Mapping Global Brain Connectivity Mediated by DISC1 Gene in Adult-born Neurons

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 DESCRIPTION (provided by applicant): Mental disorders are chronic and disabling disorders in need of effective treatments. They affect a large portion of the world's population, with significant impairment in their social function and have devastating consequence on the quality of life. Significant progress has been made in recent years to identify genetic disruptions that increase susceptibility to mental disorders, but we have little understanding of the circuitry mechanisms linking these genetic risk factors to the widespread cognitive and affective deficits associated with these disorders. Accumulating evidence suggests that brain connectivity alteration plays an important role in the pathophysiology of mental disorders. More recently, functional imaging data garnered from patients with mental disorders and animal models of schizophrenia and autism have collectively pointed to the aberrant hippocampal activity as a central feature of pathophysiology. Together, these data suggest that aberrant hippocampal activity may be a critical factor that contributes to brain network abnormalities in mental disorders. Within the hippocampus, dentate gyrus continuously generates new neurons throughout life, therefore making significant modifications to the hippocampal circuitry activity. Cumulative evidence suggests that these adult- born neurons are involved in cognition, stress response and mood regulation; and aberrant adult neurogenesis contributes to brain disorders, such as epilepsy and mental disorders. The current project is built upon our recent discoveries, including (i) identification of critical roles of DISC1 in regulating morphogenesis, cell positionig, axon/dendritic development and synapse formation of newborn granule cells in the adult hippocampus; and (ii) DISC1 deficiency in adult-born dentate granule neurons causes cognitive and affective behavioral deficits. However, how dysregulation of adult-born neurons by genetic risk factor DISC1 leads to these behavioral deficits at the circuitry level is largely unknown. Th overall goal of this proposed project is to investigate whether aberrant adult neurogenesis mediated by DISC1 deficiency serves as a critical neural substrate for brain connectivity abnormalities associated with mental disorders. To test this hypothesis, we propose to utilize in vivo multi-channel recording to examine local hippocampal activity (Aim 1) and functional magnetic resonance imaging (fMRI) to measure global brain connectivity (Aim 2) with or without DISC1 deficiency in adult-born neurons at the baseline and upon activity stimulation of those neurons. Our proposed studies will address fundamental questions on how genetic risk factors lead to the clinical manifestation of many severe psychological disorders by focusing on adult neurogenesis as a promising but ill-defined substrate in mediating global brain connectivity. Adult neurogenesis correlates with many physiological and pathological states, such as learning and memory, epilepsy, neurodegenerative diseases and mental disorders. Therefore, targeting adult neurogenesis process could constitute a novel therapeutic strategy for treating these disorders.