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Jasemi E, Razmi A, Vaseghi S, Amiri S, Najafi SMA. The effect of Psilocybe cubensis alkaloids on depressive-like behavior in mice exposed to maternal separation with respect to hippocampal gene expression and DNA methylation of Slc6a4 and Nr3c1. Behav Pharmacol 2025; 36:115-126. [PMID: 39969076 DOI: 10.1097/fbp.0000000000000813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Maternal separation as an early life stress can lead to long-lasting deleterious effects on cognitive and behavioral functions, and the mood state. On the other hand, Psilocybe cubensis (as one of the most well-known magic mushrooms) may be beneficial in the improvement or the treatment of neuropsychiatric disorders. In the present study, we aimed to investigate the effect of P. cubensis extract (PCE) on depressive-like and anxiety-like behaviors, and locomotor activity in mice exposed to early maternal separation. Also, we assessed the expression and methylation level of Slc6a4 and Nr3c1 in the hippocampus. Maternal separation was done in postnatal days (PNDs) 2-18. PCE was intraperitoneally injected at the dose of 20 mg/kg at PND 60, and our tests were done at days 1, 3, and 10, of administration. The results showed that maternal separation significantly induced depressive-like behavior in the forced swim test and anxiety-like behavior in the open field test (OFT). Also, maternal separation decreased locomotor activity in the OFT. In addition, maternal separation decreased the expression and increased the methylation level of both Slc6a4 and Nr3c1 in the hippocampus. However, PCE significantly reversed all these effects. In conclusion, it seems that P. cubensis affects serotonergic signaling via altering Slc6a4 expression and methylation level in the hippocampus of mice. The effect of P. cubensis on Nr3c1 expression and methylation level may also lead to alter the function of the hypothalamus-pituitary-adrenal axis and the stress response in mice exposed to maternal separation.
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Affiliation(s)
- Eghbal Jasemi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran
| | - Ali Razmi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Salar Vaseghi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Shayan Amiri
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
| | - S Mahmoud A Najafi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran
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Dragon J, Gołyszny M, Zieliński M, Popiołek-Barczyk K, Starowicz K, Obuchowicz E. Escitalopram reverses anxiety-like and despair behavior and affects endocannabinoid-related genes expression in the brain of adolescent male rats subjected to early life stress. Neuroscience 2025; 567:96-108. [PMID: 39761822 DOI: 10.1016/j.neuroscience.2025.01.001] [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: 08/26/2024] [Revised: 12/29/2024] [Accepted: 01/01/2025] [Indexed: 01/11/2025]
Abstract
Due to the increasing prevalence of depressive and anxiety disorders in youth, a growing interest in the endocannabinoid system (ECS) as a potential alternative target point for treatment arised. This study aimed to investigate whether chronic administration of escitalopram reverses behavioral changes induced by maternal separation in male adolescent Wistar rats and explore the corresponding neurochemical changes in the ECS. The pups were separated from their dams for 360 min daily from postnatal day (PND) 2 until PND 15. Later, male rats were administered escitalopram (10 mg/kg i.p.) during their adolescent period (PND 35 - PND 55). Behavioral assessments were conducted in late adolescence (PND 54 - PND 57) in one group, and brain structures were dissected for biochemical analysis in the subsequent group of rats on PND 56. Expression of genes encoding: CB1 receptor, enzyme that catalyzes synthesis (NAPE-PLD) and degradation (FAAH) of anandamide (a full agonist of CB1 receptor) was evaluated using qRT-PCR. The corresponding protein levels were estimated via Western blot analysis. Our study revealed that maternal separation induced anxiety and despair-like behavior in adolescent rats. Escitalopram reversed anxiety-like behavior and attenuated signs of despair behavior. The escitalopram administration has been followed by a decrease in the studied genes expression in the amygdala, the hypothalamus, and the hippocampus, what might suggest that the endocannabinoid system is involved in the mechanism of its action in adolescents. However Western blot analysis did not indicate significant alterations in the protein levels, so more detailed studies are needed to verify this hypothesis.
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Affiliation(s)
- Jonasz Dragon
- Department of Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland.
| | - Miłosz Gołyszny
- Department of Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland.
| | - Michał Zieliński
- Department of Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland.
| | - Katarzyna Popiołek-Barczyk
- Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
| | - Katarzyna Starowicz
- Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
| | - Ewa Obuchowicz
- Department of Pharmacology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland.
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Takahashi A. The role of social isolation stress in escalated aggression in rodent models. Neurosci Res 2025; 211:75-84. [PMID: 35917930 DOI: 10.1016/j.neures.2022.07.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 07/14/2022] [Accepted: 07/27/2022] [Indexed: 11/26/2022]
Abstract
Anti-social behavior and violence are major public health concerns. Globally, violence contributes to more than 1.6 million deaths each year. Previous studies have reported that social rejection or neglect exacerbates aggression. In rodent models, social isolation stress is used to demonstrate the adverse effects of social deprivation on physiological, endocrinological, immunological, and behavioral parameters, including aggressive behavior. This review summarizes recent rodent studies on the effect of social isolation stress during different developmental periods on aggressive behavior and the underlying neural mechanisms. Social isolation during adulthood affects the levels of neurosteroids and neuropeptides and increases aggressive behavior. These changes are ethologically relevant for the adaptation to changes in local environmental conditions in the natural habitats. Chronic deprivation of social interaction after weaning, especially during the juvenile to adolescent periods, leads to the disruption of the development of appropriate social behavior and the maladaptive escalation of aggressive behavior. The understanding of neurobiological mechanisms underlying social isolation-induced escalated aggression will aid in the development of therapeutic interventions for escalated aggression.
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Affiliation(s)
- Aki Takahashi
- Laboratory of Behavioral Neurobiology, Faculty of Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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Borzadaran FM, Rezakhani S, Kamali R, Esmaeilpour K. Maternal Separation Exhibits a Sex Dimorphism in Memory Impairments in Adolescent Rats: Acute Methylphenidate Administration as a Treatment. Birth Defects Res 2025; 117:e2441. [PMID: 39916605 PMCID: PMC11803433 DOI: 10.1002/bdr2.2441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/30/2024] [Accepted: 01/14/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION Rodents are highly dependent on maternal care after birth. Disturbing mother and pup interactions leads to detrimental alternations for the rat and the mother. Maternal separation (MS) is an accepted model for investigating disruption of mother and pup relationship. In addition to other detrimental effects, MS is a model known to induce permanent changes in learning and memory. Methylphenidate has been effective in memory enhancement in individuals suffering from memory deficits, attention-deficit hyperactive disorder (ADHD), as well as healthy subjects for better performance in exams. MATERIAL AND METHODS In this research, a 21-day separation for 3 h was implemented, and the effects of MS on spatial and passive avoidance learning, and memory were evaluated in the mid-adolescence period of rats, in both males and females. Also, a drug intervention of a high therapeutic dose of 5 mg per kg was used in a five-day period in different control and MS groups. Morris water maze was utilized for spatial learning and memory analysis, and a shuttle box paradigm was used for passive avoidance learning and memory. RESULTS Through our behavioral tests, we have shown that MS can alter spatial learning and memory in males. On the other hand, females are protected from the detrimental effects of MS on spatial learning and memory. Furthermore, passive avoidance learning was not different among groups, be it male or female. However, in the case of memory evaluation in the passive avoidance test, the male did not exhibit a significant difference in step-through latency. However, maternally separated females had poor performance in the memory phase with shorter step-through latencies. CONCLUSION Methylphenidate compensated for the deleterious effects of MS on learning and spatial memory for the male group and passive avoidance memory in the female group at the behavioral level.
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Affiliation(s)
| | - Soheila Rezakhani
- Neuroscience Research Center, Institute of NeuropharmacologyKerman University of Medical SciencesKermanIran
| | | | - Khadijeh Esmaeilpour
- Neuroscience Research Center, Institute of NeuropharmacologyKerman University of Medical SciencesKermanIran
- School of Public Health SciencesUniversity of WaterlooWaterlooOntarioCanada
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Choe JY, Jones HP. Methods for Modeling Early Life Stress in Rodents. Methods Mol Biol 2025; 2868:205-219. [PMID: 39546232 DOI: 10.1007/978-1-0716-4200-9_11] [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] [Indexed: 11/17/2024]
Abstract
Animal models of early life stress/adversity (ELS) have provided a foundation from which our understanding of the psychoneuroimmunology of childhood trauma has expanded over recent decades. Rodent models are a cornerstone of the ELS literature with many studies utilizing paradigms based on early life separation/deprivation protocols and manipulating the cage environment. However, no animal model is perfect. In particular, the lack of standardization across ELS models has led to inconsistent results and raised questions regarding the translational value of common preclinical models. In this chapter, we present an overview of the history of ELS rodent models and discuss considerations relevant to the ongoing efforts to both improve existing models and generate novel paradigms to meet the evolving needs of molecular- and mechanism-based ELS research.
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Affiliation(s)
- Jamie Y Choe
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA
| | - Harlan P Jones
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA.
- Institute for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, USA.
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Mundorf A, Freund N. Effects of Early Stress Exposure on Anxiety-like Behavior and MORC1 Expression in Rats. Biomolecules 2024; 14:1587. [PMID: 39766294 PMCID: PMC11674774 DOI: 10.3390/biom14121587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Exposure to stress during early and late childhood can lead to long-lasting neurobiological and behavioral impairments. Although sensitive periods for stress exposure are well established, less is known about the trajectory of induced alterations throughout development. In this study, we investigated the impact of maternal separation (MS), social isolation, and their combination on anxiety-like behavior and gene expression across developmental stages. Sprague Dawley rats were exposed to one or both stressors and later assessed for anxiety-like behavior in juvenility, adolescence, and adulthood. mRNA levels of Morc1, a gene linked to early-life stress and depression, were measured in the medial prefrontal cortex to assess developmental changes. The results showed that MS had age- and sex-dependent effects on anxiety-like behavior. Juveniles exhibited less anxiety after MS, while adolescents showed more pronounced behavioral changes following social isolation. No behavioral changes were observed in adults. Males exhibited greater anxiety-like behavior than females in adolescence and adulthood, but not in juvenility. Female adults exposed to both MS and social isolation had significantly lower Morc1 expression compared to controls. These findings highlight the dynamic effects of early stress across the lifespan, underscoring the critical role of adolescence and differential stress susceptibility by age and sex.
