RESUMEN

In this issue of Neuron, Torres-Berrío et al.1 show that stress-susceptible mice exhibit elevated H3K27me1 levels in nucleus accumbens neurons due to the action of the SUZ12 VEFS domain, strengthening the link between specific epigenetic changes and long-lasting stress-induced social, emotional, and cognitive alterations.

Asunto(s)

Histonas , Animales , Ratones , Histonas/metabolismo , Núcleo Accumbens/metabolismo , Neuronas/metabolismo , Epigénesis Genética , Estrés Psicológico/metabolismo

RESUMEN

Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect-via ventral pallidium (VP)-pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.

Asunto(s)

Dopamina , Neuronas Dopaminérgicas , Motivación , Núcleo Accumbens , Recompensa , Estrés Psicológico , Animales , Masculino , Ratones , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Ratones Endogámicos C57BL , Motivación/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Estrés Psicológico/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo

RESUMEN

The influence of gut microbiome, metabolites, omics, hormones, and stress on general and mental health is increasingly being recognized. Ancient cultures recognized the importance of diet and gut health on the overall health of an individual. Western science and modern scientific methods are beginning to unravel the foundations and mechanisms behind some of the ancient beliefs and customs. The gut microbiome, an organ itself, is now thought to influence almost all other organs, ranging from the brain to the reproductive systems. Gut microbiome, metabolites, hormones, and biological sex also influence a myriad of health conditions that range from mental health disorders, obesity, gastrointestinal disorders, and cardiovascular diseases to reproductive health. Here, we review the history and current understanding of the gut-brain axis bidirectional talk in various mental health disorders with special emphasis on anxiety and depressive disorders, whose prevalence has increased by over 50% in the past three decades with COVID-19 pandemic being the biggest risk factor in the last few years. The vagal nerve is an important contributor to this bidirectional talk, but other pathways also contribute, and most remain understudied. Probiotics containing Lactobacillus and Bifidobacterium species seem to have the most impact on improvement in mental health symptoms, but the challenge appears to be maintaining sustained levels, especially since neither Lactobacillus nor Bifidobacterium can permanently colonize the gut. Ancient endogenous retroviral DNA in the human genome is also linked to several psychiatric disorders, including depression. These discoveries reveal the complex and intricately intertwined nature of gut health with mental health disorders.

Asunto(s)

Eje Cerebro-Intestino , Microbioma Gastrointestinal , Trastornos Mentales , Humanos , Microbioma Gastrointestinal/fisiología , Eje Cerebro-Intestino/fisiología , Trastornos Mentales/metabolismo , Trastornos Mentales/microbiología , Metabolómica , Hormonas/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/microbiología , Salud Mental , COVID-19/metabolismo , COVID-19/virología , Encéfalo/metabolismo , Animales

RESUMEN

Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.

Asunto(s)

Ansiedad , Modelos Animales de Enfermedad , Hipocampo , Omeprazol , Receptor de Serotonina 5-HT1A , Estrés Psicológico , Animales , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Omeprazol/farmacología , Masculino , Ratas , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas Wistar , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Serotonina/metabolismo , Núcleos del Rafe/metabolismo , Núcleos del Rafe/efectos de los fármacos , ARN Mensajero/metabolismo , Restricción Física , Inmovilización

RESUMEN

The concept of resilience has changed over time and nowadays it refers to the positive adaptation to life adversities, rather than to the absence of a pathological response normally occurring in susceptible people. Based on our previous data showing that the exposure to the chronic mild stress (CMS) paradigm differently affected bioenergetics in the ventral hippocampus of vulnerable and resilient animals, here we investigated whether resilience is a stable trait or if the energetic strategy set in motion to sustain resilience unveils a vulnerability feature in a more dynamic situation. To this aim, vulnerable and resilient rats after 6 weeks of CMS were subjected to a further acute, unfamiliar restraint stress (ARS) and metabolomic studies were conducted in the ventral hippocampus. We observed that exposure to a single novel challenge negatively affects the fuel utilization of resilient animals. Indeed, while they increase glycolysis to sustain the non-hedonic phenotype when exposed to CMS, they shift to fatty acid ß-oxidation after ARS, as vulnerable animals following CMS, suggesting that the energy strategy that guarantees resilience is fragile and can be negatively modified by a different environmental condition. These results suggest that strengthening resilience to foster individuals to bounce back from stressful life events may represent a strategy to decrease vulnerability or prevent the risk of relapsing to a pathological state.

