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Li W, Li T, Ali T, Mou S, Gong Q, Yu ZJ, Li S. Uncoupling serotonin (2C) and dopamine (D2) receptor heterodimers ameliorate PTSD-like behaviors. J Affect Disord 2025; 380:63-77. [PMID: 40122260 DOI: 10.1016/j.jad.2025.03.127] [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: 05/18/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND G-protein-coupled receptors (GPCRs), crucial for various physiological functions, can form complexes with themselves or other GPCRs, influencing their signaling and drug interactions. GPCR oligomerization remains an active area of research in neurological diseases, including Post-Traumatic Stress Disorder (PTSD). Here, we illuminated a novel serotonin and dopamine receptor heterodimerization that played an etiological role in fear conditioning behaviors associated with memory defects in the single prolonger stress (SPS) mice and reverting effects of receptors interaction interfering with peptide. METHODS To assess our projected goal, we prepared a single prolonged stress (SPS) mice model followed by peptide treatment, behavior assays, and biochemical analysis. RESULTS Our study revealed a direct interaction between dopamine D2 receptors (D2R) and serotonin 5-HT2C receptors (5-HT2CR) via the K226-L240 region in the brains of SPS mice. This D2R/5-HT2CR interaction modulated downstream PI3K-AKT signaling and contributed to cognitive deficits in a mouse model of SPS. An interfering peptide (TAT-D2R-KL) designed to disrupt D2R/5-HT2CR heterodimerization reduced the excitatory/inhibitory neuron firing frequency ratio, attenuated PI3K/AKT signaling impairment, and alleviated cognitive deficits in SPS mice. Furthermore, treatment with the PI3K inhibitor, Bisperoxovanadium Compound bpV (pic), reversed the effects of the peptide, confirming the critical role of PI3K/AKT signaling in D2R/5-HT2CR dimerization and the associated pathophysiology of SPS. CONCLUSION These findings revealed a causative role of D2R/5-HT2CR hetero-dimer in PTSD and could be reversed by TAT-D2R-KL treatment.
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MESH Headings
- Animals
- Stress Disorders, Post-Traumatic/metabolism
- Stress Disorders, Post-Traumatic/drug therapy
- Stress Disorders, Post-Traumatic/psychology
- Receptors, Dopamine D2/metabolism
- Receptors, Dopamine D2/genetics
- Mice
- Male
- Disease Models, Animal
- Receptor, Serotonin, 5-HT2C/metabolism
- Mice, Inbred C57BL
- Fear/physiology
- Fear/drug effects
- Signal Transduction/drug effects
- Behavior, Animal
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Affiliation(s)
- Weifen Li
- School of Pharmacy, Shenzhen University, Medical School, Shenzhen University, Shenzhen 518055, China.
| | - Tianxiang Li
- Department of Infectious Diseases and Shenzhen key laboratory for endogenous infections, the 6th Affiliated Hospital of Shenzhen University Health Science Center, No 89, Taoyuan Road, Nanshan District, Shenzhen 518052, China.
| | - Tahir Ali
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518000, China.
| | - Shengnan Mou
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Qichao Gong
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
| | - Zhi-Jian Yu
- Department of Infectious Diseases and Shenzhen key laboratory for endogenous infections, the 6th Affiliated Hospital of Shenzhen University Health Science Center, No 89, Taoyuan Road, Nanshan District, Shenzhen 518052, China.
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518000, China; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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Choquet D, Opazo P, Zhang H. AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders. Transl Neurodegener 2025; 14:8. [PMID: 39934896 PMCID: PMC11817889 DOI: 10.1186/s40035-025-00470-z] [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: 08/11/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Over the past two decades, there has been a growing recognition of the physiological importance and pathological implications surrounding the surface diffusion of AMPA receptors (AMPARs) and their diffusional trapping at synapses. AMPAR surface diffusion entails the thermally powered random Brownian lateral movement of these receptors within the plasma membrane, facilitating dynamic exchanges between synaptic and extrasynaptic compartments. This process also enables the activity-dependent diffusional trapping and accumulation of AMPARs at synapses through transient binding to synaptic anchoring slots. Recent research highlights the critical role of synaptic recruitment of AMPARs via diffusional trapping in fundamental neural processes such as the development of the early phases of long-term potentiation (LTP), contextual fear memory, memory consolidation, and sensory input-induced cortical remapping. Furthermore, studies underscore that regulation of AMPAR diffusional trapping is altered across various neurological disease models, including Huntington's disease (HD), Alzheimer's disease (AD), and stress-related disorders like depression. Notably, pharmacological interventions aimed at correcting deficits in AMPAR diffusional trapping have demonstrated efficacy in restoring synapse numbers, LTP, and memory functions in these diverse disease models, despite their distinct pathogenic mechanisms. This review provides current insights into the molecular mechanisms underlying the dysregulation of AMPAR diffusional trapping, emphasizing its role as a converging point for multiple pathological signaling pathways. We propose that targeting AMPAR diffusional trapping represents a promising early therapeutic strategy to mitigate synaptic plasticity and memory deficits in a spectrum of brain disorders, encompassing but not limited to HD, AD, and stress-related conditions. This approach underscores an integrated therapeutic target amidst the complexity of these neurodegenerative and neuropsychiatric diseases.
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Affiliation(s)
- Daniel Choquet
- Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, 33000, Bordeaux, France
- Univ. Bordeaux, CNRS, INSERM, Bordeaux Imaging Center, BIC, UAR 3420, US 4, 33000, Bordeaux, France
| | - Patricio Opazo
- UK Dementia Research Institute, Centre for Discovery Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh, EH16 4SB, UK
| | - Hongyu Zhang
- Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
- Mohn Research Center for the Brain, University of Bergen, 5009, Bergen, Norway.
- Department of Radiology, Haukeland University Hospital, 5021, Bergen, Norway.
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Edlund E, Domarecka E, Olze H, Szczepek A. A Scoping Review of Corticosterone-Induced Changes in Ionotropic Glutamate Receptor Levels and Localization in the Rodent Brain: Implications for the Auditory System. Brain Sci 2025; 15:110. [PMID: 40002443 PMCID: PMC11852854 DOI: 10.3390/brainsci15020110] [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: 12/19/2024] [Revised: 01/18/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND The ionotropic glutamate receptor AMPA (AMPAR) mediates fast excitatory synaptic transmission and regulates synaptic strength in various parts of the CNS. Emotional challenges can affect these processes by influencing AMPAR levels and localization via stress hormones, resulting, e.g., in behavioral changes. AMPARs are essential for auditory processing, but their response to stress hormones in the central or peripheral auditory system remains poorly understood. Therefore, this scoping review examines the effects of corticosterone (CORT), a primary stress hormone in rodents, on AMPA receptor levels and localization in the rodent nervous system and considers potential implications for the auditory system. METHODS We systematically searched PubMed, Web of Science, and OVID EMBASE using MeSH terms related to AMPA receptors and corticosterone. Studies were screened based on predefined inclusion criteria, including original research published in English that focused on AMPA receptor subunits (e.g., GluR1-4, GluA1-4, Gria1-4). Of 288 articles screened, 17 met the criteria for final analysis. RESULTS No reports were found regarding CORT action in the auditory system. Three main experimental models used in the included research were identified: neuronal cultures, isolated tissue cultures, and animal models. Generally, short-term CORT exposure increases AMPAR surface localization and mobility in neuronal cultures, especially in the hippocampus and prefrontal cortex. However, results from animal models were inconsistent due to variations in experimental design and other factors. The isolated tissue study did not provide sufficient data for clear conclusions. CONCLUSIONS Variability in experimental models limits our ability to draw definitive conclusions about the effects of CORT on AMPARs across different regions of the nervous system. The differences in live animal studies highlight the need for standardized methods and reporting. Since AMPARs play a crucial role in auditory processing, CORT-induced changes in neuronal cultures may occur in the auditory system. Further research is needed to explore the specific responses of AMPAR subunits and how stress hormones may influence auditory disorders, which could help identify potential treatment strategies.
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Affiliation(s)
- Elsa Edlund
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (E.E.); (E.D.); (H.O.)
| | - Ewa Domarecka
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (E.E.); (E.D.); (H.O.)
| | - Heidi Olze
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (E.E.); (E.D.); (H.O.)
| | - Agnieszka Szczepek
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (E.E.); (E.D.); (H.O.)
- Faculty of Medicine and Health Sciences, University of Zielona Góra, 65-046 Zielona Góra, Poland
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Niu Y, Conrad BN, Camacho MC, Ravi S, Piersiak HA, Bailes LG, Barnett W, Manhard MK, Cole DA, Clayton EW, Osmundson SS, Smith SA, Kujawa A, Humphreys KL. Longitudinal investigation of neurobiological changes across pregnancy. Commun Biol 2025; 8:82. [PMID: 39827275 PMCID: PMC11743213 DOI: 10.1038/s42003-024-07414-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
Pregnancy is a period of profound biological transformation. However, we know remarkably little about pregnancy-related brain changes. To address this gap, we chart longitudinal changes in brain structure during pregnancy and explore potential mechanisms driving these changes. Ten participants (Mean age = 28.97 years) are assessed 1-6 times (median = 3) during their pregnancy. Each visit includes anatomical and diffusion-weighted MRI, and assessments of waking salivary hormones, hair hormones, and inflammatory cytokines. Here we observe a reduction in gray matter volume and an increase in neurite density index (NDI), a proxy of axon density, in white matter tracts across pregnancy. Progesterone levels are associated with reductions in brain volumetric measurements, and both progesterone and estradiol levels are linked to increases in NDI in white matter tracts. This study highlights the profound neurobiological changes experienced by pregnant individuals and provides insights into neuroplasticity in adulthood.
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Affiliation(s)
- Yanbin Niu
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Benjamin N Conrad
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - M Catalina Camacho
- Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
| | - Sanjana Ravi
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Hannah A Piersiak
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Lauren G Bailes
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Whitney Barnett
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Mary Kate Manhard
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - David A Cole
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Ellen Wright Clayton
- Center for Biomedical Ethics and Society, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- Law School, Vanderbilt University, Nashville, TN, USA
| | - Sarah S Osmundson
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Seth A Smith
- Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Autumn Kujawa
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA
| | - Kathryn L Humphreys
- Department of Psychology and Human Development, Peabody College, Vanderbilt University, Nashville, TN, USA.
