Differential Excitation of Cortical Neurons by Somatosensory Inputs

描述（由申请人提供）：目的：本研究旨在研究丘脑传入事件控制皮层神经元兴奋性的突触机制。它的重点是丘脑对啮齿动物体感“桶”皮层的投射，即来自触须的触觉信息的皮层输入。具体来说，我将试图确定丘脑皮层传入事件如何产生中间神经元和主细胞的差异兴奋，并表征调节从丘脑到皮层传递的受体亚型。我将使用小鼠丘脑皮质切片作为模型系统，并使用电生理学、形态学和成像技术来分析突触功能。背景：体感信息通过丘脑的传入投射进入皮层。在啮齿类动物的初级体感觉皮层中，丘脑皮层传入事件携带来自须的信息。在这里，这些传入事件在抑制性中间神经元和兴奋性主细胞上形成突触。因此，丘脑皮质纤维在两种皮层细胞之间分配信息，设定了皮层处理的初始阶段。丘脑皮层纤维向中间神经元和主细胞的分化为体感觉皮层的突触前馈抑制提供了基础，这对于加强皮层对须刺激反应的时间精度至关重要。丘脑皮层传入事件通过向中间神经元产生比主细胞更大的输入来支持这个重要的失联回路，从而建立一个“故障安全”来确保前馈抑制。然而，尚不清楚丘脑皮质纤维介导中间神经元和主细胞的差异输入的机制。目的1：确定丘脑皮质传入神经元对抑制性中间神经元的强输入的机制。通过记录丘脑皮质切片中的神经元并刺激丘脑，我将确定是什么产生了更强的输入，以抑制性中间神经元接收来自丘脑的输入。目的2：表征负责从丘脑到皮层突触传递的受体亚型，并确定它们在塑造局部前馈抑制回路行为中的作用。公共卫生相关性：通过使用丘脑皮质系统确定传递到皮层的功能特性，我希望能够深入了解丘脑受体层中控制兴奋和抑制之间平衡的机制，以及有助于皮层对触觉刺激的区分。对调节皮质兴奋性的因素的更深入的了解可能有助于开发旨在预防皮质区癫痫发生的治疗方法。

DESCRIPTION (provided by applicant): PURPOSE: This proposal addresses the synaptic mechanisms by which thalamic afferents control the excitability of cortical neurons. It is focused on the thalamic projection to the rodent somatosensory "barrel" cortex, the cortical input of tactile information originating from the whiskers. Specifically, I will seek to determine how thalamocortical afferents produce differential excitation of interneurons and principal cells, and characterize the receptor subtypes that regulate transmission from the thalamus into the cortex. I will use the mouse thalamocortical slice as a model system, and electrophysiological, morphological and imaging techniques to assay synaptic function. BACKGROUND: Somatosensory information enters the cortex via afferent projections from the thalamus. In the primary somatosensory cortex of rodents, thalamocortical afferents carry information originating from the whiskers. Here, these afferents make synapses onto both inhibitory interneurons and excitatory principal cells. Thalamocortical fibers thus distribute information between two cortical cells types, setting the initial phase of cortical processing. The divergence of thalamocortical fibers onto interneurons and principal cells provides the basis for disynaptic feed-forward inhibition in the somatosensory cortex, which is critical for enforcing the temporal precision of cortical responses to whisker stimulation. Thalamocortical afferents support this vital disynaptic circuit by producing larger inputs onto interneurons than principal cells, thereby establishing a "fail-safe" to ensure feed-forward inhibition. It is not known, however, what mechanisms allow thalamocortical fibers to mediate differential input to interneurons and principal cells. AIM 1: Determine the mechanisms underlying the stronger input of thalamocortical afferents onto inhibitory interneurons. By recording from neurons in thalamocortical slices and stimulating the thalamus, I will determine what produces stronger inputs to inhibitory interneurons receiving input from the thalamus. AIM 2: Characterize the receptor subtypes responsible for synaptic transmission from the thalamus to the cortex, and determine their role in shaping the behavior of local feed-forward inhibitory circuits. PUBLIC HEALTH RELAVENCE: By determining the functional properties of transmission into the cortex using the thalamocortical system, I hope to gain insight into the mechanisms that control the balance between excitation and inhibition in thalamic recipient layers, and that contribute to the cortical discrimination of tactile stimuli. A deeper understanding of the factors that regulate cortical excitability may contribute to the development of therapies aimed at preventing epileptogenesis in cortical areas.