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.

项目概要 超过一半正在接受药物滥用障碍 (SUD) 治疗的患者会复发。 在过去获得奖励的熟悉的习惯行为（寻求毒品）和新颖的行为之间进行选择 可能更有利的策略（康复）可能是保留 SUD 的一个因素。 建议是确定支持目标导向行动选择的神经因素，这可以提供洞察力 目标导向行动选择受损的疾病的治疗目标。 背内侧纹状体 (DMS) 是一个接收并整合谷氨酸输入的大脑区域 然而，DMS 中的因素是目标导向行动选择所需的皮质和皮质下区域。 负责协调这一传入信息的一个候选因素仍然不完全清楚。 黑皮质素-4 受体 (MC4R)，一种 α-黑素细胞刺激激素 MC4R 的高亲和力受体。 调节 GluA2-AMPA 受体 (GluA2-AMPAR) 在含有多巴胺 D1 受体的培养基上的定位 抑制纹状体中的多刺神经元可减少重复、熟悉的行为和行为的表达。 改善小鼠的灵活动作选择因此，MC4R 似乎在 DMS 中处于有利位置，可以整合传入的信息。 我将测试 MC4R 存在的假设。 通过调节 DMS 中 GluA2-AMPAR 的细胞定位来控制纹状体依赖性动作选择 （目标 1）接下来，我将识别终止于 DMS 中 Mc4r+ 神经元的传入投影并确定哪些投影。 预测对于 Mc4r 沉默所赋予的目标导向行为是必要的（目标 2）。 在目标 1 中，我将把活性依赖性 GluA2-AMPAR 内化的药理学抑制与 MC4R 激动剂的位点选择性输注并测量小鼠灵活行动的能力 因此，我将通过仪器调节分析来确定 MC4R 活性是否控制作用。 通过调节 GluA2-AMPAR 定位进行选择 然后，我将使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 控制 DMS 中谷氨酸受体亚基表达的综合视角。 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全脑输入图 然后，我将使用组合病毒载体策略来测试 DMS 中表达 Mc4r 的细胞是否能预测。 来自特定大脑区域（如眶额皮层）的信号影响由 MC4R 存在控制的动作选择 这些实验将确定纹状体 MC4R 影响的突触前伙伴。 动物倾向于灵活地寻求目标，而不是遵循熟悉的惯例。 考虑到过度依赖不灵活、不灵活，拟议的工作具有巨大的转化价值。 习惯性行为是包括 SUD 在内的许多精神疾病的核心特征。 基本解决了有关纹状体中 MC4R 功能的未解答的问题。