Castration-induced nigrostriatal deficits are linked to reduced TrkB and loss of mature spines in the dorsal striatum.

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Parkinson's disease is a neurodegenerative disorder characterized by degeneration of nigrostriatal dopamine neurons and basal ganglia dysfunction, with sex differences in risk and progression that are not yet fully understood. Here, we investigated how peripubertal loss of gonadal hormones influences nigrostriatal integrity, striatal synaptic architecture, and motor behavior in male mice. Using a castration model, we show that early androgen deprivation recapitulates key neuropathological and behavioral features of Parkinsonian hypodopaminergia, including reduced tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta, impaired motor performance on the vertical pole and rotarod, and disrupted forelimb kinematics. At the circuit level, androgen loss markedly reduced mushroom spine density on both direct- and indirect pathway striatal spiny projection neurons, with a concomitant increase in immature spine classes, consistent with impaired synaptic maturation. These structural and behavioral deficits were accompanied by reduced striatal Tyrosine receptor kinase-B (TrkB) protein, suggesting attenuation of brain derived neurotrophic factor (BDNF)/TrkB trophic signaling. Testosterone replacement preserved nigral dopaminergic neurons, normalized motor behavior, prevented mushroom spine loss across both striatal pathways, and selectively increased long/thin spines on direct-pathway neurons, suggesting enhanced synaptic plasticity. Together, these findings support a hormone-trophic model in which androgen signaling maintains nigrostriatal integrity and striatal synaptic maturation through androgen receptor-dependent BDNF/TrkB mechanisms. Although Parkinson's disease predominantly manifests with aging, these results suggest that early disruption of androgen signaling can produce lasting circuit-level alterations that influence vulnerability to degeneration over time, providing mechanistic insight into sex differences in Parkinson's Disease.

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