Restoration and Further Assessment of the Actor-Critic Circuit and Connected Areas After Cocaine Self-Administration

可卡因自我给药后演员-评论家回路和连接区域的恢复和进一步评估

• 批准号: 10087906
• 负责人: MATTHEW R ROESCH
• 金额: $ 35.34万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087906
• 关键词: Affect; Amygdaloid structure; Animals; Anterior; Area; Attention; Behavior; Behavior Control; Brain; Brain region; Chronic; Cocaine; Corpus striatum structure; Cues; Decision Making; Dependence; Development; Diagnostic; Dopamine; Dorsal; Drug usage; Equilibrium; Event; Goals; Habits; Hypersensitivity; Hypersensitivity skin testing; Impairment; Impulsivity; Investigation; Knowledge; Lateral; Lead; Learning; Lesion; Marshal; Mental disorders; Midbrain structure; Modeling; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Odors; Outcome; Policies; Predictive Value; Prevalence; Procedures; Process; Psychological reinforcement; Public Health; Rattus; Reporting; Research; Resources; Response to stimulus physiology; Rewards; Sampling; Self Administration; Side; Signal Transduction; Stimulus; System; Task Performances; Testing; Time; Work; addiction; cingulate cortex; cocaine exposure; cocaine self-administration; cocaine use; dopamine system; dopaminergic neuron; effective therapy; executive function; expectation; experimental study; improved; innovation; insight; neural correlate; neuromechanism; neurotransmission; optogenetics; relating to nervous system; repaired; response; restoration

PROJECT SUMMARY Reward-guided decision-making and impulse control are disrupted after chronic cocaine use. These changes have been attributed to altered function in brain circuits critical for computations of reward predictions and action policies. `Reward prediction' signals reflect the reward the animal expects to receive as a result of behavior, thus reflecting goals associated with decisions. `Action policies' are rules that govern behavior that at triggered by external stimuli or context, and are thought to underlie habits. Both reward predictions and action policies are modified when there are violations in predictions known as `reward prediction errors'. `Signed' reward prediction errors reflect the valence associated with an error, strengthening or weakening the associability between cues and outcomes/responses. `Unsigned' prediction errors reflect the surprise induced by errors which lead to increases in attention so that learning can occur. We have uncovered neural correlates of these constructs and the relationship between them by recording from multiple brain areas as rats perform an odor guided decision-making task in which we unexpectedly varied the delay to and size of reward across several trial blocks. We have shown that nucleus accumbens core (NAc) encodes reward predictions, firing strongly for cues that predict more valued reward, whereas firing in dorsal lateral striatum (DLS) is highly associative, encoding action policies such as stimulus-response associations and contextual bias signals (e.g., in this context bias choices to the right). We have also shown that midbrain dopamine (DA) neurons increase firing to unexpected reward and decrease firing to unexpected reward omission. During learning these signed prediction errors transfer to cues, with cues predicting more valued reward eliciting stronger firing. Unlike firing of DA neurons, our work has shown that firing in anterior cingulate cortex (ACC) better reflects an integrated unsigned reward prediction error signal, increasing during unexpected up- and down-shifts in value at the time of the error and during cue sampling on subsequent trials. This work suggests a model by which DA reward prediction errors modify reward prediction signals in NAc and action policy signals in DLS, while ACC increases attention toward stimuli after violations in reward prediction (signaled by DA) so that learning can occur. Cocaine exposure impairs reward prediction signals and prediction error signals in NAc and DA neurons, while increasing the prevalence of contextual action policies in DLS. In Aim 1 we propose to restore the cocaine induced imbalance of processing between NAc and DLS by repairing DA signals via optogenetics. In Aim 2 we will determine if attention and error correlates in ACC are altered after cocaine exposure. Finally, in Aim 3, we will determine how ACC and DA neurons interact during the computation of errors and the development of cue selectivity. By performing these experiments we will gain further insight into how the brain functions normally, how it is disrupted after chronic cocaine use, and determine if repairing neural signals might restore behavior and neural constructs in downstream regions to normal levels.

项目摘要 奖励导向的决策和冲动控制在长期使用可卡因后被破坏。这些变化 被归因于大脑回路中对奖励预测计算至关重要的功能改变， 行动政策。“奖励预测”信号反映了动物期望得到的奖励， 行为，从而反映与决策相关的目标。“行动政策”是管理行为的规则， 由外部刺激或环境触发，并被认为是习惯的基础。奖励预测和行动 当在被称为“奖励预测错误”的预测中存在违规时，修改策略。`签字' 奖励预测错误反映了与错误相关的效价，加强或削弱了 线索和结果/反应之间的关联性。“无符号”预测误差反映了 通过错误导致注意力的增加，从而可以进行学习。我们已经发现了神经系统相关的 这些结构和它们之间的关系，通过记录从多个大脑区域作为大鼠执行 一个气味引导的决策任务，在这个任务中，我们出乎意料地改变了延迟和奖励的大小。 几个试验块。我们已经证明，核丘脑核心（NAc）编码奖励预测，发射 强烈的线索，预测更有价值的奖励，而发射在背侧纹状体（DLS）是高度 关联的、编码的动作策略，例如刺激-响应关联和上下文偏差信号（例如， 在这种情况下，偏向于正确的选择）。我们还表明，中脑多巴胺（DA）神经元增加， 激发意外奖励和减少激发意外奖励遗漏。在学习过程中，这些签名 预测错误转移到线索，线索预测更有价值的奖励引发更强的放电。不像射击 我们的工作表明，前扣带皮层（ACC）的放电更好地反映了DA神经元的整合 无符号奖励预测错误信号，在当时值意外上升和下降期间增加 的错误，并在随后的试验线索采样。这项工作提出了一个模型，DA奖励 预测误差修正NAc中的奖励预测信号和DLS中的行动策略信号，而ACC 在违反奖励预测（由DA发出信号）后，增加对刺激的注意力， 发生. CO2暴露损害NAc和DA中的奖励预测信号和预测误差信号 神经元，同时增加DLS中上下文动作策略的流行。在目标1中，我们建议恢复 可卡因通过光遗传学修复DA信号，诱导NAc和DLS之间的加工失衡。 在目标2中，我们将确定在可卡因暴露后，ACC中的注意力和错误相关性是否改变。最后， 在目标3中，我们将确定ACC和DA神经元在计算误差和 线索选择性的发展。通过进行这些实验，我们将进一步了解大脑是如何 功能正常，它是如何被破坏后，慢性可卡因使用，并确定是否修复神经信号可能 使下游区域的行为和神经结构恢复到正常水平。