Mechanisms regulating the maturation of prefrontal top-down circuitry in control of attentional behavior

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Cognitive function relies on the cohesive activity of large-scale networks. Long-range cortico-cortical projections facilitate such network activities by integrating information from various inputs and then relaying it to other cortical regions. Of particular significance is the evolutionarily conserved top-down projection from prefrontal cortex (PFC) to sensory visual cortex (VIS) which integrates sensory, motor, and cognitive information to modulate sensory processing. Conserved PFC->VIS projections regulate VIS responses to visual stimuli in attention based tasks in macaque, and optogenetic manipulation in mice shows that this circuit can enhance visual discrimination sensitivity. Notably, deficits in PFC modulation of VIS activity are pervasively reported in neurodevelopmental and psychiatric disorders, and often emerge following childhood and adolescence. Yet limited knowledge of processes governing long-range cortical circuit development hinders further pathophysiological insight into these conditions. The goal of this study is to identify the developmental mechanisms of PFC circuitry that mediate top-down control of attentional network and behavior. Here we test the hypothesis that top-down PFC->VIS cortical circuits require a Lynx1, developmentally regulated nicotinic modulator,-dependent adolescent shift in the balance of local/long-range inputs to coordinate temporal dynamics between PFC and VIS modulate attentional behavior, and that Lynx1 modulation can ameliorate top- down circuit deficits in mice with a risk gene of neurodevelopmental disorders. We will test his hypothesis by integrating techniques to measure and manipulate neural activity and gene expression within specific circuits of mice tested in a translationally-relevant touchscreen system to assess attention during naturalistic freely- moving behavior.