Cholinergic contribution to pupil-linked arousal

摘要 胆碱能对瞳孔相关觉醒的贡献 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 胆碱能系统和蓝斑-去甲肾上腺素（LC-NE）系统。异常活动 胆碱能系统与影响数百万人的主要临床疾病有关，包括 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，已经被广泛用作某些中枢神经系统激活的非侵入性读出。 与瞳孔大小相关的唤醒回路，因此被用于对与瞳孔相关的唤醒进行索引。非典型瞳孔动态 在上述神经系统疾病中也有报道。然而，神经回路， 与瞳孔相关的唤醒仍不清楚。这项计划将检验我们的核心假设： 除了LC-NE系统之外，还有其他系统介导与瞳孔相关的唤醒。使用光遗传学的合成 刺激，遗传操作和钙成像，我们将在两个目标中验证这一假设。目标1将 确定胆碱能系统的激活和瞳孔大小之间的因果关系。目标2将审查 可以通过瞳孔大小追踪胆碱能活性的程度。该项目将提供急需的洞察力 关于胆碱能系统在多大程度上促进了瞳孔相关的觉醒。该等资料不 对于严格和准确地解释使用瞳孔测量法的众多研究结果至关重要， 越来越多地被用于认知神经科学和精神病学。

Abstract Cholinergic contribution to pupil-linked arousal 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 cholinergic systems and the locus coeruleus-norepinephrine (LC-NE) system. Abnormal activity in the 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, change in pupil size under constant illumination has been widely used as a non-invasive readout of the activation of certain central arousal circuits related to pupil size, and thus is used to index pupil-linked arousal. Atypical pupil dynamics have been reported in the aforementioned neurological disorders. However, the neural circuits that mediate pupil-linked arousal remain unclear. The proposed project will test our central hypothesis: the cholinergic systems mediate pupil-linked arousal, in addition to the LC-NE system. Using a synthesis of optogenetic stimulation, genetic manipulation, and calcium imaging, we will test this hypothesis in two Aims. Aim 1 will determine the causal link between activation of the cholinergic systems and pupil size. Aim 2 will examine the extent to which cholinergic activity can be tracked by pupil size. This project will provide much-needed insight about the extent to which the cholinergic systems contribute to pupil-linked arousal. Such information is essential to rigorous and accurate interpretation of results from numerous studies using pupillometry, which is increasingly popularly used in cognitive neuroscience and psychiatry.