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: 10464192
• 负责人: Oakleigh Folkes
• 金额: $ 6.76万
• 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/10464192
• 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; Lead; 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; 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 社交互动的缺陷是几种神经精神疾病的特征，包括自闭症 频谱障碍（ASD）。 ASD中社会缺陷的细胞，分子和电路机制在很大程度上是 未知并保证进一步研究。 ASD中最一致的病因结果之一是完整的 Shank3基因的缺失，该基因编码神经元中的突触后支架蛋白。我们的实验室开发了 First Shank3通过删除外显子4-22（Shank3ΔE4-22）完成淘汰模型。 Shank3ΔE4-22小鼠显示降低 社会和回报的行为以及伏隔核（NAC）对社会提示的蓝色反应。 NAC是社会行为的良好监管者。然而，NAC中神经元的特征 在社会行为或社会合奏中活跃的那些人没有很好的定义。 NAC中〜95％的神经元是 表达多巴胺接收器D1（D1+）的中型神经元（MSN），编码奖励 加固或D2（D2+），它编码厌恶响应。 NAC MSN表示高水平的shank3，并且 shank3删除会引起D2+ MSN功能的深刻变化。总之，这表明潜力 社会行为的作用机理在shank3Δe4-22小鼠中定义。 shank3支架Homer1b/c和代谢型谷氨酸受体5（mglur5） 密度（PSD）。 NAC中的HOMER1B/C和MGLUR5功能对于规范寻求社会和奖励至关重要 WT小鼠的行为。为了研究shank3-homer1b/c相互作用的作用，我们的实验室产生了第一个 shank3-homer1b/c突变小鼠，shank3pl。自加入江实验室以来，我收集了显示的试点数据 Shank3PL小鼠大大降低了社交和回报的行为。飞行员数据也指示 Shank3PL小鼠在NAC的PSD中改善了HOMER1B/C的表达。 该提议的具体目的是描述shank3缺乏症如何导致细胞和 使用我们的两个新型小鼠模型的分子故障，是异常电路和社会行为的基础： shank3Δe4-22和shank3pl。首先，我假设shank3Δe4-22小鼠中的NAC社会合奏是主要的 由D2+ MSN组成，并编码厌恶和负面的社交性；相比之下，我预测WT社交 合奏主要是D1+ MSN，并编码增强和积极的社会行为。第二，我 假设Shank3-homer1b/c支架对于社会和奖励行为至关重要。我们将测试这些 使用综合方法的假设。 这项研究将是第一个在验证良好的遗传ASD模型和 第一个研究shank3-homer1b/c支架对行为和NAC活性的作用。重要的是， 这些研究可能导致确定新的治疗靶标，以治疗社会和奖励防御 ASD和其他神经精神疾病。