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

纹状体下丘脑网络的额叶皮质阿片类药物调节：在食物奖励和冲动中的作用

• 批准号: 9098786
• 负责人: BRIAN A BALDO
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098786
• 关键词: AMPA Receptors; Adolescent; Affect; Agonist; Alcohol consumption; Amino Acids; Amygdaloid structure; Appetitive Behavior; Area; Arousal; Behavior; Behavioral; Binge Eating; Binge eating disorder; Biological Assay; Brain; Brain imaging; Brain region; Bulimia; Code; Decision Making; Development; Disease; Eating Disorders; Engineering; Estrogens; Exhibits; Failure; Fatty acid glycerol esters; Feeding behaviors; Female; Food; Food Processing; Funding; GABA Receptor; GTP-Binding Proteins; Gambling; Glutamates; Health; Hyperactive behavior; Hypothalamic structure; Impairment; Impulsivity; Individual; Investigation; Laboratories; Lateral; Ligands; Literature; Mediating; Mental disorders; Morphine; Motivation; Naltrexone; Narcotic Antagonists; Neuronal Plasticity; Neurons; Nucleus Accumbens; Opioid; Opioid Peptide; Opioid Receptor; Output; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Population; Prefrontal Cortex; Prevalence; Process; Proteins; Psychological reinforcement; RNA Interference; Rattus; Receptor Signaling; Rewards; Role; SB-334867; Sex Behavior; Sex Characteristics; Signal Transduction; Site; System; Testing; Time; Virus; Vulnerable Populations; Woman; Work; addiction; base; binge type behavior; designer receptors exclusively activated by designer drugs; disability; drug standard; effective therapy; executive function; feeding; frontal lobe; gamma-Aminobutyric Acid; gender difference; heuristics; hypocretin; improved; monoamine; motivated behavior; motivational processes; network dysfunction; network models; neural circuit; neuroadaptation; neuromechanism; novel; orexin 1 receptor; psychologic; receptor; research study; response; transmission process; treatment strategy; university student

 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.

 描述（由申请人提供）：对食欲动机行为的抑制控制的丧失，有时表现为“暴饮暴食”，是多种精神疾病中存在的一种表型。人们普遍认为，暴饮暴食是由额叶执行控制机制的功能失调引起的。控制皮层下动机系统；然而，具体的神经药理学机制和回路连接尚不清楚，阿片拮抗剂药物是唯一具有一定疗效的药物之一。改善对多种具有暴食特征的精神疾病的抑制控制因此，额叶回路中的阿片类药物的作用可能是一种。 然而，迄今为止，阿片类药物对额叶皮层的影响几乎被完全忽视，在之前的资助期间，我们发现μ-阿片受体（μOR）对大鼠腹内侧前额叶皮层（PFC）的刺激作用。该区域类似于在具有暴饮暴食特征的各种疾病中表现出异常反应的区域 - 产生强烈的非稳态进食和多动症，在渐进比例任务中增加食物动机，并产生强烈的非稳态进食和多动症PFC 敏感的抑制控制任务中的“冲动性”损伤并未通过多种单胺受体激动剂或拮抗剂重现，这表明 µOR 相对于其他 PFC 调节系统具有独特的作用。微输注研究表明，PFC µOR 信号通过下丘脑外侧角周区域 (LH-PeF) 的进食/唤醒回路参与食欲驱动，包括下丘脑分泌素/食欲素系统，同时引起 AMPA 编码的 PFC→伏隔核壳 (AcbSh) 回路的激活，从而限制食物动机。最后，我们发现，重复的“暴饮暴食”甜脂肪行为会使 AcbSh GABA 系统变得敏感，可能会削弱 GABA 系统。基于这些发现，我们提出了一种新颖的网络模型，表明当皮层下系统失去对食欲行为的控制时。由过度的 PFC-μOR 信号驱动，和/或当 PFC→LH-PeF（“食欲驱动器”）和 PFC→AcbSh（“食欲限制器”）通路不平衡时。此外，我们建议美味的食物。暴饮暴食会导致 AcbSh 氨基酸（谷氨酸，GABA）系统发生神经塑性变化，从而减弱传入的 PFC 信号，抑制“限制器电路”的影响，从而使食欲行为这样，由强烈的奖励驱动的喂养引起的神经适应可能会陷入恶性循环，导致进一步的暴饮暴食行为，我们将结合经典的药理学实验和使用病毒引入的设计受体的研究来检验这一工作假设。由设计药物 (DREADD) 独家激活。这些工程受体允许使用合成配体激活 G 蛋白；因此，可以使用病毒转导的神经元来调节特定群体的神经元活性。通过双病毒方法，我们将 DREADD 表达靶向专门投射到 AcbSh 或下丘脑的 PFC 神经元，并在执行食物激励和抑制控制操作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。 ，我们将检验这样的假设：暴食美味食物会使 vmPFC→AcbSh“限制器电路”变得不敏感，并且可能会放大 vmPFC→下脑使用受体拮抗剂，我们将研究内源性μ-阿片类药物和下丘脑分泌素/食欲素传输在调节 PFC 驱动的食物动机和冲动中的作用，最后，我们将探讨 PFC-μOR 控制中可能的性别差异。食物动机和食物冲动。