Project summary: Synaptic plasticity in brain structures like the hippocampus has been hypothesized to underlie an essential brain function - consolidating transient experiences into long-lasting memories. The importance of sleep for promoting long-term memory storage, and the disruptive effect of sleep deprivation on memory, have been appreciated for nearly a century. However, it remains unclear how sleep-associated changes in the activity of specific brain circuits contribute to synaptic plasticity in the hippocampus and other structures. The studies proposed here will test a novel hypothesis – that sleep and sleep loss differentially affect memory consolidation through their differential effects on separate subpopulations of hippocampal interneurons. We will use a simple behavioral paradigm for studying sleep-dependent memory consolidation in mice (contextual fear memory; CFM) in combination with state-targeted pharmacogenetic and optogenetic manipulations of parvalbumin-expressing (PV+) and somatostatin-expressing (SOM+) hippocampal interneurons. In the context of these experimental manipulations, we will measure downstream effects on sleep- associated CFM consolidation, hippocampal network activity, microcircuit-level changes in neuronal structure, and biochemical changes in genetically-defined cell populations. We will first assess the effects of learning itself (contextual fear conditioning; CFC) and subsequent sleep or sleep deprivation (SD) on neuronal morphology using cell type-specific Brainbow labeling, and intracellular processes using cell type-specific translating ribosome affinity purification (TRAP). We will then determine how state-specific manipulations of hippocampal PV+ interneuron activity (which disrupt of rescue sleep-dependent CFM consolidation) affect these sleep- dependent processes. Finally, we will test the hypothesis that SD disrupts CFM consolidation by selectively activating SOM+ interneurons in the hippocampus, leading to suppression of activity in neighboring neurons. We will test whether pharmacogenetic activation of these neurons (mimicking effects of SD) disrupts CFM consolidation in freely-sleeping mice, and whether inhibition of these neurons during SD (mimicking effects of sleep) rescues CFM consolidation. We will then assess the effects of changing SOM+ interneuron activity levels on post-CFC changes in hippocampal network activity patterns, neuronal morphology, and cell biology. Together, these studies will test the necessity and sufficiency of state-dependent activity in defined hippocampal neuron populations for long-term storage of new memories.