CRH

Beyond the HPA axis: Synaptic circuits of PVNCRH neurons in stress-related psychiatric disorders.

Jiayuan Zheng, Na Yue, Zhanzhuang Tian +2 more

Chronic psychosocial stress is a major risk factor for anxiety, depression and related disorders, yet a hypothalamic-pituitary-adrenal (HPA) axis centric framework alone is insufficient to explain stress-induced vulnerability and phenotypic heterogeneity. Paraventricular nucleus corticotropin-releasing hormone (PVNCRH) neurons are classically regarded as the neuroendocrine entry point for driving glucocorticoid secretion. However, accumulating evidence indicates that, beyond this endocrine role, they also use fast transmitters and CRH co-transmission to form functional projections to diverse brain regions and pre-sympathetic circuits, thereby regulating stress dimensions that extend beyond HPA axis output, including defensive behaviors, reward and motivation, arousal-sleep regulation, autonomic output and glucose homeostasis. In this review, we integrate anatomical, electrophysiological, and behavioral evidence across representative PVNCRH pathways, compare their stress-related functional specialization and shared mechanisms across synaptic and endocrine timescales, and discuss translational implications for circuit-informed pharmacological and neuromodulatory strategies in stress-related psychiatric disorders.

Norepinephrine neurons in the locus coeruleus and the nucleus of the solitary tract drive different stress-related behavioral outputs in mice.

Raoni Conceição Dos-Santos, Maria W Najjar, Carly Friedman +5 more

Norepinephrine (NE) is one of the main neuromodulators that regulate the stress response. NE-expressing neurons in the locus coeruleus (LC) and the nucleus of the solitary tract (NTS) project to the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) to regulate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. NE neurons also project to other brain regions to regulate stress outputs, including throughout the limbic system and the medial prefrontal cortex. The NE circuits, therefore, are well-positioned to regulate an integrated stress response that coordinates the activation of the HPA axis with different behavioral responses appropriate to distinct stressors. Here, we show that chemogenetic activation of LC-NE neurons induces affective stress behaviors while activation of NTS-NE neurons stimulates sickness-like behaviors. Selective activation of NE neurons in the NTS caused an increase in immobility, a decrease in mechanical nociception threshold, and reduced exploratory, grooming, and feeding behaviors. Activation of LC-NE neurons, on the other hand, caused an increase in grooming and a decrease in exploratory behaviors, but no change in immobility. Stimulation of either the NTS-NE or LC-NE neurons elicited an increase in activation of the HPA axis. Taken together, our results show that the activation of NTS-NE and LC-NE neurons stimulates both redundant and distinct aspects of the stress response, perhaps via stimulation of both discreet and overlapping populations of PVN neurons.

TRH can stimulate the release of two POMC-derived pituitary hormones, ACTH and MSH, in medaka.

Mana Yamakawa, Deodatta Shyam Gajbhiye, Matan Golan +1 more

Anterior pituitary hormone secretion is generally considered to be under the strong regulation of hypothalamic neuropeptides. In mammals, adrenocorticotropic hormone (ACTH), which plays a crucial role in the stress response, is secreted from corticotropes and is regulated primarily by corticotropin-releasing hormone (CRH). In teleosts, although the pharmacological effects of hypothalamic factors have been demonstrated, their relative importance in regulating ACTH release remains controversial. One reason for this is the lack of methods for evaluating ACTH release at cellular resolution. Using medaka as a model organism, we systematically examined the direct effects of hypothalamic peptides on ACTH cells by combining cell type-specific transcriptomics with Ca²⁺ imaging. We show that thyrotropin-releasing hormone (TRH) robustly elevates intracellular Ca²⁺ ([Ca²⁺]ᵢ) levels in ACTH cells, surpassing the responses elicited by CRH or arginine vasotocin (AVT). TRH also strongly activates MSH cells, the other POMC-derived pituitary cell population, while CRH induces only a modest response. Furthermore, in situ hybridization chain reaction analyses revealed that TRH receptor (trhra) is expressed in MSH cells, supporting their direct responsiveness to TRH signaling, whereas TRH receptor expression in ACTH cells was below thsse detection limit, leaving open the possibility that their activation is mediated by indirect or low-abundance receptor pathways. These findings suggest the existence of a novel TRH-driven regulatory pathway orchestrating both the teleost stress axis and pigmentation axis.

