Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals\' depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS, which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving unaltered improvement in the FST and TST. Mechanically, we found that ISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicating decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. The present findings further expand the potential role of ER stress in depression and provide important details for a therapeutic path forward for PERK inhibitors in mood disorders.

Insomnia is one of the most common accompanying symptoms of depression, with both sharing highly overlapping molecular pathways. The same pathological changes can trigger comorbidity of insomnia and depression, which further forms a vicious cycle with the involvement of more mechanisms and disease progression. Thus, understanding the potential interaction mechanisms between insomnia and depression is critical for clinical diagnosis and treatment. Comorbidity genetic factors, the hypothalamic-pituitary-adrenal axis, along with circadian rhythms of cortisol and the brain reward mechanism, are important ways in contributing to the comorbidity occurrence and development. However, owing to lack of pertinent investigational data, intricate molecular mechanisms necessitate further elaboration. Synaptic plasticity is a solid foundation for neural homeostasis. Pathological alterations of depression and insomnia may perturb the production and release of neurotransmitter, dendritic spine remodeling and elimination, which converges and reflects in aberrant synaptic dynamics. Hence, the introduction of synaptic plasticity research route and the construction of a comprehensive model of depression and insomnia comorbidity can provide new ideas for clinical depression insomnia comorbidity treatment plans.
失眠是抑郁症最常见的伴随症状之一，二者具有高度重合的分子机制。通过相似的病理学改变可以引发失眠和抑郁症的共病，随着病程进展可能形成恶性循环。因此，了解失眠、抑郁症二者潜在交互机制对于临床诊疗十分重要。共病基因、下丘脑-垂体-肾上腺轴与皮质醇昼夜节律、免疫炎症、大脑奖赏机制是参与共病发生、发展的重要途径，但由于缺乏相关研究数据，详细的分子机制有待进一步阐明。突触可塑性是神经功能稳定的坚实基础，抑郁症和失眠的病理改变都可能影响神经递质的产生和释放、树突棘剪切和消除等过程，表现为异常的突触活动。探究突触可塑性研究路径并构建抑郁症和失眠共病发生及影响的综合模型，可为临床抑郁症和失眠共病的治疗方案提供新思路。.

Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary-adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.

To verify the hypothesis that electroacupuncture inhibits the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis regulating the expression of glial fibrillary acidic protein (GFAP) in the hippocampus of acute myocardial ischemia (AMI) rats.
Sixty-six healthy male Sprague-Dawley rats were randomly divided into five groups: Sham, AMI (Model), electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment (EA), non-acupoint electroacupuncture (Control), and Model + corticosterone (Model + CORT). AMI was induced occlusion of the left anterior descending coronary artery, followed by 3 d of electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment. In the Control group, electroacupuncture was applied at points lying 5 and 10 mm from the base of the tail. The AMI + CORT group was injected with CORT (20 mg/kg) in saline. Hemorheology, electrocardiography (ECG), hematoxylin and eosin staining, and expression of glycogen phosphorylase BB (GPBB) and heart-type fatty acid-binding protein (H-FABP) were used to assess cardiac function. The effects of adrenocorticotropic hormone (ACTH) and CORT were evaluated by enzyme-linked immunosorbent assay. Protein expression in the Sham and Model groups were screened by tandem mass tag-based quantitative proteomics analysis. Protein expression was evaluated by Western blotting (vimentin and GFAP) and immunofluorescence staining (GFAP).
Compared with the Sham group, the hemorheology indicators, heart rate, ECG-ST segment elevation, and GPBB and H-FABP levels were higher in Model rats. The EA group showed reductions in these indicators compared with the Model group. Similarly, in Model rats, the expression of ACTH and CORT were significantly increased compared with the Sham group. The EA group also showed reduced expression of ACTH and CORT. Importantly, proteomics analysis showed that vimentin was differentially expressed in Model rats. Compared with the Sham group, vimentin and GFAP expression in the hippocampus was increased in the Model group but decreased in the AMI + EA group. Additionally, intraperitoneal injection of CORT aggravated the expression of GPBB, H-FABP and GFAP.
Our results suggested that electroacupuncture may protect against cardiac injury induced by AMI through regulation of HPA axis hyperactivity, and that hippocampal GFAP may play an important role in the regulation.

