Chronic unpredictable mild Stress- induced neurobehavioral and metabolic alteration: insights into molecular mechanisms and emerging therapeutic Strategies”

Dec 13, 2025Psychopharmacology

Long-term mild stress causes changes in behavior and metabolism: understanding the molecular causes and possible treatments

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Abstract

Chronic unpredictable mild stress (CUMS) is associated with neuroendocrine dysregulation, metabolic dysfunction, immune activation, and synaptic impairment.

Chronic stress leads to persistent stimulation of the hypothalamic-pituitary adrenal (HPA) axis, resulting in hypercortisolaemia.
Hypercortisolaemia may contribute to insulin resistance and compromised neuroplasticity through disrupted BDNF-TrkB signaling.
Stress can induce microbial dysbiosis and intestinal barrier disruption, which amplify central inflammation via altered tryptophan metabolism.
Epigenetic modifications, including DNA methylation and histone remodeling, may encode changes in gene expression linked to behavioral and cognitive deficits.
While the CUMS model has strong validity for studying stress-related disorders, its translational relevance is limited by protocol constraints.

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The chronic unpredictable mild stress (CUMS) paradigm is a well-known preclinical model used to investigate the pathophysiology of stress-induced neuropsychiatric disorders. This review integrates recent findings to elucidate how chronic stress initiates a multifaceted cascade involving neuroendocrine dysregulation, metabolic dysfunction, immune activation and synaptic impairment. Persistent stimulation of hypothalamic-pituitary adrenal (HPA) axis results in hypercortisolaemia, insulin resistance and compromised neuroplasticity through dysregulated BDNF-TrkB signalling, oxidative stress and activation of inflammatory pathways. Compelling evidence highlights both the Gut brain axis (GBA) and epigenetic alterations as central to stress-induced neuropathology. Stress-mediated microbial dysbiosis and intestinal barrier disruption amplify central inflammation through altered tryptophan metabolism and immune neurotransmitter signalling. Simultaneously, epigenetic modification including DNA methylation, histone remodelling and microRNAs encodes transcriptional changes that results in behavioural and cognitive deficits. While, CUMS model offers strong face and predictive validity but its translational relevance is constrained by protocol validity and limited modelling of psychological stressors. Nonetheless, it remains instrumental for evaluating pharmacological and non-pharmacological interventions targeting inflammatory, neurotrophic and metabolic pathways. Future refinement should incorporate biomarker discovery and gene-environment interaction paradigms. In synthesizing these diverse mechanistic insights, this review underscores the value of the CUMS model in identifying system-level therapeutic targets and advancing translational research in stress-related brain disorder.

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Chronic unpredictable mild Stress- induced neurobehavioral and metabolic alteration: insights into molecular mechanisms and emerging therapeutic Strategies”

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