The acid-sensing ion channel 1a modulates anxiety- and depression-related behaviors via its influencing on the activity of corticotropin-releasing hormone-expressing neurons in the hypothalamic paraventricular nucleus in male mice.

Jiayin Yue, Qilun Zhang, Mengyuan Wang +9 more

A variety of studies show the involvement of acid-sensing ion channel 1a (ASIC1a) in the modulation of stress, however, the precise underlying mechanisms remain unclear. In this study, we provided evidence that ASIC1a, the Ca2+-permeable cationic ion channel, was co-expressed with corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN). Downregulation of ASIC1a in the PVN CRH neuron decreased the hypothalamic-pituitary-adrenal (HPA) axis activity, which further ameliorated anxiety- and depression-related behaviors by reducing CRH neuron activity. In vitro, activation of ASIC1a elevated the intracellular Ca2+ concentration and promoted the expression of CRH by activating Ca2+/CaMKII/c-Fos signaling pathways. This study reveals a novel mechanism of the modulation of negative mood by ASIC1a and suggests a potential novel therapeutic target for stress-related diseases.

Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.

Meijia Li, Ying Wang, Zixia Liang +8 more

Aim: This study investigated the synergistic therapeutic effects and underlying mechanisms of tetrahydroberberine (THB) combined with protopanaxadiol (PPD) on p-chlorophenylalanine (PCPA)-induced insomnia in rats. Methods: Rats were randomly divided into normal, model, diazepam, THB monotherapy, PPD monotherapy, and THB + PPD combination groups. Evaluations included the pentobarbital sleep test, HE staining, ELISA, 16S rRNA sequencing, metabolomics, and Western blot. Results: Results demonstrated that the THB + PPD combination exhibited significant synergistic effects compared with monotherapies: the combination shortened sleep latency by 56.2% (vs. 44.2% for THB alone and 20.7% for PPD alone) and prolonged sleep duration by 112.8% (vs. 70.2% for THB and 59.6% for PPD) relative to the model group, while effectively restoring body weight gain. Histologically, combined treatment significantly alleviated hippocampal neuronal damage and increased the number of intact neurons in the dentate gyrus. Molecularly, it upregulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) levels, restored neurotransmitter balance (serotonin, dopamine, and glutamate), suppressed overactivation of the hypothalamic-pituitary-adrenal (HPA) axis (reducing corticotropin-releasing hormone and corticosterone), and decreased pro-inflammatory cytokine expression. Gut microbiota analysis revealed that the combination restored microbial homeostasis (increasing beneficial bacteria such as *Lactobacillus*) and modulated the glycine-serine-threonine metabolic pathway. Mechanistically, THB + PPD synergistically activated the PI3K/AKT neurotrophic pathway (p-PI3K and p-AKT expression increased by 1.9-fold and 2.5-fold, respectively, vs. model), inhibited the AGE/RAGE pro-inflammatory axis (RAGE expression decreased by 31.8%), and enhanced blood-brain barrier integrity by upregulating tight junction proteins (ZO-1, Occludin). Conclusions: THB combined with PPD exerts synergistic anti-insomnia effects through multi-level regulation of the microbiota-gut-brain axis, neurochemical balance, and key signaling pathways, providing a promising foundation for developing safe natural product-based combination therapies.

The creative mind in the shadow of depressive symptoms: Epigenetic variation in HPA axis genes is associated with the link between depressive symptoms and creative personality.

Daniel Feinmesser, Stav Shohat, Roi Gerda +6 more

This cross-sectional study investigated the relationship between depressive symptoms and creative personality through the lens of epigenetic modifications within Hypothalamic-Pituitary-Adrenal (HPA) axis genes. By analyzing DNA methylation patterns in key HPA axis genes-including corticotropin-releasing hormone (CRH), its receptor (CRHR1), CRH binding protein (CRHBP), melanocortin 2 receptor (MC2R), steroidogenic acute regulatory protein (STAR), FK506 binding protein 5 (FKBP5), and the glucocorticoid receptor (NR3C1), we examined how methylation variation was associated with the depressive symptoms-creativity link in 371 participants (190 women, 181 men). Our findings revealed that among individuals with methylation patterns putatively associated with reduced HPA axis activity, higher depressive symptoms were positively associated with creative personality, suggesting that in this biological context, introspective aspects of depressive symptoms may coincide with creative propensities. Conversely, among individuals with methylation patterns putatively associated with heightened HPA axis activity, higher depressive symptoms were negatively associated with creative personality. These results suggest that the association between depressive symptoms and creativity is not uniform but differs based on methylation variation in genes involved in stress response regulation. The findings highlight the potential role of HPA axis-related biological factors in understanding individual differences in the depression-creativity relationship, though the cross-sectional design precludes causal inference.

