Thalamostriatal processes regulating cholinergic interneurons fail with aging
•
Aged mice undergo interference between new and pre-existing goal-directed learning
•
Disruption of the PF-to-CIN pathway in young mice reproduces deficits in the aged
•
PF-to-CIN dysfunction results in faulty activation of striatal output neurons
Summary
For goal-directed action to remain adaptive, new strategies are required to accommodate environmental changes, a process for which parafascicular thalamic modulation of cholinergic interneurons in the striatum (PF-to-CIN) appears critical. In the elderly, however, previously acquired experience frequently interferes with new learning, yet the source of this effect has remained unexplored. Here, combining sophisticated behavioral designs, cell-specific manipulation, and extensive neuronal imaging, we investigated the involvement of the PF-to-CIN pathway in this process. We found functional alterations of this circuit in aged mice that were consistent with their incapacity to update initial goal-directed learning, resulting in faulty activation of projection neurons in the striatum. Toxicogenetic ablation of CINs in young mice reproduced these behavioral and neuronal defects, suggesting that age-related deficits in PF-to-CIN function reduce the ability of older individuals to resolve conflict between actions, likely contributing to impairments in adaptive goal-directed action and executive control in aging.