. Furthermore, including smoking in the model revealed lower platelet MAO activity also in females with past antisocial behaviour. A further exploratory regression analysis with antisocial behavior at two levels of frequency and consideration of self-reported use of illicit drugs either in a single occasion or repeatedly demonstrated some "dose-dependency" in the relationship of antisocial behavior and platelet MAO activity. Platelet MAO activity was lower in male but not female subjects with basic education level as compared to secondary and higher education, but it was not related to non-verbal intelligence. Neither was platelet MAO activity associated with socio- economic status. In conclusion, antisocial behavior as occurring in general population is associated with low platelet MAO activity that probably reflects low capacity of the serotonergic system.
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Affiliation(s)
- Katre Sakala
- Department of Family Medicine and Public Health, Faculty of Medicine, University of Tartu, Estonia; Department of Chronic Diseases, National Institute for Health Development, Tallinn, Estonia; School of Natural Sciences and Health, Tallinn University, Tallinn, Estonia
| | - Urmeli Katus
- Department of Family Medicine and Public Health, Faculty of Medicine, University of Tartu, Estonia
| | - Evelyn Kiive
- Division of Special Education, Department of Education, University of Tartu, Estonia
| | - Toomas Veidebaum
- Department of Chronic Diseases, National Institute for Health Development, Tallinn, Estonia
| | - Jaanus Harro
- School of Natural Sciences and Health, Tallinn University, Tallinn, Estonia; Chair of Neuropsychopharmacology, Institute of Chemistry, University of Tartu, Tartu, Estonia.
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12
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Braccagni G, Scheggi S, Bortolato M. Elevated levels of serotonin 5-HT 2A receptors in the orbitofrontal cortex of antisocial individuals. Eur Arch Psychiatry Clin Neurosci 2023; 273:411-425. [PMID: 36094569 PMCID: PMC10831872 DOI: 10.1007/s00406-022-01480-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/17/2022] [Indexed: 11/03/2022]
Abstract
Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4. Our analyses documented a significant increase in 5-HT2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.
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Affiliation(s)
- Giulia Braccagni
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, L.S. Skaggs Hall, Room 3916, 30 S 2000 E, Salt Lake City, UT, 84112, USA
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Simona Scheggi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, L.S. Skaggs Hall, Room 3916, 30 S 2000 E, Salt Lake City, UT, 84112, USA.
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13
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Ma J, Wang R, Chen Y, Wang Z, Dong Y. 5-HT attenuates chronic stress-induced cognitive impairment in mice through intestinal flora disruption. J Neuroinflammation 2023; 20:23. [PMID: 36737776 PMCID: PMC9896737 DOI: 10.1186/s12974-023-02693-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 01/03/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The microbiota-gut-brain axis plays an important role in the development of depression. The aim of this study was to investigate the effects of 5-HT on cognitive function, learning and memory induced by chronic unforeseeable mild stress stimulation (CUMS) in female mice. CUMS mice and TPH2 KO mice were used in the study. Lactococcus lactis E001-B-8 fungus powder was orally administered to mice with CUMS. METHODS We used the open field test, Morris water maze, tail suspension test and sucrose preference test to examine learning-related behaviours. In addition, AB-PAS staining, immunofluorescence, ELISA, qPCR, Western blotting and microbial sequencing were employed to address our hypotheses. RESULTS The effect of CUMS was more obvious in female mice than in male mice. Compared with female CUMS mice, extracellular serotonin levels in TPH2 KO CUMS mice were significantly reduced, and cognitive dysfunction was aggravated. Increased hippocampal autophagy levels, decreased neurotransmitter levels, reduced oxidative stress damage, increased neuroinflammatory responses and disrupted gut flora were observed. Moreover, L. lactis E001-B-8 significantly improved the cognitive behaviour of mice. CONCLUSIONS These results strongly suggest that L. lactis E001-B-8 but not FLX can alleviate rodent depressive and anxiety-like behaviours in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition.
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Affiliation(s)
- Junxing Ma
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Ran Wang
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing, 100193, China
| | - Yaoxing Chen
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Zixu Wang
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Yulan Dong
- National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
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14
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Lin X, Huang L, Huang H, Ke Z, Chen Y. Disturbed relationship between glucocorticoid receptor and 5-HT1AR/5-HT2AR in ADHD rats: A correlation study. Front Neurosci 2023; 16:1064369. [PMID: 36699537 PMCID: PMC9869156 DOI: 10.3389/fnins.2022.1064369] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/16/2022] [Indexed: 01/12/2023] Open
Abstract
Objective This work is to investigate the alterations of the central 5-hydroxytryptamine (5-HT) system in spontaneously hypertensive rats (SHR) and the correlation with the behaviors of SHR, and to explore the effects of glucocorticoid intervention on the central 5-HT system and SHR behaviors. Materials and methods Three weeks old SHR were chosen as the attention-deficit hyperactivity disorder (ADHD) model and treated with glucocorticoid receptor (GR) agonist or inhibitor, whereas Wista Kyoto rats (WKY) were chosen as the normal control group. Open-field test and Làt maze test were used to evaluate the spontaneous activities and non-selective attention. The levels of 5-HT in the extracellular fluid specimens of the prefrontal cortex of rats were analyzed by high-performance liquid chromatography. The expressions of GR, 5-HT1A receptor (5-HT1AR), and 5-HT2A receptor (5-HT2AR) in the prefrontal cortex were analyzed through immunohistochemistry. Results Our study demonstrated that the 5-HT level was lower in the prefrontal cortex of SHR compared to that of WKY. The Open-field test and Làt maze test showed that GR agonist (dexamethasone, DEX) intervention ameliorated attention deficit and hyperactive behavior, whereas GR inhibitor (RU486) aggravated the disorders. With DEX, the expression levels of 5-HT and 5-HT2AR in the prefrontal cortex of SHR were significantly higher than those in the control group, whereas the expression level of 5-HT1AR was lower. However, the expression levels of 5-HT and 5-HT2AR were significantly decreased after the intervention with RU486, while the expression level of 5-HT1AR increased. Results showed that glucocorticoid was negatively correlated with 5-HT1AR and positively correlated with 5-HT2AR. Conclusion In the prefrontal cortex of ADHD rats, the down-regulation of 5-HT and 5-HT2AR expressions and the up-regulation of 5-HT1AR, compared with WYK rats, suggested a dysfunctional central 5-HT system in ADHD rats. The GR agonist can upregulate the expression of 5-HT and 5-HT2AR and downregulate the expression of 5-HT1AR in the prefrontal cortex of SHR as well as reduce the hyperactivity and attention deficit behavior in SHR, while the opposite was true for the GR inhibitor. It is suggested that the dysfunction of the 5-HT system in ADHD rats is closely related to glucocorticoid receptor activity.
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15
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Liu T, Dai Y, Xu M, Chen Y, Xia T, Zhao X. Mild acute stress prevents the memory impairment induced by long-term isoflurane anesthesia. Transl Neurosci 2022; 13:421-429. [PMID: 36518560 PMCID: PMC9719393 DOI: 10.1515/tnsci-2022-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/26/2022] [Accepted: 11/02/2022] [Indexed: 12/05/2022] Open
Abstract
Objectives Long-term isoflurane anesthesia exposure could result in postoperative cognitive dysfunction (POCD). Preoperative stress is also reported to be a risk factor of POCD. However, it is unknown whether acute stress could impair memory after long-term isoflurane anesthesia. Methods In this study, we categorized the mice with acute stress into mild (30 min restraint stress), moderate (60 min restraint stress), and severe (120 min restraint stress) stress groups and then we used Open-Field Test (OFT) to detect whether different scales of acute restraint stress successfully induced acute stress in mice. The memory performance of mice was measured using contextual and cued memory test, and the brain-derived neurotrophic factor protein levels of hippocampus was detected by Western blot. Results We verified that mild stress has pro-cognitive effect, but severe stress has amnestic effect. Moreover, we found that mild and moderate other than severe acute stress could partially attenuate the memory impairment induced by long-term isoflurane anesthesia. Conclusion Mild and moderate acute stress could partially attenuate the memory impairment induced by long-term isoflurane anesthesia.
