Synergistic Roles of Neuropeptide S and Environmental Enrichment in Preclinical Huntington's Disease Depression...

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and psychiatric impairments, with depression as a major comorbidity. Existing treatments for Huntington-related depression are inadequate, highlighting the need for strategies that target molecular mechanisms underlying mood dysregulation.

This review examines the mechanistic interplay between environmental enrichment (EE), a paradigm enhancing sensory, cognitive, and social stimulation and Neuropeptide S (NPS), a neuropeptide involved in stress modulation and emotional regulation. It focuses on their potential synergistic effects in modulating depression-associated molecular pathways in HD.

EE activates signalling cascades that promote synaptic plasticity and neurogenesis, including the upregulation of brain-derived neurotrophic factor (BDNF), enhanced activation of cAMP response element-binding protein (CREB), and remodelling of glutamatergic and GABAergic transmission. NPS exerts antidepressant-like effects by attenuating hyperactivity of the hypothalamicpituitary- adrenal (HPA) axis, modulating corticotropin-releasing factor (CRF) signalling, and influencing monoaminergic systems. Evidence indicates that EE may enhance NPS receptor (NPSR1) expression and downstream intracellular calcium signalling, reinforcing adaptive plasticity in the striatum and prefrontal cortex regions vulnerable in HD.

Integrating EE with NPS-targeted therapy could provide a multimodal approach to restore molecular homeostasis and alleviate depressive phenotypes in HD. Further research should elucidate optimal intervention timing, dose-response relationships, and potential cross-talk between EE-induced BDNF pathways and NPS-mediated stress resilience for translational application in neurodegenerative depression.