Neuroendocrine Responses to Chronic Stress

Chronic stress engages a coordinated network between the brain and endocrine glands to maintain homeostasis in the face of prolonged challenge. Central to this network is the hypothalamus–pituitary–adrenal (HPA) axis, in which stress signals provoke hypothalamic release of corticotropin-releasing hormone (CRH), pituitary secretion of adrenocorticotropic hormone (ACTH) and adrenal production of glucocorticoids. These steroid hormones orchestrate metabolic, immune and neural adaptations via the glucocorticoid receptor (GR), exerting genomic and non-genomic effects across multiple tissues. Under sustained stress, negative-feedback mechanisms may become impaired, leading to persistently elevated glucocorticoid levels that remodel limbic circuits, alter gene expression and heighten vulnerability to mood and cognitive disorders. Key brain regions—including the prefrontal cortex, hippocampus and amygdala—undergo structural and functional changes driven by stress-induced transcription factors such as ∆FosB. Chronic exposure also reconfigures neuropeptide systems and neurotransmitter balance, influencing anxiety- and depression-like behaviours. Understanding how neural and hormonal pathways interact over time is essential for therapeutic strategies that restore physiological feedback and circuit integrity.

Research from Nature Portfolio

A circuit-targeted study demonstrated that chronic social defeat stress induces sustained ∆FosB expression in ventral hippocampal neurons projecting to mood-regulating regions, driving either susceptibility or resilience. By using projection-specific gene editing, researchers revealed that modulating ∆FosB levels in distinct hippocampal pathways bidirectionally alters anxiety- and depression-like behaviours, highlighting precise intervention points within stress-adapted circuits. In a foundational imaging investigation, manganese-enhanced MRI combined with ∆FosB mapping in a mouse model of psychosocial stress uncovered widespread activation across the prefrontal cortex, bed nucleus of the stria terminalis, ventral hippocampus and periaqueductal grey. This work established that chronic stress reshapes inter-regional synchrony and persistent neural activation patterns, providing a brain-wide atlas of stress-evoked circuit adaptations.

Neuroendocrine Responses to Chronic Stress publication trend

The graph below shows the total number of articles in neuroendocrine responses to chronic stress across all publications each year (not limited to Nature Index journals).

Technical terms

HPA axis: A hierarchical network involving the hypothalamus, pituitary gland and adrenal cortex that mediates the secretion of stress hormones.

Glucocorticoids: Steroid hormones produced by the adrenal cortex that regulate metabolism, immune function and stress responses.

Corticotropin-releasing hormone (CRH): A hypothalamic peptide that stimulates adrenocorticotropic hormone release under stress.

Glucocorticoid receptor (GR): A nuclear receptor protein that binds glucocorticoids and modulates gene transcription.

∆FosB: A stable transcription factor induced by chronic neuronal activation, involved in long-lasting changes in brain circuits.

References

1. Sex-specific cardiac remodeling in aged rats after adolescent chronic stress: associations with endocrine and metabolic factors. Biology of Sex Differences (2024).
2. Prenatal Hypoxia Triggers a Glucocorticoid-Associated Depressive-like Phenotype in Adult Rats, Accompanied by Reduced Anxiety in Response to Stress. International Journal of Molecular Sciences (2024).
3. Brain activation induced by chronic psychosocial stress in mice. Scientific Reports (2017).
4. Neural regulation of the stress response: glucocorticoid feedback mechanisms. Brazilian Journal of Medical and Biological Research (2012).
5. Circuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance. Nature Communications (2020).