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

胆碱能中间神经元 D2 受体在冲动行为中的功能：对成瘾的影响

• 批准号: 10651609
• 负责人: Eduardo Francisco Gallo
• 金额: $ 37.65万
• 依托单位: FORDHAM UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651609
• 关键词: Acetylcholine; Animals; Behavior; Behavioral; Binding; Brain; Brain imaging; Cells; Chronic; Cocaine; Cocaine Abuse; Cues; Data; Decision Making; Development; Dissection; Dopamine; Dopamine D2 Receptor; Drug Addiction; Drug abuse; Drug usage; Female; Fiber; Goals; Health; Human; Impairment; Impulsive Behavior; Impulsivity; Internal Ribosome Entry Site; Interneurons; Knock-out; Knowledge; Lead; Link; Literature; Measures; Mediating; Methods; Motivation; Mus; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Phenotype; Photometry; Play; Population; Process; Psychological reinforcement; Receptor Gene; Receptor Up-Regulation; Relapse; Research; Rewards; Rodent; Role; Shapes; Signal Transduction; Specificity; Testing; Therapeutic; Up-Regulation; Viral; addiction; cell type; cholinergic; cocaine exposure; cocaine relapse; cocaine related behaviors; discounting; dopaminergic neuron; drug of abuse; drug relapse; genetic approach; in vivo; innovation; male; nerve supply; neural circuit; neurotransmission; novel; novel therapeutic intervention; optogenetics; outcome prediction; pharmacologic; preclinical study; preference; prevent; radioligand; receptor expression; receptor function; receptor upregulation; relapse risk; response; sensor; stimulant exposure

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.

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，大脑回路基本上参与了冲动行为和他们的 慢性药物使用引起的改变还没有被很好地理解。在人类和动物身上积累的证据表明 伏核(NAC)多巴胺D2受体(D2Rs)在不同神经元中广泛表达 在人群中，目前还不清楚哪些D2R在冲动行为中起关键作用。特别是，这些贡献 胆碱能中间神经元(CINs)中仅占NAC神经元的2%-3%的D2Rs的 被忽视，尽管已知CIN对NAC功能和可卡因强化有贡献。为了填补我们在这方面的空白 知识，迫切需要阐明CIN中D2R变化对冲动行为的影响 更强的细胞类型特异性。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，可能发现减少可卡因复发的潜在治疗策略 过错。此应用程序的总体目标是使用细胞选择策略：1)确定是否和 CIN D2Rs如何调节冲动行为，以及2)CIN D2Rs是否参与可卡因诱导的增强。 冲动的情绪。我们的中心假设是，CIN D2Rs通过改变NAC-Ace来调节冲动行为。 乙酰胆碱(ACh)的释放遵循预测性线索，慢性可卡因通过CIN导致过度冲动 D2Rs。AIM 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D2R的表达 为了测试对延迟折扣任务的影响，该任务评估对小额短期奖励的偏好 更大的、延迟的奖励。利用体内纤维光度法和光遗传学相结合，Aim 2将测定ACh 在延迟折扣中的动力学，并测试ACh对线索的反应暂停是否调节了冲动选择。 目标3将确定CIN D2Rs和CIN停顿是否调节由此导致的冲动选择的增加 是长期接触可卡因造成的。本申请中提出的研究具有创新性，因为它使用了有针对性的 小鼠研究NAC CIN及其D2Rs在免疫中以前未知的作用的方法 神秘感。因此，成功完成所提出的目标将产生对神经元机制的新的剖析 在正常情况下和在反复接触可卡因后，都在冲动选择中发挥作用。这样的信息- 迫切需要信息来开发新的治疗方法来对抗药物引起的脑功能改变 会导致旧病复发。