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.

项目摘要 超过一半的物质使用障碍（SUD）治疗患者会复发。僵化 在熟悉的、习惯性的、过去得到回报的行为（吸毒）和新的行为之间进行选择。 可能更有利的策略（康复）可能是保持SUD的因素。这个目标 一项建议是确定支持目标导向行动选择的神经因素，这可以提供对以下问题的深入了解： 目标导向的行动选择受损的疾病的治疗靶点。 背内侧纹状体（DMS）是一个大脑区域，它接收和整合来自大脑皮层的神经元能输入。 目标导向行动选择所需的皮层和皮层下区域。然而，DMS中的因素 负责协调这一传入信息仍然不完全了解。一个候选因素是 黑皮质素-4受体（MC 4 R），一种α-黑素细胞刺激激素的高亲和力受体。MC4R 调节GluA 2-AMPA受体（GluA 2-AMPAR）在含多巴胺D1受体培养基上的定位 纹状体里的多刺神经元抑制MC 4 R减少了重复的、熟悉的行为的表达， 改善了小鼠的灵活动作选择。因此，MC 4 R似乎在DMS中处于良好的位置，可以集成传入的内容 神经元信号和控制灵活的，目标导向的行动。我将检验MC 4 R的存在 通过调节DMS中GluA 2-AMPAR的细胞定位来控制纹状体依赖性动作选择 (Aim 1）。接下来，我将识别终止于DMS中的Mc 4 r+神经元的传入投射，并识别 投射对于由Mc 4 r沉默赋予的目标导向行为是必需的（目的2）。 在目标1中，我将联合收割机结合活性依赖性GluA 2-AMPAR内化的药理学抑制与 位点选择性输注MC 4 R激动剂并测量小鼠参与灵活动作的能力 通过仪器条件试验进行选择。因此，我将确定MC 4 R活动是否控制行动 通过调节GluA 2-AMPAR定位进行选择。然后，我将使用突触神经体制剂， 定量多种AMPA和NMDA谷氨酸受体亚型的水平和定位，提供了一个 对MC 4 R控制DMS中的谷氨酸能受体亚单位表达的全面观点。 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个大脑范围的输入地图， DMS中的Mc 4 r表达细胞。然后，我将使用组合病毒载体策略来测试投射是否 从特定的大脑区域，如眶额皮质，影响动作选择控制MC 4 R的存在 在DMS。这些实验将确定纹状体MC 4 R影响神经元突触前活动所必需的突触前伴侣。 动物的倾向，灵活地寻求目标与从事熟悉的例程。 冲击拟议的工作具有巨大的转化价值，因为过度依赖不灵活的， 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MC 4 R在纹状体中的功能的基本未回答的问题。