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Wu M, Yan X, Huang H, Guo X, Bai M, Wang B, Su P, Li Y, Xu E. Integration of network pharmacology and experimental verification to reveal the active components and molecular mechanism of modified Danzhi Xiaoyao San in the treatment of depression. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118739. [PMID: 39197805 DOI: 10.1016/j.jep.2024.118739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/15/2024] [Accepted: 08/23/2024] [Indexed: 09/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Modified Danzhi Xiaoyao San (MDXS) is an effective clinical prescription for depression in China, which was deprived of Danzhi Xiaoyao San in the Ming Dynasty. MDSX has significant implications for the development of new antidepressants, but its pharmacological mechanism has been rarely studied. AIM OF THE STUDY To reveal the active components and molecular mechanism of MDXS in treating depression through network pharmacology and experimental verification in vivo and in vitro. MATERIALS AND METHODS UPLC-Q-TOF-MS/MS was used to identify the chemical components in the MDXS freeze-dried powder, drug-containing serum, and cerebrospinal fluid (CSF). Based on the analysis of prototype components in the CSF, the major constituents, potential therapeutic targets and possible pharmacological mechanisms of MDXS in treating depression were investigated using network pharmacological and molecular docking. Then corticosterone (CORT)-induced mice model of depression was established to investigate the antidepressant effects of MDXS. HT22 cells were cultured to verify the neuroprotective effects and core targets of the active components. RESULTS There were 81 compounds in MDXS freeze-dried powder, 36 prototype components in serum, and 13 prototype components in CSF were identified, respectively. Network pharmacology analysis showed that these 13 prototype components in the CSF shared 190 common targets with depression, which were mainly enriched in MAPK and PI3K/AKT signaling pathways. PPI analysis suggested that AKT1 and MAPK1 (ERK1/2) were the core targets. Molecular docking revealed that azelaic acid (AA), senkyunolide A (SA), atractylenolide III (ATIII), and tokinolide B (TB) had the highest binding energy with AKT1 and MAPK1. Animal experiments verified that MDXS could reverse CORT-induced depression-like behaviors, improve synaptic plasticity, alleviate neuronal injury in hippocampal CA3 regions, and up-regulate the protein expression of p-ERK1/2 and p-AKT. In HT22 cells, azelaic acid, senkyunolide A, and atractylenolide III significantly protected the cell injury caused by CORT, and up-regulated the protein levels of p-ERK1/2 and p-AKT. CONCLUSIONS These results suggested that MDXS may exert antidepressant effects partially through azelaic acid, senkyunolide A, and atractylenolide III targeting ERK1/2 and AKT.
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Affiliation(s)
- Mengdi Wu
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xiangli Yan
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Huang Huang
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xiuhui Guo
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Ming Bai
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Baoying Wang
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Pan Su
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Yucheng Li
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Erping Xu
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan Province, Henan University of Chinese Medicine, Zhengzhou, 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China; College of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
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Niu Y, Conrad BN, Camacho MC, Ravi S, Piersiak HA, Bailes LG, Barnett W, Manhard MK, Cole DA, Clayton EW, Osmundson SS, Smith SA, Kujawa A, Humphreys KL. Longitudinal Investigation of Neurobiological Changes Across Pregnancy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.08.584178. [PMID: 39763749 PMCID: PMC11702532 DOI: 10.1101/2024.03.08.584178] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Pregnancy is a period of profound biological transformation. However, we know remarkably little about pregnancy-related brain changes. To address this gap, we chart longitudinal changes in brain structure during pregnancy and explore potential mechanisms driving these changes. Ten participants (Mean age = 28.97 years) are assessed 1-6 times (median = 3) during their pregnancy. Each visit includes anatomical and diffusion-weighted MRI, and assessments of waking salivary hormones, hair hormones, and inflammatory cytokines. Here we observe a reduction in gray matter volume gestational week, while neurite density index (NDI), a proxy of axon density, in white matter tracts increase across pregnancy. Progesterone levels are associated with reductions in brain volumetric measurements, and both progesterone and estradiol levels are linked to increases in NDI in white matter tracts. This study highlights the profound neurobiological changes experienced by pregnant individuals and provides insights into neuroplasticity in adulthood.
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Wang H, Wang X, Wang H, Shao S, Zhu J. Chronic Corticosterone Administration-Induced Mood Disorders in Laboratory Rodents: Features, Mechanisms, and Research Perspectives. Int J Mol Sci 2024; 25:11245. [PMID: 39457027 PMCID: PMC11508944 DOI: 10.3390/ijms252011245] [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: 09/09/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Mood disorders mainly affect the patient's daily life, lead to suffering and disability, increase the incidence rate of many medical illnesses, and even cause a trend of suicide. The glucocorticoid (GC)-mediated hypothalamus-pituitary-adrenal (HPA) negative feedback regulation plays a key role in neuropsychiatric disorders. The balance of the mineralocorticoid receptor (MR)/glucocorticoid receptor (GR) level contributes to maintaining the homeostasis of the neuroendocrine system. Consistently, a chronic excess of GC can also lead to HPA axis dysfunction, triggering anxiety, depression, memory loss, and cognitive impairment. The animal model induced by chronic corticosterone (CORT) administration has been widely adopted because of its simple replication and strong stability. This review summarizes the behavioral changes and underlying mechanisms of chronic CORT administration-induced animal models, including neuroinflammatory response, pyroptosis, oxidative stress, neuroplasticity, and apoptosis. Notably, CORT administration at different doses and cycles can destroy the balance of the MR/GR ratio to make dose-dependent effects of CORT on the central nervous system (CNS). This work aims to offer an overview of the topic and recommendations for future cognitive function research.
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Affiliation(s)
- Hao Wang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (H.W.); (X.W.); (H.W.); (S.S.)
| | - Xingxing Wang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (H.W.); (X.W.); (H.W.); (S.S.)
| | - Huan Wang
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (H.W.); (X.W.); (H.W.); (S.S.)
| | - Shuijin Shao
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (H.W.); (X.W.); (H.W.); (S.S.)
| | - Jing Zhu
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (H.W.); (X.W.); (H.W.); (S.S.)
- Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai 201108, China
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Ryoke R, Hashimoto T, Kawashima R. Multiple Stressors Induce Amygdalohippocampal Volume Reduction in Adult Male Rats as Detected by Longitudinal Structural Magnetic Resonance Imaging. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100334. [PMID: 38974933 PMCID: PMC11225185 DOI: 10.1016/j.bpsgos.2024.100334] [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: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/04/2024] [Indexed: 07/09/2024] Open
Abstract
Background Traumatic events can cause long-lasting and uncontrollable fear and anxiety. Posttraumatic stress disorder is an intractable mental disorder, and neurobiological mechanisms using animal models are expected to help development of posttraumatic stress disorder treatment. In this study, we combined multiple stress (MS) and longitudinal in vivo magnetic resonance imaging to reveal the effects of long-lasting anxiety-like behaviors on adult male rat brains. Methods Twelve male Wistar rats (8 weeks old) were exposed to the MS of 1-mA footshocks and forced swimming, while 12 control rats were placed in a plastic cage. Contextual fear conditioning with 0.1-mA footshocks in a context different from the MS was conducted 15 days after the MS for both groups. Three retention tests were administered after 24 hours and 9 and 16 days. Two magnetic resonance imaging scans were conducted, one on the day before MS induction and one the day after the third retention test, with a 32-day interval. Results The MS group showed greater freezing responses than the control group in all retention tests. Whole-brain voxel-based morphometry analyses revealed reduced gray matter volume in the anterior amygdalohippocampal area in MS group rats compared with control rats. These volume changes were negatively associated with freezing time in the third retention test in the MS group. Conclusions These results suggest that individual variability in the amygdalohippocampal area may be related to long-lasting fear responses after severe stress.
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Affiliation(s)
- Rie Ryoke
- Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Teruo Hashimoto
- Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Ryuta Kawashima
- Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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Muhammad I, Cremonini E, Mathieu P, Adamo AM, Oteiza PI. Dietary Anthocyanins Mitigate High-Fat Diet-Induced Hippocampal Inflammation in Mice. J Nutr 2024; 154:2752-2762. [PMID: 39053605 DOI: 10.1016/j.tjnut.2024.07.028] [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: 04/25/2024] [Revised: 07/08/2024] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Obesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation. OBJECTIVES This study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice. METHODS C57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured. RESULTS Consumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1β, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases. CONCLUSIONS CDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.
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Affiliation(s)
- Imani Muhammad
- Department of Nutrition, University of California, Davis, CA, United States
| | - Eleonora Cremonini
- Department of Nutrition, University of California, Davis, CA, United States
| | - Patricia Mathieu
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Físicoquimica Biológica (IQUiFIB), Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Ana M Adamo
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Instituto de Química y Físicoquimica Biológica (IQUiFIB), Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Patricia I Oteiza
- Department of Nutrition, University of California, Davis, CA, United States; Environmental Toxicology, University of California, Davis, CA, United States.
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10
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Weiss GL, Harrison LM, Jiang Z, Nielsen AM, Feygin MS, Nguyen S, Tirrell PS, Tasker J. Glucocorticoids desensitize hypothalamic CRH neurons to norepinephrine and somatic stress activation via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.29.605704. [PMID: 39211088 PMCID: PMC11360941 DOI: 10.1101/2024.07.29.605704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive for somatic stress activation of the hypothalamic-pituitary-adrenal (HPA) axis. We showed that glucocorticoids rapidly desensitize CRH neurons to norepinephrine and suppress inflammation-induced HPA activation via a glucocorticoid receptor- and endocytosis-dependent mechanism. Here, we show that α1 adrenoreceptor (ARα1) trafficking is regulated by convergent glucocorticoid and nitric oxide synthase signaling mechanisms. Live-cell imaging of ARα1b-eGFP-expressing hypothalamic cells revealed rapid corticosterone-stimulated redistribution of internalized ARα1 from rapid recycling endosomes to late endosomes and lysosomes via a nitrosylation-regulated mechanism. Proximity assay demonstrated interaction of glucocorticoid receptors with ARα1b and β-arrestin, and showed corticosterone blockade of norepinephrine-stimulated ARα1b/β-arrestin interaction, which may prevent ARα1b from entering the rapid recycling endosomal pathway. These findings demonstrate a rapid glucocorticoid regulation of G protein-coupled receptor trafficking and provide a molecular mechanism for rapid glucocorticoid desensitization of noradrenergic signaling in CRH neurons.
