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（由申请人提供）：药物成瘾是一种慢性脑疾病，其特征是不受控制的药物服用，渴望和复发。成瘾性药物总是会引起非生理DA信号，可能会干扰持续的动机和联想学习行为，通过与这些行为的基础相似的可塑性机制来修改奖励电路，并改变这些电路与DA的反应性，而DA，使用药物的使用永久使用。多巴胺能奖励电路中特别重要的区域是前额叶皮层（PFC），它介导了动机和选择的执行控制，并与指导成瘾行为有关。假设谷氨酸能可塑性的改变是为了促进吸毒者在成瘾者中寻求毒品的强迫性，并阻碍了吸毒记忆的灭绝，从而促进了复发。与原发性皮层不同，PFC电路在某种程度上是耐剥头皮的难治性，但很容易被药物修饰，这表明在此关联皮层中，对DA的依赖性增加了。 DA在PFC中驱动突触可塑性的精确机制知之甚少。 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.我们最近的研究表明，在完整的GABA能抑制条件下，在天然PFC电路中，必须进行简短的阶段性DA，以实现依赖峰值的长期增强（T-LTP）。这种支持需要在抑制回路中进行D1级受体（D1R）与D2级受体（D2RS）之间的合作，在这种情况下，D2R激活门通过抑制局部GABA能抑制和D1R激活来抑制T-LTP的T2R激活诱导，D1R激活可控制T-LTP的时间来诱导T-LTP的时间。我们的结果揭示了先前未识别的电路级机制，通过该机制，单独的微电路中的DA受体合作以驱动Hebbian突触可塑性。该R01应用的目标是定义互连PFC兴奋性（AIM 1）和抑制性（AIM 2）电路中的分子，突触和信号细节，这些电路使DA可以增强PFC中的突触修改能力。我们还将研究重复的可卡因在体内如何改变PFC突触中的T-LTP诱导和多巴胺能教学规则（AIM 3）。将采用切片电生理，分子，生化和形态学方法的组合。这些研究涉及有关PFC抑制性和兴奋性微电路修改以及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有关上瘾的药物如何侵蚀固有规则和篡夺前额叶奖励电路的固有规则的关键见解。获得的信息将提高我们对奖励电路可塑性机制的了解，并促进对成瘾的理解和治疗。