The experiments in this proposal are designed to investigate the neurophysiology and neurochemistry underlying impulsivity in normal animals and in animal models of schizophrenia and drug abuse. Like humans, animals impulsively choose a small immediate reward over a larger delayed reward (i.e. time discounting). We will test whether impulsive choice is governed by dopaminergic modulation of time discounted reward signals to nucleus accumbens (NA) from the orbitofrontal cortex (OFC) and whether disrupted function in this circuit due to changes in encoding in OFC and dopaminergic tone in NA gives rise to abnormal levels of impulsivity in schizophrenia and drug abuse. Such complementary changes would explain the high incidence of drug abuse in schizophrenic patients. Through the Mentored Research Scientist Development Award I can acquire the necessary techniques and didactic training in new disciplines in order to achieve my immediate goal of testing these hypotheses and my long-term career goal of becoming a successful independent faculty member, competent in a variety of disciplines including neurophysiology, neuropharmacology and the study of schizophrenia and drug abuse. My training and specific research aims can be broken down into three main components: (1) To characterize neural correlates of impulsive choice in behaving animals. For this, I will continue my training under Dr. Schoenbaum, who is an expert in behavioral electrophysiology and learning theory. (2) To characterize the role of dopamine on interactions between OFC and NA. For this, I will learn how to record intracellularly in anesthetized rats during pharmacological manipulations under the mentoring of Dr. O'Donnell. (3) To characterize the impact of schizophrenia and cocaine on this circuit. For this, I will acquire new skills from both Dr. Schoenbaum and Dr. O'Donnell. In addition to technical and intellectual support from my mentors I will receive didactic training through courses, journal clubs and seminars offered at the University of Maryland and the MPRC. This research will increase our understanding of the neurobiology of impulsivity common to many psychiatric illnesses. Furthermore, it will serve as a platform to investigate impulsive choice in animal models of schizophrenia and drug abuse, which has relevance to understanding the high incidence of drug abuse comorbidity observed in the schizophrenic population. [unreadable] [unreadable] [unreadable]
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