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11
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Guarnieri L, Bosco F, Leo A, Citraro R, Palma E, De Sarro G, Mollace V. Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease. Ageing Res Rev 2024; 95:102210. [PMID: 38296163 DOI: 10.1016/j.arr.2024.102210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/10/2024] [Accepted: 01/25/2024] [Indexed: 02/13/2024]
Abstract
Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of β-amyloid (Aβ) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the cholinergic neurons in cortical, subcortical, and hippocampal areas. These effects result in decreased cognitive function, brain atrophy, and neuronal death. Malnutrition and weight loss are the most frequent manifestations of AD, and these are also associated with greater cognitive decline. Several studies have confirmed that a balanced low-calorie diet and proper nutritional intake may be considered important factors in counteracting or slowing the progression of AD, whereas a high-fat or hypercholesterolemic diet predisposes to an increased risk of developing AD. Especially, fruits, vegetables, antioxidants, vitamins, polyunsaturated fatty acids, and micronutrients supplementation exert positive effects on aging-related changes in the brain due to their antioxidant, anti-inflammatory, and radical scavenging properties. The purpose of this review is to summarize some possible nutritional factors that may contribute to the progression or prevention of AD, understand the role that nutrition plays in the formation of Aβ plaques typical of this neurodegenerative disease, to identify some potential therapeutic strategies that may involve some natural compounds, in delaying the progression of the disease.
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Affiliation(s)
- Lorenza Guarnieri
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Bosco
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
| | - Antonio Leo
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Rita Citraro
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Section of Pharmacology, Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; Research Center FAS@UMG, Department of Health Science, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
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12
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Brosens N, Lesuis SL, Rao-Ruiz P, van den Oever MC, Krugers HJ. Shaping Memories Via Stress: A Synaptic Engram Perspective. Biol Psychiatry 2023:S0006-3223(23)01720-1. [PMID: 37977215 DOI: 10.1016/j.biopsych.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 10/09/2023] [Accepted: 11/05/2023] [Indexed: 11/19/2023]
Abstract
Stress modulates the activity of various memory systems and can thereby guide behavioral interaction with the environment in an adaptive or maladaptive manner. At the cellular level, a large body of evidence indicates that (nor)adrenaline and glucocorticoid release induced by acute stress exposure affects synapse function and synaptic plasticity, which are critical substrates for learning and memory. Recent evidence suggests that memories are supported in the brain by sparsely distributed neurons within networks, termed engram cell ensembles. While the physiological and molecular effects of stress on the synapse are increasingly well characterized, how these synaptic modifications shape the multiscale dynamics of engram cell ensembles is still poorly understood. In this review, we discuss and integrate recent information on how acute stress affects synapse function and how this may alter engram cell ensembles and their synaptic connectivity to shape memory strength and memory precision. We provide a mechanistic framework of a synaptic engram under stress and put forward outstanding questions that address knowledge gaps in our understanding of the mechanisms that underlie stress-induced memory modulation.
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Affiliation(s)
- Niek Brosens
- Brain Plasticity Group, Swammerdam Institute for Life Sciences-Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.
| | - Sylvie L Lesuis
- Brain Plasticity Group, Swammerdam Institute for Life Sciences-Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands; Cellular and Cognitive Neuroscience group, Swammerdam Institute for Life Sciences-Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
| | - Priyanka Rao-Ruiz
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Michel C van den Oever
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Harm J Krugers
- Brain Plasticity Group, Swammerdam Institute for Life Sciences-Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.
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13
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Harbour K, Cappel Z, Baccei ML. Effects of Corticosterone on the Excitability of Glutamatergic and GABAergic Neurons of the Adolescent Mouse Superficial Dorsal Horn. Neuroscience 2023; 526:290-304. [PMID: 37437798 PMCID: PMC10530204 DOI: 10.1016/j.neuroscience.2023.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/14/2023]
Abstract
Stress evokes age-dependent effects on pain sensitivity and commonly occurs during adolescence. However, the mechanisms linking adolescent stress and pain remain poorly understood, in part due to a lack of information regarding how stress hormones modulate the function of nociceptive circuits in the adolescent CNS. Here we investigate the short- and long-term effects of corticosterone (CORT) on the excitability of GABAergic and presumed glutamatergic neurons of the spinal superficial dorsal horn (SDH) in Gad1-GFP mice at postnatal days (P)21-P34. In situ hybridization revealed that glutamatergic SDH neurons expressed significantly higher mRNA levels of both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) compared to adjacent GABAergic neurons. The incubation of spinal cord slices with CORT (90 min) evoked select long-term changes in spontaneous synaptic transmission across both cell types in a sex-dependent manner, without altering the intrinsic firing of either Gad1-GFP+ or GFP- neurons. Meanwhile, the acute bath application of CORT significantly decreased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), as well as the frequency of miniature inhibitory postsynaptic currents (mIPSCs), in both cell types leading to a net reduction in the balance of spontaneous excitation vs. inhibition (E:I ratio). This CORT-induced reduction in the E:I ratio was not prevented by selective antagonists of either GR (mifepristone) or MR (eplerenone), although eplerenone blocked the effect on mEPSC amplitude. Collectively, these data suggest that corticosterone modulates synaptic function within the adolescent SDH which could influence the overall excitability and output of the spinal nociceptive network.
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Affiliation(s)
- Kyle Harbour
- Molecular, Cellular and Biochemical Pharmacology Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
| | - Zoe Cappel
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Neuroscience Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; American Society for Pharmacology and Experimental Therapeutics Summer Research Program, Department of Pharmacology and Systems Physiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
| | - Mark L Baccei
- Molecular, Cellular and Biochemical Pharmacology Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; Neuroscience Graduate Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA; American Society for Pharmacology and Experimental Therapeutics Summer Research Program, Department of Pharmacology and Systems Physiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
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14
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Tian Y, Ullah H, Gu J, Li K. Immune-metabolic mechanisms of post-traumatic stress disorder and atherosclerosis. Front Physiol 2023; 14:1123692. [PMID: 36846337 PMCID: PMC9944953 DOI: 10.3389/fphys.2023.1123692] [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: 12/21/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
The interaction of post-traumatic stress disorder (PTSD) and atherosclerosis (AS) increase the risk of mortality. Metabolism and immunity play important roles in the comorbidity associated with PTSD and AS. The adenosine monophosphate-activated protein kinase/mammalian target of rapamycin and phosphatidylinositol 3-kinase/Akt pathways are attractive research topics in the fields of metabolism, immunity, and autophagy. They may be effective intervention targets in the prevention and treatment of PTSD comorbidity with AS. Herein, we comprehensively review metabolic factors, including glutamate and lipid alterations, in PTSD comorbidity with AS and discuss the possible implications in the pathophysiology of the diseases.
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Affiliation(s)
- Yali Tian
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Hanif Ullah
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China
| | - Jun Gu
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ka Li
- West China School of Nursing/West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Ka Li,
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15
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Thompson SM. Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacology 2023; 48:90-103. [PMID: 36057649 PMCID: PMC9700729 DOI: 10.1038/s41386-022-01422-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/18/2022] [Accepted: 08/01/2022] [Indexed: 11/08/2022]
Abstract
What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.
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Affiliation(s)
- Scott M Thompson
- Department of Psychiatry, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, 80045, CO, USA.
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16
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Ge J, Cai Y, Pan ZZ. Synaptic plasticity in two cell types of central amygdala for regulation of emotion and pain. Front Cell Neurosci 2022; 16:997360. [PMID: 36385947 PMCID: PMC9643269 DOI: 10.3389/fncel.2022.997360] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/07/2022] [Indexed: 07/29/2023] Open
Abstract
The amygdala is a critical brain site for regulation of emotion-associated behaviors such as pain and anxiety. Recent studies suggest that differential cell types and synaptic circuits within the amygdala complex mediate interacting and opposing effects on emotion and pain. However, the underlying cellular and circuit mechanisms are poorly understood at present. Here we used optogenetics combined with electrophysiological analysis of synaptic inputs to investigate pain-induced synaptic plasticity within the amygdala circuits in rats. We found that 50% of the cell population in the lateral division of the central nucleus of the amygdala (CeAl) received glutamate inputs from both basolateral amygdala (BLA) and from the parabrachial nucleus (PBN), and 39% of the remaining CeAl cells received glutamate inputs only from PBN. Inflammatory pain lasting 3 days, which induced anxiety, produced sensitization in synaptic activities of the BLA-CeAl-medial division of CeA (CeAm) pathway primarily through a postsynaptic mechanism. Moreover, in CeAl cells receiving only PBN inputs, pain significantly augmented the synaptic strength of the PBN inputs. In contrast, in CeAl cells receiving both BLA and PBN inputs, pain selectively increased the synaptic strength of BLA inputs, but not the PBN inputs. Electrophysiological analysis of synaptic currents showed that the increased synaptic strength in both cases involved a postsynaptic mechanism. These findings reveal two main populations of CeAl cells that have differential profiles of synaptic inputs and show distinct plasticity in their inputs in response to anxiety-associated pain, suggesting that the specific input plasticity in the two populations of CeAl cells may encode a different role in amygdala regulation of pain and emotion.
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17
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Harrison LM, Tasker JG. Multiplexed Membrane Signaling by Glucocorticoids. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2022; 26:100390. [PMID: 38075196 PMCID: PMC10703063 DOI: 10.1016/j.coemr.2022.100390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
Glucocorticoids exert pleiotropic effects either by a relatively slow mechanism involving binding to cytosolic/nuclear receptors and regulation of gene expression or by rapid activation of a putative membrane receptor and membrane signal transduction. Rapid glucocorticoid actions are initiated at the membrane and recruit intracellular signaling pathways that engage multiple downstream cellular targets, including lipid and gas intercellular messengers, membrane neurotransmitter receptor trafficking, nuclear glucocorticoid receptor activation and trafficking, and more. Thus, membrane glucocorticoid signaling diverges into a multiplexed array of signaling pathways to simultaneously regulate highly diverse cellular functions, giving these steroid hormones a broad range of rapid regulatory capabilities. In this review, we provide a brief overview of the growing body of knowledge of the cell signaling mechanisms of rapid glucocorticoid actions in the brain.
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Affiliation(s)
- Laura M Harrison
- Department of Cell and Molecular Biology, Tulane Brain Institute, Tulane University, New Orleans, LA 70118
| | - Jeffrey G Tasker
- Department of Cell and Molecular Biology, Tulane Brain Institute, Tulane University, New Orleans, LA 70118
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18
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Chenani A, Weston G, Ulivi AF, Castello-Waldow TP, Huettl RE, Chen A, Attardo A. Repeated stress exposure leads to structural synaptic instability prior to disorganization of hippocampal coding and impairments in learning. Transl Psychiatry 2022; 12:381. [PMID: 36096987 PMCID: PMC9468341 DOI: 10.1038/s41398-022-02107-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/15/2022] [Accepted: 08/05/2022] [Indexed: 12/30/2022] Open
Abstract
Stress exposure impairs brain structure and function, resulting in cognitive deficits and increased risk for psychiatric disorders such as depression, schizophrenia, anxiety and post-traumatic stress disorder. In particular, stress exposure affects function and structure of hippocampal CA1 leading to impairments in episodic memory. Here, we applied longitudinal deep-brain optical imaging to investigate the link between changes in activity patterns and structural plasticity of dorsal CA1 pyramidal neurons and hippocampal-dependent learning and memory in mice exposed to stress. We found that several days of repeated stress led to a substantial increase in neuronal activity followed by disruption of the temporal structure of this activity and spatial coding. We then tracked dynamics of structural excitatory connectivity as a potential underlying cause of the changes in activity induced by repeated stress. We thus discovered that exposure to repeated stress leads to an immediate decrease in spinogenesis followed by decrease in spine stability. By comparison, acute stress led to stabilization of the spines born in temporal proximity to the stressful event. Importantly, the temporal relationship between changes in activity levels, structural connectivity and activity patterns, suggests that loss of structural connectivity mediates the transition between increased activity and impairment of temporal organization and spatial information content in dorsal CA1 upon repeated stress exposure.
