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

项目总结/摘要 在美国，超过4000万个体患有物质使用障碍（SUD），并且用于治疗SUD的疗法具有以下优点： 几十年来基本上是不够用的。SUD治疗的关键挑战之一是许多药物 滥用，包括可卡因，对认知灵活性产生负面影响，使患者不太可能戒除药物 使用.新出现的大量文献表明，5-羟色胺2A受体（5 HT 2AR）激动剂、迷幻剂、抗抑郁剂 致幻剂，有显着的潜力，改善长期的认知灵活性与治疗的影响， 各种精神疾病，包括药物使用。5 HT 2AR在正常人肝组织中的表达密度最高， 大脑位于屏状核（CLA），这是一种研究不足的皮质下大脑结构，具有广泛的额-额神经支配， 皮质区CLA的主要投射靶区是前扣带皮层（ACC）， 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，长期服用可卡因会诱导认知灵活性， 在策略集移任务中的缺陷，并且CLA中的5 HT 2ARs同样稳健地调节集移任务 性能初步的电生理学数据表明，5-HT诱导抑制多巴胺能神经元， 通过激活CLA 5 HT 2AR，在投射到ACC的CLA神经元（CLA-ACC神经元）中的神经传递。 此外，通过5 HT 2ARs的CLA能信号传导对CLA的长期可塑性具有深远的影响 突触我的初步数据表明，应用5 HT 2AR激动剂DOI，逆转了尖峰时间- 依赖性长期抑制（t-LTD）在CLA-ACC神经元和促进，而不是，尖峰时间依赖性 在这些细胞中的谷氨酸能信号的长时程增强（t-LTP）。目前的提案将测试 可卡因改变CLA-ACC中诱导长时程突触可塑性的时间窗的假说 导致认知灵活性缺陷和增加的药物寻求行为的神经元。我推测， CLA中5 HT 2 AR的激活可逆转可卡因诱导的LTD，并长期改善认知能力 灵活性导致可卡因寻求行为的减弱恢复。我将通过有针对性的 将DOI微量注射到训练自我施用可卡因的大鼠的CLA中。我会用膜片钳 电生理学建立5-羟色胺调节尖峰定时依赖性可塑性的定时规则 兴奋性突触连接到可卡因暴露大鼠的CLA-ACC神经元。最后，我将联合收割机化学遗传学与 在含有ACC的脑切片中进行Ca 2+成像，以确定CLA神经元控制ACC兴奋性的程度 在对照组和可卡因组大鼠中。这项提案的发现将揭示CLA血清素作为一种免疫调节剂的作用。 物质使用研究的新区域目标，特别是探索CLA中5 HT 2ARs对 皮质介导的认知灵活性缺陷与可卡因使用有关。

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.