Mesocorticolimbic Generation of Motivation

项目总结 异常动机是人类多种精神障碍的重要特征。过度的食欲动机与药物成瘾和肥胖有关，有时会导致强迫性追求和过度消费药物或食物(1，2)。伏隔核(NAC)位于大脑中皮质边缘环路，在过度激励动机中起着重要作用。NAC的内侧壳层区域与食欲动机行为的产生特别相关。除了众所周知的激励激励作用外，中皮质边缘系统也可能调节一些令人恐惧的状态。本研究的重点在于NAC壳头端局部谷氨酸破坏在产生积极动机行为中的作用，如高强度摄食，以及NAC壳尾部区域谷氨酸中断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，产生食欲和恐惧的动机突显(5)：Aim 1将确定在AMPA受体阻断后，D1或D2受体亚型是否对头壳的积极动机行为(摄食)或消极动机行为(防御性踩踏)的产生是必需的。同样重要的是要了解NAC壳嵌入其中的更大的皮质边缘回路，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无条件的积极和消极动机：内侧OFC、下缘或前缘。最后，重要的是要了解心理环境是如何通过招募皮质边缘回路来调节NAC产生恐惧和进食的。这一现象可能与背景对人类病理动机的影响有关，也与治疗干预有关。目标3将确定特定的PFC对NAC的输入，这些PFC参与调节NAC的环境调节-产生动机。

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.