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Affiliation(s)
| | - Ghabiba Weston
- Max Planck Institute of Psychiatry, 80804, Munich, Germany
- Graduate School of Systemic Neurosciences GSN-LMU, 82152, Munich, Germany
| | - Alessandro F Ulivi
- Max Planck Institute of Psychiatry, 80804, Munich, Germany
- Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany
| | | | | | - Alon Chen
- Max Planck Institute of Psychiatry, 80804, Munich, Germany
- Graduate School of Systemic Neurosciences GSN-LMU, 82152, Munich, Germany
- Weizmann Institute of Science, 76100, Rehovot, Israel
| | - Alessio Attardo
- Max Planck Institute of Psychiatry, 80804, Munich, Germany.
- Graduate School of Systemic Neurosciences GSN-LMU, 82152, Munich, Germany.
- Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany.
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19
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Zhang X, Chen N, Chen H, Lei C, Sun T. Comparative analyses of copy number variations between swamp and river buffalo. Gene X 2022; 830:146509. [PMID: 35460806 DOI: 10.1016/j.gene.2022.146509] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 11/30/2022] Open
Abstract
Domestic buffalo is an important livestock in the tropical and sub-tropical region, including two types: swamp and river buffalo. The swamp buffalo is mainly used as draft animal, while the river buffalo is raised for milk production. In this study, based on the new high-quality buffalo reference genome UOA_WB_1, we firstly investigated the copy number variants in buffalo using whole-genome Illumina sequencing. A total of 3,734 CNV regions (CNVRs) were detected in 106 buffalo population with a total length of 23,429,066 bp, corresponding to ∼ 0.88% of the water buffalo genome (UOA_WB_1). Our results revealed a clear population differentiation in CNV between swamp and river buffalo. In addition, a total of 667 highly differentiated CNVRs (covering 886 genes) were detected between river and swamp buffalo population. We detected a set of CNVR-overlapping genes associated with exercise, immunity, nerve, and milk trait which exhibited different copy numbers between swamp and river buffalo population. This study provides valuable genome variation resources for buffalo and would contribute to understanding the genetic differences between swamp and river buffalo.
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Affiliation(s)
- Xianfu Zhang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection and Internet Technology, College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University, Hangzhou, Zhejiang 311300, China.
| | - Ningbo Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Hong Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Ting Sun
- College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China.
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20
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Dromard Y, Arango-Lievano M, Borie A, Dedin M, Fontanaud P, Torrent J, Garabedian MJ, Ginsberg SD, Jeanneteau F. Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway. Acta Neuropathol Commun 2022; 10:91. [PMID: 35733193 PMCID: PMC9219215 DOI: 10.1186/s40478-022-01396-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 12/22/2022] Open
Abstract
Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition.
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Affiliation(s)
- Yann Dromard
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France
| | - Margarita Arango-Lievano
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France
| | - Amelie Borie
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France
| | - Maheva Dedin
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France
| | - Pierre Fontanaud
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France
- Imagerie du Petit Animal de Montpellier, 34090, Montpellier, France
| | - Joan Torrent
- Institut de Neuroscience de Montpellier, INSERM, 34090, Montpellier, France
| | - Michael J Garabedian
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Stephen D Ginsberg
- Nathan Kline Institute, Orangeburg, NY, 10962, USA
- Departments of Psychiatry, Neuroscience & Physiology, NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Freddy Jeanneteau
- Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRS, 34090, Montpellier, France.
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21
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Prenatal glucocorticoid exposure selectively impairs neuroligin 1-dependent neurogenesis by suppressing astrocytic FGF2-neuronal FGFR1 axis. Cell Mol Life Sci 2022; 79:294. [PMID: 35562616 PMCID: PMC9106608 DOI: 10.1007/s00018-022-04313-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 11/03/2022]
Abstract
Exposure to maternal stress irreversibly impairs neurogenesis of offspring by inducing life-long effects on interaction between neurons and glia under raging differentiation process, culminating in cognitive and neuropsychiatric abnormalities in adulthood. We identified that prenatal exposure to stress-responsive hormone glucocorticoid impaired neurogenesis and induced abnormal behaviors in ICR mice. Then, we used human induced pluripotent stem cell (iPSC)-derived neural stem cell (NSC) to investigate how neurogenesis deficits occur. Following glucocorticoid treatment, NSC-derived astrocytes were found to be A1-like neurotoxic astrocytes. Moreover, cortisol-treated astrocytic conditioned media (ACM) then specifically downregulated AMPA receptor-mediated glutamatergic synaptic formation and transmission in differentiating neurons, by inhibiting localization of ionotropic glutamate receptor (GluR)1/2 into synapses. We then revealed that downregulated astrocytic fibroblast growth factor 2 (FGF2) and nuclear fibroblast growth factor receptor 1 (FGFR1) of neurons are key pathogenic factors for reducing glutamatergic synaptogenesis. We further confirmed that cortisol-treated ACM specifically decreased the binding of neuronal FGFR1 to the synaptogenic NLGN1 promoter, but this was reversed by FGFR1 restoration. Upregulation of neuroligin 1, which is important in scaffolding GluR1/2 into the postsynaptic compartment, eventually normalized glutamatergic synaptogenesis and subsequent neurogenesis. Moreover, pretreatment of FGF2 elevated neuroligin 1 expression and trafficking of GluR1/2 into the postsynaptic compartment of mice exposed to prenatal corticosterone, improving spatial memory and depression/anxiety-like behaviors. In conclusion, we identified neuroligin 1 restoration by astrocytic FGF2 and its downstream neuronal nuclear FGFR1 as a critical target for preventing prenatal stress-induced dysfunction in glutamatergic synaptogenesis, which recovered both neurogenesis and hippocampal-related behaviors.
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22
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Akinluyi E, Aderibigbe A, Adeoluwa O, Adebesin A, Adeoluwa G. Ameliorating Effect of Morin Hydrate on Chronic Restraint Stress-induced Biochemical Disruption, Neuronal, and Behavioral Dysfunctions in BALB/c Mice. Basic Clin Neurosci 2022; 13:393-406. [PMID: 36457885 PMCID: PMC9706294 DOI: 10.32598/bcn.2022.1059.2] [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: 06/27/2019] [Revised: 10/22/2020] [Accepted: 11/01/2022] [Indexed: 06/17/2023] Open
Abstract
INTRODUCTION Morin hydrate (MH) is a bioflavonoid component of many fruits and vegetables. Our previous research demonstrated that MH provides neuroprotection in mouse models of acute restraint stress and sleep deprivation by attenuating hippocampal neuronal damage and enhancing memory. Based on these findings, our study investigated the role of MH in chronic stress-induced neuronal and biochemical perturbations in BALB/c mice. METHODS Male BALB/c mice were divided into 6 groups (n=6). Groups 1 and 2 received vehicle (10 mL/kg normal saline), groups 3-5 received MH (5, 10, 20 mg/kg IP), while group 6 received ginseng (25 mg/kg) daily and 30 minutes afterward were restrained in a plastic cylindrical restrainer for 14 days. RESULTS Immobility time in the forced swim test increased in the MH-treated group, indicating an antidepressant-like effect. Also, a reduction in frequency and duration of open arms exploration was observed in the elevated plus-maze (EPM) test in stressed mice, and administration of MH (5, 10, 20 mg/kg, IP) reversed these effects. An increase in blood levels of glucose, triglycerides, total cholesterol, and brain malondialdehyde and nitrite levels was observed in the stressed groups, which was reversed by MH. Furthermore, MH reversed the stress-induced reduction in HDL cholesterol and glutathione (GSH) levels and attenuated stress-induced alterations in the prefrontal cortex and hippocampus. CONCLUSION Our findings suggest that MH attenuated chronic restraint stress-behavioral and biochemical perturbations, probably due to its capability to decrease oxidative stress and brain neuronal damage. HIGHLIGHTS Chronic stress perturbs physiological and psychological homeostasis;Morin hydrate normalized chronic stress-induced biochemical disruptions;Morin hydrate attenuated structural changes in prefrontal cortex and hippocampus. PLAIN LANGUAGE SUMMARY Stress is a state of being overwhelmed by demands exceeding the personal and social means of coping. Exposure to excessive stress has resulted in disruption of neurochemical and physiological processes, which sometimes manifest as behavioural abnormalities. Therefore to cope with the stressful life style, there is need to develop a therapeutic agent of plant origin. Morin hydrate is a flavonoid with known antioxidant and neuroprotective properties; however, its effect in a stressful condition has not been studies. The study thus evaluated ameliorating effect of Morin hydrate on chronic restraint stress-induced biochemical disruption, neuronal and behavioral dysfunctions in BALB/c mice. To achieve this, mice were exposed to chronic restraint stress protocol for fourteen days. Behavioural changes were examined using various techniques. The vital parameters like antioxidant, glucose and nitrite levels were also taken. Our findings show that Morin hydrate prevented behavioral abnormalities and damage to the brain cells. It also inhibited stress-induced biochemical disturbance.
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Affiliation(s)
- Elizabeth Akinluyi
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Adegbuyi Aderibigbe
- Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Olusegun Adeoluwa
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Adaeze Adebesin
- Department of Pharmacology and Therapeutics, College of Health Sciences, Olabisi Onabanjo University, Sagamu Campus, Ogun State, Nigeria
| | - Gladys Adeoluwa
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
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Royo M, Escolano BA, Madrigal MP, Jurado S. AMPA Receptor Function in Hypothalamic Synapses. Front Synaptic Neurosci 2022; 14:833449. [PMID: 35173598 PMCID: PMC8842481 DOI: 10.3389/fnsyn.2022.833449] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022] Open
Abstract
AMPA receptors (AMPARs) are critical for mediating glutamatergic synaptic transmission and plasticity, thus playing a major role in the molecular machinery underlying cellular substrates of memory and learning. Their expression pattern, transport and regulatory mechanisms have been extensively studied in the hippocampus, but their functional properties in other brain regions remain poorly understood. Interestingly, electrophysiological and molecular evidence has confirmed a prominent role of AMPARs in the regulation of hypothalamic function. This review summarizes the existing evidence on AMPAR-mediated transmission in the hypothalamus, where they are believed to orchestrate the role of glutamatergic transmission in autonomous, neuroendocrine function, body homeostasis, and social behavior.