Asunto(s)

Ácidos Grasos , Hipocampo , Oxidación-Reducción , Resiliencia Psicológica , Estrés Psicológico , Animales , Hipocampo/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Ratas , Masculino , Ácidos Grasos/metabolismo , Metabolismo Energético , Ratas Wistar

RESUMEN

Foster parents have been shown to report higher levels of parenting stress but also more dyadic coping (DC) behaviors in their partnership than biological parents, which might be an important protective factor that helps them cope with daily stressors. Here, we examined how parenting stress and DC are related in foster and biological parents and whether these are reflected in long-term alterations of hypothalamic-pituitary-adrenocortical (HPA) axis activity. A total of 79 foster mothers and 131 biological mothers participated in a longitudinal study. At the initial assessment, children were aged 2-7 years and lived for an average of 18 months in their current foster family. Mothers' cortisol and dehydroepiandrosterone (DHEA) concentrations and their cortisol/DHEA ratios were assessed in scalp hair twice with approximately 11 months in between, while their perceived parenting stress and DC were measured by self-report questionnaires. Results showed no significant differences between foster mothers and biological mothers in cortisol, DHEA and cortisol/DHEA concentrations. While more DC was longitudinally related to lower levels of parenting stress across both study groups, no significant associations were found to endocrine markers. Thus, these findings indicate that increased parenting stress levels were not, or not strongly, reflected in HPA axis alterations as assessed in hair. Our findings thus add evidence for non-significant associations between self-reported perceived stress and chronic HPA axis markers. Future studies may explore whether early interventions, including those aimed at promoting and maintaining positive DC, are beneficial in preventing the development of stress-related illnesses in foster parents.

Asunto(s)

Adaptación Psicológica , Deshidroepiandrosterona , Hidrocortisona , Madres , Responsabilidad Parental , Estrés Psicológico , Humanos , Femenino , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Madres/psicología , Hidrocortisona/metabolismo , Hidrocortisona/análisis , Adulto , Responsabilidad Parental/psicología , Niño , Adaptación Psicológica/fisiología , Preescolar , Deshidroepiandrosterona/metabolismo , Estudios Longitudinales , Masculino , Biomarcadores/metabolismo , Resiliencia Psicológica , Cabello/química , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Cuidados en el Hogar de Adopción/psicología

RESUMEN

Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in early life stress-induced neurobehavioral abnormalities remains unclear. Using the maternally separated (MS) mice, our research has unveiled a novel aspect of this complex relationship. We discovered that the reduced levels of amino acid transporters in the intestine of MS mice led to low glutamine (Gln) levels in the blood and synaptic dysfunction in the medial prefrontal cortex (mPFC). Abnormally low blood Gln levels limit the brain's availability of Gln, which is required for presynaptic glutamate (Glu) and γ-aminobutyric acid (GABA) replenishment. Furthermore, MS resulted in gut microbiota dysbiosis characterized by a reduction in the relative abundance of Lactobacillus reuteri (L. reuteri). Notably, supplementation with L. reuteri ameliorates neurobehavioral abnormalities in MS mice by increasing intestinal amino acid transport and restoring synaptic transmission in the mPFC. In conclusion, our findings on the role of L. reuteri in regulating intestinal amino acid transport and buffering early life stress-induced behavioral abnormalities provide a novel insight into the microbiota-gut-brain signaling basis for emotional behaviors.