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Affiliation(s)
- Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, 44801 Bochum, Germany
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School, 20457 Hamburg, Germany
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, 44801 Bochum, Germany
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Mundorf A, Merklein SA, Rice LC, Desmond JE, Peterburs J. Early Adversity Affects Cerebellar Structure and Function-A Systematic Review of Human and Animal Studies. Dev Psychobiol 2024; 66:e22556. [PMID: 39378310 DOI: 10.1002/dev.22556] [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: 01/12/2024] [Revised: 07/23/2024] [Accepted: 09/18/2024] [Indexed: 10/10/2024]
Abstract
Recent research has highlighted cerebellar involvement in cognition and several psychiatric conditions such as mood and anxiety disorders and schizophrenia. Attention-deficit/hyperactivity disorder and autism spectrum disorder have been linked to reduced cerebellar volume as well. Cerebellar alterations are frequently present after early adversity in humans and animals, but a systematic integration of results is lacking. To this end, a systematic literature search was conducted in PubMed, Web of Science, and EBSCO databases using the keywords "early adversity OR early life stress" AND "cerebellum OR cerebellar." A total of 45 publications met the inclusion criteria: 25 studies investigated human subjects and 20 reported results from animal models. Findings in healthy subjects show bilateral volume reduction and decreased functional connectivity within the cerebellum and between the cerebellum and frontal regions after adversity throughout life, especially when adversity was assessed with the Childhood Trauma Questionnaire. In clinical populations, adults demonstrate increased cerebellar volume and functional connectivity after adversity, whereas pediatric patients show reduced cerebellar volume. Animal findings reveal cerebellar alterations without necessarily co-occurring pathological behavior, highlighting alterations in stress hormone receptor levels, cell density, and neuroinflammation markers. Cerebellar alterations after early adversity are robust findings across human and animal studies and occur independent of clinical symptoms.
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Affiliation(s)
- Annakarina Mundorf
- Department of Neurology, Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Sarah A Merklein
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
- Department of Psychology, Medical School Hamburg, Hamburg, Germany
| | - Laura C Rice
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - John E Desmond
- Department of Neurology, Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jutta Peterburs
- Department of Neurology, Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
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Ojha RK, Dongre S, Singh P, Srivastava RK. Late maternal separation provides resilience to chronic variable stress-induced anxiety- and depressive-like behaviours in male but not female mice. World J Biol Psychiatry 2024; 25:393-407. [PMID: 39155532 DOI: 10.1080/15622975.2024.2390411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/10/2024] [Accepted: 08/05/2024] [Indexed: 08/20/2024]
Abstract
Maternal separation can have long-lasting effects on an individual's susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.
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Affiliation(s)
- Rajesh Kumar Ojha
- Department of Zoology, Indira Gandhi National Tribal University, Anuppur, India
| | - Shweta Dongre
- Department of Zoology, Indira Gandhi National Tribal University, Anuppur, India
| | - Padmasana Singh
- Department of Zoology, University of Allahabad, Prayagraj, India
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Gildawie KR, Wang K, Budge KE, Byrnes EM. Effects of Maternal Separation on Effort-based Responding for Sucrose Are Associated with c-Fos Expression in the Nucleus Accumbens Core. Neuroscience 2024; 537:174-188. [PMID: 38036058 PMCID: PMC10872495 DOI: 10.1016/j.neuroscience.2023.11.030] [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: 08/04/2023] [Revised: 11/06/2023] [Accepted: 11/26/2023] [Indexed: 12/02/2023]
Abstract
In both people and animals, exposure to adverse experiences early in life can alter neurodevelopment and lead to long-term behavioral effects, including effects on reward processing. In the current study, we use a well-validated rodent model of maternal neglect, maternal separation (MS), to investigate the impact of early life adversity on reward learning and motivation and identify associated modifications in cellular activation in reward-relevant areas. Litters of Long-Evans rats were separated from the dam for either 15 min (brief) or 180 min (prolonged)/day from postnatal day (PND)2 to PND14. As adults, offspring were trained to lever press for a sucrose pellet using fixed ratio (FR) schedules and motivation was tested using a progressive ratio (PR) schedule over 10 daily sessions to assess sustained effects on effort-based responding. Immunohistochemical staining for c-Fos was conducted in a subset of animals that underwent an additional PR session. While there were no effects on reward learning, both MS180 males and females demonstrated increased effort-based responding on the first day of PR testing, while only MS180 males demonstrated a sustained increase in effort across all 10 days. MS180-induced changes in c-Fos expression in the dorsal and ventral striatum were observed, with subregion-specific effects along the rostrocaudal axis. Moreover, regression analyses suggest that motivated responding for a sucrose food reward in MS180-exposed, but not MS15-exposed animals, was associated with increased c-Fos expression in the rostral nucleus accumbens core. These findings implicate specific striatal regions in sex-specific modulation of sustained effort-based reward behavior following early life adversity.
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Affiliation(s)
- Kelsea R Gildawie
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Katherine Wang
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Kerri E Budge
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA
| | - Elizabeth M Byrnes
- Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536, USA.
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Rombaut C, Roura-Martinez D, Lepolard C, Gascon E. Brief and long maternal separation in C57Bl6J mice: behavioral consequences for the dam and the offspring. Front Behav Neurosci 2023; 17:1269866. [PMID: 37936649 PMCID: PMC10626007 DOI: 10.3389/fnbeh.2023.1269866] [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: 07/31/2023] [Accepted: 10/09/2023] [Indexed: 11/09/2023] Open
Abstract
Introduction Animal models, especially rodents, have become instrumental to experimentally investigate the effects of an adverse post-natal environment on the developing brain. For this purpose, maternal separation (MS) paradigms have been widely used in the last decades. Nonetheless, how MS affects maternal behavior and, ultimately, the offspring depend on multiple variables. Methods To gain further insights into the consequences of MS, we decided to thoroughly measure and compare the effects of short (15 min, 3 times/day) vs. long (3 h, 1 time/day) separation on multiple maternally-associated behaviors and across the entire post-natal period. Results Compared to unhandled control litters, our results confirmed previous studies and indicated that SMS enhanced the time and variety of maternal care whereas LMS resulted in poor caregiving. We also showed that SMS-accrued caregiving persisted during the whole post-natal period. In contrast, LMS effects on maternal behavior were restricted to the early life (P2-P10). Finally, we also analyzed the behavioral consequences of these different rearing social environments on the offspring. We found that MS has profound effects in social tasks. We showed that affiliative touch, a type of prosocial behavior that provides comfort to others, is particularly sensitive to the modification of maternal caregiving. Discussion Our results provide further support to the contention that interactions during the early post-natal period critically contribute to emotional processing and brain co-construction.
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Affiliation(s)
| | | | | | - Eduardo Gascon
- Aix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France
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Ukyo R, Shinohara A, Koshimoto C, Nagura-Kato GA, Ieiri S, Tsuzuki Y, Sakamoto SH. Long-term behavioral effects of social separation during early life in a social mammal, Octodon degus. Sci Rep 2023; 13:9518. [PMID: 37308511 DOI: 10.1038/s41598-023-36745-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 06/08/2023] [Indexed: 06/14/2023] Open
Abstract
Social separation is thought to induce a strong stress response in social juvenile mammals, but little is known about how this response might vary throughout the development. The present study examines the long-term effects of early-life stress (ELS) induced by social separation on individual behaviors later in life using the social and precocious species Octodon degus. Four experimental groups were established a positive control group of mothers and siblings from six litters comprised the socially housed (SH) group, while pups from seven litters were randomly assigned to three treatments: pups experiencing no separation (NS) treatment while their siblings did; repeated bouts of consecutive separation (CS); intermittent separation (IS). We analyzed the effects of separation treatment on the frequency and duration of freezing, rearing and grooming behaviors. ELS was correlated with higher hyperactivity, and hyperactivity increased with more frequent separation. However, the behavioral trend of the NS group changed to hyperactive in long-term observation. The findings suggest that the NS group was indirectly affected by ELS. In addition, suggesting ELS acts to converge an individual's behavioral tendencies in a certain direction.
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Affiliation(s)
- Rina Ukyo
- Interdisciplinary Graduate School of Agriculture and Engineering, University of Miyazaki, Miyazaki, Japan
| | - Akio Shinohara
- Division of Bio-Resources, Department of Biotechnology, Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki-shi, Miyazaki, 889-1692, Japan
| | - Chihiro Koshimoto
- Division of Bio-Resources, Department of Biotechnology, Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki-shi, Miyazaki, 889-1692, Japan
| | - Goro A Nagura-Kato
- Division of Bio-Resources, Department of Biotechnology, Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki-shi, Miyazaki, 889-1692, Japan
| | - Seiji Ieiri
- Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Yasuhiro Tsuzuki
- Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan
| | - Shinsuke H Sakamoto
- Faculty of Agriculture, University of Miyazaki, Miyazaki, 889-2192, Japan.
- Center for Animal Disease Control, University of Miyazaki, Miyazaki, Japan.
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Önel T, Arıcıoğlu F, Yıldırım E, Zortul H, Yaba A. The effect of maternal separation stress-induced depression on ovarian reserve in Sprague Dawley Rats: The possible role of imipramine and agmatine through a mTOR signal pathway. Physiol Behav 2023:114270. [PMID: 37308044 DOI: 10.1016/j.physbeh.2023.114270] [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: 03/24/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
PURPOSE To examine the possible role of impramine and agmatine through a mTOR signal pathway on rat ovary after maternal separation stress-induced depression. METHODS Sprague Dawley neonatal female rats were divided into control, maternal separation (MS), MS+imipramine, and MS+agmatine groups. Rats were subjected to MS for 4 hours daily from postnatal day (PND) 2 to PND 21 and pups were exposed to social isolation (SI) on PND23 for 37 days for model establishment treated with imipramine (30 mg/kg; ip) or agmatine (40 mg/kg; ip) for 15 days. In order to examine behavioral changes rats were all subjected to locomotor activity and forced swimming tests (FST). Ovaries were isolated for morphological evaluation, follicle counting and mTOR signal pathway protein expression levels were detected. RESULTS Increased number of primordial follicles and diminished ovarian reserve in the MS groups were detected. Imipramine treatment caused diminished ovarian reserve and atretic follicle; however, agmatine treatment provided the maintenance of ovarian follicular reserve after MS. mTOR signal pathway may have an important role during rat ovarian follicular development in model of MS. CONCLUSIONS Our findings suggest that agmatine may help to protect ovarian reserve during follicular development by controlling cell growth.
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Affiliation(s)
- Tuğçe Önel
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Türkiye
| | - Feyza Arıcıoğlu
- Marmara University, Institute of Health Sciences, İstanbul, Türkiye
| | - Ecem Yıldırım
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Türkiye
| | - Hacer Zortul
- Marmara University, Institute of Health Sciences, İstanbul, Türkiye
| | - Aylin Yaba
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Türkiye..
