Mesocorticolimbic Generation of Motivation

中皮质边缘的动机产生

• 批准号: 7905506
• 负责人: Jocelyn M Richard
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905506
• 关键词: AMPA Receptors; Dopamine D2 Receptor; Drug Addiction; Food; Fright; Generations; Glutamates; Health; Health Care Costs; Human; Incentives; Medial; Mediating; Mental disorders; Motivation; Nucleus Accumbens; Obesity; Paranoia; Pharmaceutical Preparations; Play; Recruitment Activity; Role; Schizophrenia; Signal Transduction; Source; System; Therapeutic Intervention; feeding; mesolimbic system; motivated behavior; psychologic; public health relevance

DESCRIPTION (provided by applicant): PROJECT SUMMARY Aberrant motivation is an important feature of a variety of human mental disorders. Excessive appetitive motivation is implicated in drug addiction and obesity, leading to sometimes compulsive pursuit and overconsumption of drugs or food (1, 2). The nucleus accumbens (NAc), embedded within mesocorticolimbic circuits, plays an important role in excessive incentive motivation. The medial shell region of the NAc is particularly associated with the generation of appetitively motivated behaviors. Beyond the well known role in incentive motivation, mesocorticolimbic systems may also mediate some fearful states. This proposal focuses on the role of local glutamate disruptions in rostral NAc shell in producing positively-motivated behaviors like intense feeding, and the role of glutamate disruptions in caudal zones of NAc shell in producing negatively- motivated behaviors. Mesolimbic dopamine (DA) systems interact with corticolimbic glutamate disruptions for appetitive and fearful motivational salience (5): Aim 1 will identify whether D1 or D2 receptor subtypes are necessary for generation of either positively-motivated behaviors (feeding) in rostral shell or negatively- motivated behaviors (defensive treading) following AMPA receptor blockade. It is also important to understand the larger corticolimbic circuit in which NAc shell is embedded, and particularly to understand how corticolimbic top-down signals regulate generation of appetitive and defensive motivation by NAc. Aim 2 will identify which region of PFC is primarily responsible for modulation of subcortical unconditioned positive and negative motivation: medial OFC, infralimbic or prelimbic. Finally, it is important to understand how psychological context modulates NAc generation of fear and feeding by recruiting corticolimbic circuits. This phenomenon may be relevant to contextual influences on human pathological motivations, as well as to therapeutic interventions. Aim 3 will identify the particular PFC inputs to NAc that mediate environmental modulation of NAc-generation of motivation. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Motivation that is inappropriate or excessive is an important and perhaps primary feature of a variety of human mental disorders. Excessive appetitive motivation is implicated in drug addiction and obesity, which are major sources of direct and indirect health costs, and pathological fearful salience has been suggested to appear as an aspect of paranoia found in human schizophrenia. Further understanding of modulation of these motivational forces will have relevance to a variety of human health problems.

描述（由申请人提供）： 项目摘要 异常动机是多种人类精神障碍的重要特征。过度的食欲动机与毒瘾和肥胖有关，有时会导致对药物或食物的强迫性追求和过度消费 (1, 2)。伏隔核（NAc）嵌入中皮质边缘回路中，在过度激励中发挥着重要作用。 NAc 的内侧壳区域与食欲动机行为的产生特别相关。除了在激励动机中众所周知的作用之外，中皮质边缘系统还可能调节一些恐惧状态。该提案重点关注 NAc 头侧壳中局部谷氨酸破坏在产生积极动机行为（如强烈进食）中的作用，以及 NAc 壳尾部区域谷氨酸破坏在产生消极动机行为中的作用。中脑边缘多巴胺 (DA) 系统与皮质边缘谷氨酸干扰相互作用，导致食欲和恐惧动机显着性 (5)：目标 1 将确定 D1 或 D2 受体亚型对于在嘴壳中产生积极动机行为（进食）或消极行为是否是必需的。 AMPA 受体阻断后的动机行为（防御性踩踏）。了解 NAc 壳嵌入其中的更大的皮质边缘回路也很重要，特别是了解皮质边缘自上而下的信号如何调节 NAc 产生食欲和防御动机。目标 2 将确定 PFC 的哪个区域主要负责调节皮层下非条件性积极和消极动机：内侧 OFC、下边缘或前边缘。最后，重要的是要了解心理环境如何通过招募皮质边缘回路来调节 NAc 产生恐惧和进食。这种现象可能与人类病理动机的背景影响以及治疗干预有关。目标 3 将确定 NAc 的特定 PFC 输入，调节 NAc 生成动机的环境调节。 公共卫生相关性： 项目叙述 不适当或过度的动机是各种人类精神障碍的一个重要的、也许是主要的特征。过度的食欲动机与毒瘾和肥胖有关，这是直接和间接健康成本的主要来源，并且病理性恐惧显着性被认为是人类精神分裂症中发现的偏执狂的一个方面。进一步了解这些动力的调节将与各种人类健康问题相关。