Asunto(s)

Ansiedad , Microbioma Gastrointestinal , Estrés Psicológico , Animales , Microbioma Gastrointestinal/fisiología , Ratones , Ansiedad/microbiología , Ansiedad/metabolismo , Estrés Psicológico/microbiología , Estrés Psicológico/metabolismo , Aminoácidos/metabolismo , Masculino , Ratones Endogámicos C57BL , Sistemas de Transporte de Aminoácidos/metabolismo , Corteza Prefrontal/metabolismo , Conducta Animal , Disbiosis/microbiología , Privación Materna , Glutamina/metabolismo , Eje Cerebro-Intestino/fisiología , Transmisión Sináptica , Femenino , Ácido Glutámico/metabolismo

RESUMEN

OBJECTIVES: We investigated salivary biomarkers of stress, more specifically, cortisol and alpha-amylase, to evaluate effects of individualized music listening (IML) in people with dementia. METHOD: Participants were N = 64 nursing home residents with dementia (meanage = 83.53 ± 7.71 years, 68.8% female). Participants were randomly assigned to either listening to their favorite music every other day for a period of six weeks (intervention), or standard care (control). Using the Saliva Children`s Swab (SCS), saliva was collected before, after, and 20 min after IML sessions at the beginning and end of the intervention period for the analysis of salivary alpha-amylase and cortisol. RESULTS: Using the SCS was feasible in people with dementia. Nevertheless, there was no effect of IML on salivary stress markers. DISCUSSION: Although using SCS was feasible, active patient engagement is required. Future studies need to corroborate findings in larger samples. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00015641, ISRCTN registry: ISRCTN59052178.

Asunto(s)

Biomarcadores , Demencia , Estudios de Factibilidad , Hidrocortisona , Musicoterapia , Saliva , Estrés Psicológico , alfa-Amilasas , Humanos , Femenino , Hidrocortisona/metabolismo , Hidrocortisona/análisis , Masculino , Demencia/metabolismo , Saliva/metabolismo , Saliva/química , Estrés Psicológico/metabolismo , Estrés Psicológico/terapia , Anciano , Biomarcadores/metabolismo , Anciano de 80 o más Años , alfa-Amilasas/metabolismo , alfa-Amilasas/análisis , Proyectos Piloto , Musicoterapia/métodos

RESUMEN

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.

Asunto(s)

Depresión , Sistema Hipotálamo-Hipofisario , Ratones Endogámicos C57BL , MicroARNs , Núcleo Hipotalámico Paraventricular , Sistema Hipófiso-Suprarrenal , Estrés Psicológico , Animales , MicroARNs/metabolismo , MicroARNs/genética , Núcleo Hipotalámico Paraventricular/metabolismo , Masculino , Ratones , Sistema Hipotálamo-Hipofisario/metabolismo , Depresión/metabolismo , Depresión/genética , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Psicológico/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Derrota Social

RESUMEN

PURPOSE: Few longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence. METHODS: This study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models. RESULTS: Prenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression. CONCLUSIONS: Prenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy.

Asunto(s)

Trastornos de Ansiedad , Ansiedad , Proteína C-Reactiva , Depresión , Inflamación , Interleucina-6 , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico , Humanos , Femenino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Niño , Estrés Psicológico/sangre , Estrés Psicológico/metabolismo , Estrés Psicológico/inmunología , Inflamación/sangre , Adolescente , Interleucina-6/sangre , Estudios Longitudinales , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Depresión/sangre , Masculino , Trastornos de Ansiedad/sangre , Trastornos de Ansiedad/epidemiología , Adulto , Complicaciones del Embarazo/psicología , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/inmunología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Depression impairs not only central nervous system, but also peripheral systems of the host. Gut microbiota have been proved to be involved in the pathogenesis of depression. Xiaoyaosan (XYS) has a history of over a thousand years in China for treating depression, dramatically alleviating anxiety, cognitive disorders, and especially gastrointestinal dysfunctions. Yet, it still just scratches the surface of the anti-depression mechanisms of XYS. AIM OF THE STUDY: This study aims to elucidate the mechanism of actions of XYS from the perspective of "microbiota-gut-brain" axis. MATERIALS AND METHODS: We firstly evaluated the effects of XYS on the macroscopic behaviors of depressed rats that induced by chronic unpredictable mild stress (CUMS). Secondly, the effects of XYS on intestinal homeostasis of depressed rats were revealed by using dysbacteriosis model. Subsequently, the underlying mechanisms were demonstrated by 16S rRNA gene sequencing technology and molecular biology methods. Finally, correlation analysis and visualization of the anti-depression effects of XYS were performed from the "microbiota - gut - brain" perspective. RESULTS: Our data indicated that XYS ameliorated the depression-like symptoms of CUMS rats, partly depending on the presence of gut microbiota. Furthermore, we illustrated that XYS reversed CUMS-induced gut dysbiosis of depressed rats in terms of decreasing the Bacteroidetes/Firmicutes ratio and the abundances of Bacteroides, and Corynebacterium, while increasing the abundances of Lactobacillus and Adlercreutzia. The significant enrichment of Bacteroides and the level of lipopolysaccharides (LPS) suggested that depression damaged the immune responses and gut barrier. Mechanistically, XYS significantly down-regulated the expression levels of factors that involved in TLR4/NLRP3 signaling pathway in the colon and brain tissues of depressed rats. In addition, XYS significantly increased the levels of claudin 1 and ZO-1, showing that XYS positively maintained the integrity of gut and blood-brain barriers (BBB). CONCLUSION: Our study offers insights into the anti-depression effects of XYS through a lens of "microbiota-TLR4/NLRP3 signaling pathway-barriers", providing a foundation for enhancing clinical efficiency and enriching drug selection, and contributing to our understanding of the mechanisms of traditional Chinese medicines (TCMs) in treating depression.