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Shimoda M, Toyoda H, Sato H, Katagiri A, Yamada M, Murakami J, Akiyama S, Kato T. Long-term changes in oral feeding behaviors of growing rats. Odontology 2023; 111:342-349. [PMID: 36063249 DOI: 10.1007/s10266-022-00739-z] [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: 05/26/2022] [Accepted: 08/24/2022] [Indexed: 10/14/2022]
Abstract
Oral feeding is critical for survival in both humans and animals. However, few studies have reported quantitative behavioral measures associated with the development of oral feeding behaviors. Therefore, the present study investigated developmental changes in the oral feeding behaviors of rats by quantitatively assessing pasta eating and licking behaviors. In the pasta eating test, the time to finish pasta sticks of three different thicknesses (Φ = 0.9, 1.4, and 1.9 mm, 4 cm long) was recorded between postnatal day 29 (P29) and P49, because all rats were able to finish eating these pasta sticks on P29. A developmental decrease in the time to finish pasta sticks of all thicknesses was observed during the initial period of recordings and plateaued before P35. The extent of this decrease was dependent on the thickness of pasta sticks. In the licking test, the number of licks per 10 s and the total intake volume during the test were recorded between P19 and P49, because all rats were able to access and lick the solution on P19. The time courses of developmental increases in the number of licks and the total intake volume were similar to the results obtained in the pasta eating test. Collectively, these results suggest that developmental changes in pasta eating and licking behaviors markedly differed between the weanling and periadolescent periods. The present study also demonstrated the applicability of the pasta eating and licking tests to the quantification of developmental changes in the oral feeding behaviors of rats.
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Affiliation(s)
- Mao Shimoda
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Division of Special Care Dentistry, Osaka University Dental Hospital, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroki Toyoda
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hajime Sato
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Division of Pharmacology, Meikai University School of Dentistry, 1-1 Keyaki-dai, Sakado, Saitama, 350-0283, Japan
| | - Ayano Katagiri
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masaharu Yamada
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Jumpei Murakami
- Division of Special Care Dentistry, Osaka University Dental Hospital, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shigehisa Akiyama
- Division of Special Care Dentistry, Osaka University Dental Hospital, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takafumi Kato
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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14
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The lifetime impact of stress on fear regulation and cortical function. Neuropharmacology 2023; 224:109367. [PMID: 36464208 DOI: 10.1016/j.neuropharm.2022.109367] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/22/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022]
Abstract
A variety of stressful experiences can influence the ability to form and subsequently inhibit fear memory. While nonsocial stress can impact fear learning and memory throughout the lifespan, psychosocial stressors that involve negative social experiences or changes to the social environment have a disproportionately high impact during adolescence. Here, we review converging lines of evidence that suggest that development of prefrontal cortical circuitry necessary for both social experiences and fear learning is altered by stress exposure in a way that impacts both social and fear behaviors throughout the lifespan. Further, we suggest that psychosocial stress, through its impact on the prefrontal cortex, may be especially detrimental during early developmental periods characterized by higher sociability. This article is part of the Special Issue on 'Fear, Anxiety and PTSD'.
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15
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Simmons SC, Grecco GG, Atwood BK, Nugent FS. Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development. Neuropharmacology 2023; 222:109312. [PMID: 36334764 PMCID: PMC10314127 DOI: 10.1016/j.neuropharm.2022.109312] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
In this review, we focus on prenatal opioid exposure (POE) given the significant concern for the mental health outcomes of children with parents affected by opioid use disorder (OUD) in the view of the current opioid crisis. We highlight some of the less explored interactions between developmental age and sex on synaptic plasticity and associated behavioral outcomes in preclinical POE research. We begin with an overview of the rich literature on hippocampal related behaviors and plasticity across POE exposure paradigms. We then discuss recent work on reward circuit dysregulation following POE. Additional risk factors such as early life stress (ELS) could further influence synaptic and behavioral outcomes of POE. Therefore, we include an overview on the use of preclinical ELS models where ELS exposure during key critical developmental periods confers considerable vulnerability to addiction and stress psychopathology. Here, we hope to highlight the similarity between POE and ELS on development and maintenance of opioid-induced plasticity and altered opioid-related behaviors where similar enduring plasticity in reward circuits may occur. We conclude the review with some of the limitations that should be considered in future investigations. This article is part of the Special Issue on 'Opioid-induced addiction'.
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Affiliation(s)
- Sarah C Simmons
- Department of Pharmacology and Molecular Therapeutics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Greg G Grecco
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA; Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Brady K Atwood
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Fereshteh S Nugent
- Department of Pharmacology and Molecular Therapeutics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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16
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Sex differences in addiction-relevant behavioral outcomes in rodents following early life stress. ADDICTION NEUROSCIENCE 2023; 6. [PMID: 37101684 PMCID: PMC10124992 DOI: 10.1016/j.addicn.2023.100067] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In humans, exposure to early life stress (ELS) is an established risk factor for the development of substance use disorders (SUDs) during later life. Similarly, rodents exposed to ELS involving disrupted mother-infant interactions, such as maternal separation (MS) or adverse caregiving due to scarcity-adversity induced by limited bedding and nesting (LBN) conditions, also exhibit long-term alterations in alcohol and drug consumption. In both humans and rodents, there is a range of addiction-related behaviors that are associated with drug use and even predictive of subsequent SUDs. In rodents, these include increased anxiety-like behavior, impulsivity, and novelty-seeking, altered alcohol and drug intake patterns, as well as disrupted reward-related processes involving consummatory and social behaviors. Importantly, the expression of these behaviors often varies throughout the lifespan. Moreover, preclinical studies suggest that sex differences play a role in how exposure to ELS impacts reward and addiction-related phenotypes as well as underlying brain reward circuitry. Here, addiction-relevant behavioral outcomes and mesolimbic dopamine (DA) dysfunction resulting from ELS in the form of MS and LBN are discussed with a focus on age- and sex-dependent effects. Overall, these findings suggest that ELS may increase susceptibility for later life drug use and SUDs by interfering with the normal maturation of reward-related brain and behavioral function.
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17
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Jarrar Q, Ayoub R, Alhussine K, Goh KW, Moshawih S, Ardianto C, Goh BH, Ming LC. Prolonged Maternal Separation Reduces Anxiety State and Increases Compulsive Burying Activity in the Offspring of BALB/c Mice. J Pers Med 2022; 12:1921. [PMID: 36422097 PMCID: PMC9699014 DOI: 10.3390/jpm12111921] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND The elevated plus maze (EPM) and the marble burying (MB) tests are common behavioral tests used for behavioral phenotyping in mouse models for neurodevelopmental disorders. However, the behavioral effects of maternal separation (MS), a standard paradigm for early life stress in animals, in both the EPM and MB tests remain incompletely known. OBJECTIVES This study aimed to investigate the behavioral effects of prolonged MS in the offspring of mice using the EPM and MB tests. METHODS Male BALB/c mice were isolated from their mothers for 4 h each day during the first 30 days after birth. On day 50 postnatal, groups of separated and non-separated mice (n = 18/each group) were subjected to the EPM and MB tests for comparative behavioral evaluations. In addition, the locomotor activity of mice was evaluated using the actophotometer test. RESULTS The findings of the EPM test revealed that separated mice exhibited anxiolytic-like behaviors, as evidenced by a significant increase in the latency to closed arms and the time spent in the open arms compared with non-separated mice. Separated mice also showed compulsive burying activity in the MB test, as determined by a significant increase in the number of buried marbles. The results of the actophotometer test did not show any significant change in locomotor activity. CONCLUSIONS Prolonged MS caused the adult offspring of mice to exhibit a decrease in anxiety state and increased compulsive burying activity, which were not associated with a change in locomotor activity. Further investigations with validated tests are needed to support these findings.
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Affiliation(s)
- Qais Jarrar
- Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman 11622, Jordan
| | - Rami Ayoub
- Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman 11622, Jordan
| | - Kawther Alhussine
- Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman 11622, Jordan
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia
| | - Said Moshawih
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei Darussalam
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Bey Hing Goh
- Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Petaling Jaya 47500, Malaysia
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Long Chiau Ming
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei Darussalam
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
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18
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Granata L, Parakoyi A, Brenhouse HC. Age- and sex-specific effects of maternal separation on the acoustic startle reflex in rats: early baseline enhancement in females and blunted response to ambiguous threat. Front Behav Neurosci 2022; 16:1023513. [PMID: 36386786 PMCID: PMC9643533 DOI: 10.3389/fnbeh.2022.1023513] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
Abstract
Early life adversity (ELA) increases the incidence of later-life anxiety disorders. Dysregulated threat processing, including responsivity to ambiguous threats, is an indicator of anxiety disorders and can be influenced by childhood experiences. The acoustic startle response is a defensive reflex displayed by mammals when exposed to sudden intense stimuli reflecting individual variations in vigilance. These measures can be altered by previous experience and experimental modifications, including the introduction of unconditioned aversive stimuli. Rats emit ultrasonic vocalizations (USVs) in the 22 KHz range in negative contexts. As such, 22 KHz USVs are an ethologically relevant social cue of environmental threat shown to induce anxiety-like behavior in recipient rats. Because the timing of symptom manifestation after early life adversity can differ between sexes, the current study sought to identify the age- and sex-specific effects of daily maternal separation (MS) on responsivity to ambiguous threat in rats. In Experiment 1, rat pups underwent MS or control rearing from postnatal day (P) 2–20, then underwent behavioral testing beginning on P24, 34, or 54 to determine whether MS modified the baseline startle response or the modulation of startle by 22 KHz USVs. In Experiment 2, rats were tested in a light-enhanced startle paradigm at P54 after MS or control rearing to determine whether MS influenced light-enhanced startle. Results show an enhancement of the baseline startle magnitude by MS in females at P34. At P54, MS reduced the modulation of the startle response by 22 KHz USVs and prevented light-enhanced startle, indicating an MS-induced deficit in defensive responsivity when exposed to potential threat.
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19
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Rosa DS, Frias AT, Vilela-Costa HH, Junior AS, Sant’Ana AB, Fusse EJ, Suchecki D, Campos AC, Lovick TA, Zangrossi H. Neonatal maternal deprivation facilitates the expression of a panic-like escape behavior in adult rats. Behav Brain Res 2022; 434:114031. [DOI: 10.1016/j.bbr.2022.114031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 11/02/2022]
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20
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Waters RC, Gould E. Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models. Front Syst Neurosci 2022; 16:860847. [PMID: 35813268 PMCID: PMC9259886 DOI: 10.3389/fnsys.2022.860847] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 04/19/2022] [Indexed: 12/02/2022] Open
Abstract
It is now well-established that early life adversity (ELA) predisposes individuals to develop several neuropsychiatric conditions, including anxiety disorders, and major depressive disorder. However, ELA is a very broad term, encompassing multiple types of negative childhood experiences, including physical, sexual and emotional abuse, physical and emotional neglect, as well as trauma associated with chronic illness, family separation, natural disasters, accidents, and witnessing a violent crime. Emerging literature suggests that in humans, different types of adverse experiences are more or less likely to produce susceptibilities to certain conditions that involve affective dysfunction. To investigate the driving mechanisms underlying the connection between experience and subsequent disease, neuroscientists have developed several rodent models of ELA, including pain exposure, maternal deprivation, and limited resources. These studies have also shown that different types of ELA paradigms produce different but somewhat overlapping behavioral phenotypes. In this review, we first investigate the types of ELA that may be driving different neuropsychiatric outcomes and brain changes in humans. We next evaluate whether rodent models of ELA can provide translationally relevant information regarding links between specific types of experience and changes in neural circuits underlying dysfunction.
