RESUMO
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.
Assuntos
Antidepressivos , Modelos Animais de Doenças , Mitocôndrias , Córtex Pré-Frontal , Proteômica , Estresse Psicológico , Animais , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Camundongos Endogâmicos C57BL , Proteína Duplacortina , Depressão/tratamento farmacológico , Depressão/metabolismo , Comportamento Animal/efeitos dos fármacos , Derrota SocialRESUMO
Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.
Assuntos
Privação Materna , Plasticidade Neuronal , Córtex Pré-Frontal , Resiliência Psicológica , Animais , Plasticidade Neuronal/fisiologia , Masculino , Ratos , Anedonia/fisiologia , Interação Social , Derrota Social , Hipocampo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ratos Wistar , Comportamento Animal/fisiologia , Comportamento Social , Ansiedade/fisiopatologiaRESUMO
Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, we identify novel, to the best of our knowledge, stress-associated microglia in the hippocampus defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuates the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment are microglia-dependent, but social avoidance is microglia-independent. Furthermore, single-nuclei (sn)RNAseq shows robust responses to RSD in hippocampal neurons that are both microglia-dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons are microglia-dependent. Collectively, these stress-associated microglia influence transcriptional profiles in the hippocampus related to social and cognitive deficits.
Assuntos
Disfunção Cognitiva , Hipocampo , Camundongos Endogâmicos C57BL , Microglia , Derrota Social , Animais , Microglia/metabolismo , Camundongos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/etiologia , Masculino , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma , Comportamento Social , Ansiedade/metabolismo , Compostos OrgânicosRESUMO
Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD's effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (n = 32) and KD (n = 32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (n = 16), VSD-STD (n = 16), EXP-KD (n = 16), and VSD-KD (n = 16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 h after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that the KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, the KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results point to the KD as a useful tool to increase resilience to social stress in female mice.
Assuntos
Consumo de Bebidas Alcoólicas , Dieta Cetogênica , Estresse Psicológico , Animais , Feminino , Camundongos , Consumo de Bebidas Alcoólicas/psicologia , Etanol , Derrota Social , Comportamento Animal , AutoadministraçãoRESUMO
The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing, and ex vivo whole-cell patch-clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression at the DRN and VTA neurons, respectively, receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole-cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.
Assuntos
Habenula , Camundongos Endogâmicos C57BL , Neurônios , Derrota Social , Estresse Psicológico , Animais , Habenula/fisiologia , Masculino , Estresse Psicológico/fisiopatologia , Camundongos , Neurônios/fisiologia , Vias Neurais/fisiologia , Vias Neurais/fisiopatologia , Área Tegmentar Ventral/fisiologia , Optogenética , Adaptação Fisiológica/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Chronic stress leads to social avoidance and anhedonia in susceptible individuals, a phenomenon that has been observed in both human and animal models. Nevertheless, the underlying molecular mechanisms underpinning stress susceptibility and resilience remain largely unclear. There is growing evidence that epigenetic histone deacetylase (HDAC) mediated histone acetylation is involved in the modulation of depressive-related behaviors. We hypothesized that histone deacetylase 5 (HDAC5), which is associated with stress-related behaviors and antidepressant response, may play a vital role in the susceptibility to chronic stress. In the current study, we detected the levels of HDAC5 and acetylation of histone 4 (H4) in the hippocampus subsequent to chronic social defeat stress (CSDS) in C57BL/6J mice. We found that CSDS induces a notable increase in HDAC5 expression, concomitant with a reduction in the acetylation of histone H4 at lysine 12 (H4K12) in the hippocampus of susceptible mice. Meanwhile, intrahippocampal infusion of HDAC5 shRNA or HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) both reversed the depression susceptibility in susceptible mice that subjected to CSDS. Furthermore, HDAC5 overexpression was sufficient to induce depression susceptibility following microdefeat stress, accompanied by a significant reduction in H4K12 level within the hippocampus of mice. Additionally, the Morris water maze (MWM) results indicated that neither CSDS nor HDAC5 exerted significant effects on spatial memory function in mice. Taken together, these investigations indicated that HDAC5-modulated histone acetylation is implicated in regulating the depression susceptibility, and may be serve as potential preventive targets for susceptible individuals.