Asunto(s)

Antidepresivos , Eje Cerebro-Intestino , Depresión , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Eje Cerebro-Intestino/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Estrés Psicológico/metabolismo , Disbiosis/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad

RESUMEN

Postpartum depression (PPD) affects 174 million women worldwide and is characterized by profound sadness, anxiety, irritability, and debilitating fatigue, which disrupt maternal caregiving and the mother-infant relationship. Limited pharmacological interventions are currently available. Our understanding of the neurobiological pathophysiology of PPD remains incomplete, potentially hindering the development of novel treatment strategies. Recent hypotheses suggest that PPD is driven by a complex interplay of hormonal changes, neurotransmitter imbalances, inflammation, genetic factors, psychosocial stressors, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This narrative review examines recent clinical studies on PPD within the past 15 years, emphasizing advancements in neuroimaging findings and blood biomarker detection. Additionally, we summarize recent laboratory work using animal models to mimic PPD, focusing on hormone withdrawal, HPA axis dysfunction, and perinatal stress theories. We also revisit neurobiological results from several brain regions associated with negative emotions, such as the amygdala, prefrontal cortex, hippocampus, and striatum. These insights aim to improve our understanding of PPD's neurobiological mechanisms, guiding future research for better early detection, prevention, and personalized treatment strategies for women affected by PPD and their families.

Asunto(s)

Biomarcadores , Depresión Posparto , Humanos , Depresión Posparto/metabolismo , Femenino , Animales , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Estrés Psicológico/metabolismo

RESUMEN

In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.

Asunto(s)

Alostasis , Astrocitos , Cognición , Homeostasis , Corteza Prefrontal , Estrés Psicológico , Astrocitos/metabolismo , Humanos , Corteza Prefrontal/metabolismo , Homeostasis/fisiología , Alostasis/fisiología , Cognición/fisiología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Animales , Metabolismo Energético/fisiología

RESUMEN

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset.

Asunto(s)

Colesterol , Depresión , Lóbulo Frontal , Estrés Psicológico , Animales , Ratones , Colesterol/metabolismo , Depresión/metabolismo , Depresión/etiología , Estrés Psicológico/metabolismo , Lóbulo Frontal/metabolismo , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Metabolismo de los Lípidos

RESUMEN

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review.

Asunto(s)

Exosomas , Trastornos Mentales , MicroARNs , Exosomas/metabolismo , Exosomas/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Animales , Estrés Psicológico/genética , Estrés Psicológico/metabolismo

RESUMEN

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1ß) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1ß levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.

