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1.
Transl Psychiatry ; 14(1): 306, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39054336

RESUMEN

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.


Asunto(s)
Lipopolisacáridos , Estrés Psicológico , Animales , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Masculino , Humanos , Adolescente , Ratones , Lipopolisacáridos/farmacología , Niño , Femenino , Adulto Joven , Neuronas/inmunología , Derrota Social , Encéfalo/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Amígdala del Cerebelo/inmunología , Amígdala del Cerebelo/fisiopatología
2.
J Neuroimmune Pharmacol ; 19(1): 38, 2024 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-39066908

RESUMEN

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.


Asunto(s)
Lipopolisacáridos , Ratones Endogámicos C57BL , Derrota Social , Estrés Psicológico , Animales , Lipopolisacáridos/toxicidad , Ratones , Masculino , Estrés Psicológico/inmunología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/inmunología , Lipocalina 2/metabolismo
3.
eNeuro ; 11(7)2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38937108

RESUMEN

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 21 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.


Asunto(s)
Barrera Hematoencefálica , Encéfalo , Ghrelina , Ratones Endogámicos C57BL , Derrota Social , Estrés Psicológico , Animales , Ghrelina/metabolismo , Masculino , Estrés Psicológico/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Ratones , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Ghrelina/metabolismo
4.
Phytomedicine ; 132: 155332, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38851983

RESUMEN

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.


Asunto(s)
Antidepresivos , Factor Neurotrófico Derivado del Encéfalo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Ácido Glicirretínico , Ratones Endogámicos C57BL , Derrota Social , Estrés Psicológico , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ácido Glicirretínico/farmacología , Ácido Glicirretínico/análogos & derivados , Antidepresivos/farmacología , Masculino , Medicamentos Herbarios Chinos/farmacología , Ratones , Estrés Psicológico/tratamiento farmacológico , Depresión/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Receptor trkB/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo
5.
J Affect Disord ; 361: 637-650, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38914161

RESUMEN

BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression. METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS. RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice. LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored. CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.


Asunto(s)
Depresión , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Hipocampo , Ratones Endogámicos C57BL , Estrés Psicológico , Animales , Hipocampo/patología , Hipocampo/fisiopatología , Ratones , Estrés del Retículo Endoplásmico/fisiología , Masculino , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Mitocondrias , Electroacupuntura , Membranas Mitocondriales/metabolismo , Derrota Social , Conducta Animal/fisiología , Membranas Asociadas a Mitocondrias
6.
Int Immunopharmacol ; 137: 112414, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-38897132

RESUMEN

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.


Asunto(s)
Ansiedad , Dimetilfumarato , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Neuronas , Estrés Psicológico , Animales , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Masculino , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/inmunología , Ratones , Ansiedad/tratamiento farmacológico , Neuronas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Microglía/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Caspasa 1/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Transducción de Señal/efectos de los fármacos , Derrota Social
7.
Pharmacol Biochem Behav ; 241: 173794, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38834160

RESUMEN

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.


Asunto(s)
Ansiedad , Indenos , Melatonina , Derrota Social , Estrés Psicológico , Animales , Indenos/farmacología , Ratones , Masculino , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Melatonina/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/agonistas , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/psicología , Trastornos por Estrés Postraumático/metabolismo
8.
Neurobiol Dis ; 199: 106573, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38901783

RESUMEN

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-ß1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-ß1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-ß1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.


Asunto(s)
Antidepresivos , Ketamina , Ratones Endogámicos C57BL , Fosforilación Oxidativa , Bazo , Esplenectomía , Nervio Vago , Animales , Ketamina/farmacología , Antidepresivos/farmacología , Bazo/efectos de los fármacos , Bazo/metabolismo , Ratones , Masculino , Nervio Vago/efectos de los fármacos , Nervio Vago/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Derrota Social
9.
Biol Pharm Bull ; 47(6): 1172-1178, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38880625

RESUMEN

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.


Asunto(s)
Astrocitos , Corteza Cerebral , Hipocampo , Ratones Endogámicos BALB C , Derrota Social , Estrés Psicológico , Animales , Astrocitos/metabolismo , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Estrés Psicológico/metabolismo , Masculino , Ratones , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Conexina 43/metabolismo , Conexina 43/genética , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/genética , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfatasas/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética
10.
Neurosci Lett ; 835: 137851, 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-38838971

RESUMEN

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.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Hipocampo , Ratas Sprague-Dawley , Estrés Psicológico , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Masculino , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Fosforilación , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Derrota Social , Ratas , Ansiedad/metabolismo , Ansiedad/psicología , Conducta Animal/fisiología , Miedo/fisiología , Miedo/psicología , Emociones/fisiología , Depresión/metabolismo , Depresión/psicología
11.
Nat Commun ; 15(1): 5199, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38890305

RESUMEN

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.