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Yang Q, Song D, Xie Z, He G, Zhao J, Wang Z, Dong Z, Zhang H, Yang L, Jiang M, Wu Y, Shi Q, Li J, Yang J, Bai Z, Quan Z, Qing H. Optogenetic stimulation of CA3 pyramidal neurons restores synaptic deficits to improve spatial short-term memory in APP/PS1 mice. Prog Neurobiol 2021; 209:102209. [PMID: 34953962 DOI: 10.1016/j.pneurobio.2021.102209] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 12/11/2021] [Accepted: 12/20/2021] [Indexed: 12/26/2022]
Abstract
The hippocampal CA3 region, that is involved in the encoding and retrieval of spatial memory, is found to be synaptically impaired in the early-onset of Alzheimer's disease (AD). It is reported optogenetic manipulation of DG or CA1 can rescue the memory impairment of APP/PS1 mice, however, how CA3 region contributes to AD-related deficits in cognitive function is still unknown. Our work shows optogenetic stimulation of CA3 pyramidal neurons (PNs) significantly restores the impaired spatial short-term memory of APP/PS1 mice. This enhances the anatomical synaptic density/strength and synaptic plasticity as well as activates astrocytes. Chemogenetic inhibiting the activity of CA3 astrocytes reverses the effect of optogenetic stimulation of CA3 PNs that leads to reduced anatomical synaptic density/strength, decreased synaptic protein and AMPA receptors GluA3/4, thus disrupting the cognitive restoration of APP/PS1 mice. These results reveal the molecular mechanism of optogenetic activation of CA3 PNs on restoration of the spatial short-term memory of APP/PS1 mice and unveil a potential strategy of manipulating CA3 for AD treatment.
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Affiliation(s)
- Qinghu Yang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China; College of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, YananUniversity, Yanan, 716000, China
| | - Da Song
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China
| | - Zhen Xie
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China
| | - Guiqiong He
- Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, China; Department of Anatomy, Chongqing Medical University, Chongqing, 400016, China
| | - Juan Zhao
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China
| | - Zhe Wang
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China; The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhifang Dong
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Heao Zhang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China
| | - Liang Yang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China; College of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, YananUniversity, Yanan, 716000, China
| | - Ming Jiang
- College of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, YananUniversity, Yanan, 716000, China
| | - Yili Wu
- Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of mental disorders, Institute of Mental Health, Jining Medical University, 133 Hehua Road, Taibaihu New District, Jining, Shandong, 272067, China; Shandong Key Laboratory of Behavioral Medicine, Institute of Mental Health, Jining Medical University, 133 Hehua Road, Taibaihu New District, Jining, Shandong, 272067, China
| | - Qing Shi
- Beijing Advanced Innovation Center for Intelligent Robots and Systems, Beijing Institute of Technology, Beijing, 100081, China; Key Laboratory of Biomimetic Robots and Systems (Beijing Institute of Technology), Ministry of Education, Beijing, 100081, China
| | - Junjie Li
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Jun Yang
- State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China
| | - Zhantao Bai
- College of Life Sciences & Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, YananUniversity, Yanan, 716000, China
| | - Zhenzhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China.
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 10008, China.
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Ginsberg SD, Joshi S, Sharma S, Guzman G, Wang T, Arancio O, Chiosis G. The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders. J Neurochem 2021; 159:958-979. [PMID: 34657288 PMCID: PMC8688321 DOI: 10.1111/jnc.15525] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/22/2021] [Accepted: 10/13/2021] [Indexed: 02/06/2023]
Abstract
Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age- and lifestyle-related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence-based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited.
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Affiliation(s)
- Stephen D. Ginsberg
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
- Departments of Psychiatry, Neuroscience & Physiology, the NYU Neuroscience Institute, New York University Grossman School of Medicine, New York City, New York, USA
| | - Suhasini Joshi
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Sahil Sharma
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Gianny Guzman
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Tai Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Ottavio Arancio
- Department of Pathology and Cell Biology, Columbia University, New York City, New York, USA
- Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York City, New York, USA
| | - Gabriela Chiosis
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA
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Kumar A, Arya H, Tamta K, Maurya RC. Acute stress-induced neuronal plasticity in the corticoid complex of 15-day-old chick, Gallus domesticus. J Anat 2021; 239:869-891. [PMID: 34159582 PMCID: PMC8450486 DOI: 10.1111/joa.13483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/17/2021] [Accepted: 05/25/2021] [Indexed: 12/01/2022] Open
Abstract
Several studies conducted on chicken have shown that a single stress exposure may impair or improve memory as well as learning processes. However, to date, stress effects on neuronal morphology are poorly investigated wherefore it was of interest to evaluate this further in chicks. Thus, the present study aims to investigate the role of single acute stress (AS) of 24 h food and water deprivation in neuronal plasticity in terms of spine density of the corticoid complex (CC) in 15-day-old chick, Gallus domesticus, by using three neurohistological techniques: Cresyl Violet, Golgi Colonnier, and Golgi Cox technique. The dorsolateral surface of the cerebral hemisphere is occupied by CC which can be differentiated into two subfields: an intermediate corticoid (CI) subfield (arranged in layers) and a dorsolateral corticoid (CDL) subfield. Based on different criteria such as soma shape, dendritic branching pattern, and dendritic spine density, two main moderately spinous groups of neuronal cells were observed in the CC, namely, projection neurons (comprising of multipolar and pyramidal neurons) and stellate neurons. In the present study, the stellate neurons have shown a significant decrease as well as an increase in their spine density in both CI and CDL subfields, whereas the multipolar neurons had shown a significant increase in their spine density in the CDL region only. The present study shows that AS induces neuronal plasticity in terms of spine density in both CI and CDL neurons. The morphological changes in the form of decreased dendritic branches due to stress have been observed in the CI region in comparison to CDL region, which could be linked to more effect of stress in this region. The avian CDL corresponds to the entorhinal cortex of mammals on the basis of neuronal morphology and bidirectional connections between adjacent areas. The projection neurons increase their branches and also their spine number to cope with the stress effects, while the stellate neurons show contrasting effect in their spine density. Therefore, this study will establish that slight modifications in natural stimuli or environmental changes faced by the animal may affect their dorsolateral forebrain which shows neuronal plasticity that help in the development of an adaptive capacity of the animal to survive under changing environmental conditions.
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Affiliation(s)
- Adarsh Kumar
- Department of Zoology (DST‐FIST Sponsored)Kumaun UniversityAlmoraIndia
| | - Hemlata Arya
- Department of Zoology (DST‐FIST Sponsored)Kumaun UniversityAlmoraIndia
| | - Kavita Tamta
- Department of Zoology (DST‐FIST Sponsored)Kumaun UniversityAlmoraIndia
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Lesuis SL, Brosens N, Immerzeel N, van der Loo RJ, Mitrić M, Bielefeld P, Fitzsimons CP, Lucassen PJ, Kushner SA, van den Oever MC, Krugers HJ. Glucocorticoids Promote Fear Generalization by Increasing the Size of a Dentate Gyrus Engram Cell Population. Biol Psychiatry 2021; 90:494-504. [PMID: 34503674 DOI: 10.1016/j.biopsych.2021.04.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Traumatic experiences, such as conditioned threat, are coded as enduring memories that are frequently subject to generalization, which is characterized by (re-) expression of fear in safe environments. However, the neurobiological mechanisms underlying threat generalization after a traumatic experience and the role of stress hormones in this process remain poorly understood. METHODS We examined the influence of glucocorticoid hormones on the strength and specificity of conditioned fear memory at the level of sparsely distributed dentate gyrus (DG) engram cells in male mice. RESULTS We found that elevating glucocorticoid hormones after fear conditioning induces a generalized contextual fear response. This was accompanied by a selective and persistent increase in the excitability and number of activated DG granule cells. Selective chemogenetic suppression of these sparse cells in the DG prevented glucocorticoid-induced fear generalization and restored contextual memory specificity, while leaving expression of auditory fear memory unaffected. CONCLUSIONS These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by glucocorticoid stress hormones.
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Affiliation(s)
- Sylvie L Lesuis
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.
| | - Niek Brosens
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Nathalie Immerzeel
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Rolinka J van der Loo
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Miodrag Mitrić
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Pascal Bielefeld
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Carlos P Fitzsimons
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Paul J Lucassen
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands
| | - Steven A Kushner
- Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michel C van den Oever
- Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Harm J Krugers
- Brain Plasticity Group, SILS-CNS, University of Amsterdam, Amsterdam, The Netherlands.
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28
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Gazarini L, Stern CA, Takahashi RN, Bertoglio LJ. Interactions of Noradrenergic, Glucocorticoid and Endocannabinoid Systems Intensify and Generalize Fear Memory Traces. Neuroscience 2021; 497:118-133. [PMID: 34560200 DOI: 10.1016/j.neuroscience.2021.09.012] [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] [Received: 06/15/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022]
Abstract
Systemic administration of drugs that activate the noradrenergic or glucocorticoid system potentiates aversive memory consolidation and reconsolidation. The opposite happens with the stimulation of endocannabinoid signaling under certain conditions. An unbalance of these interacting neurotransmitters can lead to the formation and maintenance of traumatic memories, whose strength and specificity attributes are often maladaptive. Here we aimed to investigate whether originally low-intensity and precise contextual fear memories would turn similar to traumatic ones in rats systemically administered with adrenaline, corticosterone, and/or the cannabinoid type-1 receptor antagonist/inverse agonist AM251 during consolidation or reconsolidation. The high dose of each pharmacological agent evaluated significantly increased freezing times at test in the conditioning context one and nine days later when given alone post-acquisition or post-retrieval. Their respective low dose produced no relative changes when given separately, but co-treatment of adrenaline with corticosterone or AM251 and the three drugs combined, but not corticosterone with AM251, produced results equivalent to those mentioned initially. Neither the high nor the low dose of adrenaline, corticosterone, or AM251 altered freezing times at test in a novel, neutral context two and ten days later. In contrast, animals receiving the association of their low dose exhibited significantly higher freezing times than controls. Together, the results indicate that newly acquired and destabilized threat memory traces become more intense and generalized after a combined interference acting synergistically and mimicking that reported in patients presenting stress-related psychiatric conditions.
