State-dependent sensory processing across early development

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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.