Assuntos
Hipocampo , Histona Desacetilases , Histonas , Camundongos Endogâmicos C57BL , Derrota Social , Estresse Psicológico , Animais , Estresse Psicológico/metabolismo , Hipocampo/metabolismo , Acetilação , Histonas/metabolismo , Histona Desacetilases/metabolismo , Masculino , Depressão/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Camundongos , Vorinostat/farmacologia , Suscetibilidade a Doenças/metabolismo , Modelos Animais de DoençasRESUMO
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants.
Assuntos
Depressão , Sistema Hipotálamo-Hipofisário , Camundongos Endogâmicos C57BL , MicroRNAs , Núcleo Hipotalâmico Paraventricular , Sistema Hipófise-Suprarrenal , Estresse Psicológico , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , Masculino , Camundongos , Sistema Hipotálamo-Hipofisário/metabolismo , Depressão/metabolismo , Depressão/genética , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Derrota SocialRESUMO
Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.
Assuntos
Mesocricetus , Microglia , Córtex Pré-Frontal , Predomínio Social , Estresse Psicológico , Animais , Microglia/metabolismo , Microglia/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Masculino , Estresse Psicológico/metabolismo , Cricetinae , Plasticidade Neuronal/fisiologia , Derrota Social , Minociclina/farmacologiaRESUMO
Erasing traumatic memory during memory reconsolidation is a promising retrieval-extinction strategy for post-traumatic stress disorder (PTSD). Here, we developed an acute social defeat stress (SDS) mouse model with short-term and re-exposure-evoked long-term social avoidance. SDS-associated traumatic memories were identified to be stored in basolateral amygdala (BLA) engram cells. A single intraperitoneal administration of subanesthetic-dose ketamine within, but not beyond, the re-exposure time window significantly alleviates SDS-induced social avoidance, which reduces the activity and quantity of reactivated BLA engram cells. Furthermore, activation or inhibition of dopaminergic projections from the ventral tegmental area to the BLA effectively mimics or blocks the therapeutic effect of re-exposure with ketamine and is dopamine D2 receptor dependent. Single-cell RNA sequencing reveals that re-exposure with ketamine triggered significant changes in memory-related pathways in the BLA. Together, our research advances the understanding of how ketamine mitigates PTSD symptoms and offers promising avenues for developing more effective treatments for trauma-related disorders.
Assuntos
Aprendizagem da Esquiva , Complexo Nuclear Basolateral da Amígdala , Ketamina , Camundongos Endogâmicos C57BL , Transtornos de Estresse Pós-Traumáticos , Área Tegmentar Ventral , Animais , Ketamina/farmacologia , Ketamina/administração & dosagem , Camundongos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Masculino , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Memória/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Consolidação da Memória/efeitos dos fármacos , Derrota Social , Modelos Animais de DoençasRESUMO
Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole-a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri-exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα.
Assuntos
Cumarínicos , PPAR alfa , Derrota Social , Estresse Psicológico , Animais , Masculino , Camundongos , Administração Oral , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/administração & dosagem , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismoRESUMO
Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.
Assuntos
Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Derrota Social , Estresse Psicológico , Animais , Lipopolissacarídeos/toxicidade , Camundongos , Masculino , Estresse Psicológico/imunologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/imunologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/imunologia , Lipocalina-2/metabolismoRESUMO
Studies in adults have linked stress-related activation of the immune system to the manifestation of psychiatric conditions. Using a translational design, this study aimed to examine the impact of social stress on immune activity in adolescents and on neuronal activity in a preclinical mouse model. Participants were 31 adolescents (ages 12-19), including 25 with mood and anxiety symptoms. Whole-blood samples were collected before and after the Trier Social Stress Test (TSST), a stress-inducing public speaking task, then cultured for 6 hours in the presence and absence of the inflammatory endotoxin lipopolysaccharide (LPS). Effects of TSST and LPS on 41 immune biomarkers were examined using repeated-measures analysis of variance. Separately, juvenile (8-week-old) male mice were non-stressed or exposed to reminder social defeat then intraperitoneally injected with saline or LPS (n = 6/group). Brains were perfused and collected for immunohistochemistry and confocal microscopy at 0, 1, 6, and 24 hours post-injection. The activity was determined by the density of cFos-positive neurons in the paraventricular hypothalamus, paraventricular thalamus, and basolateral amygdala, regions known to show sustained activation to immunological challenge. Analyses in the adolescent study indicated a strong effect of LPS but no effects of TSST or TSST×LPS interaction on immune biomarkers. Similarly, reminder social defeat did not induce sustained neuronal activity changes comparable to LPS immunological challenge in juvenile mice. Our convergent findings across species suggest that the acute immune response to stress documented in adults is not present in youth. Thus, aging and chronicity effects may play an important role in the inflammatory response to acute psychosocial stress.
