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，我们常常不能做出适当的回应。肥胖的部分原因是营养物质的过度消耗，我们对愉悦食物的动机超过了我们的体内平衡信号。滥用药物导致一些人摄入非营养物质，忽视体内平衡信号。这两种疾病都涉及个体寻求奖励而忽视负面的、令人厌恶的后果。情感刺激通过连接伏隔核进入运动回路（Mogenson et al. 1980）。伏隔核（NAc）及其传入和传出连接是关键的行为导向奖励。初级奖励刺激引起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了针对奖励消费的行为。此外，NAc的药理学操作改变了对奖励刺激的享乐反应，甚至在面对负稳态信号时也促进了消费。这些发现导致一些人认为伏隔核对接近行为和针对奖励刺激的行为至关重要。如果是这样的话，那么NAc及其相关回路在对负面情感刺激和厌恶的反应中应该表现得非常不同。对于这些神经元素是如何处理厌恶刺激的，我们所知甚少。厌恶刺激似乎确实改变了这些区域的活动，但方式与厌恶刺激完全不同。行为具有明显的可塑性，通过学习和动机状态反映了情感刺激的享乐价的变化。然而，我们不知道当情感刺激改变信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，刺激的价值可以降低，也可以增加。这一建议将确定NAc和DA不同的奖励和厌恶信号的机制。此外，该提案将确定当情感刺激值发生变化时，NAc内神经生理和神经化学信号的可塑性变化。该建议将利用在传递积极和消极情感刺激时NAc活动的实时记录。这里提出的研究将对正常的神经过程提供有价值的见解，这些神经过程隐藏在给定刺激值的变化中，从而揭示了动机回路紊乱的异常信号，如肥胖和药物成瘾。中边缘系统的异常信号是导致动机紊乱的原因，如肥胖和药物成瘾。该项目的主要目标是确定影响中脑边缘信号传导的机制，以及学习和动机状态变化如何改变信号传导。这些研究有可能为情感性障碍的治疗确定新的靶点。

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.