The Role of 5HT3aR GABAergic interneuron in sensory-motor integration in cortex

描述（由申请人提供）： 在啮齿动物胡须相关的感觉运动系统中，感觉和运动处理在行为和解剖学上都密切相关。感觉和运动区域在大脑的不同阶段广泛相互连接。在主动搅拌过程中，与胡须相关的初级运动皮层（wM 1）的神经反应升高，而初级体感桶皮层（S1）的感觉诱发反应减弱。S1投射M1神经元的轴突在S1的颗粒下层分支，并投射到轴突大量分叉的浅层。在感觉皮层中，表层是处理感觉信息的中心。在到达丘脑受体层4时，感觉信息被转移到浅层，在那里它与来自其他柱和其他皮质区域的信息相结合。我们最近发现，5 HT 3a（5-羟色胺3a）受体表达的中间神经元（5 HT 3aR INs）是浅层GABA能神经元的主要群体，占总中间神经元群体的约60%，并且超过快峰（FS）小清蛋白（PV）表达神经元的比例的近两倍，传统上被认为是新皮层中的主要抑制系统。我们最近表明，所有5 HT 3aR神经元都被分别作用于离子型5 HT 3a和烟碱受体的5-羟色胺（5 HT）和乙酰胆碱（ACh）有力地调节（Lee等人，in pres）。因此，5 HT 3aR INs独特地准备通过其在特定的大脑状态和行为背景下传递会聚神经调节传入的快速效应的能力来影响皮层感觉过程。基于5 HT 3aR INs的位置和患病率以及S1浅层M1输入的广泛神经支配，我假设来自wM 1的输入直接激活5 HT 3aR INs，从而对wM 1到S1电路的感觉运动整合提供前馈抑制。我将研究M1输入到S1浅层的5 HT 3aR神经元，并使用体外和体内电生理学结合光遗传学方法通过皮层下神经调节输入来调节这些输入。这些研究将有助于理解感觉运动计算的电路机制，并为新皮层的真际通信提供原型。! 公共卫生相关性： 神经调质系统如血清素和乙酰胆碱提供了一种机制，通过这种机制，皮质下核团中的小群神经元可以广泛地影响皮质网络的活动。相反，这种皮层回路调节的中断可能会损害各种生理过程，包括认知功能，并可能导致各种神经和精神疾病，包括精神分裂症和情绪障碍。这些上行神经调节系统对皮层的深刻影响可能源于它们优先靶向皮层GABA能抑制性中间神经元。我们最近发现表达5-羟色胺3a（5- hydroxytryptamine 3a）受体的中间神经元（5 HT 3aR INs）是浅层GABA能神经元的主要群体，占总中间神经元群体的约60%。我们的研究表明，所有的5-HT 3a受体神经元都受到5-羟色胺（5-HT）和乙酰胆碱（ACh）的有效调节，分别作用于离子型5-HT 3a和烟碱受体。在感觉皮层中，表层是将感觉处理与来自其他列和其他皮层区域的信息整合的中心。因此，5 HT 3aR INs独特地准备通过其在特定的大脑状态和行为背景下传递会聚神经调节传入的快速效应的能力来影响皮层感觉过程。该项目将阐明5 HT 3aR中间神经元在皮层的跨区域通信中的作用，并将提供神经调节剂可以对正在进行的皮层活动施加控制的电路机制之一。

DESCRIPTION (provided by applicant): In the rodent whisker-related sensorimotor system, sensory and motor processing are tightly related both behaviorally and anatomically. Sensory and motor areas are extensive interconnected throughout different stages in the brain. During active whisking, neural responses in whisker-related primary motor cortex (wM1) are elevated, yet sensory-evoked responses in primary somatosensory barrel cortex (S1) are attenuated. Axons of S1-projecting M1 neurons branch off in infragranular layers of S1 and project to superficial layers where the axons ramify profusely. In sensory cortex, superficial layers are central to the processing of sensory information. Upon arrival to thalamo-recipient layer 4, sensory information is transferred to superficial layers, where it is integrated with information from other columns and other cortical areas. We recently found that 5HT3a (5-hydroxytryptamine 3a) receptor-expressing interneurons (5HT3aR INs) are the major population of GABAergic neurons in superficial layers, representing about 60% of the total interneuron population, and exceeding nearly two fold the proportion of fast-spiking (FS) parvalbumin (PV) expressing neurons, traditionally viewed as the dominant inhibitory system in neocortex. We recently showed that all 5HT3aR neurons are potently modulated by serotonin (5HT) and acetylcholine (ACh) acting on ionotropic 5HT3a and nicotinic receptors, respectively (Lee et al., in pres). Thus, 5HT3aR INs are uniquely poised to influence cortical sensory processes through their ability to convey fast effects of convergent neuromodulatory afferents during specific brain states and behavioral contexts. Based on location and prevalence of 5HT3aR INs together with extensive innervations of M1 inputs in superficial layers of S1, I hypothesize that inputs from wM1 directly activate 5HT3aR INs, thus providing feedforward inhibition in sensroimotor integration of the wM1-to-S1 circuitry. I wil investigate M1 inputs to 5HT3aR neurons in S1 superficial layers and the modulation of those inputs by subcortical neuromodulatory inputs using in vitro and in vivo electrophysiology combined with optogenetic methods. These studies will contribute to understanding circuit mechanisms of sensorimotor computation, and serve as a prototype of interareal communication in neocortex. ! PUBLIC HEALTH RELEVANCE: Neuromodulator systems such as serotonin and acetylcholine provide a mechanism by which small groups of neurons in subcortical nuclei can broadly influence activity in cortical networks. Conversely, disruption of such modulation of cortical circuits may impair various physiological processes, including cognitive function, and can potentially lead to diverse neurological and psychiatric disorders, including schizophrenia and mood disorders. The profound influence of these ascending neuromodulatory systems on cortex likely stems from their preferential targeting of cortical GABAergic inhibitory interneurons. We recently found that 5HT3a (5- hydroxytryptamine 3a) receptor-expressing interneurons (5HT3aR INs) are the major population of GABAergic neurons in superficial layers, representing about 60% of the total interneuron population. Our study showed that all 5HT3aR neurons are potently modulated by serotonin (5HT) and acetylcholine (ACh) acting on ionotropic 5HT3a and nicotinic receptors, respectively. In sensory cortex, superficial layers are central to integrate sensory processing with information from other columns and other cortical areas. Thus, 5HT3aR INs are uniquely poised to influence cortical sensory processes through their ability to convey fast effects of convergent neuromodulatory afferents during specific brain states and behavioral contexts. This project will elucidate the role of a 5HT3aR interneurons in interareal communication of cortex and will provide one of the circuit mechanisms by which neuromodulators can exert control over ongoing cortical activity.