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: 10634903
• 负责人: MATTHEW R ROESCH
• 金额: $ 38.08万
• 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 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634903
• 关键词: Affect; Amygdaloid structure; Animals; Anterior; Area; Attention; Attenuated; Behavior; Behavioral; Brain; Brain region; Cell Count; Choice Behavior; Chronic; Cocaine; Cognitive; Conflict (Psychology); Corpus striatum structure; Cues; Data; Decision Making; Development; Diffusion; Dorsal; Drug usage; Enzymes; Epigenetic Process; Event; Exhibits; Expectancy; Funding; Goals; HDAC5 gene; Habits; Impairment; Insula of Reil; Knowledge; Lateral; Lead; Learning; Mental disorders; Midbrain structure; Modeling; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Odors; Outcome; Pharmaceutical Preparations; Play; Policies; Population; Predictive Value; Process; Public Health; Publishing; Rattus; Reaction Time; Relapse; Research; Response to stimulus physiology; Rewards; Sampling; Self Administration; Shapes; Signal Transduction; Stimulus; Structure; System; Task Performances; Testing; Time; Uncertainty; Update; Ventral Tegmental Area; Work; addiction; career; cingulate cortex; cocaine exposure; cocaine self-administration; cocaine use; diagnostic strategy; dopaminergic neuron; effective therapy; executive function; experimental study; improved; innovation; insight; neural; neural correlate; neural repair; neuromechanism; neurotransmission; optogenetics; overexpression; psychologic; response; restoration; reward anticipation

PROJECT SUMMARY Reward-guided decision-making and impulse control are disrupted after chronic cocaine use. These changes have been attributed to altered functions in brain circuits critical for computation of reward predictions, action policies, prediction errors and attention. ‘Reward prediction’ signals reflect the reward the animal expects to receive as a result of behavior or presentation of a stimulus. ‘Action policies’ are rules that govern behavior that are 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, responses and outcomes. ‘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 a reward- 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) and anterior insula (AI) encode 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. 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 in ventral tegmental area (VTA), our work has shown that firing in basolateral amygdala (ABL) and anterior cingulate cortex (ACC) better reflects integrated unsigned prediction error signals and attention, increasing during unexpected up- and down-shifts in value at the time of the error and during cue sampling on subsequent trials. Here, we propose that activation of ACC increases attention and engages model-based mechanisms that govern goal-directed behavior and associated mechanisms in AI, NAc and VTA, and that chronic cocaine reduces the fidelity of reward prediction and prediction error signals, in part, by disrupting ACC function. Further, we propose that epigenetic changes in ACC, NAc and DLS after chronic drug use alter cue selectivity in a way that promotes fast, automatic behavior by altering the start point and rate of signals that drive actions. In this resubmission of my renewal application we propose to further model the normal circuit and behavior, and its disruption after cocaine-exposure by bi-directionally manipulating neural signals via optogenetics and epigenetic (histone deacetylase 5, HDAC5) manipulation. 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 in ACC and striatum might restore behavior and neural constructs in downstream regions.

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 已经被归因于大脑回路中的功能改变，这些功能对计算奖励预测、行动 政策、预测误差和注意力。“奖励预测”信号反映了动物对奖励的预期。 由于行为或刺激的表现而接受。“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”的预测中存在违反时，修改策略。“签名”奖励 预测错误反映了与错误相关的效价，加强或削弱了关联性 线索，反应和结果之间的联系“无符号”预测误差反映了由误差引起的意外， 导致“注意力”的增加，从而可以进行学习。我们已经发现了这些神经系统的相关性 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奖励- 引导决策任务，在这个任务中，我们意外地改变了延迟和奖励的大小， 试块。我们已经证明，丘脑核核心（NAc）和前丘脑（AI）编码奖励 预测，强烈地激发预测更有价值的奖励的线索，而在背外侧纹状体（DLS） 是高度关联的，编码行动政策，如刺激-反应协会和上下文偏见 信号.我们还表明，中脑多巴胺（DA）神经元增加放电，以获得意想不到的奖励， 减少对意外奖励遗漏的射击。在学习过程中，这些带符号的预测误差转移到线索， 预测更有价值的奖励的线索会引发更强烈的放电。与腹侧被盖DA能神经元的放电不同 我们的工作表明，基底外侧杏仁核（ABL）和前扣带皮层（ACC）的放电 更好地反映了集成的无符号预测误差信号和注意力，在意外上升和下降期间增加 在错误发生时以及在后续试验的线索采样期间，值向下偏移。 在这里，我们认为ACC的激活增加了注意力，并参与了基于模型的机制， 在AI、NAc和VTA中控制目标导向行为和相关机制， 部分地通过破坏ACC功能来降低奖励预测和预测误差信号的保真度。此外，本发明的目的是， 我们认为，慢性药物使用后ACC、NAc和DLS的表观遗传变化在某种程度上改变了线索选择性， 通过改变驱动动作的信号的起始点和速率来促进快速、自动的行为。在这 重新提交我的续期申请，我们建议进一步模拟正常的电路和行为， 可卡因暴露后通过光遗传学和表观遗传学双向操纵神经信号的破坏 （组蛋白脱乙酰酶5，HDAC 5）操作。通过这些实验，我们将进一步了解 大脑如何正常运作，在长期使用可卡因后如何被破坏，并确定是否修复神经系统。 ACC和纹状体中的信号可能恢复下游区域的行为和神经结构。