Restoring the youthful state of striatal plasticity in aged mice re-enables cognitive control of action

Multidisciplinary evidence suggests that the control of voluntary action arbitrates between two major forms of behavioral processing: cognitively guided (or goal directed) and autonomously guided (or habitual). Brain-state irregularities affecting the striatum—such as aging—commonly shift control toward the latter, although the responsible neural mechanisms remain unknown. Combining instrumental conditioning with cell-specific mapping and chemogenetics in striatal neurons, we explored strategies that invigorate goal-directed capacity in aged mice. We found that, under conditions favoring goal-directed control, aged animals resiliently expressed autonomously guided behavior, a response that was underpinned by a characteristic one-to-one functional engagement of the two main neuronal populations in the striatum—D1- and D2-dopamine receptor-expressing spiny projection neurons (SPNs). Chemogenetically induced desensitization of D2-SPN signaling in aged transgenic mice recapitulated the striatal plasticity state observed in young mice, an effect that shifted behavior toward vigorous, goal-directed action. Our findings contribute to the understanding of the neural bases of behavioral control and propose neural system interventions that enhance cognitive functioning in habit-prone brains. [Display omitted] •Improving action performance does not warrant goal-directed capacity in aged mice•Aged mice feature counterbalanced plasticity in striatal D1- and D2-SPN circuits•Breaking balanced SPN plasticity unleashes capacity for goal-directed control Bertran-Gonzalez et al. demonstrate that the propensity of aged mice to act autonomously relates to counterbalanced plasticity gradients in D1- and D2-SPN populations of the striatum. Breaking such balance enabled goal-directed action in aged mice, shining light on how autonomous and goal-directed controllers are represented in striatal circuits.