State-dependent sensory processing across early development

描述(申请人提供)：每种动物都必须区分自身运动产生的感觉和外部世界刺激产生的感觉(例如，抬起你的手臂或让你的手臂为你抬起)。这种自我产生的运动和其他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--机械地实例化的，这些指令使神经系统为自我产生的运动触发的感觉的到来做好准备。必然的放电信号可以选通、抵消或以其他方式修改传入的感觉信号。我们建议研究两个新的方面的必然放电：它在婴儿早期的表达和它的睡眠-觉醒状态的调节。这一提议的一个推动力是观察到，在新生大鼠中，在活跃(或快速眼动)睡眠期间自我产生的肢体抽动产生的感觉反馈会触发感觉运动皮质中的纺锤波爆发，并增加小脑皮质中的浦肯野细胞活动。相比之下，在清醒时，通常会发生剧烈的、自我产生的肢体运动，令人惊讶的是，皮质纺锤波不会爆发，浦肯野细胞基本上是沉默的。这种自相矛盾的“掩饰” 觉醒过程中的神经活动表明了一种新的假设，即必然的放电机制是以状态依赖的方式调节的。重要的是，幼年大鼠每天在睡眠中产生的数十万次(如果不是数百万次)抽搐，会触发大量的大脑活动，这非常适合促进感觉运动系统中依赖活动的发育。具体目标1将描述大鼠出生后头两周感觉运动皮质和小脑的状态依赖性神经活动，这是这些结构的快速变化期。关键是，通过比较睡眠和清醒时自发和诱发的神经活动，这一目标将建立两个新的模型，以探索必然放电的神经机制和发育起源。具体目标2将通过系统地比较脑干核团中的状态依赖性活动，提供有关婴儿早期感觉运动加工的关键新数据，这些活动涉及(A)肢体抽动的产生，(B)肢体本体感觉输入的接受，以及(C)必然放电的处理。我们还将测试新的假设，即蓝斑，一个脑干核团，既是觉醒活跃的，也是大脑皮层和小脑的去甲肾上腺素的主要来源，有助于对必然放电的状态依赖的调制。最后，特定目标3将探索感觉运动皮质和小脑相互的和状态依赖的调节的发育出现。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。美国国立卫生研究院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。这一建议通过独特地集成了几种创新的概念和方法来满足这一需求，从而为关键感觉运动系统的功能开发提供了新的见解。

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.