Neural mechanisms of ASH1L in autism spectrum disorder

ASH1L 在自闭症谱系障碍中的神经机制

• 批准号: 10725205
• 负责人: Luye Qin
• 金额: $ 41.11万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-07-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725205
• 关键词: ASD patient; ASH1L gene; Acetylcholine; Address; Affect; Attention; Automobile Driving; Autopsy; Brain; Brain region; CHRM1 gene; Child; Choline O-Acetyltransferase; Cholinergic Receptors; Cognition; Cues; Data; Detection; Enzymes; FDA approved; Female; Genetic; Genetic study; Goals; Human; Human Genetics; Impairment; Individual; Knock-out; Label; Measures; Mediating; Messenger RNA; Mus; Neuromodulator; Nicotinic Receptors; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Prefrontal Cortex; Role; Signal Transduction; Slice; Social Behavior; Social Interaction; Stimulus; Symptoms; Synapses; System; TNFSF5 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; autism spectrum disorder; autistic children; basal forebrain; brain tissue; cholinergic; cholinergic neuron; genetic technology; goal oriented behavior; high risk; histone methyltransferase; human model; in vivo; insight; loss of function mutation; male; mouse model; neural; neural circuit; neuromechanism; novel; optogenetics; pharmacologic; risk variant; social; social deficits; therapeutic development; therapeutic evaluation; tool; transmission process

Project Summary/Abstract Neural mechanisms of ASH1L in autism spectrum disorder Social deficits are the core phenotypes of children with autism spectrum disorder (ASD). One important but unresolved question is the neural mechanisms driving social deficits. Human genetic studies have identified histone methyltransferase ASH1L as a high-risk gene for ASD. We have found that Ash1l haploinsufficiency mice displayed social deficits, which recapitulated the core symptoms in ASD patients. The goal of this proposal is to determine the neural circuits driving ASH1L haploinsufficiency-associated social deficits. Pioneering studies have shown that neuromodulator acetylcholine plays an essential role in attention and cognition. Cholinergic neurons in the basal forebrain (BF) are the major acetylcholine output to the downstream regions such as prefrontal cortex (PFC), a key brain region involved in social behavior and impaired in children with ASD. However, it is unknown which if any of cholinergic projections play a causal role in ASH1L haploinsufficiency- associated social deficits. We hypothesize that impaired cholinergic circuits from BF drive social deficits in Ash1l haploinsufficiency mice. To test this, we will use combination of cutting-edge techniques to address two Specific Aims: (1) To determine diminished cholinergic neuronal activity in the BF driving social deficits in Ash1l haploinsufficiency mice. Brain slices recording, in vivo multichannel recordings and chemogenetic technology will be used to examine the cholinergic neuronal activity in the BF at cellular and in vivo levels. (2) To determine cholinergic neural circuits from BF mediating social deficits in Ash1l haploinsufficiency mice. By combining optogenetic and chemogenetic tools to manipulate cholinergic neuronal activity, we will examine specific cholinergic transmission from BF to PFC in Ash1l haploinsufficiency mice at circuit level. This proposal will address important neural underpinnings of ASD-associated social deficits. The results from this project will provide a novel cholinergic circuit driving ASH1L haploinsufficiency-related social deficits, and shed new light on the development of therapeutic interventions for ASD children by activation of cholinergic system.

项目总结/摘要 ASH 1 L在自闭症谱系障碍中的神经机制 社交缺陷是自闭症谱系障碍（ASD）儿童的核心表型。重要的是， 尚未解决的问题是神经机制驱动的社会赤字。人类基因研究已经发现 组蛋白甲基转移酶ASH 1 L是ASD的高危基因我们发现Ash 1 l单倍不足 小鼠表现出社会缺陷，这概括了ASD患者的核心症状。这项提案的目的是 是为了确定导致ASH 1 L单倍体不足相关社交缺陷的神经回路。开创性研究 已经表明，神经调节剂乙酰胆碱在注意力和认知中起着重要作用。胆碱能 基底前脑（BF）中的神经元是向下游区域输出乙酰胆碱的主要来源， 前额叶皮层（PFC），一个参与社会行为的关键大脑区域，在ASD儿童中受损。 然而，尚不清楚是否有任何胆碱能投射在ASH 1 L单倍不足中起因果作用。 相关的社会缺陷。我们假设BF引起的胆碱能回路受损导致了Ash 1 l的社交缺陷 单倍型不足小鼠。为了测试这一点，我们将使用尖端技术的组合，以解决两个具体的 目的：（1）确定在Ash 1 l中BF驱动社会缺陷的胆碱能神经元活动减少 单倍型不足小鼠。脑片记录、活体多通道记录和化学遗传学技术 将用于在细胞和体内水平上检查BF中的胆碱能神经元活性。(2)以确定 BF介导的胆碱能神经回路在Ash 1 l单倍不足小鼠中的社会缺陷。通过组合 光遗传学和化学遗传学工具来操纵胆碱能神经元的活动，我们将研究特定的 在回路水平上Ash 1 l单倍性不足小鼠BF至PFC的胆碱能传递。这项建议会 解决ASD相关社交缺陷的重要神经基础。该项目的成果将 提供了一种新的胆碱能回路，驱动ASH 1 L单倍性相关的社会缺陷，并揭示了新的光 通过激活胆碱能系统来开发ASD儿童的治疗干预措施。