State-dependent sensory processing across early development

描述（由申请人提供）：每只动物必须区分由自身运动引起的感觉和由外部世界刺激引起的感觉（例如，举起你的手臂vs.让你的手臂为你举起）。这种自我和他人产生的运动之间的区别需要精确的自我监控。自我监控是通过复制运动指令（必然的放电）来机械地实例化的，这些指令使神经系统为自我产生的运动所触发的感觉的到来做好准备。必然的放电信号可以门控、取消或以其他方式修改传入的感觉信号。我们建议调查两个新的方面的必然放电：其在婴儿早期的表达和其调制的睡眠-觉醒状态。这个提议的一个动力是观察到，在新生大鼠中，在主动（或REM）睡眠期间，来自自发肢体抽搐的感觉反馈触发了感觉运动皮层的纺锤波爆发和小脑皮层浦肯野细胞活动的增加。相比之下，在清醒状态下，当剧烈的、自发的肢体运动通常发生时，皮层纺锤体爆发令人惊讶地不存在，浦肯野细胞在很大程度上是沉默的。这种自相矛盾的“掩盖”， 清醒时的神经活动提出了一个新的假设，即必然的放电机制是以状态依赖的方式调节的。重要的是，幼鼠每天在睡眠中产生的数十万次（如果不是数百万次的话）抽搐触发了大量的大脑活动，这些活动非常适合促进感觉运动系统的活动依赖性发育。 具体目标1将表征大鼠出生后前两周感觉运动皮层和小脑中的状态依赖性神经活动，这是这些结构快速变化的时期。本研究通过比较睡眠和清醒时的自发和诱发神经活动，建立了两种新的模型，以探索伴随放电的神经机制和发育起源。具体目标2将通过系统比较脑干核团的状态依赖性活动，提供有关婴儿早期感觉运动处理的关键新数据，脑干核团涉及（a）肢体抽搐的产生，（B）肢体本体感受输入的接收，以及（c）必然放电的处理。我们还将测试新的假设，即蓝斑，脑干核，这是唤醒活跃和去甲肾上腺素的大脑皮层和小脑的主要来源，有助于状态依赖性调制的必然放电。最后，具体目标3将探讨感觉运动皮层和小脑的相互和状态依赖性调制的发展出现。这种相互作用对于整个大脑中成熟的感觉运动整合是必不可少的。NIH神经科学蓝图强调需要更多的基础研究来了解神经发育和神经可塑性。这个建议满足了这一需要，独特的集成几个创新的概念和方法的方法，提供新的见解关键感觉运动系统的功能发展。

DESCRIPTION (provided by applicant): Every animal must distinguish sensations that arise from its own movements from those arising from stimuli in the external world (e.g., lifting your arm vs. having your arm lifted for you). This distinction between self- and other-produced movements requires precise self-monitoring. Self-monitoring is instantiated mechanistically by copies of motor commands-corollary discharges-that prepare the nervous system for the arrival of sensations triggered by self-produced movements. Corollary discharge signals can gate, cancel, or otherwise modify incoming sensory signals. We propose to investigate two novel aspects of corollary discharge: Its expression in early infancy and its modulation by sleep-wake state. One impetus for this proposal is the observation that, in newborn rats, sensory feedback from self-produced limb twitches during active (or REM) sleep triggers spindle bursts in sensorimotor cortex and increased Purkinje cell activity in cerebellar cortex. In contrast, during wakefulness when vigorous, self-produced limb movements typically occur, cortical spindle bursts are surprisingly absent and Purkinje cells are largely silent. This paradoxical "masking" of neural activity during wake suggests the novel hypothesis that corollary discharge mechanisms are regulated in a state- dependent fashion. Importantly, the hundreds of thousands, if not millions, of twitches produced by infant rats each day during sleep trigger substantial brain activity that is ideally suited to promote activity-dependent development in the sensorimotor system. Specific Aim 1 will characterize state-dependent neural activity in sensorimotor cortex and cerebellum across the first two postnatal weeks in rats, a period of rapid change in those structures. Critically, by comparing spontaneous and evoked neural activity during sleep and wake, this Aim will establish two new models for exploring the neural mechanisms and developmental origins of corollary discharge. Specific Aim 2 will provide critical new data regarding sensorimotor processing in early infancy through systematic comparison of state-dependent activity in brainstem nuclei implicated in (a) the production of limb twitches, (b) the reception of proprioceptive input from limbs, and (c) the processing of corollary discharge. We will also test the novel hypothesis that the locus coeruleus, a brainstem nucleus that is both wake-active and a primary source of norepinephrine to the cerebral cortex and cerebellum, contributes to the state-dependent modulation of corollary discharge. Finally, Specific Aim 3 will explore the developmental emergence of reciprocal and state-dependent modulation of sensorimotor cortex and cerebellum. Such reciprocal interactions are essential for mature sensorimotor integration throughout the brain. The NIH Blueprint for Neuroscience emphasizes the need for more basic research to understand neurodevelopment and neuroplasticity. This proposal meets that need by uniquely integrating several innovative conceptual and methodological approaches to provide new insights into the functional development of critical sensorimotor systems.