Noradrenergic and cholinergic mechanisms underlying pupil-linked arousal modulation of thalamic sensory processing

项目摘要 瞳孔连接的丘脑唤醒调节的去甲肾上腺素能和胆碱能机制 感觉处理 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（LC-NE）系统和胆碱能系统。LC-NE异常活动 和胆碱能系统与影响数百万人的主要临床疾病有关， 精神分裂症、帕金森病（PD）和抑郁症。非亮度介导的瞳孔大小变化 几十年来，人们都知道它与行为背后的心理过程是共同变化的。最近的工作强调， 瞳孔动力学能够跟踪皮层唤醒状态的快速波动。因此，瞳孔大小的变化 在恒定照明下，已经被广泛地用作对某些激活的非侵入性读出。 中枢觉醒回路，并因此被用于指示与瞳孔相关的觉醒。非典型的瞳孔动态 在上述神经系统疾病中报告。然而，潜在的调节机制， 大脑中通过与瞳孔相关的唤醒进行的信息处理仍然鲜为人知。该项目将测试 我们的中心假设：与瞳孔相关的唤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。我们在这个项目中关注丘脑，因为大多数 外部世界的信息通过丘脑到达大脑皮层，丘脑 这是将信息传送到大脑皮层的关键。综合运用电生理学，基因操作， 和行为模式，我们将在三个目标中检验这一假设。目标1将侧重于 丘脑感觉处理及其对感知的贡献在多大程度上取决于与瞳孔相关的唤醒。 目的2将检查丘脑中去甲肾上腺素和乙酰胆碱（ACh）动力学在多大程度上可以 通过瞳孔大小来追踪。Aim 3将开发基于CRISPR/Cas9 +指导RNA的尖端遗传工具 技术选择性地敲除丘脑中肾上腺素能和胆碱能受体的每一种亚型。 此外，我们将描述NE/Ach受体的每个亚型在介导瞳孔相关唤醒中的作用。 感觉处理和知觉行为的调节。该项目将提供急需的洞察力 关于LC-NE和胆碱能系统如何有助于瞳孔相关的觉醒调节， 丘脑对感觉信息和知觉的处理。这些信息对于更好地了解 神经系统疾病，其中丘脑活动和瞳孔动力学异常已被报道。

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.