Nucleus accumbens processing of reward-predictive cues

伏隔核处理奖励预测线索

基本信息

批准号：
10802207
负责人：
SALEEM M NICOLA
金额：
$ 68.69万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10802207
关键词：
Acute Adaptive Behaviors Adenosine Affect Animals Arousal Attention Automobile Driving Behavior Behavioral Behavioral Paradigm Caffeine Cognitive Cues Disparate Dopamine Dopamine Antagonists Dopamine D1 Receptor Dopamine D2 Receptor Drug Interactions Electroencephalography Electrophysiology (science)Elements Environment Event Fiber Grant Haloperidol Health Individual Injections Literature Mediating Microdialysis Midbrain structure Modeling Motivation Motor Neurobiology Neurons Neurotransmitters Nucleus Accumbens Optics Performance Persons Pharmaceutical Preparations Photometry Play Population Process Property Publishing Rattus Readiness Resources Rewards Role Sensory Sleep Stimulus Testing Thinking Time Ventral Tegmental Area Viral Work addiction antagonist approach behavior awake behavioral response dopaminergic neuron drug abuser drug of abuse experimental study innovation neural circuit neuromechanism neuroregulation novel therapeutics predictive modeling psychostimulant receptor response reward processing

项目摘要

Project Summary Salient sensory events can elevate the arousal level, increasing the subject's readiness to engage motor, cognitive and attentional resources. For example, arousal is increased when a sleeping person is shaken awake, or when a quiescent rat is transferred to a new cage or otherwise handled. Recent evidence shows that the dopamine projection from the midbrain ventral tegmental area to the nucleus accumbens (NAc) core serves to elevate arousal in response to such events, and that this effect likely involves both D1 and D2 dopamine receptor- expressing NAc neurons. Yet, this role for mesolimbic circuitry in arousal has not been reconciled with the large literature that interprets the behavioral effects of NAc dopamine manipulations as the result of altered motivation or reward. To investigate how arousal might contribute to the reward-seeking effects of dopamine, we first established a behavioral paradigm in which rats' performance of a cued operant task declines over time due to gradually decreasing arousal. We find that simply handling the animal for a few seconds dramatically restores high levels of performance for many minutes. Handling also increases dopamine levels in the NAc and the firing response of NAc neurons to reward-predictive cues, which are known to be dopamine-dependent and causal to the cued reward-seeking behavioral response. These results suggest that the dopamine increase caused by arousing events facilitates reward seeking. This is one of the major hypotheses tested in this proposal. This hypothesis suggests an even more provocative idea: that NAc dopamine promotes reward seeking by increasing arousal. If that were the case, then dopamine should act via the same local circuit mechanism within the NAc to increase both arousal and reward seeking. Previous studies point towards (but do not conclusively demonstrate) a specific circuit mechanism common to both processes: D1 neurons are the “effector” neurons whose firing drives both arousal and reward seeking, whereas D2 neurons strongly inhibit D1 neurons. Dopamine promotes arousal and reward seeking primarily by acting at the D2 receptor to reduce the inhibitory drive from D2 neurons onto D1 neurons, and only secondarily (if at all) by directly increasing the excitability of D1 neurons by acting at the D1 receptor. This circuit model receives a great deal of indirect support from disparate published experiments, as well as our pilot experiments, that have tested individual components of the model in isolation from the others. In this proposal, we aim to test the model cohesively and thoroughly, and in doing so, to establish that dopamine increases both arousal and reward seeking by the same local NAc circuit mechanism. Doing so will reframe current thinking regarding the behavioral role of mesolimbic dopamine in two ways; first, by establishing the causal contribution of D2 neurons' inhibition of D1 neurons (and the relief of this inhibition by dopamine) to both arousal and reward seeking; and second, by showing that dopamine facilitates arousal and reward seeking via the same local circuit mechanism – which will introduce the field to the hypothesis that dopamine's well-known ability to promote reward seeking could be due in part to increased arousal.