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Affiliation(s)
| | - Elizabeth Gould
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
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21
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Sinani A, Vassi A, Tsotsokou G, Nikolakopoulou M, Kouvelas ED, Mitsacos A. Early life stress influences basal ganglia dopamine receptors and novel object recognition of adolescent and adult rats. IBRO Neurosci Rep 2022; 12:342-354. [PMID: 35572456 PMCID: PMC9092503 DOI: 10.1016/j.ibneur.2022.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022] Open
Abstract
Environmental stimuli in early life are recognized to affect brain development and behavior. Mother-pup interaction constitutes a determinant stimulus during this critical period. It is known that the dopaminergic system undergoes significant reorganization during adolescence and that dopamine receptors are involved in recognition memory. Based on the above, we examined the effects of brief and prolonged maternal separation during the neonatal period (15 or 180 min daily) on basal ganglia dopamine receptors and on the behavior in the novel object recognition task of adolescent and adult male rats. Using the NOR task, we observed that the discrimination index (DI) was decreased in rats with brief maternal separations independent of age. Using receptor autoradiography, we observed that brief maternal separation induced decreases in D1, D2 and D4 receptor binding levels in adult basal ganglia nuclei, while prolonged maternal separation induced increases in D1 receptor binding levels in caudate - putamen (CPu) of adolescent rats. With immunoblotting experiments, we found decreases in D1 and increases in D2 total protein levels in CPu of adult rats with prolonged maternal separations. Α positive correlation was observed between DI and D1 binding levels in CPu, internal globus pallidus and substantia nigra, and D2 binding levels in nucleus accumbens core in adult rats, using the Pearson correlation coefficient. Our results indicate that the long-lasting effects of neonatal mother-offspring separation on dopamine receptors depend on the duration of maternal separation and age and that this early life experience impairs recognition memory in adolescent and adult rats. Furthermore, the present results suggest that modulation of striatal dopamine receptors might underlie the reduced recognition memory of adult rats with brief neonatal maternal separations.
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Affiliation(s)
- Ada Sinani
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Andriana Vassi
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Giota Tsotsokou
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Maria Nikolakopoulou
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Elias D Kouvelas
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
| | - Ada Mitsacos
- Laboratory of Physiology, Faculty of Medicine, University of Patras, Patras, Greece
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22
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Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen. Neurobiol Stress 2022; 19:100460. [PMID: 35734023 PMCID: PMC9207718 DOI: 10.1016/j.ynstr.2022.100460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/22/2022] [Accepted: 05/10/2022] [Indexed: 12/03/2022] Open
Abstract
This manuscript is dedicated to the memory of Bruce S. McEwen, to commemorate the impact he had on how we understand stress and neuronal plasticity, and the profound influence he exerted on our scientific careers. The focus of this review is the impact of stressors on inhibitory circuits, particularly those of the limbic system, but we also consider other regions affected by these adverse experiences. We revise the effects of acute and chronic stress during different stages of development and lifespan, taking into account the influence of the sex of the animals. We review first the influence of stress on the physiology of inhibitory neurons and on the expression of molecules related directly to GABAergic neurotransmission, and then focus on specific interneuron subpopulations, particularly on parvalbumin and somatostatin expressing cells. Then we analyze the effects of stress on molecules and structures related to the plasticity of inhibitory neurons: the polysialylated form of the neural cell adhesion molecule and perineuronal nets. Finally, we review the potential of antidepressants or environmental manipulations to revert the effects of stress on inhibitory circuits.
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23
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Repeated Maternal Separation Prolongs the Critical Period of Ocular Dominance Plasticity in Mouse Visual Cortex. Neurosci Lett 2022; 776:136577. [DOI: 10.1016/j.neulet.2022.136577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 11/18/2022]
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24
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Mundorf A, Bölükbas I, Freund N. Maternal separation: Does it hold the potential to model consequences of postpartum depression? Dev Psychobiol 2022; 64:e22219. [PMID: 35050513 DOI: 10.1002/dev.22219] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/30/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
The postpartum period is a sensitive time where women are especially vulnerable to develop postpartum depression (PPD), with 10%-15% of women affected. This review investigates whether the maternal separation (MS) paradigm in rodents holds the potential to help to understand mothers suffering from PPD. MS is a well-established stress model to investigate effects on infants, whereas effects on the dam are often overlooked. The database PubMed was searched for studies investigating effects of daily MS within the first weeks after parturition on dams in rats and mice and compared to findings in PPD mothers. MS was categorized as brief MS (5-45 min) with or without handling of pups and long MS (3-4 h and longer). MS alters maternal care, depressive-like behavior, anxiety, and aggression; leads to alterations in neuronal gene expression; and affects hormone and neurotransmitter levels similar to observations in PPD patients. Even though there are disparities between human and rodent mothers, with some results differing in directionality, as well as the reason for separation (self-induced in PPD, externally induced in MS), the overall effects found on neurobiological, hormonal, and behavioral levels mostly coincide. Thus, the MS paradigm can add relevant knowledge to existing PPD animal models, further advancing the study of PPD.
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Affiliation(s)
- Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany.,Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Ibrahim Bölükbas
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany
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25
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Saad SM, Iwundu C, Ibrahim MS, Randhawa G, Pang D. Life-Course Influence of Adolescent Behaviour Problems on Type 2 Diabetes in Midlife: Results from 1958 British Birth Cohort Study. Diabetes Metab Syndr Obes 2022; 15:963-972. [PMID: 35378832 PMCID: PMC8976514 DOI: 10.2147/dmso.s308620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/26/2021] [Indexed: 11/23/2022] Open
Abstract
PURPOSE To assess whether there is a long-term relationship between childhood behaviour problems and type 2 diabetes in midlife. The study will also investigate whether any of such relationship is independent of other factors which may be associated with type 2 diabetes. DESIGN Cohort study. PARTICIPANTS A total of 9377 members of the 1958 British birth cohort participated in the biomedical survey at age 45 years. The cohort has been followed up at regular intervals in childhood (age 7, 11 and 16 years) and adulthood (23, 33, 42 and 45 years). PREDICTOR VARIABLES Information regarding childhood behaviour collected during follow-ups at ages 7, 11 and 16 years. MAIN OUTCOME VARIABLES Type 2 diabetes assessed using HbA1c at age 45 years. RESULTS Unadjusted estimates show that teachers reported adolescent behaviour problems at age of 16 are associated with increased risk of type 2 diabetes in midlife. After adjustment for potential confounders and mediators in childhood and adulthood, a relationship was observed between the severity of adolescent behaviour problems and type 2 diabetes risk in midlife (mild behaviour problems: OR 2.17, 95% CI 1.11-4.23; severe behaviour problems: OR 4.40, 95% CI 1.14-16.99). However, no such relationship was observed between behaviour problems at 7 and 11 years and type 2 diabetes in midlife. CONCLUSION There is an association between adolescent behaviour problems and an increased risk of type 2 diabetes in midlife. Further molecular/genetic studies are required to understand the biological basis for this observed association.
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Affiliation(s)
- Sadiq M Saad
- Institute for Health Research, University of Bedfordshire, Luton, Bedfordshire, LU2 8LE, England
| | - Chukwuma Iwundu
- Institute for Health Research, University of Bedfordshire, Luton, Bedfordshire, LU2 8LE, England
| | - Musa S Ibrahim
- Institute for Health Research, University of Bedfordshire, Luton, Bedfordshire, LU2 8LE, England
- Correspondence: Musa S Ibrahim, Institute for Health Research, University of Bedfordshire, Putteridge Bury, Luton, Bedfordshire, LU2 8LE, England, Tel +447918698231, Email
| | - Gurch Randhawa
- Institute for Health Research, University of Bedfordshire, Luton, Bedfordshire, LU2 8LE, England
| | - Dong Pang
- Institute for Health Research, University of Bedfordshire, Luton, Bedfordshire, LU2 8LE, England
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26
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Langlois LD, Berman RY, Shepard RD, Simmons SC, Tsuda MC, Gouty S, Choi KH, Nugent FS. Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self-administration in rats. Addict Biol 2022; 27:e13064. [PMID: 34036710 PMCID: PMC8613295 DOI: 10.1111/adb.13064] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 01/06/2023]
Abstract
Early life stress presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine pathways. Using an early life stress model for child neglect (a single 24 h episode of maternal deprivation, MD) in rats, recent published works from our lab show that MD induces dysfunction in the ventral tegmental area and its negative controller, the lateral habenula (LHb). MD-induced potentiation of glutamatergic synaptic transmission onto LHb neurons shifts the coordination of excitation/inhibition (E/I) balance towards excitation, resulting in an increase in the overall spontaneous neuronal activity with elevation in bursting and tonic firing, and in the intrinsic excitability of LHb neurons in early adolescent male rats. Here, we explored how MD affects intravenous morphine self-administration (MSA) acquisition and sucrose preference as well as glutamatergic synaptic function in LHb neurons of adult male rats self-administering morphine. We found that MD-induced increases in LHb neuronal and glutamatergic synaptic activity and E/I ratio persisted into adulthood. Moreover, MD significantly reduced morphine intake, triggered anhedonia-like behaviour in the sucrose preference test and was associated with persistent glutamatergic potentiation 24 h after the last MSA session. MSA also altered the decay time kinetics of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) currents in LHb neurons of control rats during this time period. Our data highlight that early life stress-induced glutamatergic plasticity in LHb may dampen the positive reinforcing and motivational properties of both natural rewards and opioids, and may contribute to the development of anhedonia and dysphoric states associated with opioids.
