Network modulators of auditory thalamocortical feedback inhibition

项目摘要/摘要 听觉信息的准确编码和过滤依赖于听觉丘脑皮质回路， 其功能障碍与耳鸣和自闭症谱系障碍(ASD)有关。在这个回路中，丘脑 网状核影响听觉丘脑皮质神经元编码和活动以确定参数 注意力和刺激选择，但对这一回路的理解是不完整的。显然，丘脑和大脑皮层 传入神经调节丘脑网状核，但也涉及丘脑皮质外的其他区域。 在塑造TRN的感官过滤特性方面。我们假设大脑中整合了多个- 用来形成内部预测或确定情绪状态的通道感觉信息对于“调谐”情绪很重要。 TRN神经元通过调节TRN活动、听觉编码和感觉选择的过滤特性 行为。初步数据显示，小脑输出核团(感觉运动预测)和杏仁核(情绪) 直接投射到丘脑网状核-一个抑制丘脑感觉神经元 调节刺激编码、选择和注意力。小脑和丘脑之间的这种直接联系 网状核可能是多模式感觉信息和相关信息传递的重要通道 关于时间和空间中周围事件的预测(例如，多个声刺激源的变化， 背景噪音等)。同样，从杏仁核到丘脑网状核的直接投射可能 提供控制对特定刺激的选择和注意的情感环境(例如，在 压力大的环境)。虽然这些联系的解剖学证据很清楚，但小脑和大脑的功能 杏仁核至丘脑网状核的投射、细胞类型特异性回路及随后对 听觉丘脑神经元是一个广为人知的概念。为了解决这一知识差距，并制定全面的 模型，我们将进行全细胞记录和免疫组织化学/原位杂交 丘脑网状核(目标1)、小脑核和杏仁核(目标2)中的神经元将识别 这些通路在细胞水平上的功能。使用光遗传学方法，我们将评估神经递质 由每个投射(目标1)释放，以及形成该投射的神经元的功能和分子同一性 在小脑核团和杏仁核(目标2)。这些数据将为确定功能 小脑和/或杏仁核投射至丘脑网状核的影响 网络，影响丘脑的听觉处理，以及这些投射在刺激中的参与 选择和注意。

PROJECT SUMMARY/ABSTRACT Accurate coding and filtering of auditory information depends on the auditory thalamocortical circuit, dysfunction of which is linked to tinnitus and Autism Spectrum Disorder (ASD). Within this circuit, the thalamic reticular nucleus influences auditory thalamocortical neuron coding and activity to determine parameters of attention and stimulus selection, but an understanding of this circuit is incomplete. Clearly, thalamic and cortical afferents modulate the thalamic reticular nucleus, but other extrathalamocortical brain regions are also involved in shaping the sensory filtering properties of the TRN. We hypothesize that brain regions which integrate multi- modal sensory information to form internal predictions or determine emotional state are important for ‘tuning’ the filtering properties of TRN neurons through modulation of TRN activity, auditory coding, and sensory selection behaviors. Preliminary data indicate cerebellar output nuclei (sensorimotor predictions) and amygdala (emotion) directly project to the thalamic reticular nucleus – a brain region that inhibits sensory thalamic neurons to modulate stimulus coding, selection, and attention. This direct connection between cerebellum and thalamic reticular nucleus may be an important conduit for the relay of multi-modal sensory information and related predictions about surrounding events in time and space (e.g. changes in multiple acoustic stimuli sources, background noise, etc.). Likewise, a direct projection from the amygdala to the thalamic reticular nucleus may provide emotional context regulating selection of and attention to specific stimuli (e.g. heightened perception in stressful environments). While anatomical evidence for these connections is clear, the function of cerebellar and amygdala projections to thalamic reticular nucleus, cell type-specific circuitry, and subsequent influence on auditory thalamic neurons is widely unknown. To address this knowledge gap and develop a comprehensive model of this circuitry, we will perform whole cell recordings and immunohistochemistry/in situ hybridization on neurons in the thalamic reticular nucleus (Aim 1), cerebellar nuclei, and amygdala (Aim 2) that will identify the function of these pathways at a cellular level. Using an optogenetic approach, we will assess the neurotransmitter released by each projection (Aim 1) and the functional and molecular identity of neurons forming this projection in cerebellar nuclei and amygdala (Aim 2). These data will provide a foundation for identifying the functional impact of cerebellar and/or amygdala projections to the thalamic reticular nucleus regarding dynamics of this network, influence auditory processing in the thalamus, and involvement of these projections in stimulus selection and attention.