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

通过学习、动机状态和肽调节 NAc-DA 信号传导

• 批准号: 8102152
• 负责人: MITCHELL F ROITMAN
• 金额: $ 29.81万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102152
• 关键词: Address; Affect; Affective; Amygdaloid structure; Association Learning; Aversive Stimulus; Behavior; Behavioral; Biological Assay; CNR1 gene; Cell Nucleus; Consumption; Data; Disease; Dopamine; Dopamine D2 Receptor; Drug Addiction; Elements; Exposure to; Food; Goals; Health; In Vitro; Individual; Knowledge; Learning; Light; Malaise; Measures; Mediating; Mood Disorders; Motivation; Motor; Neurons; Neurotransmitters; Nucleus Accumbens; Nutrient; Obesity; Opioid; Opioid Receptor; Pattern; Peptides; Pharmaceutical Preparations; Plastics; Play; Process; Rattus; Receptor Activation; Rewards; Role; Sensory; Signal Transduction; Sodium; Solutions; Stimulus; Sucrose; System; Taste Perception; Techniques; Time; United States; Visceral; Work; approach behavior; cannabinoid receptor; classical conditioning; cost; discounting; drug of abuse; dysphoria; experience; feeding; hedonic; in vivo; insight; kappa opioid receptors; mesolimbic system; millisecond; motivated behavior; neurochemistry; neuronal cell body; neurophysiology; novel; receptor; relating to nervous system; response; stimulus processing

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.

描述（由申请人提供）：对情感刺激的适当行为反应可以促进健康并减少伤害的机会。然而，我们常常无法做出适当的回应。肥胖在一定程度上是由于营养物质的过度消耗造成的，其中我们对美味食物的动机超越了我们的体内平衡信号。接触滥用药物会导致一些人消耗非营养物质并忽视体内平衡信号。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。情感刺激通过伏隔核连接进入运动回路（Mogenson et al. 1980）。伏隔核 (NAc) 及其传入和传出连接对于奖励行为至关重要。主要奖励刺激会引起 NAc 中神经活动和多巴胺 (DA) 释放的变化，以及伏隔核中神经和神经化学活动的变化预测针对奖励消耗的行为。此外，对 NAc 的药理学操作会改变对奖励刺激的享乐反应，并促进消费，即使面对负稳态信号也是如此。这些发现使一些人认为伏隔核对于接近行为和针对奖励刺激的行为至关重要。如果是这种情况，那么 NAc 及其相关电路对于负面情感刺激和厌恶的反应应该表现得非常不同。人们对这些神经元如何处理厌恶刺激知之甚少。厌恶刺激似乎确实会改变这些区域的活动，但方式与厌恶刺激完全不同。行为具有明显的可塑性，反映了通过学习和动机状态改变情感刺激的享乐效价。然而，我们不知道当情感刺激改变信号时伏核反应如何改变。也就是说，刺激可以贬值或升值，具体取决于习得的关联和动机状态的变化。该提案将确定 NAc 和 DA 区别奖励和厌恶信号的机制。此外，该提案还将确定当情感刺激值发生变化时，NAc 内神经生理学和神经化学信号传导的可塑性变化。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。这里提出的研究将为给定刺激值变化背后的正常神经过程提供有价值的见解，从而揭示肥胖和毒瘾等动机回路疾病的异常信号传导。中脑边缘系统的异常信号是肥胖和毒瘾等动机障碍的基础。该项目的主要目标是确定控制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该信号传导。这些研究有可能确定治疗情感障碍的新靶点。