Neural Substrates of Conditioned Cue Effects on Reward Seeking

描述（由申请人提供）：与奖励配对的刺激可以增强旨在获得奖励的行为。巴甫洛夫条件线索对奖赏寻求的这种增强作用，称为巴甫洛夫工具性转移，通常是适应性的;然而，当奖赏被过度追求或引起损害时，它可能变得适应不良，如药物成瘾和肥胖。本提案的目标是揭示巴甫洛夫工具转移的神经生物学机制。我们最近发现，暴露于奖励配对的线索诱导成年大鼠的脑桥核（NAc）中细胞外信号调节激酶（ERK）的激活的瞬时增加，并且这种激活是条件线索增强奖励寻求的能力所必需的（Shiflett等人，2008年）。这些观察结果表明，NAC ERK在调解条件线索的激励动机属性中发挥着重要作用。本提案的目标是确定参与线索驱动的ERK激活的NAc内的受体和细胞类型（具体目标1），受线索驱动的ERK激活影响的NAc的输出靶点（具体目标2），以及ERK介导的细胞内事件，通过这些事件，线索驱动的这种酶的激活可能促进奖励寻求（具体目标3）。对于每一个目标，我们的工作假设如下。CS驱动的ERK激活是NAc细胞上D1多巴胺和NMDA谷氨酸受体激活的结果。表达CS驱动的ERK激活的细胞类型是表达D1受体的投射神经元，它们是NAc核心和外壳的直接去抑制输出通路的一部分。这些投射神经元内的CS驱动的ERK激活短暂地提高了它们的兴奋性，从而促进了这些神经元向其靶点的输出。去抑制效应反过来又促进了奖励寻求的增强。我们将测试这些假设使用一个强大的和创新的组合行为，药理学，过氧化物酶和双荧光免疫组化，逆行追踪，和分子技术。这项工作的发现将促进我们对奖励预测线索行为控制的一个基本方面的理解。这些发现也将对我们理解导致昂贵行为畸变（如成瘾和肥胖）的神经过程以及制定治疗这些行为畸变的策略产生影响。

DESCRIPTION (provided by applicant): Stimuli that have been paired with reward can potentiate behavior aimed at obtaining the reward. This potentiating effect of Pavlovian conditioned cues on reward seeking, termed Pavlovian-instrumental transfer, generally is adaptive; however, it can become maladaptive when the reward is pursued in excess or induces damage, as is the case in drug addiction and obesity. The goal of the present proposal is to shed light on the neurobiological mechanisms underlying Pavlovian-instrumental transfer. We recently found that exposure to a reward-paired cue induces a transient increase in the activation of extracellular signal-regulated kinase (ERK) in the nucleus accumbens (NAc) of adult rats, and that this activation is required for the ability of the conditioned cue to potentiate reward seeking (Shiflett et al., 2008). These observations suggest an important role for NAc ERK in the mediation of the incentive-motivational properties of conditioned cues. The goal of the present proposal is to determine the receptors and cell types within the NAc involved in the cue-driven ERK activation (Specific Aim 1), the output targets of the NAc impacted by the cue-driven ERK activation (Specific Aim 2), and ERK-mediated intracellular events through which the cue-driven activation of this enzyme may facilitate reward seeking (Specific Aim 3). For each of these aims, our working hypotheses are as follows. The CS-driven ERK activation results from activation of D1 dopamine and NMDA glutamate receptors on NAc cells. The cell type that expresses CS-driven ERK activation are D1 receptor-expressing projection neurons that are part of direct, disinhibitory output pathways from the core and the shell of the NAc. CS-driven ERK activation within these projection neurons transiently raises their excitability, thereby facilitating output from these neurons onto their targets. The disinhibitory effect, in turn, promotes enhanced reward seeking. We will test these hypotheses using a powerful and innovative combination of behavioral, pharmacological, peroxidase- and double-flouresence immunohistochemical, retrograde tracing, and molecular techniques. The findings from the proposed work will advance our understanding of a fundamental aspect of behavior control by reward- predictive cues. The findings also will have implications for our understanding of the neural processes that contribute to costly behavioral aberrations, such as addiction and obesity, and the development of strategies for the treatment of these behavioral aberrations.