Dopaminergic Enabling of Synaptic Plasticity in Prefrontal Circuits

描述(申请人提供)：毒瘾是一种慢性脑部疾病，特征是无节制地服药、渴求和复发。成瘾药物总是诱导可能干扰正在进行的动机和联想学习行为的非生理性DA信号，通过类似于这些行为背后的可塑性机制来改变奖赏回路，并改变这些回路与DA的反应性，使药物的使用永久化。多巴胺能奖赏回路中一个特别重要的区域是前额叶皮质(PFC)，它调节对动机和选择的执行控制，并与指导成瘾行为有关。谷氨酸可塑性的改变被认为促进了吸毒者寻求毒品的强迫特征，并阻碍了药物使用记忆的消失，促进了复发。与初级感觉皮层不同，PFC回路在某种程度上难以经历头皮剥离，但很容易被药物改变，这表明在这个联合皮质中，独特的可塑性机制显示出对DA的依赖增加。DA驱动PFC突触可塑性的确切机制还知之甚少。特别是，尚不清楚(I)谷氨酸能突触修饰如何发生在由GABA能抑制音严格控制的自然回路中，(Ii)行为研究表明DA在使突触可塑性方面可能发挥什么确切作用，以及(Iii)成瘾药物如何改变PFC回路及其对DA的反应，导致成瘾回路。我们最近的研究表明，在完整的GABA能抑制条件下，在自然的PFC电路中，短时相DA是实现峰时依赖的长时程增强(t-LTP)所必需的。这种激活需要兴奋电路中的D1R和抑制电路中的D2R之间的合作，从而D2R激活通过抑制局部GABA能抑制来门控t-LTP诱导，D1R激活分别控制t-LTP诱导的时间窗口。我们的结果揭示了一个以前未知的电路水平的机制，通过这个机制，独立微电路中的DA受体协同驱动Hebbian突触的可塑性。此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，允许DA授权PFC中的突触修改。我们还将研究体内重复暴露可卡因如何改变PFC突触的t-LTP诱导和多巴胺能教学规则(目标3)。将结合切片电生理、分子、生化和形态学方法。这些研究涉及修饰PFC抑制和兴奋微电路的基本问题，以及DA奖励信号在这些过程中的作用。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和篡夺前额叶奖励回路提供关键见解。所获得的信息将促进我们对奖赏回路可塑性机制的了解，并有助于理解和治疗成瘾。

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.