Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in a 6-hydroxydopamine-induced Parkinson's disease mouse model.

Abstract

BACKGROUND: Depression is one of the most common non-motor disorders and neuropsychiatric comorbidities in Parkinson's disease (PD). The pathophysiology of depression in PD patients remains unclear and has been largely unexplored. METHOD: In this study, we employed chemogenetics and pharmacology to modulate the lateral habenula (LHb) and its downstream brain regions, the rostromedial tegmental nucleus (RMTg) and the ventral tegmental area (VTA) in wild type (WT) and 6-hydroxydopamine (6-OHDA) mice, to investigate the potential mechanisms underlying the improvement of PD-related depression. RESULTS: Inhibition of LHb glutamatergic neurons, as well as disruption of the LHb-RMTg pathway, along with inhibition of RMTg GABAergic neurons ameliorates depressive-like behavior in 6-OHDA mice. Conversely, activation of LHb glutamatergic neurons, the LHb-RMTg pathway, and activation of RMTg GABAergic neurons exacerbated depressive-like behavior in WT and 6-OHDA mice. Notably, either inhibition or activation of the LHb-VTA pathway did not produce any significant changes in depressive-like behavior in WT and 6-OHDA mice. Additionally, activation of VTA DAergic neurons effectively ameliorating depressive-like behavior in 6-OHDA mice. CONCLUSIONS: Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in 6-OHDA PD mice model. These findings offer new insights for advancing research and developing novel treatments for PD-related depression.