Circuit-Specific Interrogation of the Primate Claustrum

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PROJECT SUMMARY The claustrum is a narrow, subcortical sheet of gray matter with interconnections across the cerebral cortex. Its irregular shape and deep location make it difficult to study with classical neurophysiological techniques. Recent genetic technologies such as optogenetics provide new hope for understanding the claustrum. They have advanced its study in rodents, implicating the claustrum in an array of sensorimotor and cognitive functions. Circuit-specific studies are needed to resolve how these functions map to the claustrum’s widespread connections. Such studies would be especially valuable in macaque monkeys, the animal model most homologous to humans. My overall goal is to translate viral technologies to monkeys and use them to study the role of a specific claustrum-prefrontal cortical circuit in visuo-saccadic behavior. During systematic testing of viral vectors in macaques, I identified a promising candidate for delivering opsin genes to the claustrum: the retrograde virus rAAV2-retro. When injected into the frontal eye field (FEF), a prefrontal cortical area involved in vision, movement, and cognition, rAAV2-retro constructs yielded strong labeling of FEF-projecting claustrum neurons. This finding provides a long-sought, unique opportunity to study claustrum neurons with circuit-level specificity in the primate brain. I propose to validate viral techniques in the claustro-FEF circuit and use them to test my overall hypothesis that the claustrum mediates competitive selection of the most behaviorally relevant stimulus via suppression of all other stimuli. To test my hypothesis, I have three integrated aims. In Aim 1, I will conduct anatomical tracing studies to elucidate the motif of connectivity between the claustrum and FEF. In Aim 2, I will use rAAV2-retro to express an inhibitory opsin in FEF-projecting claustrum neurons. Then I will use phototagging to identify those neurons and extracellularly record from them to characterize the signals sent from the claustrum to the FEF during a battery of saccade tasks. In Aim 3, I will use the same inhibitory opsins to selectively silence FEF-projecting claustrum neurons, allowing me to determine whether they are required for competitive selection of saccade targets. The claustrum is implicated in a wide range of neurological diseases and neuropsychiatric disorders. Thus, the results of the proposed work will help reveal how pathological changes to neural activity in the claustrum may contribute to brain disorders. In addition to its clinical relevance, the proposed work will significantly expand my doctoral training to include neural recording and optogenetic methods in non-human primates.