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Affiliation(s)
- Tiantian Liu
- Medical School of Nanjing University, Nanjing, China,Department of Anesthesiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yutong Dai
- Medical School of Nanjing University, Nanjing, China,Department of Anesthesiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Minhui Xu
- Medical School of Nanjing University, Nanjing, China
| | - Ying Chen
- Medical School of Nanjing University, Nanjing, China,Department of Anesthesiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Tianjiao Xia
- Medical School of Nanjing University, Nanjing, China
| | - Xin Zhao
- Department of Anesthesiology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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16
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Zhukov IS, Karpova IV, Krotova NA, Tissen IY, Demin KA, Shabanov PD, Budygin EA, Kalueff AV, Gainetdinov RR. Enhanced Aggression, Reduced Self-Grooming Behavior and Altered 5-HT Regulation in the Frontal Cortex in Mice Lacking Trace Amine-Associated Receptor 1 (TAAR1). Int J Mol Sci 2022; 23:ijms232214066. [PMID: 36430544 PMCID: PMC9695497 DOI: 10.3390/ijms232214066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression.
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Affiliation(s)
- Ilya S. Zhukov
- Institute of Translational Biomedicine, St. Petersburg State University, University nab. 7/9, 199034 St. Petersburg, Russia
- Institute of Experimental Medicine, Acad. Pavlov str. 12, 197376 St. Petersburg, Russia
| | - Inessa V. Karpova
- Institute of Experimental Medicine, Acad. Pavlov str. 12, 197376 St. Petersburg, Russia
| | - Nataliya A. Krotova
- Institute of Translational Biomedicine, St. Petersburg State University, University nab. 7/9, 199034 St. Petersburg, Russia
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, 197341 St. Petersburg, Russia
| | - Ilya Y. Tissen
- Institute of Experimental Medicine, Acad. Pavlov str. 12, 197376 St. Petersburg, Russia
| | - Konstantin A. Demin
- Institute of Translational Biomedicine, St. Petersburg State University, University nab. 7/9, 199034 St. Petersburg, Russia
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, 197341 St. Petersburg, Russia
| | - Petr D. Shabanov
- Institute of Experimental Medicine, Acad. Pavlov str. 12, 197376 St. Petersburg, Russia
| | - Evgeny A. Budygin
- Neurobiology Program, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Allan V. Kalueff
- Institute of Translational Biomedicine, St. Petersburg State University, University nab. 7/9, 199034 St. Petersburg, Russia
- Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, 197341 St. Petersburg, Russia
- Neurobiology Program, Sirius University of Science and Technology, 354340 Sochi, Russia
- Laboratory of Preclinical Bioscreening, Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, 197758 St. Petersburg, Russia
- Neurobiology Laboratory, Ural Federal University, 620002 Yekaterinburg, Russia
- Laboratory of Cell and Molecular Biology and Neurobiology, School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Moscow, Russia
| | - Raul R. Gainetdinov
- Institute of Translational Biomedicine, St. Petersburg State University, University nab. 7/9, 199034 St. Petersburg, Russia
- St. Petersburg University Hospital, St. Petersburg State University, 199034 St. Petersburg, Russia
- Correspondence:
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17
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Meng X, Grandjean J, Sbrini G, Schipper P, Hofwijks N, Stoop J, Calabrese F, Homberg J. Tryptophan Hydroxylase 2 Knockout Male Rats Exhibit a Strengthened Oxytocin System, Are Aggressive, and Are Less Anxious. ACS Chem Neurosci 2022; 13:2974-2981. [PMID: 36197033 PMCID: PMC9585586 DOI: 10.1021/acschemneuro.2c00448] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/23/2022] [Indexed: 01/20/2023] Open
Abstract
The central serotoninergic system is critical for stress responsivity and social behavior, and its dysregulations have been centrally implicated in virtually all neuropsychiatric disorders. Genetic serotonin depletion animal models could provide a tool to elucidate the causes and mechanisms of diseases and to develop new treatment approaches. Previously, mice lacking tryptophan hydroxylase 2 (Tph2) have been developed, showing altered behaviors and neurotransmission. However, the effect of congenital serotonin deficiency on emotional and social behavior in rats is still largely unknown, as are the underlying mechanisms. In this study, we used a Tph2 knockout (Tph2-/-) male rat model to study how the lack of serotonin in the rat brain affects anxiety-like and social behaviors. Since oxytocin is centrally implicated in these behaviors, we furthermore explored whether the effects of Tph2 knockout on behavior would relate to changes in the oxytocin system. We show that Tph2-/- rats display reduced anxiety-like behavior and a high level of aggression in social interactions. In addition, oxytocin receptor expression was increased in the infralimbic and prelimbic cortices, paraventricular nucleus, dorsal raphe nucleus, and some subregions of the hippocampus, which was paralleled by increased levels of oxytocin in the medial frontal cortex and paraventricular nucleus but not the dorsal raphe nucleus, central amygdala, and hippocampus. In conclusion, our study demonstrated reduced anxiety but exaggerated aggression in Tph2-/- male rats and reveals for the first time a potential involvement of altered oxytocin system function. Meanwhile, the research of oxytocin could be distinguished in almost any psychiatric disorder including anxiety and mental disorders. This research potentially proposes a new target for the treatment of such disorders, from a genetic serotonin deficiency aspect.
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Affiliation(s)
- Xianzong Meng
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Joanes Grandjean
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
- Department
of Medical Imaging, Radboud University Medical
Centre, 6525 GA Nijmegen, The Netherlands
| | - Giulia Sbrini
- Department
of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Via Balzaretti 9, 20133 Milan, Italy
| | - Pieter Schipper
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Nita Hofwijks
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Jesse Stoop
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Francesca Calabrese
- Department
of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Via Balzaretti 9, 20133 Milan, Italy
| | - Judith Homberg
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
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Hu Y, Liu Y, Li S. Effect of Acute Cold Stress on Neuroethology in Mice and Establishment of Its Model. Animals (Basel) 2022; 12:ani12192671. [PMID: 36230412 PMCID: PMC9559653 DOI: 10.3390/ani12192671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/29/2022] Open
Abstract
Cold environment is an inevitable stress source for humans and livestock in cold areas, which easily induce a cold stress response and then cause a series of abnormal changes in energy metabolism, neuroendocrine system, behavior and emotion. Homeostasis is maintained by the unified regulation of the autonomic nervous system, endocrine system, metabolism and behavior under cold exposure. Behavior is an indispensable part of the functional regulation of the body to respond to environmental changes. At present, the behavioral changes caused by cold exposure are unclear or even chaotic due to the difficulty of defining cold stress. Therefore, this study aims to systematically observe the changes in spontaneous movement, exploratory behavior and anxiety of mice under different intensity cold exposure and summarize the characteristics and behavior traits combined with relevant blood physiological indexes under corresponding conditions. Mice models of cold stress with different intensities were established (cold exposure gradients were 22 °C, 16 °C, 10 °C and 4 °C, and time gradients of each temperature were 2 h, 4 h, 6 h, 8 h, 10 h and 12 h). After the corresponding cold exposure treatment, mice immediately carried out the open field test(OFT) and elevated plus maze test (PMT) to evaluate their spontaneous movement, exploratory behavior and anxiety. Subsequently, blood samples were collected and used for the determination of corticosterone (Cort), corticotropin-releasing hormone (CRH), epinephrine (E), norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) by enzyme-linked immunosorbent assay (ELISA). Spontaneous movement of mice increased under 22 °C cold exposure, but their exploration behavior did not significantly change, and their anxiety improved at the initial stage. The spontaneous movement and anxiety of mice increased in the initial stage and decreased in the later stage under cold exposure at 16, 10 and 4 °C and the exploratory behavior was inhibited. The hypothalamic-pituitary-adrenal (HPA) axis and locus coeruleus-noradrenergic (LC/NE) system were activated by cold stress and fluctuated with different intensities of cold exposure. Meanwhile, serum DA increased, and 5-HT was the opposite under different intensities of cold exposure. In conclusion, mild acute cold exposure promoted the spontaneous movement, increased exploratory behavior and improved anxiety. As the intensity of cold exposure increases, cold exposure had a negative effect on spontaneous movement, exploratory behavior and emotion. The physiological basis of these behavioral and emotional changes in mice under different intensity cold stimulation is the fluctuation of Cort, CRH, E, NE, DA and 5-HT.