Exploring the behavioural and biochemical effects of cordycepin in PTSD-like behaviour using an early life stress mouse model.

Subhranil Mukherjee, Anusha Govindula, Madhavan Nampoothiri +2 more

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered and precipitated by exposure to severe, life-threatening trauma. Emerging evidence implicates the involvement of neuroinflammatory processes in the exacerbation and progression of PTSD. Cordycepin (COR), a natural compound, is reported to alleviate neuroinflammation via downregulating NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes. The present study aimed to extrapolate the neuroprotective mechanism of COR against PTSD in mice. Swiss albino mice experienced PTSD-like symptoms due to sequential stressors in first 30 days at critical intervals. Mice exhibiting PTSD-like behaviour were treated with fluoxetine (FLU, 10 mg/kg), an antidepressant drug, and COR (10 and 50 mg/kg). Four behavioural tests were performed in mice to assess the four symptom clusters similar to human PTSD. At the end of the study, immunoassays were performed for serum corticotropin releasing hormone (CRH) and corticosterone (CORT) levels as well as brain neuroinflammation markers including interleukin-6 (IL-6), tumour necrosis factor- α (TNF-α), interleukin-1β (IL-1β) and NLRP3. Behavioural assays demonstrated PTSD-like clusters in mice as observed in clinics. These cluster were associated with elevated levels of brain cytokines IL-6, TNF-α, IL-1β and NLRP3. Dysregulation of hypothalamus-pituitary-adrenal (HPA) axis was evident from significant decline in CORT levels. FLU significantly attenuated the four clusters of PTSD with negative effect on brain cytokines. COR demonstrated a dose-dependent response with 50 mg/kg showing consistent improvement in both behavioural and biochemical parameters. Overall, COR exhibited promising activity in this model and may serve as a potential natural therapeutic strategy to investigate for the management of PTSD in clinics.

[Effect of different frequencies electroacupuncture at "Zusanli"(ST36) on visceral sensitivity and adrenocorticotropin releasing factor expression in IBS mice].

Rong-Lan Xiang, Fang-Yuan Liang, Su-Zhen Liu +4 more

To observe the effect of different stimulation frequencies of electroacupuncture (EA) of "Zusanli"(ST36) on the general state, visceral sensitivity, anxiety and depression, adrenocorticotropin releasing factor (CRF), adrenocorticotropin releasing factor receptor 1 (CRFR1), CRFR2 and mast cells in mice with irritable bowel syndrome (IBS), so as to explore its mechanism underlying the improvement of IBS.

Region and Cell-Selective Induction of Zbtb16/Plzf by Multiple Stressors in the Adult Murine Hypothalamus.

Mina Roueinfar, Pardis Mohammadzadeh, Luke A Schwerdtfeger +2 more

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine system that regulates responses related to feeding, reproduction, and aggression, among other homeostatic functions. Stressors significantly impact gene expression along the HPA axis and in hypothalamic nuclei that drive it, including the paraventricular nucleus (PVN). To identify genetic regulators of stress responses in the PVN, adult mice underwent 2 h of multi-modal stress before gene expression profiles were analyzed using bulk RNA sequencing. A transcription factor zinc finger and BTB domain containing 16 (Zbtb16), also known as PLZF, was identified as a stress responsive, glucocorticoid receptor (GR) target in the PVN. Zbtb16 mRNA expression was increased by two-fold in male and female mice within 2 h of restraint stress or injection of a synthetic glucocorticoid, dexamethasone (DEX). Immunohistochemistry (IHC) confirmed Zbtb16 protein expression and localization in the PVN following 20 min of restraint stress and 4 h of recovery. Cellular analyses revealed that Zbtb16 was highly expressed in CRH neurons in the PVN, neurons routinely activated post-stress as indicated by colocalization with c-FOS. Adult mice were also exposed to an immune stress by injection of tumor necrosis factor alpha (TNFα) to assess Zbtb16 regulation. Expanded analyses indicated that the cell specificity of Zbtb16 expression was region-specific, colocalizing with CRH neurons in the mid-PVN but more in astrocytes surrounding the PVN. These findings identify Zbtb16 as a glucocorticoid- and cytokine-inducible transcriptional regulator with region- and cell type-specific roles in PVN stress circuitry.