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Affiliation(s)
- Lucas Gazarini
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Universidade Federal de Mato Grosso do Sul, Três Lagoas, MS, Brazil.
| | - Cristina A Stern
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Reinaldo N Takahashi
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
| | - Leandro J Bertoglio
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
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Yoon SH, Song WS, Oh SP, Kim YS, Kim MH. The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain. Mol Brain 2021; 14:142. [PMID: 34526091 PMCID: PMC8442277 DOI: 10.1186/s13041-021-00852-0] [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] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/04/2021] [Indexed: 11/21/2022] Open
Abstract
Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number of immediate early genes (IEGs) that are rapidly transcribed in neuronal cells in response to synaptic activity have been used as markers for neuronal activity. However, protein detection of IEGs requires translation, and the amount of newly synthesized gene product is usually insufficient to detect using western blotting, limiting their utility in western blot analysis of brain tissues for comparison of basal activity between control and genetically modified animals. Here, we show that the phosphorylation status of eukaryotic elongation factor-2 (eEF2) rapidly changes in response to synaptic and neural activities. Intraperitoneal injections of the GABA A receptor (GABAAR) antagonist picrotoxin and the glycine receptor antagonist brucine rapidly dephosphorylated eEF2. Conversely, potentiation of GABAARs or inhibition of AMPA receptors (AMPARs) induced rapid phosphorylation of eEF2 in both the hippocampus and forebrain of mice. Chemogenetic suppression of hippocampal principal neuron activity promoted eEF2 phosphorylation. Novel context exploration and acute restraint stress rapidly modified the phosphorylation status of hippocampal eEF2. Furthermore, the hippocampal eEF2 phosphorylation levels under basal conditions were reduced in mice exhibiting epilepsy and abnormally enhanced excitability in CA3 pyramidal neurons. Collectively, the results indicated that eEF2 phosphorylation status is sensitive to neural activity and the ratio of phosphorylated eEF2 to total eEF2 could be a molecular signature for estimating neural activity in a specific brain area.
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Affiliation(s)
- Sang Ho Yoon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea
| | - Woo Seok Song
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea
| | - Sung Pyo Oh
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Young Sook Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Myoung-Hwan Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea. .,Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Korea. .,Seoul National University Bundang Hospital, Seongnam, 13620, Gyeonggi, Korea.
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Aji A, Aihemaiti R, Zou S, Maisiyiti A, Zhang C, Liu R, Sulidan X. BHLHE40 modulates post-traumatic stress disorder behaviors with the involvement of the PI3K/AKT signaling pathway. AN ACAD BRAS CIENC 2021; 93:e20201708. [PMID: 34161515 DOI: 10.1590/0001-3765202120201708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/10/2021] [Indexed: 11/21/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is closely related to the exposure to traumatic events and results in the structural and functional changes of hippocampus. Human basic helix-loop-helix family member e40 (BHLHE40) was reported to be implicated with neuron maturity and neuronal differentiation. The present study aimed to reveal the role of BHLHE40 on single-prolonged stress (SPS) model of PTSD in mice. The morris water maze test, open field test and contextual fear test were conducted to assess memory deficits, anxiety-like behaviors, and freezing of mice. Western blot was performed to identify proteins and reveal their levels in hippocampal tissues. We found that mice receiving SPS exhibited increased anxiety-like behaviors, memory deficits, and prolonged freezing time. The protein levels of BHLHE40 were downregulated in the hippocampal tissues of SPS mice. SPS reduced the protein levels of glutamate receptors, while overexpression of BHLHE40 promoted glutamate receptor protein levels in SPS mice. Moreover, BHLHE40 overexpression activated the PI3K/AKT pathway. BHLHE40 overexpression ameliorated the SPS-induced PTSD-like behavioral deficits. Overall, BHLHE40 promotes glutamate receptor protein levels to ameliorate PTSD-like behaviors with the involvement of the PI3K/AKT pathway. This novel discovery may provide a potential target for the improvement of PTSD.
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Affiliation(s)
- Adila Aji
- Department of Clinical Psychology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumuqi 830001, Xinjiang, China
| | - Rena Aihemaiti
- Department of Second Psychiatry, Mental Health Center of Xinjiang in China, Urumuqi 830001, Xinjiang, China
| | - Shaohong Zou
- Department of Clinical Psychology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumuqi 830001, Xinjiang, China
| | - Alimujiang Maisiyiti
- Department of minimally invasive surgery, hernia and abdominal wall surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumuqi 830001, Xinjiang, China
| | - Cheng Zhang
- Department of Clinical Psychology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumuqi 830001, Xinjiang, China
| | - Ruonan Liu
- Department of Clinical Psychology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumuqi 830001, Xinjiang, China
| | - Xiaokaiti Sulidan
- Department of Second Psychiatry, Mental Health Center of Xinjiang in China, Urumuqi 830001, Xinjiang, China
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AMPA Receptors Exist in Tunable Mobile and Immobile Synaptic Fractions In Vivo. eNeuro 2021; 8:ENEURO.0015-21.2021. [PMID: 33906969 PMCID: PMC8143022 DOI: 10.1523/eneuro.0015-21.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/24/2021] [Accepted: 04/12/2021] [Indexed: 12/16/2022] Open
Abstract
AMPA receptor (AMPAR) mobility within synapses has been extensively studied in vitro. However, whether similar mobility properties apply to AMPARs in vivo has yet to be determined. Here, we use two-photon fluorescence recovery after photobleaching (FRAP) to study AMPAR mobility within individual dendritic spines in live animals using an overexpression vector. We demonstrate the existence of mobile and immobile fractions of AMPARs across multiple cortical regions and layers. Additionally, we find that AMPAR mobility can be altered in vivo in response to administration of corticosterone, a condition that mimics exposure to stress.
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Cai YQ, Hou YY, Pan ZZ. GluA1 in central amygdala increases pain but inhibits opioid withdrawal-induced aversion. Mol Pain 2021; 16:1744806920911543. [PMID: 32162577 PMCID: PMC7068745 DOI: 10.1177/1744806920911543] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The amygdala is important in regulation of emotion-associated behavioral
responses both to positive reinforcing stimuli such as addicting
opioids and to negative aversive stimuli such as fear and pain.
Glutamatergic neurotransmission in amygdala plays a predominant role
in amygdala neuronal circuits involved in these emotional responses.
However, how specific glutamate receptors act to mediate these
amygdala functions remains poorly understood. In this study, we
investigated the role of GluA1 subunits of glutamate
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
in central amygdala in modulating behavioral response to aversive
stimuli by pain and by opioid withdrawal. We found that the protein
level of GluA1 in the central nucleus of amygdala (CeA) was
significantly increased in rats under persistent pain and viral
upregulation of CeA GluA1 increased pain responses of both
hyperalgesia and allodynia in rats. In contrast, the viral
upregulation of CeA GluA1 inhibited, while knockdown of CeA GluA1
enhanced, place aversion induced by naloxone-precipitated morphine
withdrawal. These results reveal a differential action of CeA GluA1 on
the aversive event of sensory pain and opioid withdrawal, likely
reflecting two distinct synaptic circuits of GluA1-predominant AMPA
receptors within CeA for regulation of pain sensitivity and emotional
response to opioid withdrawal.
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Affiliation(s)
- You-Qing Cai
- Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuan-Yuan Hou
- Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhizhong Z Pan
- Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Acute elevated platform triggers stress induced hyperalgesia and alters glutamatergic transmission in the adult mice anterior cingulate cortex. IBRO Neurosci Rep 2021; 10:1-7. [PMID: 33861817 PMCID: PMC8019816 DOI: 10.1016/j.ibneur.2020.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/21/2020] [Accepted: 12/09/2020] [Indexed: 11/23/2022] Open
Abstract
Pain is composed of both physiological and affective/emotional components which potentiate one another. In addition, exposure to stress modulates pain and affective behaviors including, anxiety-like behavior and/or depression-like behaviors. Indeed, chronic exposure to stress has been known to enhance stress-induced hyperalgesia (SIH). The anterior cingulate cortex (ACC) is critically involved in pain sensation and emotions. Animal models of chronic pain, but not acute nociception have been found to induce synaptic plasticity on glutamatergic and GABAergic transmission in the rodent ACC. However, it is unclear whether acute stress exposure could produce SIH and cause synaptic plasticity in the ACC. Accordingly, we studied how acute exposure of stress by the elevated open platform (EOP) could affect mechanical threshold, thermal and cold latency in the adult mice. Thirty minutes of the EOP produced mechanical hypersensitivity lasting for 60 min and thermal hypersensitivity immediately after the exposure. Next, we tested whether the stress could alter the excitatory and inhibitory synaptic transmission in the ACC. We performed whole-cell patch-clamp recordings from layer II/III pyramidal neurons in the ACC and analyzed both glutamatergic and GABAergic transmission in mice following the EOP. Thirty minutes of the EOP altered the rise and decay time of spontaneous glutamatergic AMPA/GluK receptors mediated currents, but did not change the frequency or amplitude of excitatory transmission. By contrast, the kinetics of inhibitory synaptic currents were not altered by the EOP. These results suggest that acute stress by the elevated platform produces SIH and causes synaptic plasticity on excitatory transmission, but not inhibitory transmission in the ACC.
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Environmental enrichment prevents the late effect of acute stress-induced fear extinction deficit: the role of hippocampal AMPA-GluA1 phosphorylation. Transl Psychiatry 2021; 11:18. [PMID: 33414437 PMCID: PMC7791025 DOI: 10.1038/s41398-020-01140-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 11/22/2022] Open
Abstract
The persistence of anxiety and the deficit of fear memory extinction are both phenomena related to the symptoms of a trauma-related disorder, such as post-traumatic stress disorder (PTSD). Recently we have shown that single acute restraint stress (2 h) in rats induces a late anxiety-related behavior (observed ten days after stress), whereas, in the present work, we found that the same stress impaired fear extinction in animals conditioned ten days after stress. Fourteen days of environmental enrichment (EE) prevented the deleterious effect of stress on fear memory extinction. Additionally, we observed that EE prevented the stress-induced increase in AMPA receptor GluA1 subunit phosphorylation in the hippocampus, but not in the basolateral amygdala complex and the frontal cortex, indicating a potential mechanism by which it exerts its protective effect against the stress-induced behavioral outcome.