Assuntos
Lipopolissacarídeos , Estresse Psicológico , Animais , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Masculino , Humanos , Adolescente , Camundongos , Lipopolissacarídeos/farmacologia , Criança , Feminino , Adulto Jovem , Neurônios/imunologia , Derrota Social , Encéfalo/imunologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Tonsila do Cerebelo/imunologia , Tonsila do Cerebelo/fisiopatologiaRESUMO
Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.
Assuntos
Histonas , Lisina , Núcleo Accumbens , Complexo Repressor Polycomb 2 , Estresse Psicológico , Animais , Histonas/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/genética , Camundongos , Núcleo Accumbens/metabolismo , Metilação , Lisina/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Complexo Repressor Polycomb 2/genética , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Processamento de Proteína Pós-Traducional , Derrota SocialRESUMO
Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extrahypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brainstem area postrema, whereas ghrelin does not readily enter other GHSR-expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood-brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21â d and then peripherally injected a Cy5-labelled biologically active ghrelin analog. The results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in chronically stressed mice. Further histologic analyses identified a reduction in the branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood-brain barrier and diffuse throughout the brain to target GHSR-expressing brain regions away from circumventricular organs.
Assuntos
Barreira Hematoencefálica , Encéfalo , Grelina , Camundongos Endogâmicos C57BL , Derrota Social , Estresse Psicológico , Animais , Grelina/metabolismo , Masculino , Estresse Psicológico/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de Grelina/metabolismoRESUMO
BACKGROUND: Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN: We investigated the antidepressants effects of XYS and identified 18ß-glycyrrhetinic acid (18ß-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18ß-GA. METHODS: To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS: We identified 18ß-GA as the primary compound in the brain following XYS injection. In vitro, 18ß-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18ß-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18ß-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18ß-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION: These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18ß-GA, a key component of XYS in the brain.
Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Ácido Glicirretínico , Camundongos Endogâmicos C57BL , Derrota Social , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/análogos & derivados , Antidepressivos/farmacologia , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Estresse Psicológico/tratamento farmacológico , Depressão/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Receptor trkB/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.
Assuntos
Antidepressivos , Transtorno Depressivo Maior , Núcleo Dorsal da Rafe , Histonas , Estresse Psicológico , Animais , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Histonas/metabolismo , Masculino , Feminino , Estresse Psicológico/metabolismo , Humanos , Antidepressivos/farmacologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/tratamento farmacológico , Camundongos , Serotonina/metabolismo , Camundongos Endogâmicos C57BL , Epigênese Genética/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Derrota SocialRESUMO
The increasing number of patients with depressive disorder is a serious socioeconomic problem worldwide. Although several therapeutic agents have been developed and used clinically, their effectiveness is insufficient and thus discovery of novel therapeutic targets is desired. Here, focusing on dysregulation of neuronal purinergic signaling in depressive-like behavior, we examined the expression profiles of ATP channels and ectonucleotidases in astrocytes of cerebral cortex and hippocampus of chronic social defeat stress (CSDS)-susceptible BALB/c mice. Mice were exposed to 10-d CSDS, and their astrocytes were obtained using a commercially available kit based on magnetic activated cell sorting technology. In astrocytes derived from cerebral cortex of CSDS-susceptible mice, the expression levels of mRNAs for connexin 43, P2X7 receptors and maxi anion channels were increased, those for connexin 43 and P2X7 receptors being inversely correlated with mouse sociability, and the expression of mRNAs for ecto-nucleoside triphosphate diphosphohydrase 2 and ecto-5'nucleotidase was decreased and increased, respectively. On the other hand, the alteration profiles of ATP channels and ectonucleotidases in hippocampal astrocytes of CSDS-susceptible mice were different from in the case of cortical astrocytes, and there was no significant correlation between expression levels of their mRNAs and mouse sociability. These findings imply that increased expression of ATP channels in cerebral cortex might be involved in the development of reduced sociability in CSDS-subjected BALB/c mice. Together with recent findings, it is suggested that ATP channels expressed by cortical astrocytes might be potential therapeutic targets for depressive disorder.
