Dopaminergic Enabling of Synaptic Plasticity in Prefrontal Circuits

前额叶回路中突触可塑性的多巴胺能启用

• 批准号: 8637960
• 负责人: Wei-Dong Yao
• 金额: $ 25.82万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637960
• 关键词: Addictive Behavior; Address; Arousal; Automobile Driving; Behavior; Behavioral; Biochemical; Brain Diseases; Cells; Chronic; Cocaine; Cocaine Dependence; DRD2 gene; Dependence; Dopamine; Dopamine Receptor; Drug Addiction; Drug usage; Educational process of instructing; Excitatory Synapse; Extinction (Psychology); Glutamates; Goals; Interneurons; Knowledge; Learning; Link; Long-Term Potentiation; Mediating; Memory; Modification; Molecular; Motivation; Pathway interactions; Pharmaceutical Preparations; Play; Prefrontal Cortex; Process; Property; Refractory; Relapse; Relative (related person); Rewards; Rodent Model; Role; Scalp structure; Signal Transduction; Slice; Stimulus; Synapses; Synaptic plasticity; Testing; Time; addiction; classical conditioning; cocaine exposure; craving; drug of abuse; empowered; executive function; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; learned behavior; patch clamp; postsynaptic; presynaptic; receptor; research study; reward circuitry; sensory cortex; transmission process

DESCRIPTION (provided by applicant): Drug addiction is a chronic brain disease characterized by uncontrolled drug taking, craving, and relapse. Addictive drugs invariably induce non-physiological DA signal that likely interferes with ongoing motivational and associative learning behaviors, modify reward circuits via plasticity mechanisms similar to that underlie these behaviors, and alter reactivity of these circuits with DA, perpetuating use of a drug. A particularly important region in the dopaminergic reward circuitry is the prefrontal cortex (PFC), which mediates executive control of motivation and choice and is implicated in directing addictive behaviors. Alterations in glutamatergic plasticity are hypothesized to promote the compulsive character of drug seeking in addicts and hinder extinction of drug use memories, promoting relapse. Unlike primary sensory cortices, PFC circuits are to some degree refractory to experience scalping but are readily modified by drugs, suggesting unique plasticity mechanisms that show increased dependence on DA in this associative cortex. Precise mechanisms by which DA drives synaptic plasticity in PFC are poorly understood. In particular, it is unclear (i) how glutamatergic synaptic modifications can occur in native circuits tightly controlled by GABAergic inhibitory tone, (ii) what precise roles DA might play in enabling synaptic plasticity as suggested by behavioral studies, and (iii) how addictive drugs modify PFC circuits and their reactivity to DA, resulting in an addicted circuitry. Our recent studies indicate that a brief phasic DA is necessary to enable spike-timing dependent long-term potentiation (t-LTP) in native PFC circuits under conditions of intact GABAergic inhibition. This enabling requires a cooperation between D1-class receptors (D1Rs) in excitatory circuits and D2-class receptors (D2Rs) in inhibitory circuits, whereby D2R activation gates t-LTP induction by suppressing local GABAergic inhibition and D1R activation controls the timing window for t-LTP induction, respectively. Our results reveal a previously unrecognized circuit-level mechanism by which DA receptors in separate microcircuits cooperate to drive Hebbian synaptic plasticity. The goals of this R01 application are to define the molecular, synaptic, and signaling details in interconnected PFC excitatory (Aim 1) and inhibitory (Aim 2) circuits that permit DA to empower synaptic modifications in the PFC. We will also investigate how repeated cocaine exposures in vivo alter the t-LTP induction and dopaminergic teaching rules in PFC synapses (Aim 3). A combination of slice electrophysiological, molecular, biochemical, and morphological approaches will be employed. These studies address fundamental issues concerning modifications of PFC inhibitory and excitatory microcircuits, and the roles of DA reward signal in these processes. Our studies will also provide key insights into how addictive drugs may erode intrinsic rules governing associative plasticity and usurp the prefrontal reward circuitry. The information obtained will advance our knowledge of the reward circuitry plasticity mechanisms and facilitate understanding and treatments of addiction.

描述（申请人提供）：药物成瘾是一种慢性脑部疾病，其特征是不受控制的药物服用，渴望和复发。成瘾性药物总是诱导非生理性DA信号，这可能会干扰正在进行的动机和联想学习行为，通过与这些行为基础相似的可塑性机制修改奖励回路，并改变这些回路与DA的反应性，使药物的使用持续下去。多巴胺能奖赏回路中一个特别重要的区域是前额叶皮层（PFC），它介导动机和选择的执行控制，并与指导成瘾行为有关。假设多巴胺能可塑性的改变促进成瘾者寻求药物的强迫性特征，并阻碍药物使用记忆的消失，促进复发。与初级感觉皮层不同，PFC电路在一定程度上难以被剥头皮，但很容易被药物修饰，这表明在这个联合皮层中对DA的依赖性增加的独特可塑性机制。DA驱动PFC中突触可塑性的精确机制知之甚少。特别是，目前尚不清楚（i）GABA能抑制性紧张度严格控制的天然回路中如何发生多巴胺能突触修饰，（ii）行为研究表明DA在实现突触可塑性方面可能发挥的确切作用，以及（iii）成瘾药物如何改变PFC回路及其对DA的反应性，导致成瘾回路。我们最近的研究表明，一个简短的相位DA是必要的，使尖峰时间依赖性长时程增强（t-LTP）在天然PFC电路的条件下完整的GABA能抑制。这种激活需要兴奋性回路中的D1类受体（D1 R）和抑制性回路中的D2类受体（D2 R）之间的合作，由此D2 R激活通过抑制局部GABA能抑制来门控t-LTP诱导，而D1 R激活分别控制t-LTP诱导的时间窗。我们的研究结果揭示了一个以前未被认识到的电路水平的机制，DA受体在单独的微电路合作，以推动赫布突触可塑性。这个R 01应用程序的目标是定义的分子，突触，和信号的细节在相互连接的PFC兴奋性（目标1）和抑制性（目标2）电路，允许DA授权突触修饰PFC。我们还将研究如何重复可卡因暴露在体内改变的t-LTP诱导和多巴胺能教学规则PFC突触（目标3）。将采用切片电生理学、分子、生物化学和形态学方法的组合。这些研究涉及PFC抑制和兴奋微电路的修改，以及DA奖励信号在这些过程中的作用的基本问题。我们的研究还将提供关键的见解，成瘾药物如何侵蚀内在的规则，控制联想可塑性和篡夺前额叶奖励回路。所获得的信息将促进我们对奖赏回路可塑性机制的认识，并促进对成瘾的理解和治疗。