Ventral Pallidum GABA Circuits in Risky Decision Making

腹侧苍白球 GABA 回路在危险决策中的作用

• 批准号: 9760574
• 负责人: Mitchell Farrell
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760574
• 关键词: Affect; Axon; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Cells; Clozapine; Cocaine; Cognition; Data; Decision Making; Dependence; Development; Diagnosis; Disease; Dose; Drug Addiction; Equilibrium; Evaluation; Food; Gap Junctions; Globus Pallidus; Glutamate Decarboxylase; Habenula; Health; Human; Individual; Lateral; Lead; Mediating; Mental disorders; Modeling; Modernization; Motivation; Motor output; Neurobiology; Neurons; Output; Oxides; Pathology; Pathway interactions; Performance; Pharmaceutical Preparations; Positioning Attribute; Process; Punishment; Rattus; Receptor Inhibition; Regulation; Relapse; Rewards; Risk; Rodent; Role; Self Administration; Shock; Site; Testing; Training; Transgenic Organisms; Ventral Tegmental Area; addiction; approach behavior; avoidance behavior; base; designer receptors exclusively activated by designer drugs; driving behavior; drug of abuse; effective therapy; experimental study; gamma-Aminobutyric Acid; grasp; learned behavior; neural circuit; novel; optogenetics; receptor; relating to nervous system; response; sobriety; targeted treatment; tool

Project Summary/Abstract Drug addiction is fundamentally a disorder of decision making, in that addicted individuals often choose drugs over more adaptive options. Indeed, drugs of abuse persistently alter reward-related brain regions, yet the behavioral function of such circuits in basic decision making and cognition-related processes is unclear. Understanding the neural underpinnings of decision making could lead to development of targeted therapeutics to help addicted individuals tame their unrestrained bias towards drugs. Here I seek to identify a novel circuit through which the brain promotes adaptive decision making under risky circumstances—a process that may go awry in addicted individuals. The ventral pallidum (VP) lies at the nexus of reward-seeking and harm- avoidance brain circuits, and could function as a site where motivational drives influence motor output, an ideal position for a region influencing risky decision making. Recent evidence reveals a predominant role for inhibitory, GABAergic VP (VPGABA) neurons in promoting approach behavior in rodents, but VPGABA neurons target both approach (ventral tegmental area; VTA) and avoidance (lateral habenula; LHb) brain circuits, and the roles of these projections in aversion avoidance is unknown. We propose that VPGABA neurons both promote reward seeking via VTA projections, and inhibit aversion avoidance via LHb projections, when decisions about risky reward seeking are made. To model risky decision making, I employ an operant task in which rats decide between small/safe food reward and large/risky food reward that is paired with a probabilistic mild footshock. I will examine the role of VPGABA neurons and their efferent targets to VTA or LHb using cell- and pathway-specific designer receptor inhibition approaches. My preliminary data indicates that inhibiting all VPGABA neurons shifts decision making away from risky rewards, and toward safer options. Here I will replicate and extend these findings, and determine their dependence upon divergent projections to VTA and LHb. I will also determine the specific constructs influencing changes in decision making, using specific behavioral assays of motivation for reward, and sensitivity to punishment. Our findings will greatly extend our grasp of the functional roles for VPGABA circuits in risky decision making that is likely involved in addiction.

项目总结/摘要 药物成瘾从根本上说是一种决策障碍，因为成瘾者经常选择药物 而不是更多的适应性选择。事实上，滥用药物会持续改变与奖励相关的大脑区域， 这种回路在基本决策和认知相关过程中的行为功能尚不清楚。 了解决策的神经基础可能会导致靶向治疗的发展 帮助成瘾者驯服对毒品的不受限制的偏见。在这里，我试图确定一个新颖的电路， 大脑在危险环境下促进适应性决策的过程--这一过程可能会 在成瘾的人身上是错误的。腹侧苍白球（VP）位于奖赏寻求和伤害的联结点， 回避大脑回路，并可以作为一个网站的动机驱动器影响运动输出，一个理想的 影响风险决策的区域位置。最近的证据显示， 抑制性GABA能VP（VPGABA）神经元促进啮齿类动物的接近行为，但VPGABA神经元 以接近（腹侧被盖区; VTA）和回避（外侧缰核; LHb）脑回路为目标， 这些投射在厌恶回避中的作用是未知的。我们认为，VPGABA神经元都 促进通过VTA投射寻求奖励，并通过LHb投射抑制厌恶回避，当 做出了关于冒险的奖励寻求的决定。为了模拟风险决策，我采用了一个操作性任务， 大鼠在小/安全食物奖励和大/风险食物奖励之间做出决定， 轻微的脚震我将研究的作用，VPGABA神经元和他们的传出目标，腹侧被盖区或LHb使用细胞- 和途径特异性设计受体抑制方法。我的初步数据表明，抑制所有 VPGABA神经元将决策从风险回报转向更安全的选择。在这里我将复制 并扩展这些发现，并确定其依赖于VTA和LHb的发散投影。我会 还确定影响决策变化的具体结构，使用特定的行为 奖励的动机和对惩罚的敏感性的分析。我们的发现将大大扩展我们对 VPGABA回路在可能涉及成瘾的风险决策中的功能作用。