TL;DR
In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation.
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Chronic stress is a key risk factor for depression, while conventional antidepressants, though effective, often are associated with adverse effects. Nutritional approaches such as L-methylfolate, vitamin B₂, and vitamin D₃ offer safer alternatives by supporting neurotransmitter synthesis, one-carbon metabolism, and stress regulation. This study examined the preventive effects of a multivitamin combination in a chronic unpredictable mild stress (CUMS) rat model. Male and female Sprague Dawley rats were divided into control, CUMS + saline, or CUMS + multivitamin groups and treated for 21 days. Behavioural tests, cortical morphometry, neurotransmitter receptor expression, hepatic folate levels, DNA methylation, and METTL3 expression were assessed, alongside serum cortisol and biochemical markers of liver and kidney function. CUMS induced depressive-like behaviours, elevated cortisol, impaired organ function, reduced cortical thickness, and downregulated serotonergic, dopaminergic, and adrenergic receptors. Multivitamin supplementation restored behaviour, normalized cortisol and organ function, preserved cortical integrity and hepatic methylation, and upregulated METTL3. These findings highlight multivitamins as functional food-based strategies for the prevention of depression-like behaviour.
Anorexia Nervosa (AN) is a neuropsychiatric disorder marked by compulsive weight-loss and hyperactivity, with poorly understood underlying mechanisms and limited treatment outcomes. Here we show that women with AN, at the first medical evaluation, exhibit hyperactivity and hypercortisolemia, together with a reduced immune cell count yet paradoxically showing increased levels of cell activation. One year later, only subjects considered in remission showed greater increases in cortisol and cytokine levels, along with enhanced monocyte differentiation and recruitment. Using the activity-based anorexia (ABA) rat model, we reproduced AN core features, including hypercorticosteronemia, and observed innate-skewed immune profiles, as well as persistent microglial and glucocorticoid receptor (GR) dysfunction in the ventral hippocampus. Pharmacological blockade of GR with RU486 attenuated hyperactivity and reshaped microglial phenotype in the ventral hippocampus. Our results suggest that cortisol elevation and immune cell adaptation may perpetuate disease vulnerability beyond weight normalization, challenging the notion of weight regain as an indicator of remission.
ABSTRACT Anxiety disorders pose a considerable burden on public health. While exercise has been increasingly established as a viable strategy for preventing and alleviating anxiety symptoms, the underlying molecular mechanisms of this action remain elusive. We previously conducted an 8‐week randomized controlled trial which suggested that exercise not only significantly reduced anxiety levels but also triggered the release of acidic ribosomal protein P2 (RPLP2) from peripheral tissues into the bloodstream. These elevated circulating RPLP2 levels showed an inverse association with anxiety severity in patients, suggesting a potential therapeutic role for the protein. Further experiments in mice confirmed that skeletal muscle–derived RPLP2 exerts its anxiolytic effects by facilitating hippocampal neurogenesis. Mechanistically, RPLP2 facilitates ribosomal localization and increases the efficiency of ribosomal subunit assembly, thereby increasing local protein synthesis and supporting the development and maturation of newly generated neurons. The successful maturation of these neurons, in turn, promotes morphological and functional synaptic plasticity, which is crucial for the integration and functional maturation of newborn neurons into hippocampal circuits. Collectively, our findings reveal a previously unknown muscle–brain axis mediated by RPLP2, offering mechanistic evidence for exercise‐induced stress resistance.
Hypertension prevalence rises dramatically with advancing age, is not well controlled with current therapy, and contributes substantially to cardiovascular, renal and neurologic disorders that are common in the elderly. The renin-angiotensin-aldosterone system is a hormonal pathway with multiorgan involvement critical to controlling blood pressure. The production of the steroid hormone aldosterone and the activation state of its mineralocorticoid receptor (MR) are important clinical targets for hypertension treatment and cardiorenal disease prevention. This review summarizes studies demonstrating that aging is associated with: 1) dysregulation of adrenal aldosterone production by autonomous aldosterone producing adrenal cells and, when co-morbid with obesity, by factors released from adipose tissue that promote adrenal aldosterone production; 2) increased expression of the MR due to oxidative stress- and inflammation-activated transcription factors; and 3) aldosterone-independent MR activation by oxidative stress-activated Rac1, angiotensin-II signaling, and declining expression of the cortisol-inactivating enzyme 11bHSD2. Together, these data support the concept that elderly individuals are at high risk for mineralocorticoid-driven hypertension and associated cardiovascular, renal, and neurologic disease. The review further describes the different classes of agents that inhibit this pathway, including traditional steroidal MR antagonists (sMRAs), newer nonsteroidal (nsMRAs) and aldosterone synthase inhibitors (ASIs), comparing their modes of action. The sMRAs and nsMRAs have different degrees of MR selectivity and potency, yet they all block MR activation by aldosterone, cortisol, and ligand-independent mechanisms. The ASIs block aldosterone production in the adrenal gland and attenuate aldosterone-mediated MR effects. All three drug classes raise potassium proportional to the degree of renal MR inhibition. Trials are summarized showing efficacy of the new agents in reducing MR activation, aldosterone production, blood pressure and adverse cardiorenal outcomes. Head-to-head studies in older individuals are needed to determine the relative efficacy of aldosterone synthase versus MR inhibition for blood pressure control to improve outcomes in the elderly and very old.
RATIONALE Chronic stress, frequently associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and reduced neuroplasticity, is a major risk factor for psychiatric disorders such as anxiety and depression. OBJECTIVE The present study aimed to validate a 21-day chronic unpredictable stress (CUS) model and to investigate the effects of the Mas receptor agonist AVE0991 on stress-induced behavioral and molecular alterations. METHODS Male C57BL/6J mice were exposed to a 21-day CUS protocol. Animals were randomly assigned to four groups: control + saline, CUS + saline, control + AVE0991, and CUS + AVE0991 (3 mg/kg, i.p.). AVE was administered daily during the last two weeks of the stress protocol. Behavioral tests were performed to evaluate anxiety- and depressive-like behaviors, and plasma corticosterone, blood glucose levels, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex, hippocampus, and hypothalamus were measured. RESULTS CUS exposure significantly increased plasma corticosterone and glucose levels and induced anxiety- and depressive-like behaviors. Stressed animals also showed reduced BDNF levels in the prefrontal cortex, hippocampus, and hypothalamus. Treatment with AVE0991 attenuated the increase in corticosterone and prevented stress-induced hyperglycemia. Moreover, AVE0991 reduced depressive-like behavior, increased latency to immobility, and improved anxiety-related parameters in the elevated plus maze and open field tests without affecting locomotor activity. AVE0991 also prevented the reduction of BDNF levels in stress-exposed animals. CONCLUSION These findings validate the CUS model and demonstrate that activation of the Mas receptor by AVE0991 exerts anxiolytic, antidepressant, and neuroprotective effects, supporting its potential as a therapeutic strategy for stress-related neuropsychiatric disorders.