Contributions of KCNQ2/3 channels to medium spiny neuron excitability and cocaine reward

KCNQ2/3 通道对中棘神经元兴奋性和可卡因奖励的贡献

• 批准号: 10678521
• 负责人: Emily Jorgensen
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678521
• 关键词: Action Potentials; Address; Alcohols; Animal Model; Area; Awareness; Behavior; Behavioral; Biological Models; Brain; Brain region; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Consumption; Corpus striatum structure; Cues; DRD1 gene; DRD2 gene; Data; Dimensions; Disease; Dissociation; Dopamine; Dopamine Receptor; Electrophysiology (science); Epilepsy; Family member; Foundations; Future; Genes; Genetic; Genetic Transcription; Glutamates; Infusion procedures; Injections; Ion Channel Gating; Learning; Mediating; Membrane; Memory; Molecular; Mood Disorders; Neurons; Nucleus Accumbens; Overdose; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Physiology; Play; Population; Potassium Channel; Prefrontal Cortex; Prevalence; Property; Rattus; Regimen; Relapse; Research; Rewards; Role; Substance Use Disorder; Substance abuse problem; System; Testing; United States; Ventral Tegmental Area; Voltage-Gated Potassium Channel; Withdrawal; Work; behavioral plasticity; cell type; cocaine exposure; cocaine reward; cocaine seeking; cocaine self-administration; common treatment; compulsion; dopamine system; drug of abuse; drug seeking behavior; experimental study; functional plasticity; genetic manipulation; in vivo; insight; learned behavior; mesolimbic system; motivated behavior; nervous system disorder; neuronal excitability; neuropsychiatric disorder; novel; patch clamp; patch sequencing; pharmacologic; population based; psychostimulant; response; reward processing; tool; transcriptome sequencing; transmission process; voltage

PROJECT SUMMARY Substance use disorder is a multidimensional neuropsychiatric disease increasing in prevalence across the United States despite increased awareness and substantial leaps in treatment approaches. Unfortunately, these treatments commonly fail due to strongly encoded drug-associations, often resulting in relapse. Drugs of abuse, such as cocaine, act on the mesolimbic dopamine system to increase dopaminergic transmission in the nucleus accumbens (NAc), a key brain region important for reward processing. Medium spiny neurons (MSNs) within the NAc are responsive to increases in dopamine transmission. Importantly, MSNs do not generate spontaneous action potentials so changes in excitability are dependent on dopaminergic input, in addition to input from other projecting areas. When studying MSNs in relation to substance abuse, there is substantial evidence demonstrating MSNs increase their excitability following cocaine exposure or dopamine stimulation. However, very little research has examined why this happens and how voltage-gated ion channels in the NAc are implicated in cocaine-induced physiological and behavioral plasticity. My preliminary data suggests a role for KCNQ2/3, m-current, potassium channels in MSN excitability and the rewarding effects of cocaine. Although pharmacological manipulation of KCNQ2/3 channels decreases drug seeking behaviors and KCNQ2/3 channels are important for several intrinsic properties, the role of KCNQ2/3 channels in MSN excitability and cocaine- related molecular and behavioral adaptations has never been studied. In this Proposal, I will test the overarching hypothesis that KCNQ2/3 channels in the NAc are involved in functional and behavioral plasticity associated with cocaine-seeking behaviors. Specific Aim 1 of this proposal will use multiple approaches to determine how KCNQ2/3 channels influence baseline MSN excitability and establish gene-to-function relationships between KCNQ expression and MSN physiology. Specific Aim 2 will will combine CRISPR/dCas9 tools and cocaine self- administration to target specific KCNQ2/3-mediated aspects of drug related learning and compulsive drug seeking. Together, these experiments will define how KCNQ2/3 channels regulate MSN physiology, identify the relationship between KCNQ subunits and MSN excitability, and determine if KCNQ2/3 channels in the NAc modulates cocaine-related behavioral plasticity. These studies with reveal previously unknown mechanisms by which KCNQ2/3 channels contribute to psychostimulant response, and will provide a foundation for future experiments to explore how KCNQ2/3 channels contribute to motivated behavior.

项目摘要 物质使用障碍是一种多维度的神经精神疾病， 尽管认识有所提高，治疗方法也有了实质性的飞跃。可惜这些 治疗通常由于强烈编码的药物关联而失败，常常导致复发。滥用药物， 例如可卡因，作用于中脑边缘多巴胺系统以增加核中的多巴胺能传递 大脑皮层（NAc）是大脑中对奖赏处理非常重要的区域。中棘神经元（MSNs）位于 NAc对多巴胺传递的增加有反应。重要的是，MSN不会产生自发的 因此，兴奋性的变化依赖于多巴胺能输入，除了来自其他神经元的输入外， 投影区域。在研究MSN与药物滥用的关系时，有大量证据表明， 这表明MSN在可卡因暴露或多巴胺刺激后增加了它们的兴奋性。然而，在这方面， 很少有研究探讨为什么会发生这种情况，以及NAc中的电压门控离子通道是如何 与可卡因诱导的生理和行为可塑性有关。我的初步数据显示 KCNQ 2/3，M电流，钾通道在MSN兴奋性和可卡因的奖励作用。虽然 药物操纵KCNQ 2/3通道减少药物寻求行为和KCNQ 2/3通道 对于几个内在特性是重要的，KCNQ 2/3通道在MSN兴奋性和可卡因中的作用- 相关的分子和行为适应从未被研究过。在这份提案中，我将测试 假设NAc中的KCNQ 2/3通道参与与以下相关的功能和行为可塑性： 寻求可卡因的行为本提案的具体目标1将使用多种方法来确定如何 KCNQ 2/3通道影响基线MSN兴奋性，并建立基因与功能之间的关系 KCNQ表达和MSN生理学。Specific Aim 2将结合联合收割机CRISPR/dCas 9工具和可卡因自我- 靶向特定KCNQ 2/3介导的药物相关学习和强迫性药物方面的给药 寻找总之，这些实验将定义KCNQ 2/3通道如何调节MSN生理学，识别神经元的功能。 KCNQ亚基和MSN兴奋性之间的关系，并确定NAc中的KCNQ 2/3通道是否 调节可卡因相关的行为可塑性这些研究揭示了以前未知的机制， 哪些KCNQ 2/3通道有助于精神兴奋反应，并将为未来的研究提供基础。 实验来探索KCNQ 2/3通道如何促进动机行为。