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Affiliation(s)
- Yajie Hu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yang Liu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Shize Li
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
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19
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Tanaka M, Szabó Á, Spekker E, Polyák H, Tóth F, Vécsei L. Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System. Cells 2022; 11:2607. [PMID: 36010683 PMCID: PMC9406499 DOI: 10.3390/cells11162607] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/14/2022] [Accepted: 08/19/2022] [Indexed: 02/07/2023] Open
Abstract
Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.
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Affiliation(s)
- Masaru Tanaka
- ELKH-SZTE Neuroscience Research Group, Danube Neuroscience Research Laboratory, Eötvös Loránd Research Network, University of Szeged (ELKH-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
| | - Ágnes Szabó
- Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Korányi fasor 6, H-6720 Szeged, Hungary
| | - Eleonóra Spekker
- ELKH-SZTE Neuroscience Research Group, Danube Neuroscience Research Laboratory, Eötvös Loránd Research Network, University of Szeged (ELKH-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
| | - Helga Polyák
- Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Korányi fasor 6, H-6720 Szeged, Hungary
| | - Fanni Tóth
- ELKH-SZTE Neuroscience Research Group, Danube Neuroscience Research Laboratory, Eötvös Loránd Research Network, University of Szeged (ELKH-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
| | - László Vécsei
- ELKH-SZTE Neuroscience Research Group, Danube Neuroscience Research Laboratory, Eötvös Loránd Research Network, University of Szeged (ELKH-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
- Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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20
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Coray R, Quednow BB. The role of serotonin in declarative memory: A systematic review of animal and human research. Neurosci Biobehav Rev 2022; 139:104729. [PMID: 35691469 DOI: 10.1016/j.neubiorev.2022.104729] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/13/2022] [Accepted: 06/06/2022] [Indexed: 10/18/2022]
Abstract
The serotonergic system is involved in diverse cognitive functions including memory. Of particular importance to daily life are declarative memories that contain information about personal experiences, general facts, and events. Several psychiatric or neurological diseases, such as depression, attention-deficit-hyperactivity disorder (ADHD), and dementia, show alterations in serotonergic signalling and attendant memory disorders. Nevertheless, understanding serotonergic neurotransmission and its influence on memory remained a challenge until today. In this systematic review, we summarize recent psychopharmacological studies in animals and humans from a psychological memory perspective, in consideration of task-specific requirements. This approach has the advantage that comparisons between serotonin (5-HT)-related neurochemical mechanisms and manipulations are each addressing specific mnemonic circuits. We conclude that applications of the same 5-HT-related treatments can differentially affect unrelated tasks of declarative memories. Moreover, the analysis of specific mnemonic phases (e.g., encoding vs. consolidation) reveals opposing impacts of increased or decreased 5-HT tones, with low 5-HT supporting spatial encoding but impairing the consolidation of objects and verbal memories. Promising targets for protein synthesis-dependent consolidation enhancements include 5-HT4 receptor agonists and 5-HT6 receptor antagonists, with the latter being of special interest for the treatment of age-related decline. Further implications are pointed out as base for the development of novel therapeutic targets for memory impairment of neuropsychiatric disorders.
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Affiliation(s)
- Rebecca Coray
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Switzerland.
| | - Boris B Quednow
- Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric University Hospital Zurich, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Switzerland
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21
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Depression in breast cancer patients: Immunopathogenesis and immunotherapy. Cancer Lett 2022; 536:215648. [DOI: 10.1016/j.canlet.2022.215648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/13/2022] [Accepted: 03/14/2022] [Indexed: 01/10/2023]
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22
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Wang B, Shi H, Ren L, Miao Z, Wan B, Yang H, Fan X, Gustafsson JA, Sun M, Xu X. Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway involving sexual differences in depressive behaviors. Cell Commun Signal 2022; 20:74. [PMID: 35643536 PMCID: PMC9148486 DOI: 10.1186/s12964-022-00894-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 04/27/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Depression is one of the most common psychiatric diseases. The monoamine transmitter theory suggests that neurotransmitters are involved in the mechanism of depression; however, the regulation on serotonin production is still unclear. We previously showed that Ahi1 knockout (KO) mice exhibited depression-like behavior accompanied by a significant decrease in brain serotonin. METHODS In the present study, western blot, gene knockdown, immunofluorescence, dual-luciferase reporter assay, and rescue assay were used to detect changes in the Ahi1/GR/ERβ/TPH2 pathway in the brains of male stressed mice and male Ahi1 KO mice to explain the pathogenesis of depression-like behaviors. In addition, E2 levels in the blood and brain of male and female mice were measured to investigate the effect on the ERβ/TPH2 pathway and to reveal the mechanisms for the phenomenon of gender differences in depression-like behaviors. RESULTS We found that the serotonin-producing pathway-the ERβ/TPH2 pathway was inhibited in male stressed mice and male Ahi1 KO mice. We further demonstrated that glucocorticoid receptor (GR) as a transcription factor bound to the promoter of ERβ that contains glucocorticoid response elements and inhibited the transcription of ERβ. Our recent study had indicated that Ahi1 regulates the nuclear translocation of GR upon stress, thus proposing the Ahi1/GR/ERβ/TPH2 pathway for serotonin production. Interestingly, female Ahi1 KO mice did not exhibit depressive behaviors, indicating sexual differences in depressive behaviors compared with male mice. Furthermore, we found that serum 17β-estradiol (E2) level was not changed in male and female mice; however, brain E2 level significantly decreased in male but not female Ahi1 KO mice. Further, ERβ agonist LY-500307 increased TPH2 expression and 5-HT production. Therefore, both Ahi1 and E2 regulate the ERβ/TPH2 pathway and involve sexual differences in brain serotonin production and depressive behaviors. CONCLUSIONS In conclusion, although it is unclear how Ahi1 controls E2 secretion in the brain, our findings demonstrate that Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway in the brain and possibly involves the regulation on sex differences in depressive behaviors. Video Abstract.
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Affiliation(s)
- Bin Wang
- Department of Fetology, the First Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China
| | - Haixia Shi
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China
| | - Liyan Ren
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China
| | - Zhigang Miao
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China
| | - Bo Wan
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China
| | - Hao Yang
- Department of Fetology, the First Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China
| | - Xiaotang Fan
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Jan-Ake Gustafsson
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Miao Sun
- Department of Fetology, the First Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China.
| | - Xingshun Xu
- Institute of Neuroscience, Soochow University, Suzhou, 215123, People's Republic of China.
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China.
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China.
