Dopaminergic Enabling of Synaptic Plasticity in Prefrontal Circuits

描述（由申请人提供）：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。成瘾性药物总是会诱发非生理性DA信号，可能会干扰正在进行的动机和联想学习行为，通过类似于这些行为的可塑性机制改变奖励回路，并改变这些回路对DA的反应性，使药物的使用永续下去。多巴胺能奖赏回路中一个特别重要的区域是前额皮质（PFC），它调节动机和选择的执行控制，并与指导成瘾行为有关。据推测，谷氨酸能可塑性的改变会促进成瘾者寻求药物的强迫性特征，并阻碍吸毒记忆的消失，促进复发。与初级感觉皮层不同，PFC回路在一定程度上对剥头皮不敏感，但很容易被药物修饰，这表明独特的可塑性机制表明该联想皮层对DA的依赖性增加。多巴胺驱动PFC突触可塑性的确切机制尚不清楚。特别是，目前尚不清楚(i)谷氨酸能突触修饰是如何在gaba能抑制音严格控制的天然回路中发生的，（ii）行为学研究表明，DA在激活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，从而导致成瘾回路。我们最近的研究表明，在gaba能完全抑制的条件下，短暂的相性DA对于在原生PFC回路中实现峰值时序依赖的长期增强（t-LTP）是必要的。这种激活需要兴奋回路中的d1类受体（D1Rs）和抑制回路中的d2类受体（D2Rs）之间的合作，其中D2R激活通过抑制局部gaba能抑制来抑制t-LTP诱导，D1R激活分别控制t-LTP诱导的时间窗口。我们的研究结果揭示了一种以前未被认识到的回路水平机制，通过这种机制，不同微电路中的DA受体合作驱动Hebbian突触可塑性。本R01应用程序的目标是定义相互连接的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，这些电路允许DA增强PFC突触修饰。我们还将研究体内重复可卡因暴露如何改变PFC突触中的t-LTP诱导和多巴胺能教学规则（Aim 3）。结合切片电生理，分子，生化和形态学的方法将被采用。这些研究解决了关于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。我们的研究还将为成瘾药物如何侵蚀控制联想可塑性的内在规则并篡夺前额叶奖励回路提供关键见解。所获得的信息将推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。

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. PUBLIC HEALTH RELEVANCE: Drug addiction is a chronic brain disease characterized by compulsive drug seeking, craving, and relapse. Drugs of abuse are thought to modify dopaminergic reward circuits, including the prefrontal cortex (PFC), by acting on synaptic plasticity mechanisms similar to that underlie learning and memory, leading to addiction. The purpose of this application is to delineate the rules and underlying mechanisms that govern associative synaptic plasticity in the PFC, as well as their relevance to addiction, using a rodent model of cocaine addiction. The information obtained will advance our knowledge of the reward circuitry plasticity mechanisms and facilitate understanding and treatments of addiction.