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Rubin BR, Johnson MA, Berman JM, Goldstein E, Pertsovskaya V, Zhou Y, Contoreggi NH, Dyer AG, Gray JD, Waters EM, McEwen BS, Kreek MJ, Milner TA. Sex and chronic stress alter delta opioid receptor distribution within rat hippocampal CA1 pyramidal cells following behavioral challenges. Neurobiol Stress 2020; 13:100236. [PMID: 33344692 PMCID: PMC7739044 DOI: 10.1016/j.ynstr.2020.100236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 12/17/2022] Open
Abstract
Following oxycodone (Oxy) conditioned place preference (CPP), delta opioid receptors (DORs) differentially redistribute in hippocampal CA3 pyramidal cells in female and male rats in a manner that would promote plasticity and opioid-associative learning processes. However, following chronic immobilization stress (CIS), males do not acquire Oxy-CPP and the trafficking of DORs in CA3 pyramidal neurons is attenuated. Here, we examined the subcellular distribution of DORs in CA1 pyramidal cells using electron microscopy in these same cohorts. CPP Saline (Sal)-females compared to Sal-males have more cytoplasmic and total DORs in dendrites and more DOR-labeled spines. Following Oxy-CPP, DORs redistribute from near-plasmalemma pools in dendrites to spines in males. CIS Control females compared to control males have more near-plasmalemmal dendritic DORs. Following CIS, dendritic DORs are elevated in the cytoplasm in females and near-plasmalemma in males. CIS plus CPP CIS Sal-females compared to CIS Sal-males have more DORs on the plasmalemma of dendrites and in spines. After Oxy, the distribution of DORs does not change in either females or males. Conclusion Following Oxy-CPP, DORs within CA1 pyramidal cells remain positioned in naïve female rats to enhance sensitivity to DOR agonists and traffic to dendritic spines in naïve males where they can promote plasticity processes. Following CIS plus behavioral enrichment, DORs are redistributed within CA1 pyramidal cells in females in a manner that could enhance sensitivity to DOR agonists. Conversely, CIS plus behavioral enrichment does not alter DORs in CA1 pyramidal cells in males, which may contribute to their diminished capacity to acquire Oxy-CPP.
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Affiliation(s)
- Batsheva R. Rubin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Megan A. Johnson
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Jared M. Berman
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Ellen Goldstein
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Vera Pertsovskaya
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Yan Zhou
- The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
| | - Natalina H. Contoreggi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Andreina G. Dyer
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
| | - Jason D. Gray
- Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
| | - Elizabeth M. Waters
- Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
| | - Bruce S. McEwen
- Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
| | - Mary Jeanne Kreek
- The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
| | - Teresa A. Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States
- Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States
- Corresponding author. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, RM 307 New York, NY 10065, United States.
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Al-Chami A, Ross A, Hayley S, Sun H. Early life stress facilitates synapse premature unsilencing to enhance AMPA receptor function in the developing hippocampus. J Neurophysiol 2020; 124:815-821. [PMID: 32783592 DOI: 10.1152/jn.00339.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic early life stress (ELS) increases vulnerability to psychopathologies and cognitive deficits in adulthood by disrupting the function of related neural circuits. However, whether this disruption emerges early in the developing brain remains largely unexplored. In the current study, using an established limited-bedding and nesting model of ELS in postnatal day (P)2-10 mice, we provide direct evidence that ELS caused early modification of hippocampal glutamatergic synapses in the developing brain. We demonstrated that ELS induced rapid enhancement of AMPA receptor function in hippocampal CA1 pyramidal neurons through a postsynaptic mechanism, and importantly, this was associated with premature unsilencing of NMDA receptor-only silent hippocampal synapses. These results suggest that potentiation of AMPAR function may represent an early mediator of ELS-induced alterations of neural networks in the developing brain and may potentially contribute to subsequent cognitive impairments later in life.NEW & NOTEWORTHY Early life stress (ELS) is known to increase the risk of later life cognitive deficits by disrupting neural circuit function. However, whether this disruption emerges early in the developing brain remains largely unexplored. The current study presents direct evidence that ELS prematurely unsilences hippocampal synapses to enhance AMPA receptor functions in a limited-bedding and nesting model, revealing an early mediator of ELS-induced neural circuit reorganizations.
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Affiliation(s)
- Aycheh Al-Chami
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Alysia Ross
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Hongyu Sun
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
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Ciappelloni S, Bouchet D, Dubourdieu N, Boué-Grabot E, Kellermayer B, Manso C, Marignier R, Oliet SHR, Tourdias T, Groc L. Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease. Cell Rep 2020; 27:3860-3872.e4. [PMID: 31242419 DOI: 10.1016/j.celrep.2019.05.097] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 03/08/2019] [Accepted: 05/23/2019] [Indexed: 01/21/2023] Open
Abstract
Astrocytes constantly adapt their ramified morphology in order to support brain cell assemblies. Such plasticity is partly mediated by ion and water fluxes, which rely on the water channel aquaporin-4 (AQP4). The mechanism by which this channel locally contributes to process dynamics has remained elusive. Using a combination of single-molecule and calcium imaging approaches, we here investigated in hippocampal astrocytes the dynamic distribution of the AQP4 isoforms M1 and M23. Surface AQP4-M1 formed small aggregates that contrast with the large AQP4-M23 clusters that are enriched near glutamatergic synapses. Strikingly, stabilizing surface AQP4-M23 tuned the motility of astrocyte processes and favors glutamate synapse activity. Furthermore, human autoantibodies directed against AQP4 from neuromyelitis optica (NMO) patients impaired AQP4-M23 dynamic distribution and, consequently, astrocyte process and synaptic activity. Collectively, it emerges that the membrane dynamics of AQP4 isoform regulate brain cell assemblies in health and autoimmune brain disease targeting AQP4.
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Affiliation(s)
- Silvia Ciappelloni
- Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France; INSERM U1215, Neurocentre Magendie, 33077 Bordeaux, France
| | - Delphine Bouchet
- Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France
| | - Nadège Dubourdieu
- Université de Bordeaux, 33077 Bordeaux, France; INSERM U1215, Neurocentre Magendie, 33077 Bordeaux, France
| | - Eric Boué-Grabot
- Université de Bordeaux, 33077 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France
| | - Blanka Kellermayer
- Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France
| | - Constance Manso
- Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France
| | - Romain Marignier
- INSERM U1028, CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon, France
| | - Stéphane H R Oliet
- Université de Bordeaux, 33077 Bordeaux, France; INSERM U1215, Neurocentre Magendie, 33077 Bordeaux, France
| | - Thomas Tourdias
- Université de Bordeaux, 33077 Bordeaux, France; INSERM U1215, Neurocentre Magendie, 33077 Bordeaux, France
| | - Laurent Groc
- Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France.
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Zhang H, Bramham CR. Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders. Front Synaptic Neurosci 2020; 12:26. [PMID: 32754026 PMCID: PMC7366028 DOI: 10.3389/fnsyn.2020.00026] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/28/2020] [Indexed: 12/11/2022] Open
Abstract
AMPA receptors (AMPARs) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission throughout the brain. Changes in the properties and postsynaptic abundance of AMPARs are pivotal mechanisms in synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. A wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders, despite their extremely diverse etiology, pathogenesis and symptoms, exhibit brain region-specific and AMPAR subunit-specific aberrations in synaptic transmission or plasticity. These include abnormally enhanced or reduced AMPAR-mediated synaptic transmission or plasticity. Bidirectional reversal of these changes by targeting AMPAR subunits or trafficking ameliorates drug-seeking behavior, chronic pain, epileptic seizures, or cognitive deficits. This indicates that bidirectional dysregulation of AMPAR-mediated synaptic transmission or plasticity may contribute to the expression of many brain disorders and therefore serve as a therapeutic target. Here, we provide a synopsis of bidirectional AMPAR dysregulation in animal models of brain disorders and review the preclinical evidence on the therapeutic targeting of AMPARs.
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Affiliation(s)
- Hongyu Zhang
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Clive R Bramham
- Department of Biomedicine, University of Bergen, Bergen, Norway
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39
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Carr KD. Modulatory Effects of Food Restriction on Brain and Behavioral Effects of Abused Drugs. Curr Pharm Des 2020; 26:2363-2371. [DOI: 10.2174/1381612826666200204141057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/19/2019] [Indexed: 12/14/2022]
Abstract
Energy homeostasis is achieved, in part, by metabolic signals that regulate the incentive motivating
effects of food and its cues, thereby driving or curtailing procurement and consumption. The neural underpinnings
of these regulated incentive effects have been identified as elements within the mesolimbic dopamine pathway.
A separate line of research has shown that most drugs with abuse liability increase dopamine transmission in
this same pathway and thereby reinforce self-administration. Consequently, one might expect shifts in energy
balance and metabolic signaling to impact drug abuse risk. Basic science studies have yielded numerous examples
of drug responses altered by diet manipulation. Considering the prevalence of weight loss dieting in Western
societies, and the anorexigenic effects of many abused drugs themselves, we have focused on the CNS and behavioral
effects of food restriction in rats. Food restriction has been shown to increase the reward magnitude of diverse
drugs of abuse, and these effects have been attributed to neuroadaptations in the dopamine-innervated nucleus
accumbens. The changes induced by food restriction include synaptic incorporation of calcium-permeable
AMPA receptors and increased signaling downstream of D1 dopamine receptor stimulation. Recent studies suggest
a mechanistic model in which concurrent stimulation of D1 and GluA2-lacking AMPA receptors enables
increased stimulus-induced trafficking of GluA1/GluA2 AMPARs into the postsynaptic density, thereby increasing
the incentive effects of food, drugs, and associated cues. In addition, the established role of AMPA receptor
trafficking in enduring synaptic plasticity prompts speculation that drug use during food restriction may more
strongly ingrain behavior relative to similar use under free-feeding conditions.
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Affiliation(s)
- Kenneth D. Carr
- Departments of Psychiatry, Biochemistry and Molecular Pharmacology, New York University School of Medicine, 435 East 30th Street, New York, NY 10016, United States
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40
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41
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Kuniishi H, Yamada D, Wada K, Yamada M, Sekiguchi M. Stress induces insertion of calcium-permeable AMPA receptors in the OFC-BLA synapse and modulates emotional behaviours in mice. Transl Psychiatry 2020; 10:154. [PMID: 32424318 PMCID: PMC7235080 DOI: 10.1038/s41398-020-0837-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 04/28/2020] [Accepted: 05/01/2020] [Indexed: 01/31/2023] Open
Abstract
Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. In the present study, we focused on a projection pathway from the orbitofrontal cortex (OFC) to the basolateral nucleus of the amygdala (BLA) as a crucial circuit for negative emotions and examined the effect of stress on OFC-BLA excitatory synaptic transmission using optogenetic and whole-cell patch-clamp methods in mice. As a stress-inducing procedure, we used repeated tail-shock, which increased stress-related behaviours. We found greater α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate current ratios and insertion of calcium-permeable AMPA receptors (AMPARs) in the OFC-BLA synapse after stress. These stress-induced synaptic and behavioural changes were reduced by a blockade of protein kinase A, which plays a principal role in stress-induced targeting of AMPARs into the synaptic membrane. To examine a possible causal relationship between alterations in synaptic transmission in the OFC-BLA pathway and stress-related behaviour, we performed optogenetic activation or chemogenetic inactivation of OFC-BLA transmission in mice. We found that optogenetic activation and chemogenetic inactivation of OFC-BLA transmission increased and decreased stress-related behaviour, respectively. In conclusion, we have demonstrated that stress altered the postsynaptic properties of the OFC-BLA pathway. These synaptic changes might be one of the underlying mechanisms of stress-induced behavioural alterations.