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
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23
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Efficacy and Safety of Xiaoyao Recipe in the Treatment of Poststroke Depression: A Systematic Review and Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4385783. [PMID: 35463080 PMCID: PMC9020944 DOI: 10.1155/2022/4385783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/15/2022] [Indexed: 11/17/2022]
Abstract
Background Poststroke depression (PSD) is a common neuropsychiatric disorder that affects the disability, mortality, functional recovery, and quality of daily life of patients. Xiaoyao Recipe (XYR) is often used to treat PSD and has achieved good clinical effects, but it lacks reliable evidence. Objective This study aims to evaluate the effectiveness and safety of XYR on PSD through meta-analysis. Methods A comprehensive literature search was carried out in multiple databases, including PubMed, the Cochrane Library, Chinese Biomedical Literature Service System, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and ClinicalTrials, from inception to July 1, 2021, to collect randomized controlled trials that applied XYR for patients with PSD. For a controlled trial, the search time limit was set from the time of the database's establishment to July 2021. Two experienced researchers independently screened the literature according to the inclusion and exclusion criteria, extracted data, evaluated the quality of the literature, and used RevMan 5.3 software for meta-analysis. Results A total of 12 studies were included in this study, involving 882 patients with PSD who were hospitalized or outpatients. The meta-analysis results showed that the total effective rate (p < 0.00001) of the test group (XYR or XYR combined with antidepressants) after treatment was high; Hamilton's Depression Scale score (p < 0.000001), Scandinavian Stroke Scale score (p=0.004 < 0.05), and Barthel index (p < 0.00001) were improved; the incidence of adverse reactions (p < 0.00001) was low; and the serum serotonin content (p < 0.00001) was high. Conclusion Compared with antidepressant drugs, XYR is more effective and safer in the treatment of PSD patients. However, more high-quality studies are needed to further support the above conclusions.
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24
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Svirin E, Veniaminova E, Costa-Nunes JP, Gorlova A, Umriukhin A, Kalueff AV, Proshin A, Anthony DC, Nedorubov A, Tse ACK, Walitza S, Lim LW, Lesch KP, Strekalova T. Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes. Cells 2022; 11:1036. [PMID: 35326487 PMCID: PMC8947002 DOI: 10.3390/cells11061036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/11/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2-/-) mice. In heterozygous male mice (Tph2+/-), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2+/- mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2+/- females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2+/- mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.
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Affiliation(s)
- Evgeniy Svirin
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands; (E.S.); (K.-P.L.)
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, 97080 Würzburg, Germany
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
| | - Ekaterina Veniaminova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
| | - João Pedro Costa-Nunes
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
- Institute of Molecular Medicine, New University of Lisbon, 1649-028 Lisbon, Portugal
| | - Anna Gorlova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
| | - Aleksei Umriukhin
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
| | - Allan V. Kalueff
- Neuroscience Program, Sirius University, 354340 Sochi, Russia;
- Moscow Institute of Physics and Technology, School of Biological and Medical Physics, 141701 Dolgoprudny, Russia
- Institute of Natural Sciences, Ural Federal University, 620002 Yekaterinburg, Russia
| | - Andrey Proshin
- P.K. Anokhin Research Institute of Normal Physiology, 125315 Moscow, Russia;
| | - Daniel C. Anthony
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
| | - Andrey Nedorubov
- Institute of Translational Medicine and Biotechnology, Sechenov University, 119991 Moscow, Russia;
| | - Anna Chung Kwan Tse
- Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China;
| | - Susanne Walitza
- Department for Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, 8032 Zurich, Switzerland;
| | - Lee Wei Lim
- Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China;
| | - Klaus-Peter Lesch
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands; (E.S.); (K.-P.L.)
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, 97080 Würzburg, Germany
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
| | - Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands; (E.S.); (K.-P.L.)
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315 Moscow, Russia
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia; (E.V.); (J.P.C.-N.); (A.G.); (A.U.); (D.C.A.)
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Zaniewska M, Mosienko V, Bader M, Alenina N. Tph2 Gene Expression Defines Ethanol Drinking Behavior in Mice. Cells 2022; 11:cells11050874. [PMID: 35269497 PMCID: PMC8909500 DOI: 10.3390/cells11050874] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/17/2022] [Accepted: 02/28/2022] [Indexed: 01/22/2023] Open
Abstract
Indirect evidence supports a link between disrupted serotonin (5-hydroxytryptamine; 5-HT) signaling in the brain and addictive behaviors. However, the effects of hyposerotonergia on ethanol drinking behavior are contradictory. In this study, mice deficient in tryptophan hydroxylase 2 (Tph2−/−), the rate-limiting enzyme of 5-HT synthesis in the brain, were used to assess the role of central 5-HT in alcohol drinking behavior. Life-long 5-HT depletion in these mice led to an increased ethanol consumption in comparison to wild-type animals in a two-bottle choice test. Water consumption was increased in naïve 5-HT-depleted mice. However, exposure of Tph2−/− animals to ethanol resulted in the normalization of water intake to the level of wild-type mice. Tph2 deficiency in mice did not interfere with ethanol-evoked antidepressant response in the forced swim test. Gene expression analysis in wild-type animals revealed no change in Tph2 expression in the brain of mice consuming ethanol compared to control mice drinking water. However, within the alcohol-drinking group, inter-individual differences in chronic ethanol intake correlated with Tph2 transcript levels. Taken together, central 5-HT is an important modulator of drinking behavior in mice but is not required for the antidepressant effects of ethanol.
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Affiliation(s)
- Magdalena Zaniewska
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; (V.M.); (M.B.)
- Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland
- Correspondence: (M.Z.); (N.A.); Tel.: +48-1-2662-3289 (M.Z.); +49-30-9406-3576 (N.A.)
| | - Valentina Mosienko
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; (V.M.); (M.B.)
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; (V.M.); (M.B.)
- Institute for Biology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
- Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Potsdamer Str. 58, 10785 Berlin, Germany
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; (V.M.); (M.B.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Potsdamer Str. 58, 10785 Berlin, Germany
- Correspondence: (M.Z.); (N.A.); Tel.: +48-1-2662-3289 (M.Z.); +49-30-9406-3576 (N.A.)
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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Sidorova M, Kronenberg G, Matthes S, Petermann M, Hellweg R, Tuchina O, Bader M, Alenina N, Klempin F. Enduring Effects of Conditional Brain Serotonin Knockdown, Followed by Recovery, on Adult Rat Neurogenesis and Behavior. Cells 2021; 10:3240. [PMID: 34831469 PMCID: PMC8618971 DOI: 10.3390/cells10113240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/31/2023] Open
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.
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Affiliation(s)
- Maria Sidorova
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia; (M.S.); (O.T.)
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
| | - Golo Kronenberg
- Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatrische Universitätsklinik, 8032 Zürich, Switzerland;
- Department of Psychiatry and Psychotherapy, Charité University Medicine, 10117 Berlin, Germany;
| | - Susann Matthes
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
| | - Markus Petermann
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
- Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany
| | - Rainer Hellweg
- Department of Psychiatry and Psychotherapy, Charité University Medicine, 10117 Berlin, Germany;
| | - Oksana Tuchina
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia; (M.S.); (O.T.)
| | - Michael Bader
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
| | - Natalia Alenina
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
- Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Friederike Klempin
- School of Life Sciences, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia; (M.S.); (O.T.)
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; (S.M.); (M.P.); (M.B.); (N.A.)
- Department of Psychiatry and Psychotherapy, Charité University Medicine, 10117 Berlin, Germany;
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Brancato A, Lo Russo SLM, Liberati AS, Carbone C, Zelli S, Laviola G, Cannizzaro C, Adriani W. Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy. Biomedicines 2021; 9:778. [PMID: 34356842 PMCID: PMC8301365 DOI: 10.3390/biomedicines9070778] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/22/2021] [Accepted: 06/30/2021] [Indexed: 01/01/2023] Open
Abstract
Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous "maternal" heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; "mixed" heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed an abnormal behavior, seeming not interested in socializing either with a female in estrous or with another male if MIX-HET. Focal MAT-HET males, instead, were very attracted by the female in estrous, but totally ignored the MIX-HET male. We assessed the expression of noradrenaline transporter (NET) in prefrontal cortex, hippocampus and hypothalamus, finding differences between the two offspring. MIX-HETs' hypothalamus and hippocampus showed less NET than MAT-HETs, while the latter, in turn, showed higher NET than WTs. These behavioral differences between heterozygous groups may be attributed to different maternal cares received. Results allow preclinical understanding of epigenetic factors involved in social-behavior abnormalities, typical of many psychiatric disorders.
