Melanocortin-4 receptor control of striatal-dependent action selection

Melanocortin-4 受体控制纹状体依赖性动作选择

• 批准号: 10590579
• 负责人: Elizabeth Christine Heaton
• 金额: $ 4.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590579
• 关键词: AMPA Receptors; Address; Affinity; Agonist; Anatomy; Animals; Arbitration; Behavior; Behavioral; Biological Assay; Brain; Brain region; Cell membrane; Cells; Clinical Trials; Complex; Corpus striatum structure; Data; Decision Making; Disease; Dopamine D1 Receptor; Failure; Gene Silencing; Glutamate Receptor; Glutamates; Goals; Habits; Homeostasis; Hypothalamic structure; Impairment; Individual; Infusion procedures; Investigation; Maps; Measures; Medial; Mediating; Melanocortin 4 Receptor; Mental disorders; Mus; N-Methylaspartate; Neurons; Obesity; Operant Conditioning; Outcome; Pharmaceutical Preparations; Positioning Attribute; Prefrontal Cortex; Preparation; Proteins; Rabies virus; Receptor Activation; Regulation; Rehabilitation therapy; Relapse; Rewards; Role; Sexual Dysfunction; Site; Substance Use Disorder; Synapses; Synaptosomes; System; Testing; Translational Research; Update; Ventral Striatum; Viral; Viral Vector; Work; alpha-Melanocyte stimulating hormone; combinatorial; experimental study; flexibility; glutamatergic signaling; improved; insight; interest; neural; neuronal excitability; neuropsychiatric disorder; novel; novel strategies; novel therapeutics; pharmacologic; postsynaptic; preservation; presynaptic; prevent; receptor; receptor function; receptor internalization; substance use treatment; therapeutic target

PROJECT SUMMARY More than half of all individuals in treatment for substance use disorder (SUD) will relapse. Inflexibility in selecting between familiar, habitual behaviors that have been rewarded in the past (drug seeking) and novel strategies that might be more advantageous (rehabilitation) may be a factor that preserves SUD. The goal of this proposal is to identify neural factors supporting goal-directed action selection, which could provide insight into therapeutic targets for disorders in which goal-oriented action selection is impaired. The dorsomedial striatum (DMS) is a brain region that receives and integrates glutamatergic input from cortical and subcortical regions required for goal-directed action selection. However, the factors in the DMS responsible for coordinating this incoming information remain incompletely understood. One candidate factor is the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone. MC4R regulates GluA2-AMPA receptor (GluA2-AMPAR) localization on dopamine D1 receptor-containing medium spiny neurons in the striatum. Inhibiting MC4R reduces the expression of repetitive, familiar behaviors and improves flexible action selection in mice. Thus, MC4R seems well-positioned in the DMS to integrate incoming glutamatergic signals and control flexible, goal-directed action. I will test the hypothesis that MC4R presence controls striatal-dependent action selection by regulating the cellular localization of GluA2-AMPARs in the DMS (Aim 1). Next, I will identify incoming projections that terminate on Mc4r+ neurons in the DMS and identify which projections are necessary for goal-directed behavior conferred by Mc4r silencing (Aim 2). In Aim 1, I will combine pharmacological inhibition of activity-dependent GluA2-AMPAR internalization with site-selective infusions of an MC4R agonist and measure the capacity of mice to engage in flexible action selection via instrumental conditioning assays. I will thus determine whether MC4R activity controls action selection via regulation of GluA2-AMPAR localization. Then, I will use synaptoneurosome preparations and quantify the levels and localization of multiple AMPA and NMDA glutamate receptor subtypes, providing a comprehensive perspective on MC4R control of glutamatergic receptor subunit expression in the DMS. In Aim 2, I will use rabies virus-mediated trans-synaptic tracing to create a brain-wide map of inputs onto Mc4r-expressing cells in the DMS. I will then use combinatorial viral vector strategies to test whether projections from specific brain regions, like the orbitofrontal cortex, influence action selection controlled by MC4R presence in the DMS. These experiments will identify the presynaptic partners necessary for striatal MC4R to influence an animal’s propensity to flexibly seek goals vs. engage in familiar routines. Impact. The proposed work has tremendous translational value, given that an over-reliance on inflexible, habit-like behaviors is a core feature of numerous psychiatric illnesses, including SUD. Furthermore, my proposal addresses fundamental unanswered questions regarding the function of MC4R in the striatum.

项目总结 在接受药物使用障碍(SUD)治疗的所有人中，超过一半的人将复发。缺乏灵活性 在过去被奖励的熟悉的习惯性行为(寻找毒品)和小说之间进行选择 可能更有利的策略(康复)可能是保留SUD的一个因素。这样做的目的是 建议是确定支持目标导向行动选择的神经因素，这可能为深入了解 目标导向的行动选择受损的障碍的治疗目标。 背内侧纹状体(DMS)是一个接受和整合谷氨酸能输入的大脑区域 目标导向动作选择所需的皮质和皮质下区域。然而，DMS中的因素 负责协调这一传入信息的人员仍未完全理解。一个候选因素是 黑素皮质素-4受体是一种高亲和力的α-黑素细胞刺激素受体。MC4R 调节GluA2-AMPA受体(GluA2-AMPAR)在含多巴胺D1受体的培养液中的定位 纹状体中的带刺神经元。抑制MC4R减少重复的、熟悉的行为和 提高了小鼠灵活的动作选择能力。因此，MC4R似乎在DMS中处于很好的位置，可以集成传入的 谷氨酸能信号和控制灵活的、目标导向的行动。我将测试MC4R存在的假设 通过调节GluA2-AMPAR在DMS中的细胞定位来控制纹状体依赖的动作选择 (目标1)。接下来，我将识别终止于DMS中Mc4r+神经元的传入投射，并确定哪些 投射对于Mc4r沉默所产生的目标导向行为是必要的(目标2)。 在目标1中，我将结合药物抑制活性依赖的GluA2-AMPAR内化与 选择性地输注MC4R激动剂，并测量小鼠进行灵活动作的能力 通过仪器条件分析进行选择。因此，我将确定MC4R活动是否控制行动 通过调节GluA2-AMPAR定位进行选择。然后，我会用突触神经体制剂和 量化多种AMPA和NMDA谷氨酸受体亚型的水平和定位，提供 MC4R对DMS谷氨酸受体亚单位表达调控的综合研究。 在目标2中，我将使用狂犬病病毒介导的跨突触追踪来创建一张输入到 DMS中有MC4R表达的细胞。然后我将使用组合病毒载体策略来测试投影 来自特定大脑区域，如眶前叶皮质，影响由MC4R存在控制的动作选择 在DMS里。这些实验将确定纹状体MC4R所需的突触前伙伴以影响 动物灵活地寻找目标的倾向，而不是参与熟悉的例行公事。 冲击力。考虑到过度依赖僵化、 习惯性行为是包括SUD在内的许多精神疾病的核心特征。此外，我的建议 解决了关于纹状体中MC4R功能的基本未解问题。