Role of waking activity in determining sleep-based modification of cortical circuits

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 DESCRIPTION (provided by applicant): I am an M.D., Ph.D. psychiatrist currently doing research fellowship work as an Instructor in the Weill Cornell Department of Psychiatry. My doctoral work was in the study of neocortical microcircuit activity using two-photon calcium imaging. To gain tools to study neuronal activity in the naturally behaving animal I have devoted my fellowship to training with Dr. Gyorgy Buzsaki at New York University. With Dr. Buzsaki I have mastered many aspects of silicon probe recording in rats, but here I propose further training in optogenetics with Dr. Buzsaki's group in the context of a project studying the basic neuroscience of sleep. Sleep is crucial to normal brain function and also plays a role in many neuropsychiatric diseases including depression and seizure disorders. Perhaps indicative of a more precise role for sleep: decades of research show that learning is enhanced by post-learning sleep. By contrast, other work shows that sleep homeostatically downregulates neuronal and synaptic activity. How the homeostatic role for sleep and the memory consolidation role interact is not at all clear, especially given that they make differing predictins at the level of synapses: memory consolidation predicts synaptic strengthening over sleep, homeostasis predicts synaptic weakening. This proposal aims to synthesize the memory consolidation role for sleep and the homeostatic role. My outcomes will be measured using silicon probes and my interventions will involve learning paradigms and optogenetics. My first two Aims will assess how a novel object learning paradigm prior to sleep affects how the subsequent sleep modulates neural activity in the anterior cingulate cortex. Aim 1 will use silicon probes to assess the changes over sleep in single neuron firing and neuronal assembly behavior depending on whether neurons were subjected to a pre-sleep learning paradigm. Aim 2 will use optogenetics to specifically study synaptic changes over sleep depending on whether there was learning prior to sleep. Synapses have been theorized to be particularly crucial in both learning and homeostasis. I will use optogenetics to precisely probe synapses originating from distal neurons, with optogenetics giving the advantage of less contaminated and more precise and revelatory stimulation paradigms than traditional electrical stimuli. In Aim 3 I will ue direct optogenetic manipulation of spike rates in small subsets of neurons during waking, rather than learning, to determine more precisely how prior activity affects subsequent sleep modulation. This final experiment will take advantage of new combined optogenetic-silicon probe tools developed in the Buzsaki Lab. I will receive mentorship from Dr. Buzsaki and from Dr. Francis Lee and will take biostatistical and neuroscience theory courses to add to my training. I am optimistic that the projects, and training described in this application will provid the field with new knowledge and will prepare me well for independent research. Title: Role of waking activity in determining sleep-based modification of cortical circuits.