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 慢性可卡因使用后，奖励指导的决策和冲动控制会破坏。这些变化 归因于大脑电路功能的改变，对于奖励预测的计算至关重要 行动政策。 “奖励预测”信号反映了动物期望获得的奖励 行为，因此反映了与决策相关的目标。 “行动政策”是管理行为的规则 由外部刺激或上下文触发，被认为是习惯的基础。奖励预测和行动 当被称为“奖励预测错误”的预测中存在违规行为时，政策会被修改。 “签名” 奖励预测错误反映了与错误相关的价，加强或削弱了 提示与结果/响应之间的关联。 “未签名”预测错误反映了惊喜 通过导致注意力增加的错误，可以进行学习。我们发现了神经相关性 这些结构及其之间的关系通过从多个大脑区域记录时，随着大鼠的表现 气味指导的决策任务，我们意外地将延误和奖励规模变化 几个试验块。我们已经表明，伏隔核（NAC）编码奖励预测，发射 强烈的提示可以预测更有价值的奖励，而在背侧纹状体（DLS）中发射很高 协会，编码的行动策略，例如刺激反应关联和上下文偏见信号（例如， 在这种情况下，右边的选择偏差）。我们还表明，中脑多巴胺（DA）神经元增加 发射意外奖励，并减少发射到意外的奖励遗漏。在学习这些签名期间 预测错误转移到线索中，提示预测了更有价值的奖励会引起更强的射击。与射击不同 在DA神经元中，我们的工作表明，在前扣带回皮质（ACC）中射击更好地反映了一体 未签名的奖励预测误差信号，在当时的意外上升和下降期间增加 在随后的试验中的误差和提示抽样期间。这项工作提出了一个奖励的模型 预测错误修改了NAC中的奖励预测信号和DLS中的行动策略信号，而ACC 在奖励预测中违规后，增加对刺激的关注（由DA发出信号），以便学习可以 发生。可卡因暴露会损害NAC和DA中的奖励预测信号和预测错误信号 神经元，同时增加了DLS上下文行动政策的普遍性。在目标1中，我们建议恢复 可卡因通过通过光遗传学修复DA信号引起了NAC和DLS之间的处理失衡。 在AIM 2中，我们将确定可卡因暴露后ACC中的注意力和误差是否会改变。最后， 在AIM 3中，我们将确定ACC和DA神经元在计算错误和 提示选择性的发展。通过执行这些实验，我们将进一步了解大脑的方式 正常起作用，慢性可卡因使用后如何破坏它，并确定修复神经信号是否可能 将下游区域的行为和神经结构恢复到正常水平。