Asunto(s)
Depresión , Estrés del Retículo Endoplásmico , Retículo Endoplásmico , Ratones Endogámicos C57BL , Microglía , Mitocondrias , Proteína con Dominio Pirina 3 de la Familia NLR , Derrota Social , Estrés Psicológico , Canal Aniónico 1 Dependiente del Voltaje , Animales , Mitocondrias/metabolismo , Depresión/metabolismo , Microglía/metabolismo , Microglía/patología , Ratones , Masculino , Retículo Endoplásmico/metabolismo , Estrés Psicológico/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Canal Aniónico 1 Dependiente del Voltaje/metabolismo , Canal Aniónico 1 Dependiente del Voltaje/genética , Hipocampo/metabolismo , Hipocampo/patología , Adenosina Trifosfato/metabolismo , Inflamasomas/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Conducta Animal , Membranas Asociadas a Mitocondrias , Proteínas HSP70 de Choque Térmico
12.
Nat Commun ; 15(1): 5042, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38871707

RESUMEN

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.


Asunto(s)
Antidepresivos , Trastorno Depresivo Mayor , Núcleo Dorsal del Rafe , Histonas , Estrés Psicológico , Animales , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/efectos de los fármacos , Histonas/metabolismo , Masculino , Femenino , Estrés Psicológico/metabolismo , Humanos , Antidepresivos/farmacología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Ratones , Serotonina/metabolismo , Ratones Endogámicos C57BL , Epigénesis Genética/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Derrota Social
13.
Transl Psychiatry ; 14(1): 239, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38834575

RESUMEN

Prior research has identified differential protein expression levels of linker histone H1x within the ventral hippocampus (vHipp) of stress-susceptible versus stress-resilient mice. These mice are behaviorally classified based on their divergent responses to chronic social stress. Here, we sought to determine whether elevated vHipp H1x protein levels directly contribute to these diverging behavioral adaptations to stress. First, we demonstrated that stress-susceptible mice uniquely express elevated vHipp H1x protein levels following chronic stress. Given that linker histones coordinate heterochromatin compaction, we hypothesize that elevated levels of H1x in the vHipp may impede pro-resilience transcriptional adaptations and prevent development of the resilient phenotype following social stress. To test this, 8-10-week-old male C57BL/6 J mice were randomly assigned to groups undergoing 10 days of chronic social defeat stress (CSDS) or single housing, respectively. Following CSDS, mice were classified as susceptible versus resilient based on their social interaction behaviors. We synthesized a viral overexpression (OE) vector for H1x and transduced all stressed and single housed mice with either H1x or control GFP within vHipp. Following viral delivery, we conducted social, anxiety-like, and memory-reliant behavior tests on distinct cohorts of mice. We found no behavioral adaptations following H1x OE compared to GFP controls in susceptible, resilient, or single housed mice. In sum, although we confirm elevated vHipp protein levels of H1x associate with susceptibility to social stress, we observe no significant behavioral consequence of H1x OE. Thus, we conclude elevated levels of H1x are associated with, but are not singularly sufficient to drive development of behavioral adaptations to stress.


Asunto(s)
Conducta Animal , Hipocampo , Histonas , Ratones Endogámicos C57BL , Estrés Psicológico , Animales , Masculino , Hipocampo/metabolismo , Ratones , Estrés Psicológico/metabolismo , Histonas/metabolismo , Conducta Animal/fisiología , Adaptación Psicológica/fisiología , Resiliencia Psicológica , Derrota Social , Ansiedad/metabolismo
14.
Biomed Pharmacother ; 176: 116850, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38834006

RESUMEN

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.


Asunto(s)
Adenosina Trifosfato , Conducta Animal , Depresión , Ratones Endogámicos C57BL , Mononucleótido de Nicotinamida , Corteza Prefrontal , Estrés Psicológico , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Masculino , Adenosina Trifosfato/metabolismo , Mononucleótido de Nicotinamida/farmacología , Depresión/tratamiento farmacológico , Depresión/prevención & control , Depresión/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Ratones , Conducta Animal/efectos de los fármacos , Derrota Social , NAD/metabolismo , Modelos Animales de Enfermedad
15.
Mol Brain ; 17(1): 30, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38802853

RESUMEN

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples.


