Mechanisms of persistent neural activity

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PROJECT SUMMARY / ABSTRACT Although many well-studied aspects of neural function involve activity driven by sensory inputs or occurring at the time of motor actions, the brain often links such fleeting sensory and motor signals with persistent activity. Somehow, neural circuits and individual neurons are capable of maintaining activity without additional input. This is a fundamental aspect of neural function and a critical building block of cognition. The mechanisms underlying persistent neural activity have long been considered in both experiment and theory, but there is little definitive mechanistic understanding of the circuit and cellular contributions to persistent activity. Indeed, theories of persistent activity are far more biologically nuanced than current empirical knowledge— especially in the nonhuman primate, from which our understanding should have greatest clinical relevance given the number of disorders that involve persistent activity. Here, we propose work that leverages advanced techniques for multiple scales (and specificities) of neural recordings with corresponding analyses of large- scale datasets to test detailed theories of how the brain generates and maintains persistent activity. Specific Aim 1. Establish the marmoset as a powerful complementary model system for dissecting persistent activity mechanisms in primate brains. We will demonstrate the viability of studying memory-guided saccades and persistent activity in the marmoset, using successful training approaches, electrophysiology, and calcium imaging to elicit the key behavior and to characterize the important brain areas in this exciting primate model system. Specific Aim 2. Characterize the large-scale circuitry underlying oculomotor persistent activity. Using large scale recordings of extracellular activity across multiple brain regions collecting during performance of a memory-guided saccade task, we will acquire a dataset of unprecedented scale to assess the large-scale circuitry underlying persistent activity. We will adapt, develop, and deploy advanced statistical models to capture the functional interactions between neurons and brain areas. Specific Aim 3. Test and refine theories of persistent activity with novel measurements at fine spatial and genetic resolution. We will perform both 2-photon imaging and high density electrophysiological measures of neural activity. The imaging will allow us to test the local circuit components of the theory, as well as to assess cell-type-specific contributions to persistent activity. High density electrophysiology will reveal the local circuit architecture and signal flow that are not accessible with coarser techniques. Integrated within our analysis framework, the resultant model of persistent activity will be supported and refined by multiple scales and forms of empirical evidence, all collected in the primate brain.