Aberrant hypothalamic neuronal activity blunts glucocorticoid diurnal rhythms in murine breast cancer.

Adrian M Gomez, Yue Wu, Chao Zhang +6 more

Breast cancer patients often exhibit disrupted diurnal rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality; however, the exact cause of this phenomenon remains unclear. Here, we demonstrate that breast tumor-bearing mice exhibit blunted GC rhythms and a loss of diurnal rhythms in the activity of paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (PVNCRH). This change in neuronal activity is mediated by disinhibition from upstream GABAergic neurons. Using chemogenetics to stimulate PVNCRH neurons at different times of day, we show that stimulation just before the light-to-dark transition restores normal GC rhythms, reduces tumor progression, and increases intra-tumor effector T cells (CD8+). Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control the output of the hypothalamic-pituitary-adrenal (HPA) axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression via enhancing anti-tumor immunity.

Tianwangbuxiandan decoction alleviates constipation and associated emotional disorders via regulating the brain-gut axis: Involving MAPK/ERK/JNK signaling pathways.

Shaoliang Li, Pengning Wu, Yue Wang +3 more

Tianwang Buxin Dan (TWBXD) is a classical Chinese formula traditionally prescribed to "nourish Yin, calm the mind and relieve bowel stagnation" in disorders characterized by heart-kidney disharmony, insomnia, anxiety, and constipation. However, the mechanistic basis associating its gut-regulating and emotion-modulating effects along the gut-brain axis remains unclear.

Escitalopram Oxalate Improved Insomnia by Targeting SLC6A4 to Regulate the Hypothalamic-Pituitary-Adrenal Axis.

Xin Gu, Jing An, Mingxue Zhang +3 more

Escitalopram oxalate (ESC) was extensively reported to improve insomnia in patients with depression/anxiety. The serotonin transporter gene (SLC6A4) was involved in regulating insomnia. However, it is still unclear whether ESC improves insomnia by regulating SLC6A4 expression. Therefore, this study aimed to investigate whether ESC improves insomnia by regulating SLC6A4 based on clinical and animal experiments.

Brain Kappa Opioid Receptor Availability Across Stress and Social Buffering Conditions: A Positron Emission Tomography Study in Coppery Titi Monkeys.

Claudia Manca, John P Paulus, Alita J D Almeida +6 more

Social connectedness strongly influences health and longevity, and adult pair bonds provide psychological benefits distinct from other social relationships. Oxytocin (OT), corticotropin-releasing hormone (CRH), and opioids, play an important role in the formation and maintenance of pair bonds. Evidence suggests that OT modulates the stress response via the hypothalamic-pituitary-adrenal (HPA) axis, while the kappa (κ) opioid system interacts with and may modulate OT signaling in contexts of stress and separation. In this study 20 coppery titi monkeys were exposed to a physical stressor under three social conditions: baseline (no stressor, partner present), stress (stressor, no partner present) and buffering (stressor, partner present). We predicted stress-induced dynorphin release would reduce κ-opioid receptor availability measured via [¹¹C]GR103545 Positron Emission Tomography (PET) and lower cerebrospinal fluid (CSF) OT, whereas partner presence would mitigate dynorphin release and increase CSF OT, with reduced dynorphin inferred from higher κ-opioid receptor radioligand binding. Our results show condition-dependent differences in [¹¹C]GR103545 binding in several brain regions, including the amygdala and hippocampus, with altered binding in both the stress and social buffering conditions. Cortisol levels were elevated in the stress condition compared to baseline. Females exhibited lower CSF OT levels during stress than at baseline, whereas plasma OT levels did not differ across conditions or between sexes. Spearman correlations revealed no significant associations between plasma and CSF OT. Together, these findings highlight the complex interaction between κ-opioid signaling, OT, and HPA axis activity in the context of social relationships and highlight neuroendocrine mechanisms underlying stress regulation in pair-bonded species.

Sexual aggression and prenatal stress lead to poor maternal care and aggressive behaviour in male Wistar rat offspring.