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Affiliation(s)
- Anna Brancato
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties of Excellence “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy; (A.B.); (C.C.)
| | - Sara L. M. Lo Russo
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (S.L.M.L.R.); (C.C.); (S.Z.); (G.L.)
| | - Anna Sara Liberati
- Faculty of Psychology, Università Telematica Internazionale “Uninettuno”, 00186 Rome, Italy;
| | - Cristiana Carbone
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (S.L.M.L.R.); (C.C.); (S.Z.); (G.L.)
| | - Silvia Zelli
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (S.L.M.L.R.); (C.C.); (S.Z.); (G.L.)
| | - Giovanni Laviola
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (S.L.M.L.R.); (C.C.); (S.Z.); (G.L.)
| | - Carla Cannizzaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties of Excellence “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy; (A.B.); (C.C.)
| | - Walter Adriani
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy; (S.L.M.L.R.); (C.C.); (S.Z.); (G.L.)
- Faculty of Psychology, Università Telematica Internazionale “Uninettuno”, 00186 Rome, Italy;
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Huq SN, Warner AK, Buckhaults K, Sachs BD. The Effects of Brain Serotonin Deficiency on Responses to High Fat Diet in Female Mice. Front Neurosci 2021; 15:683103. [PMID: 34276291 PMCID: PMC8282998 DOI: 10.3389/fnins.2021.683103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Clinical studies have reported an increased risk of depression and anxiety disorders among individuals who are obese, and women are more likely than men to suffer from depression, anxiety, and obesity. However, the effects of obesity-promoting diets on depression- and anxiety-like behavior remain controversial. A recent study from our group used the tryptophan hydroxylase 2 (R439H) knock-in mouse line to evaluate the impact of genetic brain serotonin (5-HT) deficiency on behavioral responses to high fat diet (HFD) in male mice. That study indicated that chronic exposure to HFD induced pro-anxiety-like effects in the open field test and antidepressant-like effects in the forced swim test in wild-type males. Interestingly, the antidepressant-like effect of HFD, but not the anxiogenic effect, was blocked by brain 5-HT deficiency in males. The current work sought to repeat these studies in females. Our new data suggest that females are less susceptible than males to HFD-induced weight gain and HFD-induced alterations in behavior. In addition, the effects of chronic HFD on the expression of inflammation-related genes in the hippocampus were markedly different in females than we had previously reported in males, and HFD was shown to impact the expression of several inflammation-related genes in a genotype-dependent manner. Together, our findings highlight the importance of brain 5-HT and sex in regulating behavioral and molecular responses to HFD. Our results may have important implications for our understanding of the clinically observed sex differences in the consequences of obesity.
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Affiliation(s)
- Shama N Huq
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Allison K Warner
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Kerry Buckhaults
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Benjamin D Sachs
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States.,Department of Psychological and Brain Sciences, Villanova University, Villanova, PA, United States
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Altered behaviour, dopamine and norepinephrine regulation in stressed mice heterozygous in TPH2 gene. Prog Neuropsychopharmacol Biol Psychiatry 2021; 108:110155. [PMID: 33127424 DOI: 10.1016/j.pnpbp.2020.110155] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 10/21/2020] [Accepted: 10/24/2020] [Indexed: 12/28/2022]
Abstract
Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation. Tph2 haploinsufficiency in animals reflects allelic variation of Tph2 facilitating the elucidation of respective GxE mechanisms. Recently, we showed excessive aggression and altered serotonin brain metabolism in heterozygous Tph2-deficient male mice (Tph2+/-) after predator stress exposure. Here, we sought to extend these studies by investigating aggressive and anxiety-like behaviours, sociability, and the brain metabolism of dopamine and noradrenaline. Separately, Tph2+/- mice were examined for exploration activity in a novel environment and for the potentiation of helplessness in the modified swim test (ModFST). Predation stress procedure increased measures of aggression, dominancy, and suppressed sociability in Tph2+/- mice, which was the opposite of that observed in control mice. Anxiety-like behaviour was unaltered in the mutants and elevated in controls. Tph2+/- mice exposed to environmental novelty or to the ModFST exhibited increased novelty exploration and no increase in floating behaviour compared to controls, which is suggestive of resilience to stress and despair. High-performance liquid chromatography (HPLC) revealed significant genotype-dependent differences in the metabolism of dopamine, and norepinephrine within the brain tissue. In conclusion, environmentally challenged Tph2+/- mice exhibit behaviours that resemble the behaviour of non-stressed null mutants, which reveals how GxE interaction studies can unmask latent genetically determined predispositions.
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Abstract
OBJECTIVE Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. METHODS Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. RESULTS The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. CONCLUSION Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.
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Serotonin deficiency induced after brain maturation rescues consequences of early life adversity. Sci Rep 2021; 11:5368. [PMID: 33686115 PMCID: PMC7940624 DOI: 10.1038/s41598-021-83592-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 01/22/2021] [Indexed: 01/31/2023] Open
Abstract
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.
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Petermann M, Kronenberg G, Mosienko V, Bader M, Alenina N, Hellweg R, Klempin F. Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis. PHARMACOPSYCHIATRY 2020; 54:101-105. [PMID: 33197939 DOI: 10.1055/a-1291-8079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 -/- mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus. METHODS Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs. RESULTS Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 -/- mice, adult neurogenesis was consistently increased. Furthermore, Tph2 -/- mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT. DISCUSSION We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.
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Affiliation(s)
- Markus Petermann
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Golo Kronenberg
- University of Leicester and Leicestershire Partnership NHS Trust, Leicester, UK.,Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - Valentina Mosienko
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,current address: University of Exeter, College of Medicine and Health, EX4 4PS, Exeter, UK
| | - Michael Bader
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Charité-University Medicine Berlin, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.,University of Lübeck, Lübeck, Germany
| | - Natalia Alenina
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.,Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia
| | - Rainer Hellweg
- Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - Friederike Klempin
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
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Sex differences in behavioral and metabolic effects of gene inactivation: The neuropeptide Y and Y receptors in the brain. Neurosci Biobehav Rev 2020; 119:333-347. [PMID: 33045245 DOI: 10.1016/j.neubiorev.2020.09.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
Brain and gonadal hormones interplay controls metabolic and behavioral functions in a sex-related manner. However, most translational neuroscience research related to animal models of endocrine and psychiatric disorders are often carried out in male animals only. The Neuropeptide Y (NPY) system shows sex-dependent differences and is sensitive to gonadal steroids. Based on published data from our and other laboratories, in this review we will discuss the sex related differences of NPY action on energy balance, bone homeostasis and behavior in rodents with the genetic manipulation of genes encoding NPY and its Y1, Y2 and Y5 cognate receptors. Comparative analyses of the phenotype of transgenic and knockout NPY and Y receptor rodents unravels sex dependent differences in the functions of this neurotransmission system, potentially helping to develop therapeutics for a variety of sex-related disorders including metabolic syndrome, osteoporosis and ethanol addiction.
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Bertocchi I, Oberto A, Longo A, Palanza P, Eva C. Conditional inactivation of Npy1r gene in mice induces sex-related differences of metabolic and behavioral functions. Horm Behav 2020; 125:104824. [PMID: 32755609 DOI: 10.1016/j.yhbeh.2020.104824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 07/15/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023]
Abstract
Sex hormone-driven differences in gene expression have been identified in experimental animals, highlighting brain neuronal populations implicated in dimorphism of metabolic and behavioral functions. Neuropeptide Y-Y1 receptor (NPY-Y1R) system is sexually dimorphic and sensitive to gonadal steroids. In the present study we compared the phenotype of male and female conditional knockout mice (Npy1rrfb mice), carrying the inactivation of Npy1r gene in excitatory neurons of the brain limbic system. Compared to their male control (Npy1r2lox) littermates, male Npy1rrfb mice exhibited hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis that is associated with anxiety and executive dysfunction, reduced body weight growth, after-fasting refeeding, white adipose tissue (WAT) mass and plasma leptin levels. Conversely, female Npy1rrfb mice displayed an anxious-like behavior but no differences in HPA axis activity, executive function and body weight, compared to control females. Moreover, conditional inactivation of Npy1r gene induced an increase of subcutaneous and gonadal WAT weight and plasma leptin levels and a compensatory decrease of Agouti-related protein immunoreactivity in the hypothalamic arcuate (ARC) nucleus in females, compared to their respective control littermates. Interestingly, Npy1r mRNA expression was reduced in the ARC and in the paraventricular hypothalamic nuclei of female, but not male mice. These results demonstrated that female mice are resilient to hormonal and metabolic effects of limbic Npy1r gene inactivation, suggesting the existence of an estrogen-dependent relay necessary to ensure the maintenance of the homeostasis, that can be mediated by hypothalamic Y1R.
