The cognitive searchlight: TRN circuit dissection in health and disease

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 DESCRIPTION (provided by applicant): Understanding the mechanisms of top-down attentional control is one of the most important endeavors in modern neuroscience. This process allows the brain to flexibly switch among processing different information streams and to extract relevant signals from equally salient noise. Top-down attention is critically disrupted n autism, schizophrenia and ADHD, and understanding its underlying mechanisms is therefore of great translational importance. While primate studies have established cortical substrates for top-down attention, our data using the mouse have revealed an unsuspected role for thalamic circuitry in this process. Specifically, we have observed rate and temporal modulation of the thalamic reticular nucleus (TRN), the major source of thalamic inhibition, in a top down attentional task. Disrupting this process diminishes task performance, suggesting causal dependency. Here, we will test the hypothesis that the TRN functions as a cognitive searchlight, translating top- down cortical input to changes in thalamic processing critical for behavioral outcome. In addition, we will investigate whether a disrupted searchlight explains distractibility and attentional impairment in a mouse model engineered to mimic a human autism variant. Our work will be enabled by a top-down attentional task we developed in mice, where animals switch between processing two sensory inputs on a trial-by-trial basis. In Aim I, we will combine multi-electrode recordings in TRN and optogenetic manipulations in prefrontal cortex, asking whether TRN attentional modulation is dependent on prefrontal top-down input. Using closed-loop optogenetic manipulations that distinguish between rate and temporal coding regimes, we will ask how TRN neural codes map onto behavioral outcomes. In Aim II, we will examine two putative mechanisms that couple TRN activity changes to downstream circuitry and behavior. For the first, we will develop a fiber photometry approach to measures dynamic changes in intracellular chloride, a proxy for synaptic inhibition. For the second, we will use a multi- electrode approach to infer dynamic changes in thalamo-cortical transmission. In Aim III, we will perform translational studies using the PTCHD1 knockout, a mouse engineered to mimic a human autism variant. PTCHD1 expression is selective to TRN in development, and we will test the relationship between diminished TRN burst generation and behavioral distractibility in the knockout. We will ask whether reversing TRN dysfunction rescues its behavioral distractibility. Because diminished top-down attention is a feature of several brain disorders, our therapeutic development will be of broad translational appeal. Overall, by providing deep insights into the circuit mechanisms of cognitive function, we aim to develop novel diagnostics and therapeutics for disorders of cognition.