Striatal dopamine release is critical for behavioral reinforcement. Manipulations in dopaminergic signaling by drugs of abuse produce aberrant behavioral reinforcement. Elucidating the neural circuits that regulate striatal dopamine release is critical to both understanding the mechanisms of drugs of abuse and developing novel treatments for addiction. I have preliminarily discovered a novel circuit that elicits dopamine release in the dorsal striatum: optogenetic activation of a glutamatergic projection arising from a rostral collection of intralaminar nuclei in the thalamus (rILN) drives striatal cholinergic interneurons (ChIs) that, in turn, axo-axonically synapse on nigrostriatal terminals to powerfully induce dopamine release in the dorsal medial striatum. In vivo activation of this pathway produces behavioral reinforcement in mice. Such direct thalamic control of local striatal dopamine release represents a paradigm shift in our understanding of the contributions of axo-axonic synapses to behavioral reinforcement. Based on my preliminary findings, I hypothesize that the rILN drives ChI-dependent striatal dopamine release for behavioral reinforcement. I will investigate this hypothesis in two aims using in vivo and ex vivo strategies: 1) I will use in vivo optogenetics, pharmacology, and viral-transgenic approaches to test my prediction that rILN-induced behavioral reinforcement is dependent on ChI activity and dopamine signaling; and 2) I will test my prediction that rILN-evoked dopamine release requires ChI-mediated activation of nicotinic acetylcholine receptors using ex vivo optogenetics and fast scan cyclic-voltammetry. I will also employ whole- cell patch clamp electrophysiology to test my prediction that rILN signaling preferentially excites D1 receptor- expressing medium spiny neurons, activation of which is linked to behavioral reinforcement. The results of this study will significantly advance our knowledge of a novel non-canonical dopamine release circuit and provide the PI with substantial training opportunities in neurophysiology.
Addiction is marked by maladaptive reinforcement of behavior mediated by dysregulated release of the neurotransmitter dopamine. This proposal will determine the mechanism by which a novel neural circuit controls dopamine release for behavioral reinforcement. The findings of this study will create a new framework for understanding dopamine release mechanisms and provide novel therapeutic targets for substance abuse treatment.