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Affiliation(s)
- Ilaria Bertocchi
- Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, 10043 Orbassano, Turin, Italy; Department of Neuroscience, University of Turin, 10126 Turin, Italy; Neuroscience Institute of Turin, Italy
| | - Alessandra Oberto
- Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, 10043 Orbassano, Turin, Italy; Department of Neuroscience, University of Turin, 10126 Turin, Italy; Neuroscience Institute of Turin, Italy
| | - Angela Longo
- Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, 10043 Orbassano, Turin, Italy
| | - Paola Palanza
- Department of Medicine and Surgery, University of Parma, 43100 Parma, Italy
| | - Carola Eva
- Neuroscience Institute of the Cavalieri-Ottolenghi Foundation, 10043 Orbassano, Turin, Italy; Department of Neuroscience, University of Turin, 10126 Turin, Italy; Neuroscience Institute of Turin, Italy.
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36
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Chang CH, Gean PW. The Ventral Hippocampus Controls Stress-Provoked Impulsive Aggression through the Ventromedial Hypothalamus in Post-Weaning Social Isolation Mice. Cell Rep 2020; 28:1195-1205.e3. [PMID: 31365864 DOI: 10.1016/j.celrep.2019.07.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 05/29/2019] [Accepted: 06/27/2019] [Indexed: 02/02/2023] Open
Abstract
Impulsively aggressive individuals may suddenly attack others when under stress, but the neural circuitry underlying stress-provoked aggression is poorly understood. Here, we report that acute stress activates ventral hippocampus (vHip) neurons to induce attack behavior in post-weaning socially isolated mice. Chemogenetic inhibition of vHip neural activity blunts stress-provoked attack behavior, whereas chemogenetic activation promotes it. The activation of cell bodies in vHip neurons projecting into the ventromedial hypothalamus (VMH) induces attack behavior, suggesting that the vHip-VMH projection contributes to impulsive aggression. Furthermore, optogenetic inhibition of vHip glutamatergic neurons blocks stress-provoked attacks, whereas optogenetic activation of vHip glutamatergic neurons drives attack behavior. These results show direct evidence that vHip-VMH neural circuitry modulates attack behavior in socially isolated mice.
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Affiliation(s)
- Chih-Hua Chang
- Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan
| | - Po-Wu Gean
- Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan; Department of Biotechnology and Bioindustry Sciences, National Cheng-Kung University, Tainan 701, Taiwan.
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Gorlova A, Ortega G, Waider J, Bazhenova N, Veniaminova E, Proshin A, Kalueff AV, Anthony DC, Lesch KP, Strekalova T. Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors. J Affect Disord 2020; 272:440-451. [PMID: 32553388 DOI: 10.1016/j.jad.2020.04.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/31/2020] [Accepted: 04/17/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically 'susceptible' heterozygous mice (Tph2+/-). METHODS Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. RESULTS Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice. LIMITATIONS Rescue experiments would help to verify causal relationships of reported changes. CONCLUSIONS The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.
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Affiliation(s)
- Anna Gorlova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
| | - Gabriela Ortega
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Jonas Waider
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Natalia Bazhenova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Ekaterina Veniaminova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands
| | - Andrey Proshin
- PK Anokhin Research Institute of Normal Physiology, Moscow
| | - Allan V Kalueff
- School of Pharmacy, Southwest University, Chongqing, China with Ural Federal University, Ekaterinburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University and Almazov Medical Research Center, Institute of Experimental Medicine, St. Petersburg Russia
| | - Daniel C Anthony
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Pharmacology, Oxford University, Oxford, United Kingdom
| | - Klaus-Peter Lesch
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Tatyana Strekalova
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Institute of General Pathology and Pathophysiology, Moscow, Russia.
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38
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Prakash N, Stark CJ, Keisler MN, Luo L, Der-Avakian A, Dulcis D. Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia. J Neurosci 2020; 40:569-584. [PMID: 31792153 PMCID: PMC6961996 DOI: 10.1523/jneurosci.1802-19.2019] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/04/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.SIGNIFICANCE STATEMENT Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.
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Affiliation(s)
- Nandkishore Prakash
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
| | - Christiana J Stark
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
| | - Maria N Keisler
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
| | - Lily Luo
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
| | - Andre Der-Avakian
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
| | - Davide Dulcis
- Department of Psychiatry, University of California San Diego, La Jolla, California 92093
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Dopamine D 2L Receptor Deficiency Causes Stress Vulnerability through 5-HT 1A Receptor Dysfunction in Serotonergic Neurons. J Neurosci 2019; 39:7551-7563. [PMID: 31371425 DOI: 10.1523/jneurosci.0079-19.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/16/2019] [Accepted: 05/28/2019] [Indexed: 12/27/2022] Open
Abstract
Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.
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40
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Zhang Z, Deng T, Wu M, Zhu A, Zhu G. Botanicals as modulators of depression and mechanisms involved. Chin Med 2019; 14:24. [PMID: 31338119 PMCID: PMC6628492 DOI: 10.1186/s13020-019-0246-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 07/10/2019] [Indexed: 12/11/2022] Open
Abstract
Depression is the most disastrous mood disorder affecting the health of individuals. Conventional treatments with chemical compounds for depression have limitations, while herbal medicine has unique therapeutic effects. This paper introduces the pharmacological basis and biological mechanisms underlying the botanical antidepressants over the past 5 years. Based upon the specific therapeutic targets or mechanisms, we analyzed the pathological roles of monoamine neurotransmitters, the hypothalamic-pituitary-adrenal axis, inflammation, oxidative stress, synaptic plasticity performed in antidepressant of the botanicals. In addition, gut flora and neurogenesis were also preferentially discussed as treatment approaches. Based on the complex pathogenesis of depression, we suggested that mixed use of botanicals, namely prescription would be more suitable for treatment of depression. In addition, neural circuit affected by botanicals or active components should also attract attention as the botanicals have potential to be developed into fast-acting antidepressants. Finally, gut flora might be a new systemic target for the treatment of depression by botanicals. This review would strength botanical medicine as the antidepressant and also provides an overview of the potential mechanisms involved.
