Frontal cortical opioid modulation of striato-hypothalamic networks: roles in food-reward and impulsivity

 描述(由申请人提供)：对食欲动机行为失去抑制控制，有时表现为‘狂欢’，是多种精神疾病的一种表型。人们普遍认为，暴饮暴食源于支配皮质下动机系统的额叶-执行控制机制的失调功能；然而，具体的神经药理学机制和电路连接尚不清楚。一条线索来自这样一个事实，即阿片拮抗剂药物是仅有的几种药物疗法之一，在改善对各种具有狂欢特征的精神疾病的抑制控制方面有一定效果。因此，额叶回路中的阿片类药物作用可能是 暴食型病理的关键底物。然而，到目前为止，额叶皮质中的阿片类药物作用几乎完全被忽视。在之前的资助期间，我们发现，刺激大鼠腹内侧前额叶皮质(PFC)中的µ-阿片受体(µOR)-这一区域类似于各种具有狂欢特征的障碍中的异常反应-可以产生强大的非稳态进食和多动，在递增比率任务中增加食物动机，在PFC敏感的抑制控制任务中产生强烈的“冲动样”损害。这些效应不能被广泛的单胺受体激动剂或拮抗剂复制，显示出与其他PFC调节系统相比，µOR的独特作用。此外，双部位药物微量输注研究显示，PFC？OR信号通过下丘脑外侧-穹隆周围区域(包括下丘脑-穹隆周围区域)的摄食/唤醒回路(包括下丘脑/食欲素系统)参与食欲驱动，同时导致AMPA编码的PFC→伏隔核外壳(AcbSh)回路的激活，从而限制食物动机。最后，我们发现反复出现的甜味脂肪“暴食”使AcbSh GABA系统变得敏感，潜在地削弱了PFC→AcbSh“限制器回路”的影响。基于这些发现，我们提出了一个新的网络模型，认为当皮层下系统受到过多的pfc-µOR信号驱动时，和/或当pfc→lh-pEF(‘食欲驱动’)和pfc→AcbSh(‘食欲限制器’)通路失衡时，就会发生对食欲行为的失控。此外，我们认为，美味的食物暴饮暴食会导致AcbSh氨基酸(谷氨酸，GABA)系统的神经可塑性变化，从而钝化传入的PFC信号，抑制“限制器回路”的影响，从而允许食欲行为不受抑制。通过这种方式，由高强度奖励驱动的进食引起的神经适应可能会引发恶性循环，导致进一步的类似狂欢的行为。我们将结合经典药理学实验和使用由设计药物(DREADD)激活的病毒引入的设计受体(DREADD)的研究来验证这一工作假设。这些工程化的受体允许用合成的配体激活G蛋白；因此，神经元的活动可以在特定的病毒转导的神经元群体中进行调节。使用双病毒方法，我们将把DREADD的表达靶向特定投射到AcbSh或下丘脑的PFC神经元，并在执行食物动机和抑制控制的可操作性任务的大鼠中选择性地操纵这些标记的神经元。此外，使用经典药理学+DREADD实验，我们将检验这样一种假设，即暴饮暴食会使vmPFC→AcbSh‘限制器电路’变得不敏感，并可能放大vmPFC→下丘脑‘食欲驱动’电路。利用受体拮抗剂，我们将研究内源性阿片类药物和下丘脑泌素/食欲素传递在调节PFC驱动的食物动机和冲动中的作用。最后，我们将探讨在控制食物动机和食物冲动方面可能存在的性别差异。

 DESCRIPTION (provided by applicant): Loss of inhibitory control over appetitively motivated behavior, sometimes manifested as `bingeing', is a phenotype present in multiple psychiatric conditions. It is widely assumed that bingeing emerges from the dysregulated function of frontal-executive control mechanisms that govern subcortical motivation systems; nevertheless, specific neuropharmacological mechanisms and circuit connections are not clearly understood. One clue derives from the fact that opiate antagonist drugs are among the only pharmacotherapies with some efficacy in improving inhibitory control across a wide variety of psychiatric disorders with binge features. Hence, opioid actions within frontal circuits could be a crucial substrate underlying binge-type pathologies. To date, however, opioid effects in frontal cortex have been almost completely overlooked. In the previous funding period, we discovered that µ-opioid receptor (µOR) stimulation in rat ventromedial prefrontal cortex (PFC) - an area analogous to those showing abnormal responses in a variety of disorders with binge features - engenders robust non-homeostatic feeding and hyperactivity, increased food motivation in a progressive-ratio task, and robust `impulsivity-like' impairments in a PFC-sensitive task of inhibitory control. These effects were not reproduced by a wide array of monoamine receptor agonists or antagonists, demonstrating unique actions of µORs relative to other PFC modulatory systems. Furthermore, dual-site drug microinfusion studies revealed that PFC µOR signaling engages appetitive drive via feeding/arousal circuits in the lateral-perifornical hypothalamic region (LH-PeF), including the hypocretin/orexin system, while concurrently causing activation of an AMPA-coded PFC→nucleus accumbens shell (AcbSh) circuit that limits food motivation. Finally, we found that repeated episodes of sweetened-fat `gorging' sensitize AcbSh GABA systems, potentially blunting the effect the PFC→AcbSh `limiter circuit'. Based on these findings, we propose a novel network model stating that loss of control over appetitive behavior occurs when subcortical systems are driven by excessive PFC-µOR signaling, and/or when there is an imbalance in the PFC→LH-PeF (`appetitive-driver') and PFC→AcbSh (`appetitive limiter') pathways. Moreover, we propose that palatable food gorging causes neuroplastic changes in AcbSh amino-acid (glutamate, GABA) systems that blunt incoming PFC signals, curbing the influence of the `limiter circuit', thereby allowing appetitive behavior to go unchecked. In this way, the neuroadaptations caused by intense reward-driven feeding could engage a vicious cycle, leading to further binge-like behavior. We will test this working hypothesis with a combination of classic pharmacology experiments and studies using virally introduced Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). These engineered receptors permit the activation of G-proteins with a synthetic ligand; thus, neuronal activity can be modulated within specific populations of virally transduced neurons. Using a dual-virus approach, we will target DREADD expression to PFC neurons specifically projecting either to the AcbSh or to the hypothalamus, and selectively manipulate these tagged neurons in rats performing operant tasks of food motivation and inhibitory control. Furthermore, using classic pharmacology + DREADD experiments, we will test the hypothesis that palatable-food bingeing desensitizes vmPFC→AcbSh `limiter circuit' and perhaps amplifies the vmPFC→hypothalamus `appetitive-driver' circuit. Using receptor antagonists, we will examine the role of endogenous µ-opioid and hypocretin/orexin transmission in mediating PFC-driven food motivation and impulsivity. Finally, we will explore possible gender differences in PFC-µOR control of food motivation and food impulsivity.