Elvis Mbiydzenyuy Ngala, Sian Megan Joanna Hemmings, Jacqueline Samantha Womersley +2 more

Sexual aggression and prenatal stress can exert profound intergenerational effects, disrupting maternal care and enhancing aggression in offspring via alterations to the hypothalamic-pituitary-adrenal (HPA) axis and related neurochemical systems. This study in Wistar rats examined the combined impact of male sexual aggression and prenatal stress on maternal caregiving behaviours, and the neurobiological mechanisms underlying sexually aggressive behaviours in male offspring (F1). Following exposure to sexual aggression, females were mated with group-housed or isolated males and assigned to prenatal stress or control conditions. Maternal care was quantified from postnatal day (PND) 2-8, while F1 male aggression was assessed in resident-intruder and sexual aggression paradigms. Neurochemical analyses measured arginine vasopressin (AVP), corticotropin-releasing hormone (CRH), serotonin, oxytocin, corticosterone, and neurokinin B in the prefrontal cortex, hippocampus, amygdala, and hypothalamus, alongside gene expression profiling. Prenatal stress significantly reduced maternal care-particularly nursing and licking-across PND 2-8, with deficits most pronounced when paired with paternal isolation. High-quality maternal care was associated with reduced F1 aggression, longer attack latencies, and lower CRHR1 expression in the hippocampus, suggesting a neuroprotective role. Prenatal stress increased CRHR1 expression in the amygdala and amplified aggression, anxiety-like behaviours, and reduced sociability. Serotonin correlated negatively with aggression and positively with non-social exploration, while corticosterone correlated positively with aggression. Oxytocin was linked to social behaviours, and CRH to exploratory behaviours, indicating distinct neuromodulatory pathways. These findings highlight the interactive effects of maternal and paternal environments on intergenerational behavioural programming and identify key neurochemical targets for mitigating stress-related aggression.

Peripartum Depression as a Heart-Brain-Endocrine-Immune Syndrome: Neuroendocrine, Cardiovascular, and Inflammatory Pathways Underlying Maternal Vulnerability.

Giuseppe Marano, Marianna Mazza

Peripartum depression (PPD) represents one of the most prevalent and disabling psychiatric conditions among women, yet its underlying biology remains poorly integrated across medical disciplines. Emerging evidence highlights PPD as a prototypical disorder of the heart-brain axis, where neuroendocrine changes, immune activation, and cardiovascular dysregulation converge to shape maternal vulnerability. During pregnancy and the postpartum period, abrupt fluctuations in estrogen, progesterone (P4), and placental corticotropin-releasing hormone (CRH) interact with a sensitized hypothalamic-pituitary-adrenal (HPA) axis, altering neural circuits involved in mood regulation, stress reactivity, and maternal behavior. Parallel cardiovascular adaptations, including endothelial dysfunction, altered blood pressure variability, and reduced heart rate variability (HRV), suggest a profound perturbation of autonomic balance with potential long-term implications for maternal cardiovascular health. Neuroinflammation, microglial activation, and systemic cytokine release further mediate the bidirectional communication between the heart and the brain, linking emotional dysregulation with vascular and autonomic instability. Evidence also indicates that conditions such as preeclampsia and peripartum cardiomyopathy share biological pathways with PPD, reinforcing the concept of a unified pathophysiological axis. This review synthesizes current knowledge on the neurobiological, cardiovascular, endocrine, and inflammatory mechanisms connecting PPD to maternal heart-brain health, while discussing emerging biomarkers and therapeutic strategies aimed at restoring integrative physiology. Understanding PPD as a multisystem heart-brain disorder offers a transformative perspective for early detection, risk stratification, and personalized intervention during one of the most biologically vulnerable periods of a woman's life.

Modulation of Corticotropin-Releasing Hormone Receptor Expression During In Vitro Keratinocyte Differentiation.

Carole-Anne Martins, Sara Lesink, Angéline Roux +2 more

Corticotropin-releasing hormone (CRH) and its receptors CRHR1 and CRHR2 are major actors in the stress response and are well established as components of the hypothalamic-pituitary-adrenal (HPA) axis. Evidence also suggests they are expressed in peripheral tissues and, more interestingly, in the skin. While CRHR1 expression in keratinocytes is documented in terms of presence or absence, data on CRHR2 remain sparse. Moreover, there is no detailed description of the exact localization of CRHR1/2 receptors within the different layers of the epidermis, leaving this question fully unexplored. To better understand the link between stress and skin disorders, we aimed to investigate the differential expression of CRHR1 and CRHR2 in keratinocytes, depending on their level of differentiation. In vitro results demonstrated that CRHR1 appears to be more abundant at early stages of differentiation and CRHR2 at more advanced stages.