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Affiliation(s)
- Zhengrong Zhang
- Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Meishan Road 103, Hefei, 230038 China
| | - Taomei Deng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230038 China
| | - Manli Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230038 China
| | - Aisong Zhu
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053 China
| | - Guoqi Zhu
- Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Meishan Road 103, Hefei, 230038 China
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41
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Lieb MW, Weidner M, Arnold MR, Loupy KM, Nguyen KT, Hassell JE, Schnabel KS, Kern R, Day HEW, Lesch KP, Waider J, Lowry CA. Effects of maternal separation on serotonergic systems in the dorsal and median raphe nuclei of adult male Tph2-deficient mice. Behav Brain Res 2019; 373:112086. [PMID: 31319134 DOI: 10.1016/j.bbr.2019.112086] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 06/18/2019] [Accepted: 07/13/2019] [Indexed: 12/13/2022]
Abstract
Previous studies have highlighted interactions between serotonergic systems and adverse early life experience as important gene x environment determinants of risk of stress-related psychiatric disorders. Evidence suggests that mice deficient in Tph2, the rate-limiting enzyme for brain serotonin synthesis, display disruptions in behavioral phenotypes relevant to stress-related psychiatric disorders. The aim of this study was to determine how maternal separation in wild-type, heterozygous, and Tph2 knockout mice affects mRNA expression of serotonin-related genes. Serotonergic genes studied included Tph2, the high-affinity, low-capacity, sodium-dependent serotonin transporter (Slc6a4), the serotonin type 1a receptor (Htr1a), and the corticosterone-sensitive, low-affinity, high-capacity sodium-independent serotonin transporter, organic cation transporter 3 (Slc22a3). Furthermore, we studied corticotropin-releasing hormone receptors 1 (Crhr1) and 2 (Crhr2), which play important roles in controlling serotonergic neuronal activity. For this study, offspring of Tph2 heterozygous dams were exposed to daily maternal separation for the first two weeks of life. Adult, male wild-type, heterozygous, and homozygous offspring were subsequently used for molecular analysis. Maternal separation differentially altered serotonergic gene expression in a genotype- and topographically-specific manner. For example, maternal separation increased Slc6a4 mRNA expression in the dorsal part of the dorsal raphe nucleus in Tph2 heterozygous mice, but not in wild-type or knockout mice. Overall, these data are consistent with the hypothesis that gene x environment interactions, including serotonergic genes and adverse early life experience, play an important role in vulnerability to stress-related psychiatric disorders.
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Affiliation(s)
- Margaret W Lieb
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - Magdalena Weidner
- Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany; Department of Psychiatry and Psychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands.
| | - Mathew R Arnold
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - Kelsey M Loupy
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - Kadi T Nguyen
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - James E Hassell
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - K'Loni S Schnabel
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - Raphael Kern
- Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
| | - Heidi E W Day
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA.
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany; Department of Psychiatry and Psychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
| | - Jonas Waider
- Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Department of Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO 80045, USA; Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA.
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Kulikova EA, Kulikov AV. Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models. Expert Opin Ther Targets 2019; 23:655-667. [PMID: 31216212 DOI: 10.1080/14728222.2019.1634691] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Tryptophan hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human Tph2 gene are associated with psychiatric disorders. Area covered: This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse Tph2 gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy. Expert opinion: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.
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Affiliation(s)
- Elizabeth A Kulikova
- a Federal Research Center Institute of Cytology and Genetics , Siberian Division of the Russian Academy of Science , Novosibirsk , Russia
| | - Alexander V Kulikov
- a Federal Research Center Institute of Cytology and Genetics , Siberian Division of the Russian Academy of Science , Novosibirsk , Russia
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Pratelli M, Pasqualetti M. Serotonergic neurotransmission manipulation for the understanding of brain development and function: Learning from Tph2 genetic models. Biochimie 2019; 161:3-14. [DOI: 10.1016/j.biochi.2018.11.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 11/24/2018] [Indexed: 01/04/2023]
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Weidner MT, Lardenoije R, Eijssen L, Mogavero F, De Groodt LPMT, Popp S, Palme R, Förstner KU, Strekalova T, Steinbusch HWM, Schmitt-Böhrer AG, Glennon JC, Waider J, van den Hove DLA, Lesch KP. Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala. Front Neurosci 2019; 13:460. [PMID: 31133792 PMCID: PMC6524554 DOI: 10.3389/fnins.2019.00460] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/24/2019] [Indexed: 01/05/2023] Open
Abstract
Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2 -/-) and heterozygous (Tph2 +/-) mice, and their wildtype littermates (Tph2 +/+) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2 -/- mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2 +/- mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2 +/- mice when compared to their Tph2 -/- littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.
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Affiliation(s)
- Magdalena T. Weidner
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
- Department of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roy Lardenoije
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Department of Psychiatry and Psychotherapy, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, Germany
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, United States
| | - Lars Eijssen
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Departments of Bioinformatics, Psychiatry & Neuro Psychology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Floriana Mogavero
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | | | - Sandy Popp
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
| | - Rupert Palme
- Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Konrad U. Förstner
- Core Unit Systems Medicine, Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
- ZB MED – Information Centre for Life Sciences, Cologne, Germany
- TH Köln, Faculty of Information Science and Communication Studies, Cologne, Germany
| | - Tatyana Strekalova
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I. M. Sechenov First Moscow State Medical University and Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Harry W. M. Steinbusch
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
| | - Angelika G. Schmitt-Böhrer
- Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Jeffrey C. Glennon
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | - Jonas Waider
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
| | - Daniel L. A. van den Hove
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
| | - Klaus-Peter Lesch
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands
- Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany
- Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I. M. Sechenov First Moscow State Medical University and Institute of General Pathology and Pathophysiology, Moscow, Russia
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Waider J, Popp S, Mlinar B, Montalbano A, Bonfiglio F, Aboagye B, Thuy E, Kern R, Thiel C, Araragi N, Svirin E, Schmitt-Böhrer AG, Corradetti R, Lowry CA, Lesch KP. Serotonin Deficiency Increases Context-Dependent Fear Learning Through Modulation of Hippocampal Activity. Front Neurosci 2019; 13:245. [PMID: 31068767 PMCID: PMC6491456 DOI: 10.3389/fnins.2019.00245] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 03/01/2019] [Indexed: 12/21/2022] Open
Abstract
Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
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Affiliation(s)
- Jonas Waider
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Sandy Popp
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Boris Mlinar
- Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
| | - Alberto Montalbano
- Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
| | - Francesco Bonfiglio
- Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
| | - Benjamin Aboagye
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Elisabeth Thuy
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Raphael Kern
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Christopher Thiel
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Naozumi Araragi
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Evgeniy Svirin
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Angelika G Schmitt-Böhrer
- Department of Psychiatry, Psychosomatics, and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Renato Corradetti
- Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
| | - Christopher A Lowry
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, United States
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany.,Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Department of Translational Psychiatry, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
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Hudon Thibeault AA, Sanderson JT, Vaillancourt C. Serotonin-estrogen interactions: What can we learn from pregnancy? Biochimie 2019; 161:88-108. [PMID: 30946949 DOI: 10.1016/j.biochi.2019.03.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/28/2019] [Indexed: 02/07/2023]
Abstract
We have reviewed the scientific literature related to four diseases in which to serotonin (5-HT) is involved in the etiology, herein named 5-HT-linked diseases, and whose prevalence is influenced by estrogenic status: depression, migraine, irritable bowel syndrome and eating disorders. These diseases all have in common a sex-dimorphic prevalence, with women more frequently affected than men. The co-occurrence between these 5-HT-linked diseases suggests that they have common physiopathological mechanisms. In most 5-HT-linked diseases (except for anorexia nervosa and irritable bowel syndrome), a decrease in the serotonergic tone is observed and estrogens are thought to contribute to the improvement of symptoms by stimulating the serotonergic system. Human pregnancy is characterized by a unique 5-HT and estrogen synthesis by the placenta. Pregnancy-specific disorders, such as hyperemesis gravidarum, gestational diabetes mellitus and pre-eclampsia, are associated with a hyperserotonergic state and decreased estrogen levels. Fetal programming of 5-HT-linked diseases is a complex phenomenon that involves notably fetal-sex differences, which suggest the implication of sex steroids. From a mechanistic point of view, we hypothesize that estrogens regulate the serotonergic system, resulting in a protective effect against 5-HT-linked diseases, but that, in turn, 5-HT affects estrogen synthesis in an attempt to retrieve homeostasis. These two processes (5-HT and estrogen biosynthesis) are crucial for successful pregnancy outcomes, and thus, a disruption of this 5-HT-estrogen relationship may explain pregnancy-specific pathologies or pregnancy complications associated with 5-HT-linked diseases.
