DRN-SNc serotonergic circuit drives stress-induced motor deficits and Parkinson's disease vulnerability

Stress is a recognized risk factor for Parkinson's disease (PD), but the mechanisms by which stress exacerbates PD symptoms through the serotonergic system are not fully understood. This study investigates the role of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) in mediating stress-induced motor deficits and PD progression. Acute and chronic stress were induced in mice using an elevated platform (EP) and combined with MPTP administration to model early-stage PD. Acute EP stress caused transient motor deficits and significant activation of DRN^5-HT neurons projecting to substantia nigra compacta (SNc) dopaminergic (DA) neurons. Manipulating the DRN-SNc pathway with optogenetics and chemogenetics confirmed its critical role in stress-induced motor deficits. Activation of the SNc 5-HT2C receptor with an agonist replicated these deficits, while receptor inhibition prevented them, underscoring its importance. Chronic EP stress worsened MPTP-induced deficits and caused significant SNc^DA neurons loss, suggesting it accelerates PD progression. Prolonged chemogenetic inhibition of the DRN-SNc circuit mitigated chronic stress effects in MPTP-treated mice. These findings highlight the crucial role of the DRN-SNc serotonergic circuit and 5-HT2C receptors in stress-related motor deficits, suggesting potential targets for therapies aimed at treating both stress-related motor disorders and Parkinson's disease.