Aging-Related Dysfunction of Striatal Cholinergic Interneurons Produces Conflict in Action Selection

• Published in: Neuron (Cambridge, Mass.) Mass.), 2016-04, Vol.90 (2), p.362-373
• Main Authors: Matamales, Miriam, Skrbis, Zala, Hatch, Robert J., Balleine, Bernard W., Götz, Jürgen, Bertran-Gonzalez, Jesus
• Format: Article
• Language: English
• Subjects: Aging; Aging - physiology; Animal cognition; Animals; Cholinergic Neurons - physiology; Corpus Striatum - cytology; Corpus Striatum - physiology; Experiments; Interneurons - physiology; Learning - physiology; Memory; Mice; Mice, Mutant Strains; Neural Pathways - physiology; Neurons; Rodents; Studies; Thalamus - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.03.006

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. [Display omitted] •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 Updating previously acquired memories is essential to adapt to changing conditions. Matamales et al. show that aged mice fail to integrate new and existing learning due to deficits in the thalamic-to-striatal cholinergic pathway, which results in inflexible goal-directed action.