Asunto(s)

Antidepresivos , Astrocitos , Depresión , Modelos Animales de Enfermedad , Hipocampo , Microglía , Enfermedades Neuroinflamatorias , Estrés Psicológico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fluoxetina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Fármacos Neuroprotectores/farmacología , Conducta Animal/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo

RESUMEN

OBJECTIVE: To observe the effects of electroacupuncture (EA) on fear extinction and sleep phase in single prolonged stress (SPS) mice, and explore its mechanism in view of the expression of relevant synaptic proteins. METHODS: Thirty-two C57BL/6J male mice were randomly divided into a control group, a model group, an EA group and a paroxetine (PRX) group, with 8 mice in each one. Modified SPS method was used to establish PTSD model in the model group, the EA group and the PRX group. Seven days after modeling completion, in the EA group, the intervention was delivered at "Baihui" (GV 20) and bilateral "Zusanli" (ST 36), with disperse-dense wave, 3 Hz/15 Hz in frequency and 1 mA in current intensity, for 30 min. In the PRX group, paroxetine solution (2.5 g/L) was administered intragastrically (10 mg/kg). The intervention was given once daily and for consecutive 10 days in the above two groups. The fear conditioning task and the elevated plus-maze test were adopted to evaluate the fear extinction and anxiety of the mice in each group. Using Medusa electroencephalogram (EEG) and electromyography (EMG) recording system from rats and mice, the sleep phase was determined in the mice. With Western blot method adopted, the protein expression of the postsynaptic density protein 95 (PSD95), activity-regulated cytoskeleton-associated protein (ARC), brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartic acid receptor 2A (GluN2A), N-methyl-D-aspartic acid receptor 2B (GluN2B) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor 1 (GluA1) in the hippocampus was detected in the mice. RESULTS: Compared with the control group, the freezing time for the fear re-exposure in 3 min to 15 min and the fear extinction in 0 min to 3 min were prolonged (P<0.05), the fear extinction index decreased (P<0.05), and the open arm time (OT) of the elevated plus-maze was shortened (P<0.05) in the model group. When compared with the model group, in the EA group and the PRX group, the freezing time for the fear re-exposure in 3 min to 6 min and 12 min to 15 min, as well as the fear extinction in 0 min to 3 min was shortened (P<0.05), the fear extinction index increased (P<0.05); the OT in elevated plus-maze was longer in the mice of the EA group (P<0.05). The period of wake (Wake) was prolonged (P<0.05), the non-rapid eye movement period (NREM) and the total sleep time (Sleep) were reduced in the model group (P<0.05) in comparison with the control group. Compared with the model group, the Wake was declined (P<0.05), and the NREM and Sleep increased in the EA group and the PRX group (P<0.05). When compared with the control group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus decreased (P<0.05), and that of GluN2B increased (P<0.05) in the model group. In the EA group and the PRX group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus was elevated (P<0.05), and that of GluN2B reduced (P<0.05) when compared with the model group. CONCLUSION: Electroacupuncture at "Baihui" (GV 29) and "Zusanli" (ST 36) can ameliorate anxiety-like behavior, fear extinction disorder and abnormal sleep phase in SPS mice, which may be related to the regulation of synaptic transmission and synaptic plasticity expression in the hippocampus.

Asunto(s)

Electroacupuntura , Miedo , Ratones Endogámicos C57BL , Sueño , Animales , Masculino , Ratones , Humanos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Hipocampo/metabolismo , Estrés Psicológico/terapia , Estrés Psicológico/metabolismo , Memoria , Puntos de Acupuntura , Homólogo 4 de la Proteína Discs Large/metabolismo

