Gender differences in depressive-like behavior in Parkinson's disease

A Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms, including depression, which markedly impairs patients' quality of life. Although sex differences have been described in PD progression, the mechanisms underlying gender-specific susceptibility to depressive symptoms remain poorly understood.

This study investigated sex-dependent differences in depressive-like behaviors and their underlying molecular mechanisms in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration, using adult male and female CD1 mice.

Our results demonstrated that MPTP administration induced nigrostriatal degeneration and α-synuclein accumulation in both sexes, with more pronounced alterations in males. Male mice also exhibited greater depressive- and anxiety-like behaviors, accompanied by a marked reduction in 5-HT2C receptor expression, increased hippocampal acetylcholine levels, impaired expression of the synaptic markers PSD-95 and synaptophysin, and a stronger downregulation of the BDNF/PI3K/AKT pathway compared with females.

These findings demonstrate that sex significantly influences vulnerability to PD-associated depressive symptoms, with males showing greater behavioral and molecular impairment. Overall, our results highlight the importance of considering sex as a biological variable in PD research and support the development of personalized therapeutic strategies targeting non-motor symptoms.