Mesolimbic Dopamine Modulation of Cue-Enhanced Ventral Pallidal Activity

描述（由申请人提供）：本提案的长期目标是了解成瘾药物如何“劫持”参与中性环境刺激与奖励关联的大脑回路。安非他明等精神兴奋剂被认为会导致源自腹侧被盖区的中脑边缘神经元释放过量的多巴胺，这反过来会激活丘脑腹侧苍白球奖赏回路。增加的多巴胺和相关的回路变化可能是一种病理状态的基础，在这种状态下，与奖励相关的线索变得过于有吸引力，并导致过度的“想要”奖励。目前的建议的目标将是识别，以及比较和对比，中脑边缘多巴胺释放的关键大脑区域，使奖励相关的线索激活腹侧苍白球神经元。还将评估中脑边缘多巴胺对安非他明加强腹侧苍白球放电率的线索诱导的增加和招募更大的腹侧苍白球细胞响应群体的能力的贡献。多巴胺神经元的预测从腹侧被盖区的核腹侧苍白球被假设为是至关重要的奖励相关的线索激活腹侧苍白球神经元，并为安非他明，以提高奖励相关的腹侧苍白球放电的线索的效力。我们将用6-羟基多巴胺（6-OHDA）损伤腹侧被盖区（Aim 1）、丘脑核（Aim 2）或腹侧苍白球（Aim 3）的多巴胺神经元。恢复后，腹侧苍白球神经元的细胞外记录将在清醒的行为大鼠中获得，这些大鼠呈现先前学习的奖励（口内蔗糖）相关线索。在溶剂和安非他明条件下，将多巴胺耗尽大鼠在线索前后的放电率以及反应神经群的大小与假损伤大鼠进行比较。6-预期每个区域的OHDA损伤破坏或完全阻断这些神经元的线索引发的激活。这两种途径是否都是必要的，或者一种途径是否可以弥补另一种途径的损失，将受到考验。这项研究将深入了解大脑回路中对奖励至关重要的信息处理，重要的是，成瘾药物如何干扰与信息奖励相关的神经处理。这些信息将有助于了解成瘾和开发新的治疗方法。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how addictive drugs "hijack" brain circuits involved in the association of neutral environmental stimuli with reward. Psychostimulants such as amphetamine are thought to cause excessive dopamine release from mesolimbic neurons originating in the ventral tegmental area, which in turn would activate the nucleus accumbens to ventral pallidum reward circuit. Increased dopamine and associated circuit changes may underlie a pathological state in which reward-associated cues become overly attractive and cause excessive "wanting" of reward. Goals of the current proposal will be to identify, as well as compare and contrast, brain regions critical for mesolimbic dopamine release to enable reward-related cues to activate ventral pallidal neurons. Mesolimbic dopamine contributions to the ability of amphetamine to strengthen cue-induced increases in ventral pallidal firing rates and recruit larger responsive populations of ventral pallidal cells will also be evaluated. Dopamine neuronal projections from the ventral tegmental area to the nucleus accumbens and the ventral pallidum are hypothesized to be crucial for reward-related cues to activate ventral pallidal neurons, and for amphetamine to enhance the potency of cues on reward-related ventral pallidal firing. We will lesion dopamine neurons with 6- hydroxydopamine (6-OHDA) in the ventral tegmental area (Aim 1), nucleus accumbens (Aim 2), or ventral pallidum (Aim 3). After recovery, extracellular recordings of ventral pallidal neurons will be obtained in awake, behaving rats that are presented with previously learned reward (intraoral sucrose)-associated cues. Under vehicle and amphetamine conditions, firing rates before and after the cues and the sizes of responsive neural populations for dopamine-depleted rats will be compared to rats with sham lesions. 6- OHDA lesions of each region are expected disrupt or completely block cue-elicited activation of these neurons. Whether both pathways are necessary or if one can compensate for the loss of the other will be tested. This research will provide insight into information processing in brain circuits essential for reward, and importantly, how information reward-related neural processing might be disturbed by addictive drugs. Such information will be useful for understanding addiction and developing new therapies for treatment.