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，减少伤害的机会。然而，我们往往不能作出适当的反应。肥胖的部分原因是过度消耗营养，我们对愉快食物的动机压倒了我们的自我平衡信号。暴露于滥用药物导致一些人消耗非营养物质，忽视体内平衡信号。这两种疾病都涉及个人寻求奖励，忽视负面的，令人厌恶的后果。情感刺激通过与延髓核的连接进入运动回路（Mogenson et al. 1980）。丘脑核（NAc）及其传入和传出连接对奖励行为至关重要。初级奖励刺激引起NAc神经活动和多巴胺（DA）释放的变化，中脑核神经和神经化学活动的变化预测奖励消费的行为。此外，药理学操纵的NAc改变享乐反应奖励刺激和促进消费，即使在面对负稳态信号。这些发现使一些人认为，丘脑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，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。我们对这些神经元如何处理厌恶性刺激知之甚少。厌恶刺激似乎确实改变了这些区域的活动，但与厌恶刺激的方式完全不同。行为具有明显的可塑性，并通过学习和动机状态反映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符号时，丘脑核的反应是如何改变的。也就是说，刺激可以贬值或增值，这取决于习得的联想和动机状态的变化。这个提议将确定NAc和DA区别地发出奖励和厌恶信号的机制。此外，该提案将确定当情感刺激值改变时，NAc内神经生理学和神经化学信号传导的塑性变化。该提案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。这里提出的研究将提供有价值的洞察正常的神经过程的潜在变化的价值，一个给定的刺激，从而揭示了异常信号的潜在障碍的动机电路，如肥胖和药物成瘾。中脑边缘系统的异常信号传导是动机障碍的基础，如肥胖和药物成瘾。这个项目的主要目标是确定在影响中的中脑边缘信号的机制，以及如何通过学习和动机状态的变化来改变这种信号。这些研究有可能确定情感障碍治疗的新靶点。

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.