The effects of early life pain and juvenile fear conditioning on CRF-receptor expression in the amygdala and hypothalamus of the juvenile rat.

Michael A Burman, Jared T Zuke

Early life pain and stress have lasting consequences on nervous system development that can interact with later stress or trauma to create a susceptibility to fear, anxiety, depression and chronic pain among other psychological disorders. Recent work has identified changes in corticotropin releasing factor signaling in limbic system structures, such as the amygdala and hypothalamus, as a key mechanism behind these changes - albeit in a sex-dependent manner. CRF has two major receptors, CRFR1 and CRFR2 which have also been shown to play key roles in fear and pain expression. The current work examines the effects of early life pain designed to mimic the neonatal medical trauma that occurs in the Neonatal Intensive Care Unit (NICU), paired with a juvenile trauma in the form of fear conditioning, on expression of crhr1 and crhr2 mRNA in the central nucleus (CeA) and basolateral nucleus (BLA) of the amygdala as well as the paraventricular nucleus (PVN) and ventromedial nucleus (VMH) hypothalamus of the juvenile rat. While prior work has demonstrated that early life pain significantly impacts expression of the CRF ligand mRNA, this study examines the effects of early life pain and stress, as well as adolescent fear conditioning, on CRF receptor expression. The data demonstrate that early life pain and fear conditioning have only modest effects on CRF receptor expression in the amygdala and hypothalamus in a sex dependent manner. In both sexes, fear conditioning increased crhr2 mRNA in the CeA only in neonatally undisturbed subjects. In addition, there was a trend towards altered crhr2 mRNA following neonatal manipulation in the PVN. In females specifically, we observed significant changes in crhr2 mRNA expression following fear conditioning in the right BLA. There were no female-specific changes following neonatal pain and stress. In males, we observed significant changes in crhr1 mRNA in the posterior PVN and trends toward changes in crhr2 mRNA in the CeA and VMH following neonatal manipulation. Together, these data confirm prior work that early life pain and stress alter the neural circuitry of pain and stress in a sex-specific manner. However, given the limited changes observed, in it unlikely that CRH receptor alterations are a major mechanism of action of early life pain.

Aster yomena Alleviates Chronic Unpredictable Mild Stress (CUMS)-Induced Depressive Cognitive Dysfunction by Regulating the HPA Axis and TLR4/NF-κB Pathway.

In Young Kim, Jong Min Kim, Hyo Lim Lee +4 more

The purpose of this study was to assess the effects of a 60% ethanolic extract of Aster yomena (EAY) on chronic unpredictable mild stress (CUMS)-induced depressive cognitive dysfunction. The results showed that EAY mitigated CUMS-induced depressive-like behaviors, as confirmed by the sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST). In addition, EAY showed protective effects on cognitive function in the Y-maze and the Morris water maze (MWM) tests. In this regard, EAY alleviated hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis through regulation of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cytochrome P450 family 11 subfamily B member 1 (CYP11B1), thereby improving the levels of serum cortisol. It suppressed neuroinflammation, oxidative stress, and mitochondrial dysfunction by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor κ-light-chain-enhancer of the activated B cells (NF-κB) pathway. As a result, cognitive dysfunction was ameliorated through modulation of the cholinergic system, including acetylcholinesterase (AChE), acetylcholine (ACh), and choline acetyltransferase (ChAT), and synaptic plasticity-related factors such as postsynaptic density protein 95 (PSD-95) and growth-associated protein 43 (GAP-43). Based on these results, EAY could potentially be used as a natural therapeutic for prevention of major depressive cognitive impairment.

Correlation of anxiety/depression status with stress-related markers and cancer-related fatigue in patients with colon cancer.

Ling Zhao, Bin Jian, Duan-Hong Chen

Anxiety and depression are significant contributors to adverse outcomes in patients with colon cancer (CC). Therefore, investigating the key determinants of this psychological distress in such patients is essential.

Correlation between life satisfaction, pleasure level, and negative emotion in patients with chronic renal failure.

Lin-Lin Zhang, You-Li Zhang, Ting Liu +3 more

Anxiety, depression, and other negative emotions are common among patients with chronic renal failure (CRF). Analyzing the factors related to negative emotions is necessary to provide targeted nursing care.

Clinical efficacy and effects on hypothalamic-pituitary-adrenal axis function of proscar combined with selective serotonin reuptake inhibitor in post-stroke depression.

