Neural Substrates of Conditioned Cue Effects on Reward Seeking

条件提示对奖励寻求影响的神经基础

基本信息

批准号：
8104571
负责人：
EDDA THIELS
金额：
$ 33.49万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8104571
关键词：
Adult Animals Behavior Behavior Control Behavior Therapy Behavioral Biological Cells Chemosensitization Confocal Microscopy Corpus striatum structure Cues Deposition Development Dopamine Dopamine Antagonists Dopamine D1 Receptor Dorsal Drug Addiction Enzyme Activation Event Exhibits Exposure to Food Gambling Glutamate Receptor Goals Immediate-Early Genes Impairment Incentives Light Mediating Mediation Mitogen-Activated Protein Kinases Molecular N-Methylaspartate Neurons Nucleus Accumbens Obesity Output Pathway interactions Peroxidases Phosphorylation Play Potassium Channel Process Property Rattus Receptor Activation Receptor Cell Regulation Resources Rewards Role Signal Transduction Site Stimulus Techniques Testing Tracer Work addiction cell type classical conditioning conditioning fitness innovation male neural circuit neurobiological mechanism receptor relating to nervous system response sensor treatment strategy

项目摘要

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. PUBLIC HEALTH RELEVANCE: The proposed studies will uncover the neurobiological mechanisms through which conditioned cues potentiate reward-seeking behavior. The findings will advance our understanding of a basic kind of behavior control by environmental stimuli and have important implications for the development of strategies to treat drug addiction and obesity.

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。帕夫洛夫条件提示对寻求奖励的这种增强作用通常是适应性的；但是，当追求奖励过剩或诱发损害时，它可能会变得不良适应，就像药物成瘾和肥胖一样。本提案的目的是阐明帕夫洛维亚 - 乐器转移的神经生物学机制。我们最近发现，接触奖励提示会引起成年大鼠伏伏核（NAC）的细胞外信号调节激酶（ERK）激活的瞬态增加，并且这种激活对于条件提示具有增强奖励寻求的能力是必需的（Shiflett等人（Shiflett等人）。这些观察结果表明，NAC ERK在调节线索的激励动机特性中的介导。本提案的目的是确定与提示驱动的ERK激活相关的NAC中的受体和细胞类型（特定目标1），NAC的输出靶标受提示驱动的ERK激活影响（特定的目标2）以及ERK介导的细胞内事件，通过这些事件，该enzyme的cue-drived驱动式激活可能会奖励目标3（特定的目标）3（特定的目标）3（特定的目标）3个3）。对于这些目标中的每一个，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受体的投影神经元，它们是NAC的核心和壳的直接抑制输出途径的一部分。这些投影神经元中的CS驱动的ERK激活会瞬时提高其兴奋性，从而促进这些神经元的输出到其靶标上。反过来，抑制效果促进了增强的奖励寻求。我们将使用行为，药理，过氧化物酶和双流质的免疫组织化学，逆行跟踪以及分子技术的强大而创新的组合来检验这些假设。提议的工作的发现将通过奖励预测提示来提高我们对行为控制基本方面的理解。这些发现还将对我们理解神经过程的理解，这些神经过程有助于昂贵的行为畸变，例如成瘾和肥胖，以及制定治疗这些行为畸变的策略。公共卫生相关性：拟议的研究将揭示有条件提示的奖励行为的神经生物学机制。这些发现将通过环境刺激来提高我们对基本行为控制的理解，并对治疗药物成瘾和肥胖的策略的发展具有重要意义。