Cholinergic interneuron D2 receptor function in impulsive behavior: implications for addiction

项目摘要 慢性可卡因滥用与冲动控制和决策的长期损害有关， 增加复发的风险。然而，大脑回路从根本上涉及冲动行为及其 慢性药物使用引起的改变尚不清楚。在人类和动物身上积累的证据表明 多巴胺D2受体（D2 Rs），但由于它们在不同的神经元中广泛表达， 虽然D2 R在冲动行为中起关键作用，但仍不清楚。特别是捐款 胆碱能中间神经元（CINs）仅占NAc神经元的2-3%， 尽管已知CIN对NAc功能和可卡因强化的贡献，但这一点被忽视了。为了填补这个空白， 知识，迫切需要阐明的后果，D2 R的改变，在CIN的冲动行为， 更高的细胞类型特异性。我们的长期目标是阐明NAc的细胞和电路机制， CINs调节冲动行为，这可能揭示减少可卡因再利用的潜在治疗策略。 失效本申请的总体目标是使用细胞选择性策略来：1）确定是否和 CIN D2 Rs如何介导冲动行为，以及2）CIN D2 Rs是否参与可卡因诱导的augmen- 抑制冲动。我们的中心假设是CIN D2 Rs通过改变NAc ace介导冲动行为， 乙酰胆碱（ACh）释放预测线索，慢性可卡因通过CIN导致过度冲动 D2R。目的1将在小鼠中使用细胞类型特异性遗传方法双向改变CIN中D2 R的表达 为了测试对延迟折扣任务的影响，该任务评估了对小的，短期奖励的偏好， 更大的延迟奖励。采用在体光纤光度法结合光遗传学，Aim 2将测定ACh 动态延迟折扣和测试是否ACh暂停响应线索调制冲动的选择。 目标3将确定CIN D2 Rs和CIN暂停是否介导冲动选择的增加， 长期接触可卡因这项申请中提出的研究是创新的，因为它使用了有针对性的 方法在行为小鼠检查一个以前未被认识的作用NAc CIN和它的D2 Rs在冲动， 热情成功地完成所提出的目标，从而产生一个新的解剖神经元的机制 在正常情况下和反复接触可卡因后，这样的信息- 开发新的治疗方法来对抗药物引起的脑功能改变， 会导致复发

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.