Serotonergic Modulation of Fast-Spiking Interneurons in Medial Prefrontal Cortex

项目总结/摘要 前额叶皮层（PFC）是一个高度进化的大脑区域，负责指挥更高的秩序， 从决策到社会认知的认知功能。这些复杂的行为 来自PFC中单个神经元的同步放电，这一过程引起了 神经元振荡或脑节律。伽马频率范围（30 - 90 Hz）内的振荡可能会播放 在行为过程中，前额叶皮层在信息编码中起着关键作用。重要的是， 在精神分裂症患者中观察到PFC γ节律，这意味着PFC的改变 γ振荡可能有助于这种疾病的病理生理学，或作为生物标志物， 疾病快速发放中间神经元（FSI）是PFC中抑制性中间神经元的一个子集， 通过躯体抑制控制兴奋性神经元放电的时间来控制伽马节律。有效 集成输入，PFC必须灵活地调节行为期间的伽马振荡功率。 5-羟色胺（5-HT），一种在脑干中产生并分泌的调节性神经递质 在整个大脑中，可以影响其他皮层区域的大脑节律，但目前还不清楚， 5 HT通过FSI调节PFC节律。前额叶和FSI功能障碍都是 精神分裂症和第二代抗精神病药物以高亲和力靶向5 HT受体。因此，我们认为， 确定5 HT如何通过FSI调节前额γ振荡将广泛地告知我们， 了解精神分裂症的病因，并可能导致这种流行的新疗法 disorder. 我将使用体外电生理学结合尖端的光遗传学和 化学遗传学工具，双光子显微镜，谷氨酸释放，和体内生理学，以确定 5 HT介导的FSI兴奋性在细胞和网络水平的变化的功能后果。 然后，我将使用行为分析，以确定如何在FSI兴奋性的变化影响行为， 精神分裂症的动物模型。

PROJECT SUMMARY/ABSTRACT The prefrontal cortex (PFC) is a highly evolved brain region that is responsible for directing higher order cognitive functions ranging from decision making to and social cognition. These complex behaviors emerge from the synchronous firing of individual neurons in the PFC, a process which gives rise to neuronal oscillations, or brain rhythms. Oscillations in the gamma frequency range (30 – 90Hz) may play a key role in information encoding in the PFC during behavior. Importantly, deficits in the generation of PFC gamma rhythms are observed in patients with schizophrenia, which implies that alterations in PFC gamma oscillations may contribute to the pathophysiology of this disorder, or act as a biomarker for disease. Fast-spiking interneurons (FSIs), a subset of inhibitory interneurons in the PFC, coordinate gamma rhythms by controlling the timing of excitatory neuron firing via somatic inhibition. To effectively integrate inputs, the PFC must flexibly regulate the power of gamma oscillations during behavior. Serotonin (5HT), a modulatory neurotransmitter that is produced in the brain stem and secreted throughout the brain, can influence the power of brain rhythms in other cortical regions but it is unclear if 5HT modulates PFC rhythms via FSIs. Both prefrontal and FSI dysfunction are prominent features of schizophrenia, and second-generation antipsychotic drugs target 5HT receptors with high affinity. Therefore, identifying how 5HT modulates prefrontal gamma oscillations via FSIs will broadly inform our understanding of the etiology of schizophrenia and potentially lead to novel therapies for this prevalent disorder. I will use a combination of in vitro electrophysiology coupled with cutting-edge optogenetic & chemogenetic tools, two-photon microscopy, glutamate uncaging, and in vivo physiology to determine the functional consequences of 5HT-mediated changes in FSI excitability at the cellular and network levels. Then I will use a behavioral assay to determine how changes in FSI excitability influence behavior in an animal model of schizophrenia.