Aging-Related Dysfunction of Striatal Cholinergic Interneurons Produces Conflict in Action Selection.
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. VIDEO ABSTRACT.
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4000, Australia.
Miriam
M
Matamales
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4000, Australia.
Zala
Z
Skrbis
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4000, Australia.
Robert J
RJ
Hatch
Brain and Mind Centre, University of Sydney, Camperdown, NSW 2050, Australia; School of Psychology, University of NSW, Kensington, NSW 2033, Australia.
Bernard W
BW
Balleine
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4000, Australia.
Jürgen
J
Götz
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4000, Australia. Electronic address: j.bertrangonzalez@uq.edu.au.
Jesus
J
Bertran-Gonzalez
D000375:Aging / Q000502:physiology*; D000818:Animals; D059329:Cholinergic Neurons / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology* / Q000502:physiology*; D007395:Interneurons / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009434:Neural Pathways / Q000502:physiology; D013788:Thalamus / Q000502:physiology