Orchiectomy increases sensitivity to effort-related costs and alters mesoaccumbal circuit function in male mice.

Hypogonadism in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making, and here we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. Male mice underwent orchiectomy (ORX) either before puberty onset or in adulthood and were tested in a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was probed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and its metabolites, while whole-cell recordings assessed the intrinsic excitability of NAc spiny projection neurons (SPNs). ORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Postpubertal ORX increased NAc dopamine content and reduced metabolite-to-dopamine ratios, whereas prepubertal ORX did not alter dopamine neurochemistry. Prepubertal ORX selectively reduced excitability of NAc core D1R+ SPNs, whereas postpubertal ORX increased excitability across both D1R+ and D1R- populations. Together, these findings demonstrate that ORX increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although similar behavioral phenotypes emerged following pre- and postpubertal ORX, distinct neurochemical and cellular adaptations suggest that timing may shape the neural response to ORX. These results provide insight into the circuit mechanisms that may underlie altered motivation following testicular hormone loss.