Schizophrenia is among the most severe and burdensome medical conditions worldwide, yet the brain alterations that lead to the symptoms of schizophrenia remain unknown. This K01 application presents a research and training program that will support the applicant on a path towards becoming an NIH-funded independent investigator focused on understanding the neurobiology of schizophrenia and related psychotic disorders. The activities in this application build on the candidate's prior training and are set i a resource-rich environment that will foster his development of expertise in 1) principles of clinica imaging in schizophrenia, 2) neuroanatomy of subcortical circuitry relevant to schizophrenic illness, 3) methods for collection and analysis of high-resolution functional connectivity Magnetic Resonance Imaging data in psychosis, and 4) responsible conduct of research. The overarching goal of the research to be carried out in this application is to take findings from animal models o schizophrenia, which were motivated by original research in patients with the disorder, back to the clinical setting in order to determine whether the brain alterations observed in the animal models are observable in human patients. Specifically, findings in the dopamine D2 receptor over expressing mouse model, which was developed to model the excess of D2 receptor activity in the associative striatum of patients with schizophrenia, suggest an alteration in anatomical projections from the associative striatum to the external segment of the globus pallidus. In addition, findings in the 22q11 deletion syndrome mouse model, which was developed to model a known genetic risk factor for schizophrenia in humans with 22q11 deletion, suggest an alteration in the functional strength of connections from the medial geniculate nucleus of the thalamus to the auditory cortex. This project will directly test the existence of these alterationsin brain connectivity in medication-nave patients with schizophrenia using functional connectivity Magnetic Resonance Imaging. If such evidence is found, it would have important implications for our understanding of the brain bases of schizophrenia, and would generate new molecular and anatomical targets for treatment of this devastating illness.
Schizophrenia poses a great social and economic burden in a significant percentage of patients, including increased risk for unemployment, homelessness, incarceration, chronic disability, and reduced life expectancy. By seeking to understand alterations in brain connectivity in this disorder, this project hopes to improve our understanding of the brain basis of schizophrenia, which may lead to improved treatment options for patients and the ability to identify individuals at risk for the disorder.
| Van Snellenberg, Jared X; Girgis, Ragy R; Horga, Guillermo et al. (2016) Mechanisms of Working Memory Impairment in Schizophrenia. Biol Psychiatry 80:617-26 |
