Mesolimbic Dopamine Modulation of Cue-Enhanced Ventral Pallidal Activity

描述(申请人提供)：这项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赏关联的大脑回路。精神刺激剂，如苯丙胺，被认为引起起源于腹侧被盖区的中脑边缘神经元过度释放多巴胺，进而激活伏隔核至腹侧苍白球奖励回路。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，与奖励相关的暗示变得过于吸引人，并导致过度的“渴望”奖励。当前提案的目标将是识别、比较和对比大脑中缘多巴胺释放的关键区域，以使与奖励相关的线索能够激活腹侧苍白球神经元。中脑边缘多巴胺对苯丙胺增强线索诱导的腹侧苍白球放电频率的增加和招募更多的腹侧苍白球细胞反应群体的能力的贡献也将被评估。从腹侧被盖区到伏隔核和腹侧苍白球的多巴胺神经元投射被认为是与奖赏相关的线索激活腹侧苍白球神经元的关键，而苯丙胺则对增强奖赏相关腹侧苍白球放电的线索的效力至关重要。我们将用6-羟基多巴胺(6-OHDA)损毁腹侧被盖区(目标1)、伏隔核(目标2)或腹侧苍白球(目标3)的多巴胺神经元。恢复后，将在清醒的行为大鼠中获得腹侧苍白球神经元的细胞外记录，这些大鼠被呈现先前学习到的奖赏(口腔内蔗糖)相关的线索。在车辆和安非他命的条件下，多巴胺耗竭的大鼠在线索前后的放电速度和反应神经群的大小将与假损伤的大鼠进行比较。每个区域的6-OHDA损伤预计会扰乱或完全阻断线索诱导的这些神经元的激活。这两条道路是否都是必要的，或者其中一条是否能够弥补另一条的损失，将受到考验。这项研究将深入了解大脑回路中对奖赏至关重要的信息处理，以及重要的是，成瘾药物如何干扰与奖赏相关的信息神经处理。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.