Sunday, May 4, 2025
5/4/2025
Cholinergic interneuron D2 receptor function in impulsive behavior: implications for addiction - Project Summary Chronic cocaine abuse is associated with long-lasting impairments in impulse control and decision-making that increase the risk for relapse. However, the brain circuits fundamentally involved in impulsive behavior and their alteration by chronic drug use are not well understood. Accumulating evidence in humans and animals implicates nucleus accumbens (NAc) dopamine D2 receptors (D2Rs), yet given their wide expression in different neuronal populations, it remains unclear which D2Rs play a key role in impulsive behavior. In particular, the contributions of D2Rs in cholinergic interneurons (CINs), which constitute only 2-3% of neurons in the NAc, have been largely overlooked, despite known CIN contributions to NAc function and cocaine reinforcement. To fill this gap in our knowledge, it is urgent to elucidate the consequences of D2R alterations in CINs on impulsive behavior with greater cell-type specificity. Our long-term goal is to elucidate the cellular and circuit mechanisms by which NAc CINs regulate impulsive behavior, which may uncover potential therapeutic strategies for reducing cocaine re- lapse. The overall objective of this application is to use cell-selective strategies to: 1) determine whether and how CIN D2Rs mediate impulsive behavior, and 2) whether CIN D2Rs participate in cocaine-induced augmen- tation of impulsivity. Our central hypothesis is that CIN D2Rs mediate impulsive behaviors by altering NAc ace- tylcholine (ACh) release following predictive cues, and that chronic cocaine causes excessive impulsivity via CIN D2Rs. Aim 1 will use cell type-specific genetic approaches in mice to bidirectionally alter D2R expression in CINs to test the impact on a delay discounting task, which assesses preference for small, short-term rewards over larger, delayed rewards. Using in vivo fiber photometry combined with optogenetics, Aim 2 will determine ACh dynamics in delay discounting and test whether the ACh pause in response to cues modulates impulsive choice. Aim 3 will determine whether CIN D2Rs and the CIN pause mediate the increase in impulsive choice resulting from chronic cocaine exposure. The research proposed in this application is innovative because it uses targeted approaches in behaving mice to examine a previously unrecognized role for the NAc CIN and its D2Rs in impul- sivity. Successful completion of the proposed aims will thus generate a novel dissection of neuronal mechanisms at play in impulsive choice, both under normal conditions and following repeated cocaine exposure. Such infor- mation is urgently needed for developing new treatments to counter drug-induced alterations in brain function that contribute to relapse.
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