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Affiliation(s)
- Hiroshi Kuniishi
- grid.419280.60000 0004 1763 8916Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo Japan ,grid.419280.60000 0004 1763 8916Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo Japan
| | - Daisuke Yamada
- grid.419280.60000 0004 1763 8916Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo Japan
| | - Keiji Wada
- grid.419280.60000 0004 1763 8916Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo Japan
| | - Mitsuhiko Yamada
- Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
| | - Masayuki Sekiguchi
- Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
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Hou SJ, Yang AC, Tsai SJ, Shen CC, Lan TH. Tinnitus Among Patients With Anxiety Disorder: A Nationwide Longitudinal Study. Front Psychiatry 2020; 11:606. [PMID: 32670119 PMCID: PMC7329992 DOI: 10.3389/fpsyt.2020.00606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/11/2020] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVES The association between tinnitus and anxiety disorder remains debated. We used a retrospective cohort study to investigate the relationship between anxiety disorder and tinnitus, aiming to decipher possible risk factors for tinnitus in patients with anxiety disorder. METHOD Data on a total of 7,525 patients with anxiety disorder and 15,050 patients without (comparison cohort) were extracted from the Longitudinal Health Insurance Database 2005 in Taiwan. The Kaplan-Meier estimator with the log rank test and the Cox proportional-hazard regression model were used to compare the incidence of tinnitus in both groups and to identify risk factors that predicted tinnitus. RESULTS After adjusting for related covariates, the hazard ratio for the development of tinnitus during the follow-up period was 3.54 (95% confidence interval: 3.11-4.02, P < .001) for anxiety disorder cohort relative to comparison cohort. Age ≧ 60 years, female sex, hypertension, and hyperlipidemia were statistically significant predictive risk factors of tinnitus in patients with anxiety disorder. CONCLUSION A significant increase in the lifetime incidence of tinnitus was exhibited in patients with anxiety disorder. Elderly subjects, female sex, hypertension, and hyperlipidemia were risk factors. Clinicians should be alert to the possibility of tinnitus in subjects with anxiety disorder.
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Affiliation(s)
- Sheue-Jane Hou
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Albert C Yang
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Shih-Jen Tsai
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Che Shen
- Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan
| | - Tsuo-Hung Lan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Tsaotun Psychiatric Center, Ministry of Health and Welfare, Nantou, Taiwan
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Yang N, Zhang Y, Wang JT, Chen C, Song Y, Liang JM, Ma DH, Zhang YF. Effects of Dexamethasone on Remodeling of the Hippocampal Synaptic Filamentous Actin Cytoskeleton in a Model of Pilocarpine-induced Status Epilepticus. Int J Med Sci 2020; 17:1683-1691. [PMID: 32714071 PMCID: PMC7378655 DOI: 10.7150/ijms.44927] [Citation(s) in RCA: 5] [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: 02/14/2020] [Accepted: 06/18/2020] [Indexed: 12/28/2022] Open
Abstract
The filamentous actin (F-actin) cytoskeleton is progressively damaged after status epilepticus (SE), which is related to delayed neuronal death, aberrant recurrent circuits and epileptogenesis. Glucocorticoids regulate dendritic spine remodeling by acting on glucocorticoid receptors and the dynamics of the F-actin cytoskeleton. Our previous study showed that administration of dexamethasone (DEX) in the latent period of the pilocarpine epileptic model reduces damage to the hippocampal filamentous actin cytoskeleton and the loss of hippocampal neurons and aids in maintaining the synaptic structures, but it is not sufficient to stop epileptogenesis. In this work, we focused on the role of glucocorticoids in regulating the hippocampal F-actin cytoskeleton during SE. We examined the abundance of synaptic F-actin, analyzed the hippocampal F-actin/G-actin (F/G) ratio and pCofilin, and evaluated the number of hippocampal neurons and pre/postsynaptic markers in pilocarpine-induced status epilepticus mice with or without administration of dexamethasone (DEX). We found that the latency of Stage 3 seizures increased, the mortality decreased, the damage to the synaptic F-actin cytoskeleton in the hippocampal subfields was significantly attenuated, and a greater number of postsynaptic structures were retained in the hippocampal subfields after treatment with DEX. These results indicate that treatment with dexamethasone stabilizes the synaptic F-actin cytoskeleton and reduces the damage to the brain due to SE. This approach is expected to be beneficial in alleviating delayed neuron damage and the process of epileptogenesis.
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Affiliation(s)
- Nuo Yang
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China.,Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Yan Zhang
- College of Life Sciences, Jilin University; Jilin Province, 130021, PR China
| | - Jiang-Tao Wang
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Chen Chen
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Yan Song
- Nursing College, Beihua University, 3999 Huashan Road, Jilin 132013, PR China
| | - Jian-Min Liang
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Di-Hui Ma
- Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Yan-Feng Zhang
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
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Zhang HH, Meng SQ, Guo XY, Zhang JL, Zhang W, Chen YY, Lu L, Yang JL, Xue YX. Traumatic Stress Produces Delayed Alterations of Synaptic Plasticity in Basolateral Amygdala. Front Psychol 2019; 10:2394. [PMID: 31708835 PMCID: PMC6824323 DOI: 10.3389/fpsyg.2019.02394] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 10/07/2019] [Indexed: 12/19/2022] Open
Abstract
Acute traumatic event exposure is a direct cause of post-traumatic stress disorder (PTSD). Amygdala is suggested to be associated with the development of PTSD. In our previous findings, different activation patterns of GABAergic neurons and glutamatergic neurons in early or late stages after stress were found. However, the neural plastic mechanism underlying the role of basolateral amygdala (BLA) in post-traumatic stress disorder remains unclear. Therefore, this study mainly aimed at investigating time-dependent morphologic and electrophysiological changes in BLA during the development of PTSD. We used single prolonged stress (SPS) procedure to establish PTSD model of rats. The rats showed no alterations in anxiety behavior as well as in dendritic spine density or synaptic transmission in BLA 1 day after SPS. However, 10 days after SPS, rats showed enhancement of anxiety behavior, and spine density and frequency of miniature excitatory and inhibitory postsynaptic currents in BLA. Our results suggested that after traumatic stress, BLA displayed delayed increase in both spinogenesis and synaptic transmission, which seemed to facilitate the development of PTSD.
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Affiliation(s)
- Huan-Huan Zhang
- Department of Psychiatry, Tianjin Medical University, Tianjin, China
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shi-Qiu Meng
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Xin-Yi Guo
- Department of Psychiatry, Tianjin Medical University, Tianjin, China
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Liang Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy and Purdue Institute for Integrative Neuroscience, West Lafayette, IN, United States
| | - Wen Zhang
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Ya-Yun Chen
- National Institute on Drug Dependence, Peking University, Beijing, China
| | - Lin Lu
- National Institute on Drug Dependence, Peking University, Beijing, China
- Peking University Sixth Hospital/Peking University Institute of Mental Health, Peking University, Beijing, China
| | - Jian-Li Yang
- Department of Psychiatry, Tianjin Medical University, Tianjin, China
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yan-Xue Xue
- National Institute on Drug Dependence, Peking University, Beijing, China
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Quantitative analysis of Gria1, Gria2, Dlg1 and Dlg4 expression levels in hippocampus following forced swim stress in mice. Sci Rep 2019; 9:14060. [PMID: 31575955 PMCID: PMC6773768 DOI: 10.1038/s41598-019-50689-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 09/18/2019] [Indexed: 01/09/2023] Open
Abstract
AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, Gria1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.
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Silvestro S, Bramanti P, Mazzon E. Role of miRNAs in Alzheimer's Disease and Possible Fields of Application. Int J Mol Sci 2019; 20:E3979. [PMID: 31443326 PMCID: PMC6720959 DOI: 10.3390/ijms20163979] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/07/2019] [Accepted: 08/14/2019] [Indexed: 01/02/2023] Open
Abstract
miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3' and 5' untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.
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Affiliation(s)
- Serena Silvestro
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
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Mahmoudi E, Sahraei H, Bahari Z, Afarinesh MR, Jahromi GP, Hatef B, Meftahi GH. Prenatal Immobilization Stress-Induced Spatial Memory, Depression and Anxiety-Like Behavior Deficit on the F1 Generation in the Female Mice: Possible Involvement of the Brain-Derived Neurotrophic Factor. NEUROCHEM J+ 2019. [DOI: 10.1134/s1819712419020065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Dexamethasone ameliorates the damage of hippocampal filamentous actin cytoskeleton but is not sufficient to cease epileptogenesis in pilocarpine induced epileptic mice. Epilepsy Res 2019; 154:26-33. [PMID: 31022637 DOI: 10.1016/j.eplepsyres.2019.04.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/02/2019] [Accepted: 04/17/2019] [Indexed: 01/28/2023]
Abstract
Rogressive deconstruction of filament actin (F-actin) in hippocampal neurons in the epileptic brain have been associated with epileptogenesis. Previous clinical studies suggest that glucocorticoids treatment plays beneficial roles in refractory epilepsy. Glucocorticoids treatment affects dendritic spine morphology by regulating local glucocorticoid receptors and F-actin cytoskeleton dynamics. However, how glucocorticoids regulate epileptogenesis by controlling F-actin cytoskeleton is not clear yet. Here we study the function of glucocorticoids in epileptogenesis by examining F-actin abundance, hippocampal neuron number, and synaptic markers in pilocarpine-induced epileptic mice in the presence or absence of dexamethasone (DEX) treatment. We found that spontaneous seizure duration was significantly reduced; F-actin damage in hippocampal subfields was remarkably attenuated; loss of pyramidal cells was dramatically decreased; more intact synaptic structures indicated by pre- and postsynaptic markers were preserved in multiple hippocampal regions after DEX treatment. However, the number of ZNT3 positive particles in the molecular layer in the hippocampus of pilocarpine epileptic mice was not altered after DEX treatment. Although not sufficient to cease epileptogenesis, our results suggest that dexamethasone treatment ameliorates the damage of epileptic brain by stabilizing F-actin cytoskeleton in the pilocarpine epileptic mice.
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Abstract
In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activity-dependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.
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Affiliation(s)
- Rianne R Campbell
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, Center for Addiction Neuroscience, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
| | - Marcelo A Wood
- Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, Center for Addiction Neuroscience, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
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