Removal of D2 receptors on striatal cholinergic interneurons impairs sequence learning

FARE Award Winner

Authors

• JH Chancey
• DM Lovinger

Abstract

Dorsal striatum (dStr) encodes action initiation and sequences. Medium spiny neurons (MSNs) in dStr, change their firing rate at the start and stop or throughout learned action sequences. Acetylcholine (ACh) released by striatal cholinergic interneurons (CINs) modulates striatal function by regulating dopamine and glutamate release, and governing MSN excitability. CINs are spontaneously active and pause their firing during action sequences. We hypothesize that this pause is critical for regulating neurotransmitter release and MSN excitability, allowing for plasticity necessary for learning. Slice physiology suggests that pausing occurs via activation of D2 dopamine receptors (D2Rs) on CINs. Here we test how removing D2Rs from CINs affects learning a sequence of actions to obtain sucrose. Using a fixed-ratio lever-pressing paradigm that produces reliable performance of action sequences in mice, we found that eliminating D2Rs from CINs by crossing D2flox/flox x Chat-Cre mice (D2F-ChatCre) caused deficits in sequence learning. D2F-ChatCre mice learned the task at at a slower, demonstrated less lever pressing overall, and received fewer reinforcers than control littermates. D2F-ChatCre had no general deficits in motor skill learning or motivation, as they performed similar to controls in accelerated rotarod, home cage sucrose intake, and progressive ratio tasks. Thus, the deficits in sequence learning may be specific to action chunking or behavioral flexibility. We are currently using behavioral paradigms to investigate these possibilities and performing in vivo recordings of unit activity in dStr throughout training to gain a better understanding of the role of CIN activity in striatal encoding of learned action sequences.

Scientific Focus Area: Neuroscience

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