Linking hippocampal plasticity to mental health: Sharp/wave ripple related replay

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DESCRIPTION (provided by applicant): The ability to encode and recall memories of experiences and environments allows adaptation to the world through subsequent behavioral change. In mammals, the hippocampus is known to be a key component of the neural circuitry involved in learning, particularly episodic memory. The hippocampus is responsible for integrating the encoding, storage and recall of memories, binding the spatio-temporal and sensory information that constitutes experience. Primary excitatory neurons of the CA1 region of the hippocampus, the pyramidal cells, fire with remarkable spatial precision during exploration. This phenomenon has led these cells to be known as place cells. When an animal is actively exploring, place cells fire as the animal passes through a neurons' corresponding spatial field. Most intriguing is a phenomena known as replay, where place cells fire in a temporally compressed, but spatially conserved order. Replay occurs during high frequency events, known as ripples, which take place in both sleep and quiet wake after active exploration4-6. Ripple disruption leads to reduced spatial learning, further supporting the association between ripple events, replay and learning. These studies provide support for the hypothesis that replay is involved in and is not simply a byproduct of spatial learning. Our preliminary data together with published reports suggest that synaptic plasticity in the hippocampus may be tuning SWR events, and likely replay, potentially providing the link between aberrant plasticity and spatial learning defects. Furthermore, many mouse models of mental disorders have abnormal hippocampal synaptic plasticity and impaired spatial learning. We have preliminary data from several distinct mouse models that show changes to their SWR events supporting the hypothesis that SWR events are a circuit level motif connecting plasticity to learning. This proposal seeks to characterize the relationship between high frequency ripple events and hippocampal replay, to connect our understanding of this phenomenon to synaptic plasticity and begin to understand its role in disease. The experiments outlined in this proposal 1. Establish a clear relationship between SWR events and replay, 2. Systematically study the effects of synaptic plasticity changes on SWR events, and 3. Begin to relate these changes to neurological disease. Specifically, we will be examining a mouse model of schizophrenia. This mouse has been previously shown to have working memory impairments and show phenotypes relatable to the human disorder. The research plan outlined here is a novel approach that will allow an unprecedented understanding of the role of synaptic plasticity on regulating neural circuits and ultimately behavior. This research has the potential to uncover new mechanisms of learning and should prove informative in studying the way in which neural circuits are disrupted in mouse models of disease.