Sex-Dependent Effects of Glutamatergic Disruption on Dopaminergic Neuron Subtype Vulnerable in Parkinson’s Disease

Aldehyde dehydrogenase 1A1-positive (ALDH1A1 ⁺ ) dopaminergic neurons (DANs) are preferentially vulnerable in Parkinson’s disease (PD), yet how their activity is modulated by presynaptic inputs remains poorly defined. Here we investigated the role of glutamatergic input by conditionally deleting Grin1 , which encodes a critical NMDA receptor (NMDAR) subunit, in ALDH1A1 ⁺ DANs. Grin1 conditional knockout (cKO) mice displayed normal locomotion and motor learning; however, females exhibited enhanced operant reward acquisition and excessive feeding with transient weight gain following food restriction. To determine regional contributions, Grin1 was selectively knocked down in ALDH1A1 ⁺ DANs of either the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc). VTA-specific knockdown in females was sufficient to reproduce the post-restriction feeding and weight gain phenotype. Bulk whole-brain mRNA sequencing revealed pronounced sex-dependent transcriptional changes, primarily in female Grin1 cKO mice after food restriction. Many differentially expressed genes were associated with mitochondrial function, energy metabolism, and synaptic signaling. Together, these findings reveal a sex-specific role for NMDAR–mediated glutamatergic input to ALDH1A1 ⁺ VTA DANs in regulating feeding behavior, providing mechanistic insight into how dysfunction of this vulnerable subpopulation may contribute to PD-associated compulsive eating disorders.