Investigations of Neuronal Ensembles and Shank3-Homer Scaffolds on Reward and Social Behavior in a Shank3 model of Autism

神经元集成和 Shank3-Homer 支架对自闭症 Shank3 模型中奖励和社会行为的研究

• 批准号: 10617704
• 负责人: Oakleigh Folkes
• 金额: $ 7.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617704
• 关键词: Behavior; Behavioral; Behavioral Paradigm; Binding; Biological Assay; Bipolar Disorder; Calcium; Characteristics; Cues; Data; Disease model; Dopamine D1 Receptor; Etiology; Exons; Fragile X Syndrome; Functional disorder; Genes; Genetic; Goals; Image; Immunohistochemistry; Investigation; Knock-out; Measures; Methodology; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Nucleus Accumbens; Point Mutation; Population; Proline-Rich Domain; Proteins; Psychological reinforcement; Research; Research Domain Criteria; Research Personnel; Rewards; Risk Factors; Role; Scaffolding Protein; Schizophrenia; Social Behavior; Social Interaction; Synapses; Techniques; Testing; Time; Western Blotting; autism spectrum disorder; density; experimental study; in vivo; metabotropic glutamate receptor 5; mouse model; neural circuit; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; post-doctoral training; postsynaptic; preference; recruit; response; scaffold; social; social deficits

PROPOSAL SUMMARY Deficits in social interaction are characteristic of several neuropsychiatric disorders, including Autism Spectrum Disorder (ASD). The cellular, molecular, and circuit mechanisms of social deficits in ASD are largely unknown and warrants further research. One of the most consistent etiological findings in ASD is a complete deletion of the SHANK3 gene, which encodes a postsynaptic scaffold protein in neurons. Our lab developed the first Shank3 complete knockout model by deleting exons 4-22 (Shank3∆e4-22). Shank3∆e4-22 mice show decreased social and reward-seeking behavior and blunted response of the Nucleus Accumbens (NAc) to social cues. The NAc is a well-established regulator of social behavior. Yet, the characteristics of neurons in the NAc that are active during social behavior, or social ensembles, are not well defined. ~95% of neurons in the NAc are medium-spiny neurons (MSNs) that express either dopamine receptor D1 (D1+), which encode reward reinforcement, or D2 (D2+), which encode aversive responses. NAc MSNs express high levels of SHANK3, and Shank3 deletion induces profound changes in D2+ MSN function. Taken together, this indicates a potential mechanism of action for social behavior deficits in Shank3∆e4-22 mice. SHANK3 scaffolds HOMER1b/c and metabotropic glutamate receptor 5 (mGluR5) to the postsynaptic density (PSD). HOMER1b/c and mGluR5 function in the NAc is crucial for regulating social and reward-seeking behaviors in WT mice. To study the role of SHANK3-HOMER1b/c interaction, our lab generated the first SHANK3-HOMER1b/c mutant mouse, Shank3PL. Since joining the Jiang lab, I have collected pilot data showing that Shank3PL mice have significantly decreased social and reward-seeking behavior. Pilot data also indicate Shank3PL mice have decreased HOMER1b/c expression in the PSD of the NAc. The specific objective of this proposal is to delineate how SHANK3 deficiency causes cellular and molecular malfunctions that underlie abnormal circuit and social behavior using our two novel mouse models: Shank3∆e4-22 and Shank3PL. First, I hypothesize that NAc social ensembles in Shank3∆e4-22 mice are primarily composed of D2+ MSNs and encode aversion and negative sociability; in contrast, I predict WT social ensembles are predominantly D1+ MSNs and encode reinforcement and positive social behavior. Second, I hypothesize that SHANK3-HOMER1b/c scaffolds are crucial for social and reward behavior. We will test these hypotheses using comprehensive methodologies. This study will be the first to characterize social ensembles in a well-validated genetic ASD model and the first to investigate the role of SHANK3-HOMER1b/c scaffolds on behaviors and NAc activity. Importantly, these studies may lead to the identification of novel therapeutic targets for treating social and reward deficits in ASD and other neuropsychiatric disorders.

提案摘要 社交互动缺陷是包括自闭症在内的多种神经精神疾病的特征 自闭症谱系障碍（ASD）的社会缺陷的细胞、分子和回路机制主要是 ASD 最一致的病因学发现之一是完整的。 SHANK3 基因的缺失，该基因编码神经元中的突触后支架蛋白。 第一个通过删除外显子 4-22 的 Shank3 完全敲除模型 (Shank3Δe4-22) 小鼠表现出下降。 社交和寻求奖励行为以及伏隔核 (NAc) 对社交线索的反应迟钝。 NAc 是公认的社会行为调节器，但 NAc 中神经元的特征仍然存在。 NAc 中约 95% 的神经元在社交行为或社交群体中活跃的神经元尚未明确定义。 表达多巴胺受体 D1 (D1+) 的中棘神经元 (MSN)，编码奖励 强化，或 D2 (D2+)，编码厌恶反应，表达高水平的 SHANK3，以及 Shank3 缺失会引起 D2+ MSN 功能的深刻变化，这表明了潜在的潜力。 Shank3Δe4-22 小鼠社会行为缺陷的作用机制。 SHANK3 将 HOMER1b/c 和代谢型谷氨酸受体 5 (mGluR5) 支架到突触后 NAc 中的 HOMER1b/c 和 mGluR5 功能对于调节社交和奖励寻求至关重要。 为了研究 SHANK3-HOMER1b/c 相互作用的作用，我们的实验室生成了第一个模型。 自从加入姜实验室以来，我收集了 SHANK3-HOMER1b/c 突变小鼠 Shank3PL。 试验数据还表明，Shank3PL 小鼠的社交和寻求奖励行为显着减少。 Shank3PL 小鼠在 NAc 的 PSD 中 HOMER1b/c 表达降低。 该提案的具体目标是描述 SHANK3 缺陷如何导致细胞和 使用我们的两种新颖的小鼠模型来研究异常电路和社会行为背后的分子故障： Shank3Δe4-22 和 Shank3PL 首先，我发现 Shank3Δe4-22 小鼠的 NAc 社交群体主要是。 由 D2+ MSN 组成，编码厌恶和消极社交；相比之下，我预测 WT 社交； 合奏主要是 D1+ MSN，编码强化和积极的社交行为 其次，I。 SHANK3-HOMER1b/c 支架对于社交和奖励行为至关重要，我们将对其进行测试。 使用综合方法的假设。 这项研究将是第一个在经过充分验证的遗传自闭症谱系障碍模型中描述社会群体特征的研究， 第一个研究 SHANK3-HOMER1b/c 支架对行为和 NAc 活性的作用。 这些研究可能会导致确定治疗社交和奖励缺陷的新治疗靶点 自闭症谱系障碍（ASD）和其他神经精神疾病。