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

项目摘要/摘要 在美国，有超过4000万人患有物质使用障碍(SUD)，治疗SUD的疗法有 几十年来仍然基本上是不够的。SUD治疗的关键挑战之一是许多药物 滥用，包括可卡因，对认知灵活性有负面影响，使患者不太可能戒毒 使用。一项新的文献表明，5-羟色胺2A受体(5HT2AR)的激动剂，迷幻剂 迷幻剂在改善长期认知灵活性方面具有显著的潜力，并对治疗产生影响 各种精神障碍，包括药物使用。5HT2AR在卵巢癌中的表达密度最高 大脑位于屏状核(CLA)，这是一种未被研究的皮质下结构，具有广泛的额叶神经支配。 皮质区域。CLA的主要投射靶点是前扣带回，CLA和CLA 而ACC被认为与药物寻觅行为和认知灵活性的调节有关。我的初选 大鼠的行为数据显示，延长自我注射可卡因的途径可诱导认知灵活性 在策略集转移任务中存在缺陷，而CLA中5HT2AR同样强健地调节集转移任务 性能。初步电生理数据显示，5-羟色胺对谷氨酸能有抑制作用 CLA神经元通过激活CLA 5HT2ARs投射到ACC(CLA-ACC神经元)的神经传递。 此外，通过5HT2ARs传递的5-羟色胺能信号对CLA的长期可塑性有深远的影响 突触。我的初步数据显示，5HT2AR激动剂DOI的应用逆转了峰波时序- 依赖的长时程增强抑制(t-LTD)在CLA-ACC神经元中的作用，而不是促进时间依赖性的峰电位 这些细胞中谷氨酸能信号的长时程增强(t-ltp)。目前的提案将考验 可卡因改变CLA-ACC长时程突触可塑性的假说 神经元导致认知灵活性缺陷和寻求药物行为的增加。我推测一张单曲 CLA中5HT2ARs的激活逆转可卡因诱导的LTD，并长期改善认知功能 灵活性导致寻求可卡因行为的减弱恢复。我将通过有针对性的测试来检验这个假设 将DOI微量注射到接受过自我注射可卡因训练的大鼠的CLA。我会用膜片钳 电生理学建立5-羟色胺能调节依赖于峰时的可塑性的时序规则 可卡因暴露大鼠CLA-ACC神经元上的兴奋性突触。最后，我将把化学遗传学与 在含有ACC的脑片上进行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大鼠。这项提议的发现将揭示CLA 5-羟色胺作为一种 物质使用研究的新区域目标，并具体探讨CLA中5HT2ARs对 皮质调节的认知灵活性缺陷与可卡因的使用有关。

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.