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<p>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.</p> Graphical abstract <p>The scientific illustration above shows how metabolic and gut-brain axis (GBA) equilibrium are disrupted in CUMS. The HPA axis is triggered by chronic stress, which raises cortisol levels and cause peripheral insulin resistance, hyperglycaemia leading to neuroinflammation. At the same time, pro-inflammatory cytokines release is encouraged by gut dysbiosis and increased intestinal permeability, which possesses the ability to penetrate blood-brain barrier (BBB). This further intensify neuroinflammatory transmission through Vagus nerve and contributes to brain dysfunction. </p> <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年12月13日

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  • Drishti Panjwani,
  • Souvik Banerjee,
  • Aziz Hassan,
  • Shareen Singh,
  • Thakur Gurjeet Gurjeet Singh

摘要

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.

Graphical abstract

The scientific illustration above shows how metabolic and gut-brain axis (GBA) equilibrium are disrupted in CUMS. The HPA axis is triggered by chronic stress, which raises cortisol levels and cause peripheral insulin resistance, hyperglycaemia leading to neuroinflammation. At the same time, pro-inflammatory cytokines release is encouraged by gut dysbiosis and increased intestinal permeability, which possesses the ability to penetrate blood-brain barrier (BBB). This further intensify neuroinflammatory transmission through Vagus nerve and contributes to brain dysfunction.