Mesocorticolimbic Generation of Motivation

描述（由申请人提供）： 异常动机是各种人类精神障碍的一个重要特征。过度的食欲动机与毒瘾和肥胖有关，有时会导致强迫性追求和过度消费药物或食物（1，2）。位于中皮层边缘回路的丘脑核（NAc）在过度激励中起着重要作用。NAc的内侧壳区域特别与食欲动机行为的产生相关。除了在激励动机中众所周知的作用，中皮质边缘系统也可能介导一些恐惧状态。该提议集中于NAc壳的喙部中的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壳的尾区中的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）系统与皮层边缘谷氨酸破坏相互作用，以产生食欲和恐惧的动机显著性（5）：目标1将确定D1或D2受体亚型是否是在AMPA受体阻断后产生喙壳中的积极动机行为（进食）或消极动机行为（防御性踩踏）所必需的。同样重要的是要了解更大的皮质边缘电路，其中NAc壳嵌入，特别是要了解皮质边缘自上而下的信号如何调节NAc的食欲和防御动机的产生。目的2将确定PFC的哪个区域主要负责皮层下非条件性积极和消极动机的调制：内侧OFC，边缘下或边缘前。最后，重要的是要了解心理环境如何调节NAc产生的恐惧和喂养招募皮质边缘电路。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将确定特定的PFC输入NAc介导的环境调制的NAc产生的动机。 公共卫生相关性： 不适当或过度的动机是一个重要的，也许是各种人类精神障碍的主要特征。过度的食欲动机与药物成瘾和肥胖有关，这是直接和间接健康成本的主要来源，病理性恐惧突出性被认为是人类精神分裂症中偏执狂的一个方面。进一步了解这些动力的调节将与各种人类健康问题有关。

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.