Cortico-cortical Projections Driving Frontal-sensory Neural Oscillatory Synchrony to Mediate Attention

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Project Summary Neural oscillations had previously been considered to be a consequence of cognitive function, but recent evidence suggests they rather play a central role in communicating neural information across distributed brain networks during complex cognitive processes such as attention. Desynchronized neural oscillatory activity is frequently reported in psychiatric disorders, including autism, depression, and schizophrenia, leading to cognitive impairments, including attentional deficits. Little is known about the underlying circuit mechanisms that drive neural oscillations supporting attention or how they are disrupted to produce desynchronization. Our comprehensive idea to aid in the recovery of attention is to take a circuit-based approach to resynchronize cortical regions to healthy states and subsequently reestablish proper attentional performance. This proposal aims to identify novel circuit mechanisms driving synchronous neural oscillations required for attention. Our preliminary study found that chemogenetic inactivation of top-down cortical projections from anterior cingulate cortex (ACC) to the visual cortex (VIS) disrupts visual attentional behavior in mice. Furthermore, we show that circuit-specific optogenetic activation of this top-down circuit enhances attention performance. Of note, both attention 15q13.3 significant schizophrenia. is microdeletion, or deficits and reduced cortical gamma oscillation microdeletion, one of the major copy number well documented in association with a minority of individuals diagnosed with various neurodevelopmental disorder such as autism and Although our preliminary results implicate a circuit-specific mechanism of attentional control, it unknown whether 1) ACC  VIS activity increased during attention and by 15q13.3 2) ACC-VIS sychronization is associated with attention and disrupted by 15q13.3 microdeletion, if 3) the top-down circuit can be modulated to rescue attention deficits. in mice were reported to be caused by chromosomal variants is disrupted We hypothesize that this prefrontal top-down projection to visual cortex synchronizes activity between ACC and VIS during attention and that ACCVIS projection can be leveraged to improve synchronization and attention deficits caused by a 15q13.3 microdeletion. Our experimental design uses an intersectional viral approach and cutting-edge fiber photometry, in vivo electrophysiology and optogenetic techniques to simultaneously monitor and manipulate this top-down circuit as mice perform a naturalistic free moving attention task to test this hypothesis. We anticipate our study will shed novel fundamental mechanistic insight into the role of neural synchronization during attention and provide a unique opportunity to identify novel circuit-based targets for neuromodulation treatments of psychiatric disorders.