Ming-Yang Xu, Yi Lu, Guo-Mei Shi +3 more

Post-stroke depression (PSD) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction and neurotransmitter deficits. Selective serotonin reuptake inhibitors (SSRIs) are commonly used, but their efficacy is limited. This study investigated whether combining SSRIs with traditional Chinese medicine (TCM) Free San could enhance their therapeutic effects.

Acute Stress Attenuates Hepatic Ischemia-Reperfusion Injury via Hypothalamic CRH Neuron-Induced HPA Axis Activation.

Xiaoqi Lin, Dan Yang, Shuyang Wang +10 more

Hepatic ischemia-reperfusion injury (HIRI) is a pathologic process commonly encountered during liver surgery, which seriously threatens patient prognosis. Currently, effective interventions or preventive measures are still lacking. Notably, patients with liver disease commonly experience brief acute stress prior to surgery; however, the impact of acute stress on HIRI remains unclear.

Social stress worsens colitis through β-adrenergic-driven oxidative stress in intestinal mucosal compartments.

Maria Elisa Caetano-Silva, Miranda E Hilt, Ivan Valishev +10 more

Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either Citrobacter rodentium infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (Duox2), Dual oxidase maturation factor 2 (Duoxa2), and inducible nitric oxide synthase 2 (Nos2) in IECs (2- to 8-fold, p < 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α -diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (C. rodentium) and chemically induced (DSS) colitis, amplifying colonic expression of Duox2, Nos2, and Ccl2, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase-driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.

Genetic inactivation of the CRF1 receptor eliminates age-linked elevation of hippocampal 11β-hydroxysteroid dehydrogenase type 1 activity in female mice.

Julie Brossaud, Alessandro Piccin, Angelo Contarino +1 more

Glucocorticoids are produced through activation of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF1 and CRF2 receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF1 or CRF2 receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF1 and CRF2 wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF1 WT and HET mice but not in CRF1 KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF1 genotype. In CRF1 males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF1 females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF1 deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF1 deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF2 mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF2 deficiency. Moreover, CRF2 deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF1 receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF1 function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.

Psilocybin induces sex- and context-specific recruitment of the stress axis.

Sarah Gibson Cook, Stephanie Lee, Emma Ference +7 more

Following decades of prohibition, psychedelic drugs have reemerged as promising therapeutics for stress-related conditions, including depression and post-traumatic stress disorder. Still, their impact on stress-related brain regions and the hypothalamic-pituitary-adrenal (HPA) axis remains unclear. This work explores the acute effects of psilocybin on the primary regulators of the HPA axis: corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). Here, using blood plasma measurements and in vivo single-fiber photometry, we demonstrate that psilocybin induces robust activation of the HPA axis via CRHPVN neurons, with more pronounced responses observed in female mice and a reliance on serotonergic 5-HT2A and 5-HT2C receptors. Ex vivo electrophysiology indicates that the 5-HT2A-receptor-mediated effects involve dual mechanisms: direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Our findings also reveal that psilocybin alters how CRHPVN neurons react to environmental changes, resulting in a surprising decrease in activity that contrasts with typical elevated stress responses. This context-specific modulation may be a key mechanism underlying the therapeutic potential of psychedelics to recalibrate maladaptive stress reactivity. Our findings emphasize the interplay between the serotonergic and stress systems and support the considerable influence of contextual factors, i.e., "setting," on the psychedelic experience. This study provides the first real-time in vivo evidence of neuronal activation of the stress system following psilocybin administration and has significant implications for optimizing the therapeutic efficacy of psychedelic-assisted therapy.

The effect of chronic stress on sensitivity to dexamethasone treatment of HPA axis gene expression in C57Bl/6 mice.

Rasha Salman, Polina Ritter, Yuliya Ryabushkina +2 more

Chronic social stress is a major risk for psychopathologies such as depression, often leading to altered hypothalamic-pituitary-adrenal (HPA) axis function and glucocorticoid resistance. This study examines how chronic social defeat stress (CSDS) affects sensitivity to dexamethasone by analyzing HPA axis genes expression in C57Bl/6 mice. Adult male mice were subjected to 30 days of stress, followed by dexamethasone or saline administration. Genes expression was analyzed in the hypothalamus, prefrontal cortex (PFC; Nr3c1 only), and adrenal glands at multiple time points post-treatment. CSDS induced marked dysregulation of HPA axis-related genes, including a decrease in hypothalamic Crh and Crhbp, and adrenal Mc2r, Nr3c1, alongside an upregulation of steroidogenic enzymes Cyp11a1 and Cyp11b1, which may account for the elevated corticosterone levels observed under chronic stress conditions. CSDS alters the genes expression response to dexamethasone, indicating a delayed recovery of glucocorticoid receptor signaling in the brain and adrenal glands. Our findings reveal significant stress-induced alterations in the expression of key HPA axis genes, suggesting impaired glucocorticoid receptor signaling and potential glucocorticoid resistance in stressed mice.