RESUMEN

Stress-related disorders are becoming increasingly common and are often associated with cognitive impairments. Within this context, the endocannabinoid (ECB) system, particularly the type 1 cannabinoid (CB1) receptor, seems to play a decisive role in restoring body homeostasis. There is consistent evidence in the literature that disrupted CB1-mediated neurotransmission can ultimately contribute to stress-related diseases. Therefore, the present study aimed to evaluate the participation of CB1 receptors in the integrity of stress-induced peripheral and behavioral responses. For this purpose, male adult Wistar rats underwent physical restraint (1 h/day, for 7 days), followed by a single administration of rimonabant (CB1 receptor antagonist, 3 mg/Kg, intraperitonial) at the end of stress protocol. Animals were then subjected to evaluation of neuroendocrine responses, behavioral tests and quantification of Iba-1 (microglial) immunoreactivity in the parvocellular subdivisions of the paraventricular nucleus of the hypothalamus (PVN). No effects of restraint stress or rimonabant administration were detected on body mass variation. However, stress significantly increased adrenal relative mass and corticosterone secretion, and reduced thymus relative size. The stress effects on adrenal size and corticosterone plasma levels were absent in rimonabant-treated rats, but the thymus size was further reduced in the restraint-rimonabant group. Restraint stress also induced anhedonia, a depression-like behavior, and reduced object recognition index, indicating memory recovery impairment. Treatment with the CB1 antagonist significantly reversed stress-induced anhedonia and memory deficit. In the PVN, restraint stress reduced the number of Iba-1 positive cells in the medial parvocellular region of vehicle- but not rimonabant-treated animals. Taken together, these results indicate that the acute inhibition of the CB1-mediated endogenous pathway restores stress-induced depression-like behaviors and memory loss, suggesting a role for endocannabinoids in the neuro-immune-endocrine interplay at both peripheral and hypothalamic levels.

Asunto(s)

Anhedonia , Antagonistas de Receptores de Cannabinoides , Corticosterona , Trastornos de la Memoria , Ratas Wistar , Receptor Cannabinoide CB1 , Restricción Física , Rimonabant , Estrés Psicológico , Animales , Rimonabant/farmacología , Masculino , Estrés Psicológico/metabolismo , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Ratas , Trastornos de la Memoria/tratamiento farmacológico , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Corticosterona/sangre , Antagonistas de Receptores de Cannabinoides/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología

RESUMEN

Lactate is a critical metabolite during the body's adaption to exercise training, which effectively relieves anxiety-like disorders. The biological mechanism of lactate in the exercise-mediated anxiolytic effect has, however, not been comprehensively investigated. Here, we report that exercise-induced lactate markedly potentiates the lactylation of multiple synaptic proteins, among which synaptosome-associated protein 91 (SNAP91) is the critical molecule for synaptic functions. Both anatomical evidence and in vivo recording data showed that the lactylation of SNAP91 confers resilience against chronic restraint stress (CRS) via potentiating synaptic structural formation and neuronal activity in the medial prefrontal cortex (mPFC). More interestingly, exercise-potentiated lactylation of SNAP91 is necessary for the prevention of anxiety-like behaviors in CRS mice. These results collectively suggest a previously unrecognized non-histone lactylation in the brain for modulating mental functions and provide evidence for the brain's metabolic adaption during exercise paradigms.

Asunto(s)

Ratones Endogámicos C57BL , Condicionamiento Físico Animal , Estrés Psicológico , Animales , Ratones , Masculino , Estrés Psicológico/metabolismo , Corteza Prefrontal/metabolismo , Ansiedad/metabolismo , Sinapsis/metabolismo , Ácido Láctico/metabolismo

RESUMEN

Posttraumatic stress disorder (PTSD) is a pervasive issue within military populations, with approximately 29 % of post-9/11 service members experience PTSD at some point in their lifetime. One potentially important factor in PTSD development and treatment response is dysregulation of the stress response system stemming from exposure to multiple traumas and sustained operational stress associated with military training and deployment. In particular, the end-product of the hypothalamic-pituitary-adrenal (HPA) axis, cortisol, is of particular interest to researchers examining physiological stress response in the context of mental health. Research exploring cortisol has been ongoing for decades, both to further understand its pathways and mechanisms, and to develop potential novel PTSD treatments. This paper provides a narrative review of some of the published literature examining cortisol's role in PTSD as a potential factor in development, maintenance, and treatment augmentation, with emphasis on military populations. The results of this review highlight the importance of exploring alterations to the stress response system, and cortisol in particular, for the evaluation and treatment of PTSD in the military, the need for more comprehensive work towards understanding development of these alterations through military training and service, and its impact on long-term PTSD outcomes.

Asunto(s)

Hidrocortisona , Sistema Hipotálamo-Hipofisario , Personal Militar , Sistema Hipófiso-Suprarrenal , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/terapia , Trastornos por Estrés Postraumático/fisiopatología , Hidrocortisona/metabolismo , Personal Militar/psicología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Psicológico/metabolismo