Modulatory control of basal ganglia microcircuitry in cognitive flexibility and psychiatric disease

摘要 纹状体是基底神经节的主要输入结构。而纹状体则与 对于许多神经精神和神经障碍，这些障碍背后的电路机制是 很大程度上是未知的。其中几种障碍，包括强迫症(OCD)、多发性抽动症 综合征和肌张力障碍与快速放电中间神经元(FSIS)的缺陷有关，FSIS是GABA的一类 纹状体中的中间神经元。我的初步数据建立了纹状体FSIS、前馈 抑制性微电路，以及与运动障碍相关的运动序列学习。通过 建议的研究，我将调查纹状体抑制微电路的作用机制 神经精神疾病和认知灵活性。Ragozzino和他的同事已经证明了乙酰胆碱 纹状体中的水平在认知灵活性的反向学习测试中升高，认知灵活性是一种与基底神经节相关的物质。 在神经精神障碍中受损的一种学习形式。他们还表明，任务绩效依赖于 纹状体M受体(MAChR)信号的研究。我的初步结果显示 纹状体mAChR信号主要抑制FSI介导的前馈抑制，支持这一观点 FSIS的调制对任务绩效至关重要。事实上，当啮齿类动物做出 选择，特别是在冲突情况下的决策，因此很可能涉及认知灵活性。 因此，我将结合切片生理学、行为和活体记录来测试激活的假设 MAChRs抑制FSI介导的前馈抑制以增加纹状体网络的变异性 对反转学习和认知灵活性的反应。借助切片生理学，我将研究微电路， 将前馈抑制与网络变异性联系起来的神经调节和生理机制 回应。通过我开发的一个新的反转学习任务，我将测试mAChR的重要性 信号和纹状体FSIS在认知灵活性中的作用。然后，通过光遗传操作和体内生理学，我 将回答一个有争议的问题，即FSIS是否在体内抑制中棘神经元(MSN)。这就做 通过操纵FSIS和直接测试该电路如何影响活体网络反应的可变性 在反转学习中记录纹状体网络活动时的胆碱能信号。这些实验将 扩展我在认知灵活性行为分析和体内生理学数据分析方面的专业知识。我有过 召集了一个杰出的咨询委员会，其中包括基底节生理学、解剖方面的世界专家 抑制性微电路和神经调节。这个团队中的两名精神病学家将提供指导 疾病相关性的实验设计和结果。拟议中的工作将使我获得 建立和运行富有成效的独立研究计划所需的技能和初步数据 成功争取R01资金，研究纹状体微回路的认知灵活性和神经精神病学 疾病。

ABSTRACT The striatum is the primary input structure of the basal ganglia. While the striatum has been associated with many neuropsychiatric and neurological disorders, the circuit mechanisms underlying these disorders are largely unknown. Several of these disorders, including obsessive-compulsive disorder (OCD), Tourette's syndrome, and dystonia, have been linked to defects in fast-spiking interneurons (FSIs), a class of GABAeric interneurons in the striatum. My preliminary data established a connection between striatal FSIs, feed-forward inhibitory microcircuits, and motor-sequence learning that is relevant to movement disorders. Through the proposed research, I will investigate the mechanisms by which the striatal inhibitory microcircuitry contributes to neuropsychiatric disease and cognitive flexibility. Ragozzino and colleagues have shown that acetylcholine levels in the striatum are elevated during reversal learning tests of cognitive flexibility, a basal ganglia-related form of learning that is impaired in neuropsychiatric disorders. They also showed that task performance relies on muscarinic acetylcholine receptor (mAChR) signaling in the striatum. My preliminary results show that striatal mAChR signaling predominantly suppresses FSI-mediated feed-forward inhibition, supporting the idea that modulation of FSIs is critical for task performance. Indeed, striatal FSIs are active when rodents make choices, especially in decision-making under conflict, and are therefore likely involved in cognitive flexibility. Thus, I will combine slice physiology, behavior, and in vivo recordings to test the hypothesis that activation of mAChRs suppresses FSI-mediated feed-forward inhibition to increase the variability of striatal network responses for reversal learning and cognitive flexibility. With slice physiology, I will investigate the microcircuit, neuromodulatory, and physiological mechanisms linking feed-forward inhibition to variability in network responses. With a novel reversal-learning task that I developed, I will then test the importance of mAChR signaling and striatal FSIs in cognitive flexibility. Then, with optogenetic manipulation and in vivo physiology, I will answer the controversial question of whether FSIs inhibit medium spiny neurons (MSNs) in vivo. I will directly test how this circuit affects the variability of network responses in vivo by manipulating FSIs and cholinergic signaling while recording striatal network activity during reversal learning. These experiments will expand my expertise in behavioral assays of cognitive flexibility and analysis of in vivo physiology data. I have assembled an outstanding Advisory Council that includes world experts in basal ganglia physiology, dissection of inhibitory microcircuitry, and neuromodulation. Two psychiatrists on this team will provide guidance on disease relevance of the experimental design and results. The proposed work will allow me to gain the necessary skills and preliminary data to establish and run a productive independent research program and successfully compete for R01 funding to study striatal microcircuitry in cognitive flexibility and neuropsychiatric disease.