Eric Landsness, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): We spend a third of our life asleep, and even partial sleep deprivation has serious consequences on cognition, mood, and health, suggesting that sleep must serve some fundamental functions. Presently, we lack a neurobiological understanding of what these functions might be. We know that sleep is tightly regulated as a function of prior wakefulness and sleep pressure is reflected by the amount of slow wave activity (SWA) in the EEG of non-rapid eye movement (NREM) sleep. SWA (the EEG power density between 0.5 and 4.5 Hz) increases in proportion to the time spent awake and decreases during sleep, but why this is the case remains unclear. The overall goal of this proposal is to test a recent hypothesis concerning the function of NREM sleep - the synaptic homeostasis hypothesis (SHY). The hypothesis states that plastic processes during wakefulness result in a net increase in synaptic strength in many brain circuits; such increased synaptic weight comes at the expense of increased metabolic consumption. Strengthened brain circuits lead to larger SWA during subsequent sleep. In turn, sleep SWA renormalizes synaptic strength to a baseline level that is energetically sustainable and beneficial for memory and performance. This proposal will test two predictions of SHY: sleep slow waves are necessary for the renormalization of cortical circuits after learning (Aim 1); and sleep slow waves are necessary for the enhancement of performance after sleep (Aim 2). To do so, I will use high density EEG recordings in humans while performing a visuomotor learning task (rotation learning) that involves right parietal cortex and during post learning sleep. Sleep slow waves will be suppressed using mild acoustic stimuli that do not fragment sleep. Control experiments will apply the same number of stimuli during stage 2 sleep. The specific aims are designed to evaluate if, as predicted by SHY, learning leaves a local trace in the waking EEG that is renormalized after sleep, and if the selective deprivation of sleep slow waves leads to a persistence of such EEG traces and to a suppression of post-sleep performance enhancement. PUBLIC HEALTH RELEVANCE: There is overwhelming evidence that restorative sleep is necessary to human health, that sleep deprivation and restriction have enormous social costs, and that sleep disorders are extremely common and are frequently associated with psychiatric and neurological disorders. By tying brain plasticity and performance to SWA, the results of this investigation will advance our understanding of the function of sleep at a fundamental level, lend support to SHY, and provide a rational basis for designing therapeutic approaches that focus on the quality of SWA and enhance the restorative effects of sleep in health and disease. [unreadable] [unreadable] [unreadable]

The goal of this mentored career development award is to enable the candidate?s transition to independence as a physician-scientist studying the connection between plasticity, sleep and stroke. The candidate is an MD, PhD sleep neurologist with a background in engineering, human sleep electrophysiology and how it relates to brain plasticity. The award will help the candidate gain experience in basic genetic, molecular and in-vivo imaging techniques as well as an in-depth knowledge of the cellular and molecular mechanisms involved in plasticity mediated neuronal repair. This award will help the candidate to become an independent physician scientist using sleep as way to accelerate the pace of scientific discovery and its application to the care of individuals with neurological disease. This career development award brings together three experts covering the diverse fields of sleep (Landsness ? PI), plasticity of brain recovery (Lee ? Mentor) and optical neuroimaging (Culver ? Mentor) to tackle this innovative concept and potentially open-up a new field of research. The research environment in which this career development award is proposed is outstanding. Dr. Jin Moo Lee, a translational neuroscientist and vascular neurologist with an interest in the plasticity of stroke recovery, has a long track record of both scientific and mentorship success. Dr. Joe Culver, is a long-time collaborator of the Lee lab and highly experienced in the imaging techniques the candidate will use. Finally, the Washington University neuroscience community emphasizes high quality research, career development of young faculty and collaboration, all keys to his success. An objective of this proposal is to understand the role of slow wave sleep (SWS) in repair and recovery after focal ischemic brain injury. Local SWS is critical for learning-related brain plasticity. Mechanisms involved in brain plasticity have been postulated to be necessary for successful neural repair and recovery after brain injury. Neuronal activity in somatostatinergic interneurons (SOMi) has recently been shown to critically mediate SWS. We propose to 1) determine the role of global SWS in a mouse model of brain repair following focal ischemia (photothrombosis) in somatosensory cortex and 2) locally manipulate SWS (via SOMi using chemogenetics) to determine if modulating local SWS affects cortical remapping, synaptogenesis, and sensorimotor recovery. If the hypothesis is correct, it will show that locally manipulating SWS can selectivity drive plasticity and ultimately recovery from stroke. It will also determine if SOMi might be amenable to targeting and may help shape a novel therapeutic approach to enhancing plasticity and recovery following stroke. This career development award is the ideal platform for the candidate to acquire important training in basic research techniques, deepen his understanding of the role SWS in repair and recovery of stroke, and will launch him towards an independent research career focused on using sleep to aid in care of individuals suffering from stroke.