Orbitofrontal-Accumbens Interactions, Dopamine Modulation and Impulsive Choice

描述（由申请方提供）：本提案中的实验旨在研究正常动物以及精神分裂症和药物滥用动物模型中冲动性的神经生理学和神经化学基础。和人类一样，动物也会冲动地选择一个小的即时奖励，而不是一个更大的延迟奖励（即时间折扣）。我们将测试冲动选择是否受多巴胺能调节从眶额皮质（OFC）发送到伏核（NA）的时间折扣奖励信号的支配，以及由于OFC编码的变化和NA中多巴胺能张力的变化而导致的该回路功能中断是否会导致精神分裂症和药物滥用中的冲动水平异常。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。通过指导研究科学家发展奖，我可以获得必要的技术和新学科的教学培训，以实现我的测试这些假设的近期目标和我的长期职业目标，成为一名成功的独立教师，胜任各种学科，包括神经生理学，神经药理学和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组成部分：（1）描述行为动物冲动选择的神经相关性。为此，我将继续接受舍恩鲍姆博士的培训，他是行为电生理学和学习理论方面的专家。(2)探讨多巴胺在眶额皮层与NA相互作用中的作用。为此，我将在奥唐纳博士的指导下学习如何在麻醉大鼠的细胞内记录药理学操作。(3)以描述精神分裂症和可卡因对这个回路的影响。为此，我将从舍恩鲍姆博士和奥唐纳博士那里获得新的技能。除了来自导师的技术和智力支持外，我还将通过马里兰州大学和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许多精神疾病常见的冲动性神经生物学的理解。此外，它将作为一个平台，调查冲动的选择精神分裂症和药物滥用的动物模型，这与了解在精神分裂症人群中观察到的药物滥用并发症的高发病率。

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.