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: 10386342
• 负责人: Elizabeth Christine Heaton
• 金额: $ 4.68万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386342
• 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; Pharmacology; Positioning Attribute; Prefrontal Cortex; Preparation; Proteins; Rabies virus; Receptor Activation; Regulation; Rehabilitation therapy; Relapse; Research Proposals; 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; base; combinatorial; experimental study; flexibility; glutamatergic signaling; improved; insight; interest; neuropsychiatric disorder; novel; novel strategies; novel therapeutics; postsynaptic; preservation; presynaptic; prevent; receptor; receptor function; relating to nervous system; 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.

项目摘要 在治疗药物使用障碍（SUD）治疗中，超过一半将缓解。不灵活 在过去（寻求毒品）和新颖的熟悉的习惯行为之间选择 可能更有利的（康复）的策略可能是保留SUD的一个因素。目标的目标 建议是确定支持目标指导行动选择的神经因素，这可以洞悉 疾病的治疗靶标会损害以目标为导向的动作。 背侧纹状体（DMS）是一个大脑区域，从 目标指导作用选择所需的皮质和皮层区域。但是，DMS中的因素 负责协调这一传入信息仍然不完全理解。一个候选因素是 黑色素皮质素-4受体（MC4R），一种用于α-核细胞刺激马的高亲和力受体。 MC4R 调节在多巴胺D1受体培养基上的GLUA2-AMPA受体（GLUA2-AMPAR）定位 纹状体中的刺神经元。抑制MC4R会降低重复，熟悉的行为的表达和 改善小鼠的灵活动作选择。那就是，MC4R似乎在DMS中置于良好的位置以整合传入 谷氨酸能信号和控制灵活的目标指导动作。我将测试MC4R存在的假设 通过对DMS中GLUA2-AMPAR的细胞定位进行反思来控制纹状体依赖的作用选择 （目标1）。接下来，我将确定在DMS中终止MC4R+神经元上终止的传入项目，并确定哪个项目 预测对于由MC4R沉默赋予的目标指导行为是必需的（AIM 2）。 在AIM 1中，我将结合对活性依赖性GLUA2-AMPAR内在化的药物抑制作用 MC4R激动剂的现场选择性输注并测量小鼠进行灵活动作的能力 通过仪器调节测定法选择。因此，我将确定MC4R活动是否控制动作 通过调节GLUA2-AMPAR定位的选择。然后，我将使用SynaptoneRosome体的准备工作，并且 量化多个AMPA和NMDA谷氨酸受体亚型的水平和定位，提供A DMS中谷氨酸能受体亚基表达的MC4R控制的全面观点。 在AIM 2中，我将使用兔子病毒介导的反式突触追踪来创建脑范围的输入图 DMS中表达MC4R的细胞。然后，我将使用组合病毒矢量策略来测试是否项目 从特定的大脑区域（例如眶额皮层）影响MC4R存在控制的作用选择 在DMS中。这些实验将确定纹状体MC4R所必需的突触前伴侣 动物的承诺灵活地寻求目标与参与熟悉的常规。 影响。鉴于对不灵活的过度依赖，拟议的工作具有巨大的翻译价值， 类似习惯的行为是包括SUD在内的众多精神病的核心特征。此外，我的建议 解决有关MC4R在纹状体中功能的基本问题。