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Affiliation(s)
- Andrée-Anne Hudon Thibeault
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (Cinbiose), Université du Québec à Montréal, C.P.8888, succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
| | - J Thomas Sanderson
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada.
| | - Cathy Vaillancourt
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (Cinbiose), Université du Québec à Montréal, C.P.8888, succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
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Nishitani N, Nagayasu K, Asaoka N, Yamashiro M, Andoh C, Nagai Y, Kinoshita H, Kawai H, Shibui N, Liu B, Hewinson J, Shirakawa H, Nakagawa T, Hashimoto H, Kasparov S, Kaneko S. Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats. Neuropsychopharmacology 2019; 44:721-732. [PMID: 30377380 PMCID: PMC6372597 DOI: 10.1038/s41386-018-0254-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 10/16/2018] [Accepted: 10/21/2018] [Indexed: 01/21/2023]
Abstract
Major depression and anxiety disorders are a social and economic burden worldwide. Serotonergic signaling has been implicated in the pathophysiology of these disorders and thus has been a crucial target for pharmacotherapy. However, the precise mechanisms underlying these disorders are still unclear. Here, we used species-optimized lentiviral vectors that were capable of efficient and specific transduction of serotonergic neurons in mice and rats for elucidation of serotonergic roles in anxiety-like behaviors and active coping behavior in both species. Immunohistochemical analyses revealed that lentiviral vectors with an upstream sequence of tryptophan hydroxylase 2 gene efficiently transduced serotonergic neurons with a specificity of approximately 95% in both mice and rats. Electrophysiological recordings showed that these lentiviral vectors induced sufficient expression of optogenetic tools for precise control of serotonergic neurons. Using these vectors, we demonstrate that acute activation of serotonergic neurons in the dorsal raphe nucleus increases active coping with inescapable stress in rats and mice in a time-locked manner, and that acute inhibition of these neurons increases anxiety-like behaviors specifically in rats. These findings further our understanding of the pathophysiological role of dorsal raphe serotonergic neurons in different species and the role of these neurons as therapeutic targets in major depression and anxiety disorders.
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Affiliation(s)
- Naoya Nishitani
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
- Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Yoshidahommachi, Sakyo-ku, Kyoto, 606-8501, Japan.
| | - Nozomi Asaoka
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Mayumi Yamashiro
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Chihiro Andoh
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yuma Nagai
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Haruko Kinoshita
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Hiroyuki Kawai
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Norihiro Shibui
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Beihui Liu
- School of Physiology and Pharmacology, University of Bristol, Bristol, UK
| | - James Hewinson
- School of Physiology and Pharmacology, University of Bristol, Bristol, UK
| | - Hisashi Shirakawa
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Takayuki Nakagawa
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hitoshi Hashimoto
- Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Sergey Kasparov
- School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
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Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions. Neuropsychopharmacology 2019; 44:703-710. [PMID: 30188511 PMCID: PMC6372643 DOI: 10.1038/s41386-018-0189-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/06/2018] [Accepted: 08/20/2018] [Indexed: 01/20/2023]
Abstract
15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to severe clinical outcomes. The reasons for these varying phenotypic outcomes remain unknown. Using a mouse model of hemizygous deletion of the orthologous region of 15q13.3, the present study examined whether exposure to stressful life events might interact with hemizygous 15q13.3 microdeletion in the development of behavioral dysfunctions. We show that hemizygous 15q13.3 microdeletion alone induces only limited effects on adult behaviors, but when combined with psychological stress in pubescence (postnatal days 30-40), it impairs sensorimotor gating and increases the sensitivity to the psychostimulant drug, amphetamine, at adult age. Stress exposure in adolescence (postnatal days 50-60) did not induce similar interactions with 15q13.3 microdeletion, but led to impaired emotional learning and memory and social behavior regardless of the genetic background. The present study provides the first evidence for interactive effects between hemizygous 15q13.3 microdeletion and exposure to stressful life events, and at the same time, it emphasizes an important influence of the precise timing of postnatal stress exposure in these interactions. Our findings suggest that hemizygous 15q13.3 microdeletion can act as a "disease primer" that increases the carrier's vulnerability to the detrimental effects of peripubertal stress exposure on adult behaviors.
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Abstract
The neurotransmitter serotonin plays a key role in the control of aggressive behaviour. While so far most studies have investigated variation in serotonin levels, a recently created tryptophan hydroxylase 2 (Tph2) knockout mouse model allows studying effects of complete brain serotonin deficiency. First studies revealed increased aggressiveness in homozygous Tph2 knockout mice in the context of a resident-intruder paradigm. Focussing on females, this study aimed to elucidate effects of serotonin deficiency on aggressive and non-aggressive social behaviours not in a test situation but a natural setting. For this purpose, female Tph2 wildtype (n = 40) and homozygous knockout mice (n = 40) were housed with a same-sex conspecific of either the same or the other genotype in large terraria. The main findings were: knockout females displayed untypically high levels of aggressive behaviour even after several days of co-housing. Notably, in response to aggressive knockout partners, they showed increased levels of defensive behaviours. While most studies on aggression in rodents have focussed on males, this study suggests a significant involvement of serotonin also in the control of female aggression. Future research will show, whether the observed behavioural effects are directly caused by the lack of serotonin or by potential compensatory mechanisms.
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50
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Runions KC, Morandini HAE, Rao P, Wong JWY, Kolla NJ, Pace G, Mahfouda S, Hildebrandt CS, Stewart R, Zepf FD. Serotonin and aggressive behaviour in children and adolescents: a systematic review. Acta Psychiatr Scand 2019; 139:117-144. [PMID: 30446991 DOI: 10.1111/acps.12986] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The role of serotonin (5-HT) in human aggression has been the subject of a large number of studies, mostly with adults. Meta-analyses indicate a small but significant inverse relationship between central nervous 5-HT availability and aggression, but genetically informed studies suggest two pathways: one to reactive aggression and the other to proactive aggression. METHOD We conducted a systemic review on central nervous 5-HT function in children and adolescents, with attention to the function of aggression. RESULTS In total, 675 articles were screened for relevance, with 45 reviewed. These included blood assays (e.g. plasma, 5-HIAA; platelet 5-HTR2A ), epigenetic studies, retrospective PET studies and 5-HT challenge paradigms (e.g. tryptophan depletion). Overall, findings were mixed, with support both for negative and for positive associations of central nervous 5-HT function with aggression in children and adolescents. CONCLUSION We propose factors that may be blurring the picture, including problems in the conceptualization and measurement of aggression in young people, the lack of prospective designs and the bias towards clinical samples of boys. Research needs to account for variance in the both motivation for and implementation of aggression, and look to the behavioural economics literature to consider the roles of reward, vengeance and self-control more clearly.
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Affiliation(s)
- K C Runions
- Department of Health, Child and Adolescent Mental Health Services, Bentley, WA, Australia.,Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.,Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia
| | - H A E Morandini
- Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia
| | - P Rao
- Department of Health, Child and Adolescent Mental Health Services, Bentley, WA, Australia.,Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia
| | - J W Y Wong
- Department of Health, Child and Adolescent Mental Health Services, Bentley, WA, Australia.,Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.,Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia
| | - N J Kolla
- Centre for Addictions and Mental Health, University of Toronto, Toronto, ON, Canada
| | - G Pace
- Department of Health, Child and Adolescent Mental Health Services, Bentley, WA, Australia
| | - S Mahfouda
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.,School of Psychological Sciences, Faculty of Sciences, University of Western Australia, Perth, WA, Australia
| | - C S Hildebrandt
- Jülich Aachen Research Alliance, JARA Translational Brain Medicine, Aachen, Germany.,Child and Adolescent Psychiatry and Psychotherapy, Clinics of the City Cologne GmbH, Cologne, Germany
| | - R Stewart
- Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia
| | - F D Zepf
- Division of Psychiatry and Clinical Neurosciences and Division of Paediatrics and Child Health, Centre & Discipline of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, School of Medicine, University of Western Australia, Perth, WA, Australia.,Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Clinics of the Friedrich Schiller University, Jena, Germany
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