Integrative Analysis of Long-range Top-down Cortical Circuit for Attentional Behavior

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Attention deficit symptoms are frequently observed in psychiatric disorders, yet finite understanding of the neural circuits mediating attentional behavior has limited pathophysiologic insight. Previous studies in humans and rodent demonstrate that the frontal cortex—especially the anterior cingulate cortex (ACC)— plays a key role in implementing a top-down control of attention. However, the precise neural circuit mechanisms mediating attention remain largely unknown. The goal of this study is to identify the specific frontal cortex projecting neural circuits that mediate top-down control of attentional behavior. Conserved long-range frontal cortico- cortical projections regulate visual cortex (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. Improper frontal modulation of VIS activity in ADHD, schizophrenia, and autism accompanying visual attention deficits may be in part due to the dysfunction of direct long-range projections. However, activity in this circuit has never been directly and specifically examined during attentional behavior, nor has been selectively manipulated to causally improve attentional behavior. Here we will test the hypothesis that long-range top- down cortical circuits directly projecting from frontal cortex to sensory cortex coordinate temporal dynamics between these regions to effectively modulate attentional behavior by implementing an intersectional viral strategy to combinatorially (1) monitor and (2) manipulate neural activity within specific circuits of mice with a translation touchscreen system to assess attention during naturalistic freely moving behavior. In Aim1, we will identify when top-down circuits are activated during attentional behavior. In Aim2, we will manipulate top-down cortical circuit activity to modulate attentional behavior. Here, we will test the hypothesis that top-down cortical circuits coordinate temporal dynamics between ACC and VIS to effectively modulate attentional behavior. At the completion of this study, we will have established a strong basis for the causal role of top-down cortical circuit on attentional behavior.