Existing literature provides extended evidence of the close relationship between stress dysregulation, environmental insults, and psychosis onset. Early stress can sensitize genetically vulnerable individuals to future stress, modifying their risk for developing psychotic phenomena. Neurobiological substrate of the aberrant stress response to hypothalamic-pituitary-adrenal axis dysregulation, disrupted inflammation processes, oxidative stress increase, gut dysbiosis, and altered brain signaling, provides mechanistic links between environmental risk factors and the development of psychotic symptoms. Early-life and later-life exposures may act directly, accumulatively, and repeatedly during critical neurodevelopmental time windows. Environmental hazards, such as pre- and perinatal complications, traumatic experiences, psychosocial stressors, and cannabis use might negatively intervene with brain developmental trajectories and disturb the balance of important stress systems, which act together with recent life events to push the individual over the threshold for the manifestation of psychosis. The current review presents the dynamic and complex relationship between stress, environment, and psychosis onset, attempting to provide an insight into potentially modifiable factors, enhancing resilience and possibly influencing individual psychosis liability.

UNASSIGNED: Cortisol, a hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, has been linked to attention deficit hyperactivity disorder (ADHD). The nature of the relationship between cortisol and ADHD, and whether it is causal or explained by reverse causality, remains a matter of debate.
UNASSIGNED: This study aims to evaluate the bidirectional causal relationship between morning plasma cortisol levels and ADHD.
UNASSIGNED: This study used a bidirectional 2-sample Mendelian randomization (MR) design to analyze the association between morning plasma cortisol levels and ADHD using genetic information from the authoritative Psychiatric Genomics Collaboration (PGC) database (n = 55,347) and the ADHD Working Group of the CORtisol NETwork (CORNET) Consortium (n = 12,597). MR analyses were employed: inverse variance weighting (IVW), MR-Egger regression, and weighted medians. OR values and 95% CI were used to evaluate whether there was a causal association between morning plasma cortisol levels on ADHD and ADHD on morning plasma cortisol levels. The Egger-intercept method was employed to test for level pleiotropy. Sensitivity analysis was performed using the \"leave-one-out\" method, MR pleiotropy residual sum, and MR pleiotropy residual sum and outlier (MR-PRESSO).
UNASSIGNED: Findings from bidirectional MR demonstrated that lower morning plasma cortisol levels were associated with ADHD (ADHD-cortisol OR = 0.857; 95% CI, 0.755-0.974; P = 0.018), suggesting there is a reverse causal relationship between cortisol and ADHD. However, morning plasma cortisol levels were not found to have a causal effect on the risk of ADHD (OR = 1.006; 95% CI, 0.909-1.113; P = 0.907), despite the lack of genetic evidence. The MR-Egger method revealed intercepts close to zero, indicating that the selected instrumental variables had no horizontal multiplicity. The \"leave-one-out\" sensitivity analysis revealed stable results, with no instrumental variables significantly affecting the results. Heterogeneity tests were insignificant, and MR-PRESSO did not detect any significant outliers. The selected single-nucleotide polymorphisms (SNPs) F were all >10, indicating no weak instrumental variables. Thus, the overall MR analysis results were reliable.
UNASSIGNED: The study findings suggest a reverse causal relationship between morning plasma cortisol levels and ADHD, with low cortisol levels associated with ADHD. No genetic evidence was found to support a causal relationship between morning plasma cortisol levels and the risk of ADHD. These results suggest that ADHD may lead to a significant reduction in morning plasma cortisol secretion.

Post-stroke depression (PSD) is the most frequent and important neuropsychiatric consequence of stroke. It is strongly associated with exacerbated deterioration of functional recovery, physical and cognitive recoveries, and quality of life. However, its mechanism is remarkably complicated, including the neurotransmitters hypothesis (which consists of a monoaminergic hypothesis and glutamate-mediated excitotoxicity hypothesis), inflammation hypothesis, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotrophic hypothesis and neuroplasticity. So far, the underlying pathogenesis of PSD has not been clearly defined yet. At present, selective serotonin reuptake inhibitors (SSRIs) have been used as the first-line drugs to treat patients with PSD. Additionally, more than SSRIs, a majority of the current antidepressants complied with multiple side effects, which limits their clinical application. Currently, a wide variety of studies revealed the therapeutic potential of natural products in the management of several diseases, especially PSD, with minor side effects. Accordingly, in our present review, we aim to summarize the therapeutic targets of these compounds and their potential role in-clinic therapy for patients with PSD.

