Claustral Control of Cortical Networks by Serotonin

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Project Summary Cognitive flexibility deficits are a major contributor to diminished life and therapeutic outcomes across myriad neuropsychiatric disorders including Alzheimer’s, depression, and schizophrenia. The classical psychedelic, psilocybin, induces long-lasting improvement of cognitive flexibility, but widespread use is infeasible due to legislative restrictions and undesirable non-therapeutic effects. Ideally, the therapeutic pro-cognitive effects of psychedelics could be dissociated from the psychedelic trip, though this requires investigation as to the mechanisms of psychedelic cognitive effects. Cognition, and cognitive flexibility, is achieved through cortical networks: frontal cortically-directed coactivated cortical regions that engage in cooperative processing to meet cognitive demands. Understanding how psychedelics impact neural circuits underlying cortical network regulation is necessary for the development of therapeutics that reproduce the pro-cognitive psychedelic effect. The claustrum, a subcortical nucleus, connects frontal cortical and parietal cortical network nodes via “cortico- claustro-cortical circuits”, is required for optimal task performance in cognitively demanding tasks over nondemanding tasks, and is activated at the emergence of a task-positive cortical networks in response to a difficult cognitive task. The claustrum expresses serotonin receptors targeted by psilocin, the active metabolite of psilocybin (5-HTR2a,1d, and 1b) and claustrum deactivation during psilocybin administration is associated with psilocybin-mediated cortical network dysfunction. As such the claustrum represents a prime target for investigation of the cognitive effects of psychedelics. Our preliminary data in mice leads to our hypothesis that serotonin signaling acutely suppresses cortico-claustro-cortical circuits by: suppression of frontal cortical input to claustrum (Aim 1), increased local inhibition of claustrum projection neurons (Aim 2), and decreasing excitability of claustrum projection neurons (Aim 3). To test this novel hypothesis, I will determine the receptor responsible for each serotonin mediated neuromodulatory effect, confirm that the effect is also recruited by the psylocibin metabolite psilocin, and assess corresponding changes to the cortico-claustro-cortical circuit strength for each Aim/neuromodulatory effect. This will be performed using a combination of optogenetics, viral tract- tracing, and whole-cell electrophysiology. Whole-cell electrophysiology and optogenetics represent the primary technical training in this proposal. The results of this study stand to introduce a novel circuit mechanism for the pro-cognitive effects of psychedelics and set the foundation for the development of pro-cognitive therapies applicable across a wide range of neuropsychiatric disorders. Taken together, this innovative proposal will provide substantial conceptual and technical training opportunities that are necessary for the PI to ultimately gain research independence.