Asunto(s)
Hipotálamo , Ratones Endogámicos C57BL , Derrota Social , Estrés Psicológico , Animales , Hipotálamo/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/sangre , Masculino , Proteómica/métodos , Ratones , Proteoma/metabolismo
16.
Am J Physiol Regul Integr Comp Physiol ; 327(1): R66-R78, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38708545

RESUMEN

The stress-induced cardiovascular response is based on the defensive reaction in mammals. It has been shown that the sympathetic vasomotor pathway of acute psychological stress is indirectly mediated via neurons in the rostroventral medulla (RVM) from the hypothalamic stress center. In this study, direct projections to the RVM and distribution of neuroexcitatory marker c-Fos-expressed neurons were investigated during social defeat stress (SDS) in conscious rats. The experimental rat that was injected with a neural tracer, FluoroGold (FG) into the unilateral RVM, was exposed to the SDS. Double-positive neurons of both c-Fos and FG were locally distributed in the lateral/ventrolateral periaqueductal gray matter (l/vl PAG) in the midbrain. These results suggest that the neurons in the l/vl PAG contribute to the defensive reaction evoked by acute psychological stress, such as the SDS. During the SDS period, arterial pressure (AP) and heart rate (HR) showed sustained increases in the rat. Therefore, we performed chemical stimulation by excitatory amino acid microinjection within the l/vl PAG and measured cardiovascular response and sympathetic nerve activity in some anesthetized rats. The chemical stimulation of neurons in the l/vl PAG caused significant increases in arterial pressure and renal sympathetic nerve activity. Taken together, our results suggest that neurons in the l/vl PAG are a possible candidate for the cardiovascular descending pathway that modulates sympathetic vascular resistance evoked by acute psychological stress, like the SDS.NEW & NOTEWORTHY The sympathetic vasomotor pathway of an acute psychological stress-induced cardiovascular response is mediated via neurons in the RVM indirectly from the hypothalamus. In this study, we showed the relaying area of the efferent sympathetic vasomotor pathway from the hypothalamus to the RVM. The results suggested that the pressor response during psychological stress is mediated via neurons in the lateral/ventrolateral PAG to the RVM.


Asunto(s)
Bulbo Raquídeo , Sustancia Gris Periacueductal , Derrota Social , Estrés Psicológico , Sistema Vasomotor , Animales , Estrés Psicológico/fisiopatología , Masculino , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiopatología , Bulbo Raquídeo/fisiopatología , Bulbo Raquídeo/metabolismo , Sistema Vasomotor/fisiopatología , Ratas , Frecuencia Cardíaca , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Wistar , Sistema Nervioso Simpático/fisiopatología , Ratas Sprague-Dawley , Presión Arterial , Conducta Animal
17.
Sci Rep ; 14(1): 10867, 2024 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740863

RESUMEN

Chronic psychosocial stress induced by the chronic subordinate colony housing (CSC, 19 Days) paradigm promotes functional splenic in vitro glucocorticoid (GC) resistance, but only if associated with significant bite wounding or prior abdominal transmitter implantation. Moreover, sensory contact to social defeat of conspecifics represents a social stressor for the observer individual. As the occurence and severity of bite wounding is not adequately controllable, the present study aimed to develop an animal model, allowing a bite wound-independent, more reliable generation of chronically-stressed mice characterized by functional splenic in vitro GC resistance. Therefore, male C57BL/6N mice received a standardized sterile intraperitoneal (i.p.) incision surgery or SHAM treatment one week prior to 19-days of (i) CSC, (ii) witnessing social defeat during CSC exposure in sensory contact (SENS) or (iii) single-housing for control (SHC), before assessing basal and LPS-induced splenic in vitro cell viability and GC resistance. Our results indicate that individually-housed SENS but not CSC mice develop mild signs of splenic in vitro GC resistance, when undergoing prior i.p.-wounding. Taken together and considering that future studies are warranted, our findings support the hypothesis that the combination of repeated standardized i.p.-wounding with chronic sensory stress exposure represents an adequate tool to induce functional splenic in vitro GC resistance independent of the occurrence of uncontrollable bite wounds required in social stress paradigms to induce a comparable phenotype.


