Sleep, proprioception, and forebrain activity in infant mutant mice

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DESCRIPTION (provided by applicant): Sleep occupies one-third of our adult lives and yet its function is still not known. In infants, sleep is even more prominent, as are the spontaneous myoclonic twitches that are a defining feature of active (or REM) sleep. In infant rats, twitches are produced tens of thousands of times each day, and sensory feedback from twitching produces substantial stimulation to the primary somatosensory cortex. In fact, each day in neocortex, sleep- related twitches trigger thousands of cortical oscillatory events - called spindl bursts. This sleep-related activation of neocortex is channeled subsequently to the hippocampus, whose activity in early infancy appears to be driven primarily during sleep. Accordingly, it has been suggested that spontaneous, sleep-related motor activity contributes to the development of neural circuits within and between neocortex and hippocampus, just as retinal waves are thought to contribute to the development of visual cortex and related structures. Interestingly, work in our laboratory suggests that it may be the proprioceptive feedback from limb twitches that specifically trigger spindle bursts; tactile stimulation of the limbs appears insufficient for producing a spindle burst. Thus, this R21 exploratory/developmental application aims to investigate the specific contributions of proprioceptive feedback from twitching to neocortical and hippocampal activity and development. Because surgical and pharmacological methods of disrupting proprioception are not sufficiently specific to that modality - and may also disrupt motor outflow and thus disrupt twitching itself - we propose here to test infant mutant mice that are genetically engineered such that they fail to develop muscle spindles, the sensory organs essential for proprioception. These mutants develop neuromuscular junctions and Ia afferent connections from muscle to spinal cord. Importantly, we have also confirmed the presence of twitching in these infant mutant mice and its similarity to that in wild-types. Using methods that were developed in our laboratory for recording neurophysiological activity in unanesthetized infant rats as they cycle spontaneously between sleep and wakefulness and respond to experimenter-controlled delivery of peripheral tactile and proprioceptive stimuli, we will record sleep-wake activity and neocortical and hippocampal activity in infant mutant and wild-type mice across early development. The innovation of this application lies in the use of state-of-the-art recording techniques in conditional knockout mice to test specific, mechanistic hypotheses concerning the phenomenology and function of sleep-related motor activity in somatosensory development. Also, this application will provide a foundation for future developmental studies of neurophysiological and sleep-wake activity in mice that can take full advantage of the molecular tools that are readily available in that species. Finally, this application is compatible with the IH Blueprint for Neuroscience, which emphasized the need for more basic research to understand neurodevelopment, neurodegeneration, and neuroplasticity. PUBLIC HEALTH RELEVANCE: The NIH Blueprint for Neuroscience emphasized the need for interdisciplinary basic research that addresses critical issues concerning neurodegeneration, neurodevelopment, and neuroplasticity. The current application fits well with the Blueprint by focusing on the role of sensory feedback from sleep-related "twitch" movements - which are especially prominent during the prenatal and early postnatal period - in the construction of the nervous system, including the cerebral cortex and hippocampus. By understanding how the brain interprets these twitch movements and how interrupting sensory feedback from twitches alters the course of development, we will begin to shed light on how early somatosensory experiences during sleep and wakefulness help to shape both normal and pathological outcomes.