State-dependent sensory processing across early development

描述（由申请人提供）：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，举起手臂与别人为你举起手臂）。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。自我监控是通过运动命令的副本（必然的放电）机械地实例化的，这为神经系统为自我产生的运动触发的感觉的到来做好准备。随之而来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。我们建议研究伴随放电的两个新方面：其在婴儿早期的表达及其受睡眠-觉醒状态的调节。该提议的一个推动力是观察到，在新生大鼠中，主动（或快速眼动）睡眠期间自生肢体抽搐的感觉反馈会触发感觉运动皮层的纺锤体爆发，并增加小脑皮层的浦肯野细胞活性。相比之下，在清醒期间，通常会发生剧烈的、自发的肢体运动，但令人惊讶的是，皮质纺锤体爆发却没有出现，浦肯野细胞基本上保持沉默。这种自相矛盾的“掩盖” 清醒期间的神经活动提出了一个新的假设，即推论放电机制以状态依赖的方式受到调节。重要的是，幼鼠每天在睡眠期间产生数十万甚至数百万次抽搐，会触发大量的大脑活动，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 将描述大鼠出生后前两周感觉运动皮层和小脑的状态依赖性神经活动，这是这些结构快速变化的时期。重要的是，通过比较睡眠和清醒期间的自发和诱发神经活动，该目标将建立两个新模型来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重要新数据，这些活动涉及（a）肢体抽搐的产生，（b）从四肢接收本体感觉输入，以及（c）伴随放电的处理。我们还将测试新的假设，即蓝斑（一种脑干核，既具有唤醒活性，又是大脑皮层和小脑去甲肾上腺素的主要来源）有助于状态依赖性的伴随放电调节。最后，具体目标 3 将探索感觉运动皮层和小脑的相互和状态依赖性调节的发育出现。这种相互的相互作用对于整个大脑成熟的感觉运动整合至关重要。美国国立卫生研究院神经科学蓝图强调需要进行更多基础研究来了解神经发育和神经可塑性。该提案通过独特地整合几种创新的概念和方法来满足这一需求，为关键感觉运动系统的功能开发提供新的见解。

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.