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。这种巴甫洛夫条件线索对奖励寻求的增强作用，称为巴甫洛夫-工具转移，通常是适应性的；然而，当过度追求奖励或造成损害时，它就会变得不适应，就像吸毒成瘾和肥胖的情况一样。本提案的目标是阐明巴甫洛夫-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会导致成年大鼠伏隔核（NAc）细胞外信号调节激酶（ERK）激活的短暂增加，而这种激活是条件提示增强寻求奖励能力所必需的（Shiflett等人，2008）。这些观察结果表明，NAc ERK在条件线索的激励-动机特性的中介中起着重要作用。本研究的目的是确定NAc内参与线索驱动的ERK激活的受体和细胞类型（Specific Aim 1），受线索驱动的ERK激活影响的NAc的输出靶标（Specific Aim 2），以及ERK介导的细胞内事件，通过这些事件，该酶的线索驱动激活可能促进寻求奖励（Specific Aim 3）。对于每一个目标，我们的工作假设如下。cs驱动的ERK激活是由NAc细胞上D1多巴胺和NMDA谷氨酸受体的激活引起的。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核心和外壳直接去抑制输出通路的一部分。在这些投射神经元中，cs驱动的ERK激活会短暂地提高它们的兴奋性，从而促进这些神经元向目标的输出。这种去抑制效应反过来又促进了奖励寻求的增强。我们将使用行为学、药理学、过氧化物酶和双荧光免疫组织化学、逆行示踪和分子技术的强大和创新组合来检验这些假设。这项工作的发现将促进我们对奖赏预测线索的行为控制的一个基本方面的理解。这些发现还将对我们理解导致昂贵的行为异常（如成瘾和肥胖）的神经过程以及治疗这些行为异常的策略的发展产生影响。

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.