Modulation of NAc-DA signaling by learning, motivational state and peptides

描述(由申请人提供)：对情感刺激的适当行为反应促进健康并减少伤害的机会。然而，我们经常没有做出适当的回应。肥胖的部分原因是过度摄入营养物质，我们对愉悦食物的动力凌驾于我们的体内平衡信号之上。接触滥用药物会导致一些人摄入非营养物质，忽视体内平衡信号。这两种疾病都涉及到个人寻求回报，而忽视负面的、令人厌恶的后果。情感刺激通过连接伏核进入运动回路(Mogenson等人)。1980)。伏隔核(NAC)及其传入和传出联系对指向奖赏的行为至关重要。初级奖赏刺激引起NAC神经活动和多巴胺(DA)释放的变化，伏隔核神经和神经化学活动的变化预测针对奖赏消费的行为。此外，对NAC的药理操作改变了对奖励刺激的享乐反应，即使面对负面的体内平衡信号也能促进消费。这些发现导致一些人提出，伏隔核对于接近行为和针对奖励刺激的行为是必不可少的。如果是这样的话，NAC及其相关电路对负面情感刺激和厌恶的反应应该是非常不同的。关于这些神经元素是如何处理厌恶刺激的，我们知之甚少。厌恶刺激似乎确实会改变这些区域的活动，但改变的方式与厌恶刺激完全不同。行为显然是可塑性的，它通过学习和动机状态改变了情感刺激的享乐主义价态。然而，我们不知道当情感刺激改变符号时，伏隔核的反应是如何改变的。也就是说，根据习得的联想和动机状态的变化，刺激可以贬值，也可以增值。这项提议将决定NAC和DA发出奖励和厌恶的不同信号的机制。此外，该提案将确定当情感刺激的值发生变化时，NAC内神经生理和神经化学信号的可塑性变化。这项提议将利用在传递积极和消极情感刺激期间进行的NAC活动的实时记录。本文提出的研究将对特定刺激价值变化背后的正常神经过程提供有价值的见解，从而阐明肥胖和药物成瘾等动机回路障碍背后的异常信号。中脑边缘系统的异常信号是肥胖和药物成瘾等动机障碍的基础。这个项目的主要目标是确定影响中脑边缘信号的机制，以及该信号如何通过学习和动机状态的改变而改变。这些研究有可能在情感障碍的治疗中确定新的靶点。

DESCRIPTION (provided by applicant): Appropriate behavioral responses to affective stimuli promote health and reduce the chance of harm. However, we often fail to respond appropriately. Obesity results, in part, from the overconsumption of nutrients where our motivation for pleasurable food overrides our homeostatic signals. Exposure to drugs of abuse leads some individuals to consume non-nutritive substances and ignore homeostatic signals. Both diseases involve individuals seeking reward and ignoring negative, aversive consequences. Affective stimuli gain access to motor circuitry by interfacing at the nucleus accumbens (Mogenson et al. 1980). The nucleus accumbens (NAc) and its afferent and efferent connections are critical for behavior directed at rewards. Primary rewarding stimuli evoke changes in neural activity and dopamine (DA) release in the NAc and changes in neural and neurochemical activity in the nucleus accumbens predict behavior directed at reward consumption. Furthermore, pharmacological manipulations of the NAc alter hedonic responses to rewarding stimuli and promote consumption even in the face of negative homeostatic signals. These findings have led some to suggest that the nucleus accumbens is essential for approach behavior and behavior directed at rewarding stimuli. If this is the case, then the NAc and its associated circuitry should behave very differently in response to negative affective stimuli and aversion. Far less is known about how aversive stimuli are processed by these neural elements. Aversive stimuli do seem to alter activity in these regions but in an entirely different manner than aversive stimuli. Behavior is obviously plastic and reflects changes the hedonic valence of affective stimuli through learning and motivational state. We do not know, though, how nucleus accumbens responses are altered when affective stimuli change sign. That is, stimuli can either be devalued or increase in value depending on learned associations and changes in motivational state. This proposal will determine the mechanisms by which the NAc and DA differentially signal reward and aversion. In addition, the proposal will determine plastic changes in neurophysiological and neurochemical signaling within the NAc when the value of affective stimulus changes. This proposal will utilize real-time recordings of NAc activity made during the delivery of positive and negative affective stimuli. The studies proposed here will give valuable insight into normal neural processes underlying changes in value of a given stimulus and thus, shed light on the aberrant signaling underlying disorders of motivational circuitry such as obesity and drug addiction. Aberrant signaling of the mesolimbic system underlie disorders of motivation such as obesity and drug addiction. The major goal of this project is to determine the mechanisms governing mesolimbic signaling in affect and how that signaling is altered by learning and motivational state changes. These studies have the potential for identifying new targets in the treatment of affective disorders.