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Affiliation(s)
- Ludovic D. Langlois
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology, Bethesda, Maryland 20814, USA
| | - Rina Y. Berman
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Psychiatry, Bethesda, Maryland 20814, USA
| | - Ryan D. Shepard
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology, Bethesda, Maryland 20814, USA
| | - Sarah C. Simmons
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology, Bethesda, Maryland 20814, USA
| | - Mumeko C. Tsuda
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Rat Behavior Core, Bethesda, Maryland 20814, USA
| | - Shawn Gouty
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology, Bethesda, Maryland 20814, USA
| | - Kwang H. Choi
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Psychiatry, Bethesda, Maryland 20814, USA
| | - Fereshteh S. Nugent
- Uniformed Services University of the Health Sciences, Edward Hebert School of Medicine, Department of Pharmacology, Bethesda, Maryland 20814, USA
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The underestimated sex: a review on female animal models of depression. Neurosci Biobehav Rev 2021; 133:104498. [PMID: 34953920 DOI: 10.1016/j.neubiorev.2021.12.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 01/19/2023]
Abstract
Major depression (MD) is the most common psychiatric disorder, predicted to affect around 264 million people worldwide. Although the etiology of depression remains elusive, the interplay between genetics and environmental factors, such as early life events, stress, exposure to drugs and health problems appears to underlie its development. Whereas depression is twice more prevalent in women than in men, most preclinical studies are performed in male rodents. In fact, females' physiology and reproductive experience are associated with changes to brain, behavior and endocrine profiles that may influence both stress, an important precipitating factor for depression, and response to treatment. These specificities emphasize the need to choose the most suitable models and readouts in order to better understand the pathophysiological mechanisms of depression in females. With this review, we aim to provide an overview of female animal models of depression highlighting the major differences between models, regarding behavioral, physiological, and molecular readouts, but also the major gaps in research, attending to the role of etiological factors, protocol variability and sex.
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Elliot-Portal E, Arias-Reyes C, Laouafa S, Tam R, Kinkead R, Soliz J. Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress. Front Physiol 2021; 12:701344. [PMID: 34987412 PMCID: PMC8720854 DOI: 10.3389/fphys.2021.701344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/22/2021] [Indexed: 11/29/2022] Open
Abstract
Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.
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Affiliation(s)
- Elizabeth Elliot-Portal
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
| | - Christian Arias-Reyes
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
| | - Sofien Laouafa
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
| | - Rose Tam
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
| | - Richard Kinkead
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
| | - Jorge Soliz
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, QC, Canada
- High Altitude Pulmonary and Pathology Institute (HAPPI–IPPA), La Paz, Bolivia
- *Correspondence: Jorge Soliz,
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Abellán-Álvaro M, Stork O, Agustín-Pavón C, Santos M. MeCP2 haplodeficiency and early-life stress interaction on anxiety-like behavior in adolescent female mice. J Neurodev Disord 2021; 13:59. [PMID: 34895132 PMCID: PMC8903671 DOI: 10.1186/s11689-021-09409-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early-life stress can leave persistent epigenetic marks that may modulate vulnerability to psychiatric conditions later in life, including anxiety, depression and stress-related disorders. These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the MECP2 gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits. METHODS Using Mecp2 heterozygous and wild-type female mice we investigated the effects of the interaction of Mecp2 haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation. RESULTS In wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in Mecp2 heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation. CONCLUSIONS Our data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.
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Affiliation(s)
- María Abellán-Álvaro
- Unitat Mixta d'Investigació en Neuroanatomia Funcional, Departamento de Biologia Cel·lular, Biologia Funcional i Antropologia Física, Universitat de València, 46100 Burjassot, València, Spain
| | - Oliver Stork
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, 39120, Magdeburg, Germany
| | - Carmen Agustín-Pavón
- Unitat Mixta d'Investigació en Neuroanatomia Funcional, Departamento de Biologia Cel·lular, Biologia Funcional i Antropologia Física, Universitat de València, 46100 Burjassot, València, Spain
| | - Mónica Santos
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
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Davis SM, Burman MA. Maternal separation with neonatal pain influences later-life fear conditioning and somatosenation in male and female rats. Stress 2021; 24:504-513. [PMID: 33043804 PMCID: PMC8039057 DOI: 10.1080/10253890.2020.1825674] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Early life adversity, including that which occurs in a medical setting, has been increasingly shown to have lasting consequences on both physical and mental health. In order to understand the lasting effects of early-life adversity, such as that might occur in the neonatal intensive care unit (NICU), several rodent models have been developed including maternal separation, neonatal handling, and repeated needle prick pain. However, in the clinical scenario, these stressors are often combined. Thus, the current study seeks to observe the lasting impacts of both neonatal pain and maternal separation in a rodent model. Rats were separated from their dam for 6 h per day during the first 7 days of life, during which they were subjected to repeated needle prick pain or handling. A separate group was left undisturbed. All rats were subsequently tested for threat processing using a 3-day Pavlovian fear conditioning model and for somatosensation using measures of mechanical and thermal thresholds. Results indicated that rats subjected to maternal separation and pain had enhanced fear conditioning in adolescence as well as displaying a modest age-independent tactile hypersensitivity compared to undisturbed controls. These data show that experiencing combined neonatal pain and maternal separation may create a latent vulnerability to subsequent stressors.
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Affiliation(s)
- Seth M. Davis
- Department of Psychology, University of New England
- Center for Excellence in the Neurosciences, University of
New England
| | - Michael A. Burman
- Department of Psychology, University of New England
- Center for Excellence in the Neurosciences, University of
New England
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Kinkead R, Gagnon M, Joseph V, Sériès F, Ambrozio-Marques D. Stress and Loss of Ovarian Function: Novel Insights into the Origins of Sex-Based Differences in the Manifestations of Respiratory Control Disorders During Sleep. Clin Chest Med 2021; 42:391-405. [PMID: 34353446 DOI: 10.1016/j.ccm.2021.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The respiratory system of women and men develops and functions in distinct neuroendocrine milieus. Despite differences in anatomy and neural control, homeostasis of arterial blood gases is ensured in healthy individuals regardless of sex. This convergence in function differs from the sex-based differences observed in many respiratory diseases. Sleep-disordered breathing (SDB) results mainly from episodes of upper airway closure. This complex and multifactorial respiratory disorder shows significant sexual dimorphism in its clinical manifestations and comorbidities. Guided by recent progress from basic research, this review discusses the hypothesis that stress is necessary to reveal the sexual dimorphism of SDB.
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Affiliation(s)
- Richard Kinkead
- Department of Pediatrics, Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec G1V 4G5, Canada.
| | - Marianne Gagnon
- Department of Pediatrics, Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec G1V 4G5, Canada
| | - Vincent Joseph
- Department of Pediatrics, Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec G1V 4G5, Canada
| | - Frédéric Sériès
- Department of Medicine, Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, Québec, Québec, Canada
| | - Danuzia Ambrozio-Marques
- Department of Pediatrics, Université Laval, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec G1V 4G5, Canada
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Takahashi A. Social Stress and Aggression in Murine Models. Curr Top Behav Neurosci 2021; 54:181-208. [PMID: 34432257 DOI: 10.1007/7854_2021_243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Throughout life, animals engage in a variety of social interactions ranging from the affiliative mother-offspring interaction and juvenile play to aggressive conflict. Deprivation of the appropriate social interaction during early development is stressful and disrupts the development of appropriate social behaviors and emotional responses later in life. Additionally, agonistic encounters can induce stress responses in both dominant and subordinate individuals. This review focuses on the social stress that escalates aggressive behavior of animals and discusses the known neurobiological and physiological mechanisms underlying the link between social stress and aggression. Social instigation, a brief exposure to a rival without physical contact, induces aggressive arousal in dominant animals and escalates aggressive behaviors in the following agonistic encounter. Furthermore, the experience of winning an aggressive encounter is known to be as rewarding as addictive drugs, and the experience of repeatedly winning induces addiction-like behavioral and neurobiological changes and leads to abnormal aggressive behaviors. Social isolation stress in early development from neonatal to juvenile and adolescent periods also affects aggressive behavior, but these effects largely depend on the strain, sex, and species as well as the stage of development in which isolation stress is experienced. In conclusion, understanding neurobiological mechanisms underlying the link between social stress and aggression will provide an important insight for the development of more effective and tolerable treatments for maladaptive aggression in humans.
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Affiliation(s)
- Aki Takahashi
- Laboratory of Behavioral Neuroendocrinology, Faculty of Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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Kreiker M, Perez K, Brown KL. The effects of early weaning on Pavlovian fear conditioning in young rats. Dev Psychobiol 2021; 63:e22133. [PMID: 34423435 DOI: 10.1002/dev.22133] [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: 01/17/2021] [Revised: 04/29/2021] [Accepted: 05/02/2021] [Indexed: 11/09/2022]
Abstract
Early life stress enhances memory for Pavlovian fear conditioning. Stress enhancements on fear conditioning following early weaning, however, have yet to be studied in periweaning rats. Early weaning is a relevant animal model for human early life trauma, and Pavlovian fear conditioning is useful for identifying links between stress-induced developmental changes and behavior. We hypothesized that early weaning-on postnatal day (P)15-would lead to higher levels of conditional freezing relative to rats weaned later in life. Periweaning rats were trained with a discrete conditional stimulus (CS) and a shock unconditional stimulus (US), and tested 1 or 15 days later. Enhanced retention was observed in early weaned rats receiving forward paired CS-US training in Experiment 1, though this did not replicate in the second experiment. Despite overall enhancements in early weaned rats in Experiment 1, infantile amnesia effects were not overcome in young rats tested 15 days after training. Enhanced freezing levels in early weaned rats were not observed in subjects receiving unpaired CS, US training, and sensitivity to the US was not different due to age at weaning. Potential mechanisms underlying weaning-related enhancements and considerations for future studies including the role of social transmission of fear information are discussed.
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Affiliation(s)
- Malaz Kreiker
- Department of Psychology and Neuroscience, Drake University, Des Moines, Iowa, USA
| | - Katelyn Perez
- Department of Psychology and Neuroscience, Drake University, Des Moines, Iowa, USA
| | - Kevin L Brown
- Department of Psychology and Neuroscience, Drake University, Des Moines, Iowa, USA
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Tsotsokou G, Nikolakopoulou M, Kouvelas ED, Mitsacos A. Neonatal maternal separation affects metabotropic glutamate receptor 5 expression and anxiety-related behavior of adult rats. Eur J Neurosci 2021; 54:4550-4564. [PMID: 34137089 DOI: 10.1111/ejn.15358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 01/15/2023]
Abstract
Exposure to early life stress leads to long-term neurochemical and behavioral alterations. Stress-induced psychiatric disorders, such as depression, have recently been linked to dysregulation of glutamate signaling, mainly via its postsynaptic receptors. The role of metabotropic glutamate receptor 5 (mGluR5) in stress-induced psychopathology has been the target of several studies in humans. In rodents, blockade of mGluR5 produces antidepressant-like actions, whereas mice lacking mGluR5 exhibit altered anxiety-like behaviors and learning. In this study, we used well-known rodent models of early life stress based on mother-infant separation during the first 3 weeks of life in order to examine the effects of neonatal maternal separation on mGluR5 expression and on anxiety-related behavior in adulthood. We observed that brief (15 min) neonatal maternal separation, but not prolonged (3 h), induced increases in mGluR5 mRNA and protein expression levels in medial prefrontal cortex and mGluR5 protein levels in dorsal, but not ventral, hippocampus of adult rat brain. Behavioral testing using the open-field and the elevated-plus maze tasks showed that brief maternal separations resulted in increased exploratory and decreased anxiety-related behavior, whereas prolonged maternal separations resulted in increased anxiety-related behavior in adulthood. The data indicate that the long-lasting effects of neonatal mother-offspring separation on anxiety-like behavior and mGluR5 expression depend on the duration of maternal separation and suggest that the increased mGluR5 receptors in medial prefrontal cortex and hippocampus of adult rats exposed to brief neonatal maternal separations may underlie their heightened ability to cope with stress.