Assuntos
Astrócitos , Córtex Cerebral , Hipocampo , Camundongos Endogâmicos BALB C , Derrota Social , Estresse Psicológico , Animais , Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Masculino , Camundongos , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Conexina 43/metabolismo , Conexina 43/genética , 5'-Nucleotidase/metabolismo , 5'-Nucleotidase/genética , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genéticaRESUMO
Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial prefrontal cortex (mPFC). It remains unclear whether facilitating endogenous ATP production and subsequently increasing extracellular ATP level in the mPFC can exert a prophylactic effect against chronic social defeat stress (CSDS)-induced depressive-like behaviors and enhance stress resilience. Here, we found that nicotinamide mononucleotide (NMN) treatment effectively elevated nicotinamide adenine dinucleotide (NAD+) biosynthesis and extracellular ATP levels in the mPFC. Moreover, both the 2-week intraperitoneal (i.p.) injection and 3-week oral gavage of NMN prior to exposure to CSDS effectively prevented the development of depressive-like behavior in mice. These protective effects were accompanied with the preservation of both NAD+ biosynthesis and extracellular ATP level in the mPFC. Furthermore, catalyzing ATP hydrolysis by mPFC injection of the ATPase apyrase negated the prophylactic effects of NMN on CSDS-induced depressive-like behaviors. Prophylactic NMN treatment also prevented the reduction in GABAergic inhibition and the increase in excitability in mPFC neurons projecting to the lateral habenula (LHb). Collectively, these findings demonstrate that the prophylactic effects of NMN on depressive-like behaviors are mediated by preventing extracellular ATP loss in the mPFC, which highlights the potential of NMN supplementation as a novel approach for protecting and preventing stress-induced depression in susceptible individuals.
Assuntos
Trifosfato de Adenosina , Comportamento Animal , Depressão , Camundongos Endogâmicos C57BL , Mononucleotídeo de Nicotinamida , Córtex Pré-Frontal , Estresse Psicológico , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Masculino , Trifosfato de Adenosina/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Depressão/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Camundongos , Comportamento Animal/efeitos dos fármacos , Derrota Social , NAD/metabolismo , Modelos Animais de DoençasRESUMO
Chronic psychosocial stress stands as a significant heterogeneous risk factor for psychiatric disorders. The brain's physiological response to such stress varies based on the frequency and intensity of stress episodes. However, whether stress episodes divergently could affect hippocampal cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling remains unclear, a key regulator of psychiatric symptoms. We aimed to assess how two distinct patterns of social defeat stress exposure impact anxiety- and depression-like behaviors, fear, and hippocampal CREB-BDNF signaling in adult male rats. To explore this, adult male Sprague-Dawley rats were subjected to psychosocial stress using a Resident/Intruder paradigm for ten consecutive days (continuous social defeat stress: [CS]) or ten social defeat stress over the course of 21 days (intermittent social defeat stress [IS]). Behavioral tests (including novelty-suppressed feeding test, forced swimming test, and contextually conditioned fear) were conducted. Protein expression levels of phosphorylated CREB and BDNF in the dorsal and ventral hippocampi were examined. CS led to heightened anxiety-like behavior, fear, and increased levels of phosphorylated CREB in both the dorsal and ventral hippocampi. Conversely, IS resulted in increased anxiety-like behavior and behavioral despair alongside decreased levels of phosphorylated CREB and BDNF, particularly in the dorsal hippocampus. These findings indicate that chronic psychosocial stress divergently affects hippocampal CREB-BDNF signaling and emotional regulation depending on the stress episode. Such insights could enhance our understanding of the molecular basis of the heterogeneity of psychiatric disorders and facilitate the development of innovative treatment approaches to patients with psychiatric disorders.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Hipocampo , Ratos Sprague-Dawley , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Masculino , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Fosforilação , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Derrota Social , Ratos , Ansiedade/metabolismo , Ansiedade/psicologia , Comportamento Animal/fisiologia , Medo/fisiologia , Medo/psicologia , Emoções/fisiologia , Depressão/metabolismo , Depressão/psicologiaRESUMO
BACKGROUND: Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown. METHODS: We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1ß. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1+ microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons. RESULTS: DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1ß signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons. CONCLUSIONS: Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1ß signaling pathway and alleviating hyperactivity of BLA neurons.