Claustrum serotonin and spike-timing plasticity associated with cognitive deficits after cocaine

克劳斯特鲁姆血清素和峰值时间可塑性与可卡因后认知缺陷相关

基本信息

批准号：
10604448
负责人：
Tanner Anderson
金额：
$ 3.62万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-11-01 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604448
关键词：
Agonist Animals Anterior Area Attenuated Behavior Behavioral Bilateral Brain Cells Cerebral Dominance Claustral structure Cocaine Cognitive Cognitive deficits Data Drug Regulations Drug usage Electrophysiology (science)Excitatory Synapse Functional Magnetic Resonance Imaging Genetic Glutamates Goals Habits Hallucinogens Human Image Individual Insula of Reil Investigation Link Literature Long-Term Depression Long-Term Potentiation Major Depressive Disorder Mediating Mediator Mental disorders Microinjections Modeling Modification Neurons Output Patients Pattern Pharmaceutical Preparations Picrotoxin Protocols documentation Rattus Recording of previous events Regulation Relapse Research Role Saline Scientist Serotonin Serotonin Agonists Serotonin Receptor 5-HT2A Signal Transduction Slice Structure Substance Use Disorder Substance abuse problem Symptoms Synapses Synaptic plasticity Task Performances Testing Therapeutic Training Withdrawal antagonist behavioral phenotyping career development cingulate cortex cocaine exposure cocaine seeking cocaine self-administration cocaine use density drug development drug of abuse drug relapse drug seeking behavior experience experimental study flexibility glutamatergic signaling improved in vivo in vivo Model nerve supply neurotransmission novel patch clamp putamen receptor substance use substance user synaptic inhibition

项目摘要

Project Summary/Abstract Over 40 million individuals in the US have a substance use disorder (SUD), and therapies for treating SUD have remained largely inadequate for decades. One of the key challenges in SUD treatment is that many drugs of abuse, including cocaine, negatively impact cognitive flexibility, leaving patients less likely to abstain from drug use. An emerging body of literature shows that agonists of the serotonin 2A receptor (5HT2AR), psychedelic hallucinogens, have remarkable potential for improving long-term cognitive flexibility with implications for treating various psychiatric disorders, including substance use. The highest density of the 5HT2AR expression in the brain is in the claustrum (CLA), an understudied subcortical brain structure with extensive innervation of fronto- cortical areas. The main projection target of the CLA is the anterior cingulate cortex (ACC), and both the CLA and the ACC have been implicated in regulation of drug-seeking behavior and cognitive flexibility. My preliminary behavioral data in rats show that extended access to self-administered cocaine induces cognitive flexibility deficits in a strategy set-shift task, and that 5HT2ARs in the CLA likewise robustly modulate set-shift task performance. Preliminary electrophysiology data show that 5HT induces inhibition of glutamatergic neurotransmission in CLA neurons projecting to the ACC (CLA-ACC neurons) by activating CLA 5HT2ARs. Furthermore, serotonergic signaling via the 5HT2ARs has a profound impact on long-term plasticity of CLA synapses. My preliminary data indicate that application of 5HT2AR agonist, DOI, reverses spike timing- dependent long-term depression (t-LTD) in CLA-ACC neurons and promotes, instead, spike timing-dependent long-term potentiation (t-LTP) of glutamatergic signaling in these cells. The current proposal will test the hypothesis that cocaine changes the timing window for induction of long-term synaptic plasticity in CLA-ACC neurons resulting in cognitive flexibility deficits and increased drug seeking behavior. I speculate that a single activation of 5HT2ARs in the CLA reverses cocaine-induced LTD, with a long-term improvement of cognitive flexibility leading to attenuated reinstatement of cocaine-seeking behavior. I will test this hypothesis by targeted microinjections of DOI into the CLA of rats trained to self-administer cocaine. I will use patch-clamp electrophysiology to establish the timing rules for serotonergic modulation of spike-timing dependent plasticity of excitatory synapses onto CLA-ACC neurons of cocaine exposed rats. Finally, I will combine chemogenetics with Ca2+ imaging in ACC-containing brain slices to establish the extent to which CLA neurons control ACC excitability in control and cocaine experienced rats. The findings of this proposal will reveal the role of CLA serotonin as a novel regional target for substance use research and specifically explore the impact of 5HT2ARs in the CLA on cortically-mediated cognitive flexibility deficits linked to cocaine use.

项目概要/摘要在美国，超过 4000 万人患有物质使用障碍 (SUD)，治疗 SUD 的疗法已几十年来仍然基本不足。 SUD 治疗的主要挑战之一是许多药物包括可卡因在内的滥用会对认知灵活性产生负面影响，使患者戒毒的可能性降低使用。大量新兴文献表明，血清素 2A 受体 (5HT2AR) 激动剂具有迷幻作用致幻剂，具有改善长期认知灵活性的显着潜力，对治疗具有影响各种精神疾病，包括药物滥用。 5HT2AR表达密度最高大脑位于屏状核（CLA），这是一种尚未研究的皮层下大脑结构，具有广泛的额叶神经支配皮质区域。 CLA的主要投射目标是前扣带皮层（ACC），CLA ACC 与药物寻求行为和认知灵活性的调节有关。我的初步大鼠的行为数据表明，延长自我施用可卡因的使用范围可诱导认知灵活性策略设置转换任务中的缺陷，并且 CLA 中的 5HT2AR 同样可以有力地调节设置转换任务表现。初步电生理学数据显示 5HT 会抑制谷氨酸能通过激活 CLA 5HT2AR，CLA 神经元中的神经传递投射到 ACC（CLA-ACC 神经元）。此外，通过 5HT2AR 的血清素信号对 CLA 的长期可塑性具有深远的影响突触。我的初步数据表明，5HT2AR 激动剂 DOI 的应用可逆转尖峰时间 - CLA-ACC 神经元中依赖性长期抑制（t-LTD）并促进尖峰时间依赖性这些细胞中谷氨酸信号的长期增强（t-LTP）。目前的提案将测试假设可卡因改变了 CLA-ACC 中诱导长期突触可塑性的时间窗口神经元导致认知灵活性缺陷和寻药行为增加。我推测单个 CLA 中 5HT2AR 的激活可逆转可卡因诱导的 LTD，从而长期改善认知能力灵活性导致可卡因寻求行为的恢复减弱。我将有针对性地检验这个假设将 DOI 显微注射到接受过自我注射可卡因训练的大鼠的 CLA 中。我将使用膜片钳电生理学建立了峰值时间依赖性可塑性的血清素调节的时间规则可卡因暴露大鼠的 CLA-ACC 神经元上的兴奋性突触。最后，我将把化学遗传学与对含有 ACC 的脑切片进行 Ca2+ 成像，以确定 CLA 神经元控制 ACC 兴奋性的程度在对照组和可卡因经历过的老鼠中。该提案的研究结果将揭示 CLA 血清素作为物质使用研究的新区域目标，并专门探讨 CLA 中 5HT2AR 的影响与可卡因使用相关的皮质介导的认知灵活性缺陷。