项目概要显着的感官事件可以提高唤醒水平，增加受试者参与运动的准备度，例如，当熟睡的人被摇醒时，觉醒度会增加。或者当静止的老鼠被转移到新的笼子或以其他方式处理时。多巴胺从中脑腹侧被盖区投射到伏隔核（NAc）核心提高对此类事件的反应，并且这种效应可能涉及 D1 和 D2 多巴胺受体 - 然而，中脑边缘回路在唤醒中的作用尚未与大的神经元相一致。将 NAc 多巴胺操纵的行为效应解释为动机的结果的文献为了研究唤醒如何促进多巴胺的奖励寻求效应，我们首先建立了一种行为范式，其中大鼠对提示操作任务的表现随着时间的推移而下降，原因是我们发现，只要触摸动物几秒钟，兴奋度就会逐渐降低。长时间的高水平表现也会增加NAc和放电中的多巴胺水平。 NAc 神经元对奖励预测线索的反应，已知这些线索是多巴胺依赖性的，并且与这些结果表明多巴胺增加引起的。激发事件促进奖励寻求，这是本提案中测试的主要假设之一。这一假设提出了一个更具挑衅性的想法：NAc 多巴胺通过以下方式促进奖励寻求：如果是这样的话，那么多巴胺应该通过内部相同的局部回路机制发挥作用。先前的研究表明，NAC 可以增加唤醒和奖励寻求（但并未得出结论）。演示）两个过程共有的特定电路机制：D1 神经元是“效应器”神经元多巴胺的放电会驱动唤醒和奖励寻求，而 D2 神经元强烈抑制 D1 神经元。主要通过作用于 D2 受体以减少来自 D2 神经元作用于 D1 神经元，并且仅通过直接增加 D1 神经元的兴奋性来进行次要的（如果有的话）通过作用于 D1 受体，该电路模型得到了不同发表的文献的大量间接支持。实验以及我们的试点实验，单独测试了模型的各个组成部分在这个提案中，我们的目标是连贯而彻底地测试该模型，并在此过程中建立模型。多巴胺通过相同的局部 NAc 回路机制增加唤醒和奖励寻求。首先将通过两种方式重新构建当前关于中脑边缘多巴胺的行为作用的想法；确定 D2 神经元抑制 D1 神经元的因果关系（以及通过多巴胺）对唤醒和奖励寻求都有影响；第二，通过证明多巴胺促进唤醒和奖励通过相同的本地电路机制寻求奖励——这将向该领域引入这样的假设：多巴胺众所周知的促进奖励寻求的能力可能部分归因于兴奋的增加。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Limbic-motor integration by neural excitations and inhibitions in the nucleus accumbens.

DOI：
10.1152/jn.00465.2017
发表时间：
2017-08
期刊：
Journal of neurophysiology
影响因子：
2.5
作者：
Sara E. Morrison;V. McGinty;Johann du Hoffmann;S. Nicola
通讯作者：
Sara E. Morrison;V. McGinty;Johann du Hoffmann;S. Nicola

Basolateral amygdala neurons facilitate reward-seeking behavior by exciting nucleus accumbens neurons.

DOI：
10.1016/j.neuron.2008.07.004
发表时间：
2008-08-28
期刊：
Neuron
影响因子：
16.2
作者：
Ambroggi F;Ishikawa A;Fields HL;Nicola SM
通讯作者：
Nicola SM

Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens.

DOI：
10.1016/j.neuron.2013.04.010
发表时间：
2013-06-05
期刊：
Neuron
影响因子：
16.2
作者：
McGinty VB;Lardeux S;Taha SA;Kim JJ;Nicola SM
通讯作者：
Nicola SM

The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior.

DOI：
10.1523/jneurosci.3958-10.2010
发表时间：
2010-12-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Nicola SM
通讯作者：
Nicola SM

Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition.

DOI：
10.1523/jneurosci.6491-10.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Ambroggi F;Ghazizadeh A;Nicola SM;Fields HL
通讯作者：
Fields HL