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Affiliation(s)
- Giota Tsotsokou
- School of Health Sciences, Department of Medicine, Laboratory of Physiology, University Campus, University of Patras, Patras, Greece
| | - Maria Nikolakopoulou
- School of Health Sciences, Department of Medicine, Laboratory of Physiology, University Campus, University of Patras, Patras, Greece
| | - Elias D Kouvelas
- School of Health Sciences, Department of Medicine, Laboratory of Physiology, University Campus, University of Patras, Patras, Greece
| | - Ada Mitsacos
- School of Health Sciences, Department of Medicine, Laboratory of Physiology, University Campus, University of Patras, Patras, Greece
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Tenorio-Lopes L, Kinkead R. Sex-Specific Effects of Stress on Respiratory Control: Plasticity, Adaptation, and Dysfunction. Compr Physiol 2021; 11:2097-2134. [PMID: 34107062 DOI: 10.1002/cphy.c200022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
As our understanding of respiratory control evolves, we appreciate how the basic neurobiological principles of plasticity discovered in other systems shape the development and function of the respiratory control system. While breathing is a robust homeostatic function, there is growing evidence that stress disrupts respiratory control in ways that predispose to disease. Neonatal stress (in the form of maternal separation) affects "classical" respiratory control structures such as the peripheral O2 sensors (carotid bodies) and the medulla (e.g., nucleus of the solitary tract). Furthermore, early life stress disrupts the paraventricular nucleus of the hypothalamus (PVH), a structure that has emerged as a primary determinant of the intensity of the ventilatory response to hypoxia. Although underestimated, the PVH's influence on respiratory function is a logical extension of the hypothalamic control of metabolic demand and supply. In this article, we review the functional and anatomical links between the stress neuroendocrine axis and the medullary network regulating breathing. We then present the persistent and sex-specific effects of neonatal stress on respiratory control in adult rats. The similarities between the respiratory phenotype of stressed rats and clinical manifestations of respiratory control disorders such as sleep-disordered breathing and panic attacks are remarkable. These observations are in line with the scientific consensus that the origins of adult disease are often found among developmental and biological disruptions occurring during early life. These observations bring a different perspective on the structural hierarchy of respiratory homeostasis and point to new directions in our understanding of the etiology of respiratory control disorders. © 2021 American Physiological Society. Compr Physiol 11:1-38, 2021.
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Affiliation(s)
- Luana Tenorio-Lopes
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, Alberta, Canada
| | - Richard Kinkead
- Département de Pédiatrie, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada
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Wang X, Fukui H, Ran Y, Xu X, Ebisutani N, Nakanishi T, Tanaka Y, Maeda A, Makizaki Y, Tomita T, Oshima T, Miwa H. Probiotic Bifidobacterium bifidum G9-1 Has a Preventive Effect on the Acceleration of Colonic Permeability and M1 Macrophage Population in Maternally Separated Rats. Biomedicines 2021; 9:biomedicines9060641. [PMID: 34204993 PMCID: PMC8229252 DOI: 10.3390/biomedicines9060641] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/19/2022] Open
Abstract
Although probiotics may be useful for the treatment of irritable bowel syndrome (IBS), it is unclear how probiotics play a role in colonic mucosal integrity and immunity. Here, we aimed to investigate the effect of Bifidobacterium bifidum G9-1 (BBG9-1) on colonic mucosal integrity and macrophage behavior in rats subjected to maternal separation (MS) as a model of IBS. MS pups were individually separated from their mother rats, and a proportion of the MS rats were orally administered BBG9-1. The colonic mucosal permeability was evaluated by Ussing chamber assay. The expression of tight junction proteins and cytokines and the population of CD80-positive cells was examined in the colonic tissues by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Caco2 cells were stimulated with cytokines and the transepithelial electric resistance (TEER) was measured. MS rats showed significantly higher colonic permeability and lower claudin 4 expression in the colonic epithelium relative to controls. The number of CD80-positive macrophages was significantly increased in the colonic mucosa of MS rats, accompanied by the increase of IL-6 and IFN-γ expression. BBG9-1 treatment ameliorated the increase of M1 macrophage and IL-6/IFN-γ expression in the colonic tissue of MS rats. Simultaneously, BBG9-1 treatment improved the enhanced mucosal permeability and the decreased claudin 4 expression in the colon of MS rats. IL-6 and IFN-γ, whose expression is enhanced in the colon of MS rats, significantly decreased TEER in Caco2 cells in vitro. Probiotic BBG9-1 has a preventive effect on the acceleration of colonic permeability and M1 macrophage population in maternally separated rats.
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Affiliation(s)
- Xuan Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Correspondence: ; Tel.: +81-798-45-6662
| | - Ying Ran
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xin Xu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Nobuhiko Ebisutani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Takashi Nakanishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Yoshiki Tanaka
- R&D Center, Biofermin Pharmaceutical Co., Ltd., 7-3-4 Higashi-machi, Ibukidai, Nishi-ku, Kobe 651-2242, Japan; (Y.T.); (A.M.); (Y.M.)
| | - Ayako Maeda
- R&D Center, Biofermin Pharmaceutical Co., Ltd., 7-3-4 Higashi-machi, Ibukidai, Nishi-ku, Kobe 651-2242, Japan; (Y.T.); (A.M.); (Y.M.)
| | - Yutaka Makizaki
- R&D Center, Biofermin Pharmaceutical Co., Ltd., 7-3-4 Higashi-machi, Ibukidai, Nishi-ku, Kobe 651-2242, Japan; (Y.T.); (A.M.); (Y.M.)
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, l-1, Mukogawa, Nishinomiya 663-8501, Japan; (X.W.); (Y.R.); (X.X.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
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Čater M, Majdič G. How early maternal deprivation changes the brain and behavior? Eur J Neurosci 2021; 55:2058-2075. [PMID: 33870558 DOI: 10.1111/ejn.15238] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 01/30/2023]
Abstract
Early life stress can adversely influence brain development and reprogram brain function and consequently behavior in adult life. Adequate maternal care in early childhood is therefore particularly important for the normal brain development, and adverse early life experiences can lead to altered emotional, behavioral, and neuroendocrine stress responses in the adulthood. As a form of neonatal stress, maternal deprivation/separation is often used in behavioral studies to examine the effects of early life stress and for modeling the development of certain psychiatric disorders and brain pathologies in animal models. The temporary loss of maternal care during the critical postpartum periods remodels the offspring's brain and provokes long-term effects on learning and cognition, the development of mental disorders, aggression, and an increased tendency for the drug abuse. Early life stress through maternal deprivation affects neuroendocrine responses to stress in adolescence and adulthood by dysregulating the hypothalamic-pituitary-adrenal axis and permanently disrupts stress resilience. In this review, we focused on how improper maternal care during early postnatal life affects brain development resulting in modified behavior later in life.
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Affiliation(s)
- Maša Čater
- Veterinary Faculty, Laboratory for Animal Genomics, Institute for Preclinical Studies, University of Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, Institute of Physiology, University of Maribor, Maribor, Slovenia
| | - Gregor Majdič
- Veterinary Faculty, Laboratory for Animal Genomics, Institute for Preclinical Studies, University of Ljubljana, Ljubljana, Slovenia.,Faculty of Medicine, Institute of Physiology, University of Maribor, Maribor, Slovenia
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Stoneham ET, McHail DG, Samipour-Biel S, Liehr N, Lee CM, Evans JC, Boggs K, Dumas TC. Spatial Learning Is Impaired in Male Pubertal Rats Following Neonatal Daily but Not Randomly Spaced Maternal Deprivation. Front Cell Dev Biol 2021; 9:621308. [PMID: 33816470 PMCID: PMC8012507 DOI: 10.3389/fcell.2021.621308] [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: 10/26/2020] [Accepted: 02/26/2021] [Indexed: 01/06/2023] Open
Abstract
Severe early life stress has long been associated with neuropsychological disorders in adulthood, including depression, schizophrenia, post-traumatic stress disorder, and memory dysfunction. To some extent, all of these conditions involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced negative feedback inhibition of cortisol release in adulthood. However, the time course for mental health and hormonal outcomes across life stages and the attributes of early life stress that direct the behavioral and biological alterations is not fully understood. We designed our studies to compare outcomes of the two most common maternal deprivation schedules on cognitive ability prior to adulthood. We exposed rat pups to daily or randomly spaced maternal separation bouts within the first 3 weeks of life and examined cognitive performance, neurotrophic signaling, and stress and immune system markers during puberty. We found that the daily separation schedule impaired spatial learning while the randomly spaced schedule did not alter maze performance relative to normally reared control animals. Animals that underwent daily separation showed a tendency for reduced body weight compared to the randomly spaced condition, but there were no differences in adrenal weight. Thymus weight normalized by body weight was increased following daily separation compared to random separation and control conditions. Plasma corticosterone levels measured after behavior testing did not differ amongst experimental groups and there was no impact of TrKB receptor inhibition. Combined, the results show that different early life stress schedules produce different behavioral and biological outcomes when measured at puberty. Combined with prior findings from more mature animals, the results presented here suggest that daily neonatal stress produces varied alterations in spatial cognition at different life stages with a transient learning deficit at puberty preceding a more persistent and a progressive memory impairment through adulthood and into aging.