Asunto(s)
Glucocorticoides , Ratones Endogámicos C57BL , Bazo , Estrés Psicológico , Animales , Masculino , Bazo/metabolismo , Ratones , Modelos Animales de Enfermedad , Derrota Social
18.
Neurochem Int ; 177: 105748, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38703789

RESUMEN

Adaptation to psychosocial stress is psychologically distressing, initiating/promoting comorbidity with alcohol use disorders. Emerging evidence moreover showed that ethanol (EtOH) exacerbates social-defeat stress (SDS)-induced behavioral impairments, neurobiological sequelae, and poor therapeutic outcomes. Hence, this study investigated the effects of geraniol, an isoprenoid monoterpenoid alcohol with neuroprotective functions on EtOH escalated SDS-induced behavioral impairments, and neurobiological sequelae in mice. Male mice chronically exposed to SDS for 14 days were repeatedly fed with EtOH (2 g/kg, p. o.) from days 8-14. From days 1-14, SDS-EtOH co-exposed mice were concurrently treated with geraniol (25 and 50 mg/kg) or fluoxetine (10 mg/kg) orally. After SDS-EtOH translational interactions, arrays of behavioral tasks were examined, followed by investigations of oxido-inflammatory, neurochemicals levels, monoamine oxidase-B and acetylcholinesterase activities in the striatum, prefrontal-cortex, and hippocampus. The glial fibrillary acid protein (GFAP) expression was also quantified in the prefrontal-cortex immunohistochemically. Adrenal weights, serum glucose and corticosterone concentrations were measured. EtOH exacerbated SDS-induced low-stress resilience, social impairment characterized by anxiety, depression, and memory deficits were attenuated by geraniol (50 and 100 mg/kg) and fluoxetine. In line with this, geraniol increased the levels of dopamine, serotonin, and glutamic-acid decarboxylase enzyme, accompanied by reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal-cortex, hippocampus, and striatum. Geraniol inhibited SDS-EtOH-induced adrenal hypertrophy, corticosterone, TNF-α, IL-6 release, malondialdehyde and nitrite levels, with increased antioxidant activities. Immunohistochemical analyses revealed that geraniol enhanced GFAP immunoreactivity in the prefrontal-cortex relative to SDS-EtOH group. We concluded that geraniol ameliorates SDS-EtOH interaction-induced behavioral changes via normalization of neuroimmune-endocrine and neurochemical dysregulations in mice brains.


Asunto(s)
Monoterpenos Acíclicos , Etanol , Estrés Psicológico , Terpenos , Animales , Monoterpenos Acíclicos/farmacología , Monoterpenos Acíclicos/uso terapéutico , Masculino , Estrés Psicológico/psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/complicaciones , Ratones , Etanol/toxicidad , Etanol/farmacología , Terpenos/farmacología , Terpenos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Derrota Social
19.
J Affect Disord ; 358: 270-282, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38723681

RESUMEN

OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.


Asunto(s)
Conducta Animal , Depresión , Modelos Animales de Enfermedad , Lanosterol , Ratones Endogámicos C57BL , Corteza Prefrontal , Proteómica , Derrota Social , Estrés Psicológico , Animales , Ratones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Masculino , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Lanosterol/análogos & derivados , Lanosterol/farmacología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Imipramina/farmacología , Proteína Doblecortina , Ácidos Heptanoicos
20.
J Vis Exp ; (205)2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38557733

RESUMEN

Social adversity in adolescence is prevalent and can negatively impact mental health trajectories. Modeling social stress in adolescent male and female rodents is needed to understand its effects on ongoing brain development and behavioral outcomes. The chronic social defeat stress paradigm (CSDS) has been widely used to model social stress in adult C57BL/6 male mice by leveraging on the aggressive behavior displayed by an adult male rodent to an intruder invading its territory. An advantage of this paradigm is that it allows to categorize defeated mice into resilient and susceptible groups based on their individual differences in social behavior 24 h after the last defeat session. Implementing this model in adolescent C57BL/6 mice has been challenging because adult or adolescent mice do not typically attack early adolescent male or female mice and because adolescence is a short period of life, encompassing discreet temporal windows of vulnerability. This limitation was overcome by adapting an accelerated version of the CSDS to be used for adolescent male and female mice. This 4-day stress paradigm with 2 physical attack sessions per day uses a C57BL/6 male adult to prime the CD-1 mouse for aggressiveness such that it readily attacks the male or female adolescent mouse. This model was termed accelerated social defeat stress (AcSD) for adolescent mice. Adolescent exposure to AcSD induces social avoidance 24 h later in both males and females, but only in a subset of defeated mice. This vulnerability occurs despite the number of attacks being consistent across sessions between resilient and susceptible groups. The AcSD model is short enough to allow exposure during discrete periods within adolescence, allows the segregation of mice according to the presence or absence of social avoidance behavior, and is the first model available to study social defeat stress in adolescent C57BL/6 female mice.


Asunto(s)
Conducta Social , Derrota Social , Masculino , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Estrés Psicológico/psicología
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