Noradrenergic and Cholinergic Mechanisms Underlying Pupil-linked Arousal Modulation of Thalamic Sensory Processing

项目摘要 丘脑去甲肾上腺素和胆碱能兴奋调节机制的研究 感觉加工 行为状态，包括注意力和唤醒，对神经表征、知觉、 认知和行为表现，并由几个神经调节系统调节，包括 蓝斑-去甲肾上腺素系统和胆碱能系统。LC-NE的异常活动 胆碱能系统与影响数百万人的重大临床疾病有关，包括 精神分裂症、帕金森氏病(PD)和抑郁症。非亮度调节的瞳孔大小的变化 几十年来，人们一直知道心理处理与潜在的行为是不同的。最近的研究强调了 瞳孔动力学能够跟踪大脑皮层觉醒状态的快速波动。因此，瞳孔大小的变化 在恒定光照下已被广泛用作非侵入性读出的某些激活 中枢唤醒回路，因此被用来标示与瞳孔相关的唤醒。非典型的瞳孔动力学一直是 前述神经性疾病的报告。然而，潜在的调节机制 大脑中的信息处理是由与瞳孔有关的唤醒引起的，目前还知之甚少。拟议中的项目将测试 我们的中心假设：与瞳孔相关的觉醒调节丘脑的感觉处理和知觉行为 通过肾上腺素能和胆碱能受体。我们在这个项目中重点关注丘脑，因为大多数 关于外部世界的信息通过丘脑到达大脑皮层，丘脑发挥作用 在将信息传递到大脑皮层的过程中起着关键作用。综合运用电生理学、基因操作、 和行为范式，我们将在三个目标上检验这一假设。目标1将专注于描述 丘脑感觉处理及其对知觉的贡献在多大程度上依赖于与瞳孔相关的唤醒。 目标2将检查丘脑中去甲肾上腺素和乙酰胆碱(ACh)动态变化的程度 根据瞳孔大小进行跟踪。AIM 3将开发基于CRISPR/Cas9指南RNA的尖端基因工具 选择性地敲除丘脑中肾上腺素能和胆碱能受体的每一亚型的技术。 此外，我们还将研究NE/Ach受体各亚型在调节与瞳孔相关的觉醒中的作用 感觉加工和知觉行为的调节。这个项目将提供急需的洞察力 LC-NE和胆碱能系统如何参与瞳孔相关的觉醒调节 丘脑处理感觉信息和知觉。这些信息对于更好地理解 据报道丘脑活动和瞳孔动力学异常的神经性疾病。

Project Summary Noradrenergic and cholinergic mechanisms underlying pupil-linked arousal modulation of thalamic sensory processing Behavioral state, including attention and arousal, exerts heavy influences on neural representation, perception, cognition, and behavioral performance and is regulated by several neuromodulatory systems, including the locus coeruleus-norepinephrine (LC-NE) system and the cholinergic system. Abnormal activity in the LC-NE and cholinergic systems has been implicated in major clinical disorders that affect millions of people, including schizophrenia, Parkinson’s disease (PD), and depression. Non-luminance mediated changes in pupil size have been known to co-vary with mental processing underlying behavior for decades. Recent work highlighted that pupil dynamics were able to track rapid fluctuation of cortical arousal state. Therefore, changes in pupil size under constant illumination have been widely used as a non-invasive read out of the activation of certain central arousal circuits, and thus are used to index pupil-linked arousal. Atypical pupil dynamics have been reported in the aforementioned neurological disorders. However, the mechanisms underlying modulation of information processing in the brain by pupil-linked arousal remain little known. The proposed project will test our central hypothesis: pupil-linked arousal modulates thalamic sensory processing and perceptual behavior through both adrenergic and cholinergic receptors. We focus on the thalamus in this project because most information about the external world reaches the cerebral cortex through the thalamus, and the thalamus plays a critical role in gating information to the cortex. Using a synthesis of electrophysiology, genetic manipulations, and behavioral paradigms, we will test this hypothesis in three Aims. Aim 1 will focus on characterization of the extent to which thalamic sensory processing and its contribution to perception depend on pupil-linked arousal. Aim 2 will examine the extent to which norepinephrine and acetylcholine (ACh) dynamics in the thalamus can be tracked by pupil size. Aim 3 will develop cutting-edge genetic tools based on CRISPR/Cas9 + guide RNA technology to selectively knock out each subtype of adrenergic and cholinergic receptor in the thalamus. Further, we will characterize the role of each subtype of NE/Ach receptor in mediating pupil-linked arousal modulation of sensory processing and perceptual behavior. This project will provide much-needed insight about how the LC-NE and cholinergic systems contribute to pupil-linked arousal modulation of thalamic processing of sensory information and perception. Such information is essential to better understand neurological disorders in which abnormal thalamic activity and pupil dynamics have been reported.