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，感觉和运动加工在行为和解剖学上都有着密切的联系。感觉和运动区在大脑的不同阶段有着广泛的相互联系。在主动甩动过程中，与胡须相关的初级运动皮质(WM1)的神经反应升高，而初级躯体感觉桶皮质(S1)的感觉诱发反应减弱。投射S1的M1神经元的轴突在S1的颗粒下层中分支，并投射到浅层，在那里轴突大量分支。在感觉皮层，浅层是处理感觉信息的中心。当到达丘脑接受层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整合在一起。我们最近发现，表达5HT3a(5-羟色胺3a)受体的中间神经元(5HT3aR Ins)是浅层GABA能神经元的主要组成部分，约占中间神经元总数的60%，是传统上被认为是新皮质优势抑制系统的快速峰(FS)小白蛋白(PV)表达神经元的近两倍。我们最近发现，所有的5HT3aR神经元都分别受到作用于电离型5HT3a和烟碱受体的5-羟色胺(5HT)和乙酰胆碱(ACh)的有效调制(Lee等人，在PRES中)。因此，5HT3aR INS通过其在特定大脑状态和行为环境中传递汇聚神经调制传入的快速效应的能力，独特地准备影响皮质感觉过程。根据5HT3aR INS的位置和流行情况，以及M1输入在S1浅层的广泛神经支配，我假设来自WM1的输入直接激活5HT3aR INS，从而在WM1到S1电路的感觉运动整合中提供前馈抑制。我将利用体外和体内电生理学与光遗传学相结合的方法，研究M1对S1浅层5HT3aR神经元的传入以及皮质下神经调制传入对这些传入的调节。这些研究将有助于理解感觉运动计算的回路机制，并作为新皮质区域间通信的原型。好了！ 公共卫生相关性： 5-羟色胺和乙酰胆碱等神经调节系统提供了一种机制，通过这种机制，皮质下核团中的小群神经元可以广泛影响皮质网络的活动。相反，这种皮层回路调制的中断可能会损害包括认知功能在内的各种生理过程，并可能导致各种神经和精神障碍，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质GABA能抑制性中间神经元。我们最近发现，表达5HT3a(5-羟色胺3a)受体的中间神经元(5HT3aR Ins)是浅层GABA能神经元的主要组成部分，约占中间神经元总数的60%。我们的研究表明，所有的5HT3aR神经元都受到5-羟色胺(5-HT)和乙酰胆碱(ACh)分别作用于电离型5HT3a和烟碱受体的有效调制。在感觉皮层，浅层是将感觉处理与来自其他柱和其他皮质区域的信息整合在一起的中心。因此，5HT3aR INS通过其在特定大脑状态和行为环境中传递汇聚神经调制传入的快速效应的能力，独特地准备影响皮质感觉过程。该项目将阐明5HT3aR中间神经元在皮层区域间通信中的作用，并将提供神经调节剂对正在进行的皮质活动进行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.