Mild traumatic brain injury (mTBI) is the most common form of TBI, with more than 2.5 million TBI cases in the United States annually. Identification of easily obtainable biomarkers that track strongly with mTBI symptoms may improve our understanding of biological factors that contribute to mTBI symptom profiles and long-term outcomes. Notably, some individuals with mTBI exhibit circadian disruptions and elevated stress sensitivity, which in other clinical groups often correlate with disrupted secretion of cortisol, a glucocorticoid hormone that coordinates circadian and stress physiology. Here, we examined whether cortisol profiles could serve as a biomarker to complement the assessment of neurobehavioral sequelae after mTBI. We partnered with our on-campus health clinic to recruit college students seeking medical care after mTBI (n = 46) and compared this population to a well-matched non-injured student control group (n = 44). We collected data at an initial visit (shortly after injury in mTBI subjects) and one week later. At each visit, we evaluated neurobehavioral function using the Automated Neuropsychological Assessment Metric (ANAM). The subjects also provided cortisol samples through at-home saliva collection. We observed strong coherence between ANAM subjective and objective measures, indicating significant multi-dimensional impairment in subjects with mTBI. Further, female mTBI subjects exhibited diminished neurobehavioral function compared with males. Regardless of sex, decreased amplitude of diurnal cortisol and a blunted cortisol awakening response were associated with mTBI symptom severity and neurobehavioral impairment. Taken together, these findings suggest that salivary cortisol profiles may be a sensitive biomarker for studying underlying biological factors that impact mTBI symptoms and outcomes.

Post-ischemic peripheral immunosuppression increases vulnerability to infection which is a common complication and worsens outcome in ischemic stroke patients. Hypothalamic-pituitary-adrenal (HPA) axis plays a key role in post-ischemic immunosuppression. Astragaloside IV (ASIV), isolated from Astragalus membranaceus, possesses immunomodulatory and neuroprotective effects against cerebral ischemic injury. This study investigated the effect of ASIV on cerebral ischemia-induced peripheral immunosuppression and the underlying mechanism in a mouse model of middle cerebral artery occlusion (MCAO). Our results showed that ASIV significantly prevented the atrophy of spleen and the reduction of splenic cell count. Meanwhile, ASIV preserved cell numbers of splenic NK, T, and B cells in the spleen. ASIV also suppressed apoptosis of splenic cells and preserved their proliferation ability. In addition, ASIV robustly reduced the mRNA expression of TNF-α, IL-1β, IL-6 and CRH in the hypothalamus, as well as the enlargement of adrenal gland and the increase of corticosterone in blood, indicating the inhibition of HPA axis by ASIV. Furthermore, ASIV did not enhance the effect of HPA inhibition on reducing splenic atrophy and preserving splenic NK, T, and B cell numbers in MCAO mice. Of note, ASIV did not attenuate splenic cell apoptosis induced by prednisolone, suggesting that ASIV may ameliorate splenic apoptosis through reducing peripheral glucocorticoid level. Our findings demonstrate that ASIV ameliorates post-ischemic peripheral immunosuppression through inhibiting the activation of HPA axis and targeting HPA activation to ameliorate peripheral immunosuppression may be a promising strategy to improve clinical outcomes of ischemic stroke.

Pathologic stress (distress) disturbs immune, cardiovascular, metabolic, and behavioral homeostasis. Individuals living with HIV and those at risk are vulnerable to stress disorders. Corticotropin-releasing hormone (CRH) is critical in neuroendocrine immune regulation. CRH, a neuropeptide, is distributed in the central and peripheral nervous systems and acts principally on CRH receptor type 1 (CRHR1). CRH in the brain modulates neuropsychiatric disorders. CRH and stress modulation of immunity is two-pronged; there is a direct action on hypothalamic-pituitary-adrenal secretion of glucocorticoids and through immune organ sympathetic innervation. CRH is a central and systemic proinflammatory cytokine. Glucocorticoids and their receptors have gene regulatory actions on viral replication and cause central and systemic immune suppression. CRH and stress activation contributes to central nervous system (CNS) viral entry important in HIV-associated neurocognitive disorders and HIV-associated dementia. CNS CRH overproduction short-circuits reward, executive, and emotional control, leading to addiction, cognitive impairment, and psychiatric comorbidity. CRHR1 is an important therapeutic target for medication development. CRHR1 antagonist clinical trials have focused on psychiatric disorders with little attention paid to neuroendocrine immune disorders. Studies of those with HIV and those at risk show that concurrent stress-related disorders contribute to higher morbidity and mortality; stress-related conditions, addiction, immune dysfunction, and comorbid psychiatric illness all increase HIV transmission. Neuropsychiatric disease, chronic inflammation, and substance abuse are endemic, and chronic distress is a pathologic factor. It is being understood that stress and CRH are fundamental to neuroendocrine immunity; therapeutic interventions with existing and novel agents hold promise for restoring homeostasis, reducing morbidity and mortality for those with HIV and possibly reducing future disease transmission.