Chronic Stress Segregates Mice into Distinct Behavioral Phenotypes Based on Glucocorticoid Sensitivity.

Polina Ritter, Rasha Salman, Yuliya Ryabushkina +1 more

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA-axis-related genes in the hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) were performed. K-means cluster analysis identified three distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.

rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood.

Adele Leggieri, Judit García-González, Saeedeh Hosseinian +7 more

Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss of function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation - traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 mutants showed increased cortisol levels and disrupted expression of key stress-related genes (bdnf, trkb2, pac1a-hop, crhb, nr3c2). Pharmacological intervention targeting TRKB restored crhb and nr3c2 gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of crhb, nr3c2 and bdnf/trkb2 genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.

Chronic stress and the IL-10-mediated immunoregulatory loop in the pathogenesis of periodontitis.

Maksym Skrypnyk, Axel Spahr, Shlomo Berkovsky +9 more

Periodontitis is a chronic inflammatory condition that gradually destroys the tissues supporting the teeth, including the gingiva, periodontal ligament, and alveolar bone. Emerging evidence suggests that psychological stress plays a significant role in the initiation and progression of periodontal disease, primarily through its impact on immune regulation. Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticotropin-releasing hormone (CRH) from the hypothalamus and, in turn, adrenocorticotropic hormone (ACTH) from the pituitary gland. Activation of the HPA axis and the sympathetic-adrenal-medullary (SAM) system during stress triggers the systemic release of cortisol, epinephrine, norepinephrine, and cytokines. The HPA, SAM, and cytokines interact in both direct and indirect ways. Not only does stress induce interleukin-10 (IL-10), but IL-10 also helps regulate the stress response and cortisol levels. IL-10 can stimulate the release of CRH and ACTH, while concurrently inhibiting cortisol secretion from the adrenal glands. IL-10 has drawn increasing attention within the oral cavity owing to its dual role in modulating immune responses and maintaining periodontal tissue homeostasis. This review outlines the current understanding of stress-related neuroendocrine pathways and their relevance to periodontal health. It explores the involvement of HPA axis effectors-cortisol and IL-10-in modulating the inflammatory milieu associated with periodontitis. This includes recent insights into IL-10-expressing regulatory B cells and the potential role of IL-10 in mitigating alveolar bone loss. By integrating recent advances in neuroendocrinology, immunology, and oral biology, this review clarifies how systemic stress responses contribute to local inflammatory changes in the periodontium. Understanding the mechanisms linking psychological stress, cortisol dynamics, and IL-10-mediated regulation may offer new opportunities for early diagnosis and intervention in stress-exacerbated periodontitis.

Impact of glucocorticoid therapy on hypothalamic-pituitary-adrenal axis function in pediatric nephrotic syndrome: A narrative review.

Subhankar Sarkar, Asiri Samantha Abeyagunawardena, Rajiv Sinha

Glucocorticoids (GCs) such as prednisolone are widely used in conditions like nephrotic syndrome, asthma, and autoimmune diseases. However, prolonged or high-dose use may suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to secondary adrenal insufficiency (AI). This condition occurs when the adrenal glands fail to produce adequate cortisol, which is essential for regulating metabolism, immune response, and stress adaptation. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which then triggers cortisol production in the adrenal glands. Prolonged GC use disrupts this system by inhibiting CRH and ACTH secretion, leading to adrenal atrophy and reduced cortisol production. HPA axis suppression is primarily diagnosed through dynamic tests. Early morning cortisol levels above > 18 ng/mL typically indicate normal function, while levels < 3 ng/mL suggest AI. Intermediate values require additional testing, such as the insulin tolerance test, ACTH stimulation test, and metyrapone test. Prednisolone in nephrotic syndrome suppresses the HPA axis, heightening AI risk, influenced by dose, duration, and timing of administration. Careful GC management is essential to balance disease control with risks of HPA axis suppression. Early recognition and timely intervention can prevent adrenal crises and improve outcomes in pediatric patients.