Orbitofrontal-Accumbens Interactions, Dopamine Modulation and Impulsive Choice

描述（由申请人提供）：本提案中的实验旨在研究正常动物和精神分裂症和药物滥用动物模型中冲动的神经生理学和神经化学。和人类一样，动物会冲动地选择小的即时奖励，而不是大的延迟奖励（即时间折扣）。我们将测试冲激选择是否受多巴胺能调制的时间折扣奖励信号从眶额皮质（OFC）到伏隔核（NA）的控制，以及由于OFC编码和NA多巴胺能张力的改变而导致的该回路功能紊乱是否会导致精神分裂症和药物滥用中的冲激水平异常。这种互补的变化可以解释精神分裂症患者滥用药物的高发生率。通过导师研究科学家发展奖，我可以获得必要的技术和新学科的教学培训，以实现我的近期目标，即测试这些假设，以及我的长期职业目标，即成为一名成功的独立教师，胜任各种学科，包括神经生理学，神经药理学以及精神分裂症和药物滥用的研究。我的训练和具体的研究目标可以分为三个主要部分：(1)表征行为动物冲动选择的神经关联。为此，我将继续接受Schoenbaum博士的培训，他是行为电生理学和学习理论方面的专家。(2)研究多巴胺在OFC和NA相互作用中的作用。为此，我将在Dr. O'Donnell的指导下学习如何在麻醉大鼠的药物操作过程中记录细胞内。(3)表征精神分裂症和可卡因对该回路的影响。为此，我将向舍恩鲍姆博士和奥唐纳博士学习新技能。除了导师提供的技术和智力支持外，我还将通过马里兰大学和MPRC提供的课程、期刊俱乐部和研讨会接受教学培训。这项研究将增加我们对冲动性的神经生物学的理解，冲动性是许多精神疾病的共同特征。此外，它将为研究精神分裂症和药物滥用动物模型中的冲动选择提供一个平台，这与理解在精神分裂症人群中观察到的药物滥用合并症的高发有关。

DESCRIPTION (provided by applicant): 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.