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Affiliation(s)
- Emily T Stoneham
- Krasnow Institute for Advanced Studies, George Mason University, Fairfax, VA, United States
| | - Daniel G McHail
- Krasnow Institute for Advanced Studies, George Mason University, Fairfax, VA, United States
| | | | - Nicole Liehr
- George Mason University, Fairfax, VA, United States
| | | | | | | | - Theodore C Dumas
- Krasnow Institute for Advanced Studies, George Mason University, Fairfax, VA, United States
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39
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Gildawie KR, Ryll LM, Hexter JC, Peterzell S, Valentine AA, Brenhouse HC. A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior. Dev Cogn Neurosci 2021; 48:100924. [PMID: 33515957 PMCID: PMC7847967 DOI: 10.1016/j.dcn.2021.100924] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
Adversity early in life substantially impacts prefrontal cortex (PFC) development and vulnerability to later-life psychopathology. Importantly, repeated adverse experiences throughout childhood increase the risk for PFC-mediated behavioral deficits more commonly in women. Evidence from animal models points to effects of adversity on later-life neural and behavioral dysfunction; however, few studies have investigated the neurobiological underpinnings of sex-specific, long-term consequences of multiple developmental stressors. We modeled early life adversity in rats via maternal separation (postnatal day (P)2-20) and juvenile social isolation (P21-35). In adulthood, anxiety-like behavior was assessed in the elevated zero maze and the presence and structural integrity of PFC perineuronal nets (PNNs) enwrapping parvalbumin (PV)-expressing interneurons was quantified. PNNs are extracellular matrix structures formed during critical periods in postnatal development that play a key role in the plasticity of PV cells. We observed a female-specific effect of adversity on hyperactivity and risk-assessment behavior. Moreover, females – but not males – exposed to multiple hits of adversity demonstrated a reduction in PFC PV cells in adulthood. We also observed a sex-specific, potentiated reduction in PV + PNN structural integrity. These findings suggest a sex-specific impact of repeated adversity on neurostructural development and implicate PNNs as a contributor to associated behavioral dysfunction.
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Affiliation(s)
| | - Lilly M Ryll
- Department of Psychology, Northeastern University, Boston, MA, USA
| | - Jessica C Hexter
- Department of Psychology, Northeastern University, Boston, MA, USA
| | - Shayna Peterzell
- Department of Psychology, Northeastern University, Boston, MA, USA
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40
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Masrouri H, Azadi M, Semnanian S, Azizi H. Early life maternal deprivation attenuates morphine induced inhibition in lateral paragigantocellularis neurons in adult rats. Brain Res Bull 2021; 169:128-135. [PMID: 33482287 DOI: 10.1016/j.brainresbull.2021.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/29/2020] [Accepted: 01/15/2021] [Indexed: 02/04/2023]
Abstract
Early life stress can serve as one of the principle sources leading to individual differences in confronting challenges throughout the lifetime. Maternal deprivation (MD), a model of early life stress, can cause persistent alterations in brain function, and it may constitute a risk factor for later incidence of drug addiction. It is becoming more apparent that early life MD predisposes opiate abuse in adulthood. Although several behavioral and molecular studies have addressed this issue, changes in electrophysiological features of the neurons are yet to be understood. The lateral paragigantocellularis (LPGi) nucleus, which participates in the mediation of opiate dependence and withdrawal, may be susceptible to modifications following MD. This study sought to find whether early life MD can alter the discharge activity of LPGi neurons and their response to acute morphine administration in adult rats. Male Wistar rats experienced MD on postnatal days (PNDs) 1-14 for three h per day. Afterward, they were left undisturbed until PND 70, during which the extracellular activities of LPGi neurons were recorded in anesthetized animals at baseline and in response to acute morphine. In both MD and control groups, acute morphine administration induced heterogeneous (excitatory, inhibitory, and no effect) responses in LPGi neurons. At baseline recording, the interspike interval variability of the LPGi neurons was attenuated in both inhibitory and excitatory responses in animals with the history of MD. The extent of morphine-induced discharge inhibition was also lower in deprived animals compared to the control group. These findings suggest that early life MD induces long-term alterations in LPGi neuronal activity in response to acute administration of morphine. Therefore, the MD may alter the vulnerability to develop opiate abuse in adulthood.
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Affiliation(s)
- Hossein Masrouri
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Azadi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Azizi
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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41
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Portugalov A, Akirav I. Do Adolescent Exposure to Cannabinoids and Early Adverse Experience Interact to Increase the Risk of Psychiatric Disorders: Evidence from Rodent Models. Int J Mol Sci 2021; 22:ijms22020730. [PMID: 33450928 PMCID: PMC7828431 DOI: 10.3390/ijms22020730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 12/30/2022] Open
Abstract
There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis is harmless. At the same time, studies suggest that cannabinoids may have therapeutic potential against the impacts of stress on the brain and behavior, and that young people sometimes use cannabinoids to alleviate feelings of depression and anxiety (i.e., “self-medication”). Exposure to early adverse life events may predispose individuals to developing psychopathology in adulthood, leading researchers to study the causality between early life factors and cognitive and emotional outcomes in rodent models and to probe the underlying mechanisms. In this review, we aim to better understand the long-term effects of cannabinoids administered in sensitive developmental periods (mainly adolescence) in rodent models of early life stress. We suggest that the effects of cannabinoids on emotional and cognitive function may vary between different sensitive developmental periods. This could potentially affect decisions regarding the use of cannabinoids in clinical settings during the early stages of development and could raise questions regarding educating the public as to potential risks associated with cannabis use.
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Affiliation(s)
- Anna Portugalov
- Department of Psychology, School of Psychological Sciences, University of Haifa, 3498838 Haifa, Israel;
- The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, 3498838 Haifa, Israel
| | - Irit Akirav
- Department of Psychology, School of Psychological Sciences, University of Haifa, 3498838 Haifa, Israel;
- The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, 3498838 Haifa, Israel
- Correspondence:
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42
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Bölükbas I, Mundorf A, Freund N. Maternal separation in rats induces neurobiological and behavioral changes on the maternal side. Sci Rep 2020; 10:22431. [PMID: 33384453 PMCID: PMC7775452 DOI: 10.1038/s41598-020-80087-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 12/16/2020] [Indexed: 12/22/2022] Open
Abstract
The time after parturition is a sensitive period for mothers where they are prone to develop psychopathological symptoms. Studies investigating dams after separation from their pups (maternal separation, MS) showed that MS induces alterations similar to postpartum depression. This study aims to give further details on affected behavior and neurobiology of dams after MS. MS in rats from postnatal day 2-20 over four hours daily was performed. Upon reunion, maternal behavior, and ultrasonic vocalization (USV) of dams were measured. On the day of weaning, dams were tested for anxiety-like behavior in the elevated-plus-maze and marble burying test. Then Morc1 mRNA in the medial prefrontal cortex and Nr3c1 encoding the glucocorticoid receptor mRNA in the hippocampus were measured using real-time PCR to examine possible neurobiological correlates in psychopathology and social behavior. GABA and glutamate serum levels were analyzed by high-performance liquid chromatography as peripheral markers for stress-induced psychopathology. MS in dams increased maternal care towards pups even though both groups show high levels of maternal behavior even in late lactation. Furthermore, the emission of 50-kHz and 22-kHz USVs increased significantly. No differences in anxiety-like behavior were detected. MS further reduced Morc1 but not Nr3c1 expression. Serum GABA but not glutamate levels were significantly increased in separated dams. This study reinforces the benefit of investigating dams after MS for studying postpartum stress. Subclinical markers mainly connected to depression, namely Morc1 and GABA, proved to be useful allowing for earlier detection of symptoms of critical postpartum stress.
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Affiliation(s)
- Ibrahim Bölükbas
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, 44780, Bochum, Germany
| | - Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, 44780, Bochum, Germany.
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, 44780, Bochum, Germany
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43
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Moussa-Tooks AB, Hetrick WP, Green JT. Differential effects of two early life stress paradigms on cerebellar-dependent delay eyeblink conditioning. Neurobiol Stress 2020; 13:100242. [PMID: 33344698 PMCID: PMC7739029 DOI: 10.1016/j.ynstr.2020.100242] [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: 04/30/2020] [Revised: 06/23/2020] [Accepted: 07/14/2020] [Indexed: 11/11/2022] Open
Abstract
Early life stress paradigms have become prominent in the animal literature to model atypical development. Currently, two models have prevailed within the literature: (1) limited bedding or nesting and (2) maternal separation or deprivation. Both models have produced aberrations spanning behavior and neural circuitry. Surprisingly, these two models have yet to be directly compared. The current study utilized delay eyeblink conditioning, an associative learning task with a well-defined cerebellar circuit, to compare the behavioral effects of standard limited bedding (postnatal day 2–9, n = 15) and maternal separation (60 min per day during postnatal day 2–14, n = 13) early life stress paradigms. Animals in all groups exhibited robust learning curves. Surprisingly, facilitated conditioning was observed in the maternal separation group. Rats that underwent limited bedding did not differ from the control or maternal separation groups on any conditioning measures. This study contributes to a clearer understanding of early life stress paradigms and the claims made about their mechanisms, which if better clarified can be properly leveraged to increase translational value.
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Affiliation(s)
- Alexandra B Moussa-Tooks
- Psychological & Brain Sciences, Indiana University, Bloomington, IN, United States.,Program in Neuroscience, Indiana University, Bloomington, IN, United States
| | - William P Hetrick
- Psychological & Brain Sciences, Indiana University, Bloomington, IN, United States.,Program in Neuroscience, Indiana University, Bloomington, IN, United States.,Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
| | - John T Green
- Department of Psychological Science, University of Vermont, Burlington, VT, United States
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44
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Orso R, Creutzberg KC, Kestering-Ferreira E, Wearick-Silva LE, Tractenberg SG, Grassi-Oliveira R. Maternal Separation Combined With Limited Bedding Increases Anxiety-Like Behavior and Alters Hypothalamic-Pituitary-Adrenal Axis Function of Male BALB/cJ Mice. Front Behav Neurosci 2020; 14:600766. [PMID: 33304248 PMCID: PMC7693708 DOI: 10.3389/fnbeh.2020.600766] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/15/2020] [Indexed: 11/13/2022] Open
Abstract
Early life stress (ELS) is considered a risk factor for the development of psychiatric conditions, including depression and anxiety disorder. Individuals that live in adverse environments are usually exposed to multiple stressors simultaneously, such as maternal neglect, maltreatment, and limited resources. Nevertheless, most pre-clinical ELS models are designed to explore the impact of these events separately. For this reason, this study aims to investigate the effects of a combined model of ELS on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis related targets. From PND 2 to PND 15 BALB/cJ mice were exposed simultaneously to maternal separation (MS; 3 h per day) and limited bedding (LB; ELS group) or left undisturbed (CT group). Maternal behavior was recorded in intercalated days, from PND 1 to PND 9. Male offspring were tested for anxiety-like behavior from PND 53 to PND 55 in the open field test (OF), elevated plus-maze (EPM), and light/dark test (LD). After behavioral testing, animals were euthanized, and glucocorticoid receptor (Nr3c1), corticotrophin-releasing hormone (Crh), and its receptor type 1 (Crhr1) gene expression in the hypothalamus were measured. Moreover, plasma corticosterone levels were analyzed. We observed that ELS dams presented altered quality of maternal care, characterized by a decrease in arched-back nursing, and an increase in passive nursing. Stressed dams also showed an increase in the number of exits from the nest when compared to CT dams. Furthermore, ELS animals showed increased anxiety-like behavior in the OF, EPM, and LD. Regarding gene expression, we identified an increase in hypothalamus Crh levels of ELS group when compared to CT animals, while no differences in Nr3c1 and Crhr1 expression were observed. Finally, stressed animals showed decreased levels of plasma corticosterone when compared to the CT group. In conclusion, we observed an alteration in maternal behavior in ELS dams. Later in life, animals exposed to the combined model of ELS showed increased levels of anxiety-like behavior. Moreover, the central and peripheral HPA measures observed could indicate a dysregulation in HPA function provoked by ELS exposure.
