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）：对食欲驱动行为的抑制控制丧失，有时表现为“暴食”，是多种精神疾病中存在的一种表型。人们普遍认为，暴饮暴食是由控制皮层下动机系统的额叶执行控制机制的功能失调引起的;然而，具体的神经药理学机制和回路连接尚不清楚。一个线索来自于这样一个事实，即阿片拮抗剂药物是唯一一种在改善各种具有狂欢特征的精神疾病的抑制控制方面具有一定疗效的药物疗法。因此，额叶回路中的阿片类药物作用可能是一种 是导致暴食症的关键底物然而，到目前为止，阿片类药物对额叶皮层的影响几乎完全被忽视了。在上一个资助期，我们发现大鼠腹内侧前额叶皮层（PFC）中的μ-阿片受体（µOR）刺激-一个类似于在各种具有狂欢特征的疾病中显示异常反应的区域-产生了强大的非稳态进食和多动，增加了累进比率任务中的食物动机，以及抑制控制PFC敏感任务中的强大的“冲动样”损伤。这些效应没有被广泛的单胺受体激动剂或拮抗剂复制，证明了µ OR相对于其他PFC调节系统的独特作用。此外，双位点药物微输注研究表明，PFC µOR信号通过外侧-穹窿周围下丘脑区域（LH-PeF）的进食/唤醒回路（包括下丘脑泌素/食欲素系统）参与食欲驱动，同时引起AMPA编码的PFC→核内壳（AcbSh）回路的激活，限制食物动机。最后，我们发现，反复发作的甜脂肪“狼吞虎咽”敏感的AcbSh GABA系统，潜在的钝化PFC→AcbSh的“限制电路”的影响。基于这些发现，我们提出了一个新的网络模型，指出当皮层下系统被过多的PFC-µOR信号驱动时，和/或当PFC→LH-PeF（“食欲驱动者”）和PFC→AcbSh（“食欲限制者”）通路失衡时，就会发生对食欲行为的失控。此外，我们提出，可口的食物狼吞虎咽导致AcbSh氨基酸（谷氨酸，GABA）系统的神经可塑性变化，钝化传入PFC信号，抑制“限制电路”的影响，从而使食欲行为不受抑制。通过这种方式，由强烈的奖励驱动的进食引起的神经适应可能会陷入恶性循环，导致进一步的暴食行为。我们将通过经典药理学实验和使用病毒引入的设计者受体（DREADD）的研究相结合来测试这一工作假设。这些工程化受体允许用合成配体激活G蛋白;因此，可以在病毒转导的神经元的特定群体内调节神经元活性。使用双病毒的方法，我们将目标DREADD表达PFC神经元专门投射到AcbSh或下丘脑，并选择性地操纵这些标记的神经元在大鼠执行操作性任务的食物动机和抑制控制。此外，使用经典的药理学+ DREADD实验，我们将测试这一假设，即美味的食物暴食脱敏vmPFC→AcbSh“限制电路”，并可能放大vmPFC→下丘脑“食欲驱动器”电路。使用受体拮抗剂，我们将研究内源性μ-阿片和下丘脑泌素/食欲素传递在介导PFC驱动的食物动机和冲动中的作用。最后，我们将探讨在PFC-µOR控制食物动机和食物冲动方面可能存在的性别差异。