Cell-type specific role of the circadian molecular clock in regulating hippocampal physiology and cognition

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Project Summary The overarching goal of this proposal is to investigate the cell-specific expression and role of the molecular clock within the hippocampus, a brain region critically important for learning and memory and affected by neurological disorders that also present with circadian rhythm disruptions, e.g. epilepsy and neurodegenerative diseases. Circadian rhythms are biological processes that cycle every 24 hours and are exhibited in many physiological functions throughout the body. At the cellular level, circadian rhythms are maintained by an oscillating transcriptional and translational feedback loop of ‘clock’ genes known as the molecular clock. This molecular clock is differentially expressed across tissue and cell-types and drives expression of many other genes, giving rise to the diversity of circadian-influenced physiological processes. Thus, it is important to examine the molecular clock and its impact on physiology in a tissue and cell-specific manner. Hippocampal-dependent memory exhibits circadian regulation, with peak performance on memory tasks occurring at night in nocturnal rodents. The hippocampus expresses core molecular clock components, however, the cell-specific expression of the molecular clock and its impact on cellular physiology in the hippocampus is unknown. This is complicated by the complexity of the hippocampal network, composed of heterogeneous neuronal populations, each with distinct physiological properties and gene expression profiles. This study will examine the physiological role of the molecular clock in two hippocampal neuron populations: excitatory pyramidal and parvalbumin-containing (PV) interneurons. First, the endogenous circadian expression of core clock genes will be measured over 24hrs in these two neuronal populations. Next, the role of the molecular clock within these two neuronal populations in regulating hippocampal physiology and memory will be assessed. To do this, the clock will be selectively ablated in either excitatory pyramidal cells or PV-interneurons using Cre/lox recombination and then neuronal excitability, synaptic plasticity, and hippocampal-dependent learning and memory will be assessed during the day and night. This proposal utilizes single-molecule in situ hybridization, whole-cell and extracellular electrophysiology, and hippocampal-dependent learning and memory assays to determine the cell-specific role of the molecular clock in regulating hippocampal physiology and function. This proposal will generate novel insight into the cell-specific expression and function of the molecular clock in the hippocampus and has the potential to impact research and disease treatment strategies in the hippocampus. Given that many neurological diseases have circadian disruptions, understanding molecular and physiological rhythms across the brain is critically important for human health and disease treatment, as this knowledge can be used to generate therapeutics targeting circadian disruptions and inform the timing of administration for existing therapeutics.