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Affiliation(s)
- Rodrigo Orso
- Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | | | - Erika Kestering-Ferreira
- Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Luis Eduardo Wearick-Silva
- Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Saulo Gantes Tractenberg
- Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Rodrigo Grassi-Oliveira
- Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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45
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White JD, Arefin TM, Pugliese A, Lee CH, Gassen J, Zhang J, Kaffman A. Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning. eLife 2020; 9:58301. [PMID: 33259286 PMCID: PMC7725504 DOI: 10.7554/elife.58301] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 11/30/2020] [Indexed: 12/26/2022] Open
Abstract
It is currently unclear whether early life stress (ELS) affects males and females differently. However, a growing body of work has shown that sex moderates responses to stress and injury, with important insights into sex-specific mechanisms provided by work in rodents. Unfortunately, most of the ELS studies in rodents were conducted only in males, a bias that is particularly notable in translational work that has used human imaging. Here we examine the effects of unpredictable postnatal stress (UPS), a mouse model of complex ELS, using high resolution diffusion magnetic resonance imaging. We show that UPS induces several neuroanatomical alterations that were seen in both sexes and resemble those reported in humans. In contrast, exposure to UPS induced fronto-limbic hyper-connectivity in males, but either no change or hypoconnectivity in females. Moderated-mediation analysis found that these sex-specific changes are likely to alter contextual freezing behavior in males but not in females.
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Affiliation(s)
- Jordon D White
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States
| | - Tanzil M Arefin
- Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States
| | - Alexa Pugliese
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States
| | - Choong H Lee
- Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States
| | - Jeff Gassen
- Department of Psychology, Texas Christian University, Fort Worth, United States
| | - Jiangyang Zhang
- Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States
| | - Arie Kaffman
- Department of Psychiatry, Yale University School of Medicine, New Haven, United States
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46
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Cordier JM, Aguggia JP, Danelon V, Mir FR, Rivarola MA, Mascó D. Postweaning Enriched Environment Enhances Cognitive Function and Brain-Derived Neurotrophic Factor Signaling in the Hippocampus in Maternally Separated Rats. Neuroscience 2020; 453:138-147. [PMID: 33039520 DOI: 10.1016/j.neuroscience.2020.09.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022]
Abstract
Adverse environments during early life may lead to different neurophysiological and behavioral consequences, including depression and learning and memory deficits that persist into adulthood. Previously, we demonstrated that exposure to an enriched environment during adolescence mitigates the cognitive impairment observed after maternal separation in a task-specific manner. However, underlying neural mechanisms are still not fully understood. The current study examines the effects of neonatal maternal separation (MS) and postweaning environmental enrichment (EE) on spatial learning and memory performance in a short version of the Barnes Maze, active and passive behaviors in the forced swim test, and on TrkB/BDNF receptor expression in the hippocampus. Our results revealed that MS impaired acquisition learning and that enriched rats performed better than non-enriched rats in acquisition trials, regardless of early conditions. During the probe, enriched-housed rats demonstrated better performance than those reared in standard conditions. No significant differences between groups were found in the forced swim test. Both MS and EE increase full-length TrkB expression, and the combination of MS and EE treatment caused the highest levels of this protein expression. Similarly, truncated TrkB expression was higher in the MS/EE group. Animal facility rearing (AFR) non-enriched groups present the lowest activation of phosphorylated Erk, a canonical downstream kinase of TrkB signaling. Taken together, our results demonstrate the importance of enriched environment as an intervention to ameliorate the effects of maternal separation on spatial learning and memory. TrkB/BDNF signaling could mediate neuroplastic changes related to learning and memory during exposure to enriched environment.
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Affiliation(s)
- Javier Maximiliano Cordier
- Instituto de Diversidad y Ecología Animal (IDEA), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad Nacional de Córdoba -Córdoba, Argentina
| | - Julieta Paola Aguggia
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo. Ciudad Universitaria, CP: 5016, Córdoba, Argentina
| | - Víctor Danelon
- Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, CP: 5016, Córdoba, Argentina
| | - Franco Rafael Mir
- Cátedra de Fisiología Animal, Departamento de Ciencias Exactas Físicas y Naturales, Universidad Nacional de La Rioja, Av. Luis M. de la Fuente S/N, Ciudad Universitaria de la Ciencia y de la Técnica, F5300 La Rioja, Argentina; Cátedra de Fisiología Animal, Facultad de Ciencias Exactas Físicas y Naturales, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 299 X5000JJC- Córdoba, Argentina
| | - María Angélica Rivarola
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo. Ciudad Universitaria, CP: 5016, Córdoba, Argentina; Cátedra de Fisiología Animal, Facultad de Ciencias Exactas Físicas y Naturales, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 299 X5000JJC- Córdoba, Argentina.
| | - Daniel Mascó
- Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, CP: 5016, Córdoba, Argentina
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47
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Alves RL, Portugal CC, Summavielle T, Barbosa F, Magalhães A. Maternal separation effects on mother rodents' behaviour: A systematic review. Neurosci Biobehav Rev 2020; 117:98-109. [PMID: 31499082 DOI: 10.1016/j.neubiorev.2019.09.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/30/2019] [Accepted: 09/05/2019] [Indexed: 12/21/2022]
Abstract
Maternal separation (MS) is a widely-used paradigm to study the effect of early-life adversity on brain development and resilience to psychopathology. Most of the related literature focuses on MS impact on offspring, however, it should ideally also consider the impact of altered maternal behaviour caused by MS itself. This systematic review aimed at providing a comprehensive compilation of the effects of MS on key maternal behaviour aspects. We performed a keyword literature search using Boolean operators. Databases were searched between 2000-2018. Additional studies were included from manual search. Twenty-nine articles addressing the impact of MS on maternal behaviour and/or mothers' anxiety, depression-like behaviour, memory and consequences on underlying mechanisms. The methodological aspects and main conclusions were extracted from each study. This review shows that MS induces changes in dams. Results are particularly robust for increased anxiety and depressive-like symptoms, and altered maternal behaviours, predominantly for longer periods of MS. Finally, research in the field could strongly benefit from the establishment of guidelines to reduce the methodological inconsistencies here identified.
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Affiliation(s)
- Renata L Alves
- Addiction Biology, Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, 4200-135, Portugal; Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences (FPCEUP), University of Porto, Porto, 4200-135, Portugal
| | - Camila Cabral Portugal
- Glial Cell Biology, Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, 4200-135, Portugal
| | - Teresa Summavielle
- Addiction Biology, Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, 4200-135, Portugal; Functional Sciences Department, Escola Superior de Saúde (ESS), Politécnico do Porto, Porto, 4200-072, Portugal
| | - Fernando Barbosa
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences (FPCEUP), University of Porto, Porto, 4200-135, Portugal
| | - Ana Magalhães
- Addiction Biology, Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, 4200-135, Portugal.
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48
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Asymmetry of turning behavior in rats is modulated by early life stress. Behav Brain Res 2020; 393:112807. [DOI: 10.1016/j.bbr.2020.112807] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 12/23/2022]
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49
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Mooney-Leber SM, Brummelte S. Neonatal pain and reduced maternal care alter adult behavior and hypothalamic-pituitary-adrenal axis reactivity in a sex-specific manner. Dev Psychobiol 2020; 62:631-643. [PMID: 31788799 DOI: 10.1002/dev.21941] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [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: 10/20/2019] [Indexed: 01/06/2023]
Abstract
Preterm infants often spend a significant amount of time in the neonatal intensive care unit (NICU) where they are exposed to many stressors including pain and reduced maternal care. These early-life stressful experiences can have negative consequences on brain maturation during the neonatal period; however, less is known about the long-term cognitive and affective outcomes. Thus, this study was conducted to investigate the impact of neonatal pain and reduced maternal care on adult behavior and HPA axis reactivity in an animal model. Male and female rats underwent a series of repetitive needle pokes and/or reduced maternal care (through a novel tea ball infuser encapsulation method) during the first 4 days of life and were then assessed in a battery of behavioral tests as adults. We found that early-life pain enhanced spatial learning independent of the animal's sex, but altered HPA recovery from an acute stressor in females only. Moreover, reduced maternal care altered long-term spatial memory and reversal learning in males. These findings indicate that neonatal stressors have unique sex-dependent long-term biobehavioral effects in rodents. Continued examination of the behavioral consequences of these stressors may help explain varying vulnerability and resiliency in preterm infants who experienced early stress in the NICU.
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Wang D, Levine JLS, Avila-Quintero V, Bloch M, Kaffman A. Systematic review and meta-analysis: effects of maternal separation on anxiety-like behavior in rodents. Transl Psychiatry 2020; 10:174. [PMID: 32483128 PMCID: PMC7264128 DOI: 10.1038/s41398-020-0856-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 05/06/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
The mechanisms by which childhood maltreatment increases anxiety is unclear, but a propensity for increased defensive behavior in rodent models of early life stress (ELS) suggests that work in rodents may clarify important mechanistic details about this association. A key challenge in studying the effects of ELS on defensive behavior in rodents is the plethora of inconsistent results. This is particularly prominent with the maternal separation (MS) literature, one of the most commonly used ELS models in rodents. To address this issue we conducted a systematic review and meta-analysis, examining the effects of MS on exploratory-defensive behavior in mice and rats using the open field test (OFT) and the elevated plus maze (EPM). This search yielded a total of 49 studies, 24 assessing the effect of MS on behavior in the EPM, 11 tested behavior in the OFT, and 14 studies provided data on both tasks. MS was associated with increased defensive behavior in rats (EPM: Hedge's g = -0.48, p = 0.02; OFT: Hedge's g = -0.33, p = 0.05), effect sizes that are consistent with the anxiogenic effect of early adversity reported in humans. In contrast, MS did not alter exploratory behavior in mice (EPM: Hedge's g = -0.04, p = 0.75; OFT: Hedge's g = -0.03, p = 0.8). There was a considerable amount of heterogeneity between studies likely related to the lack of standardization of the MS protocol. Together, these findings suggest important differences in the ability of MS to alter circuits that regulate defensive behaviors in mice and rats.
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Affiliation(s)
- Daniel Wang
- grid.47100.320000000419368710Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
| | - Jessica L. S. Levine
- grid.47100.320000000419368710Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519 USA
| | - Victor Avila-Quintero
- grid.47100.320000000419368710Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519 USA
| | - Michael Bloch
- grid.47100.320000000419368710Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA ,grid.47100.320000000419368710Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06519 USA
| | - Arie Kaffman
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT, 06511, USA.
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