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.

项目摘要/摘要 自闭症谱系障碍中ASH11的神经机制 社会缺陷是自闭症谱系障碍(ASD)儿童的核心表型。一个重要的问题是 尚未解决的问题是驱动社会缺陷的神经机制。人类遗传学研究已经确定 组蛋白甲基转移酶ash11是ASD的高危基因。我们发现阿什利单倍体不足 小鼠表现出社交缺陷，这概括了ASD患者的核心症状。这项提案的目标是 就是确定驱动与单倍体功能不全相关的社会缺陷的神经回路。开创性研究 研究表明，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)中的神经元是输出到下游区域的主要乙酰胆碱，如 前额叶皮质(PFC)，是参与社会行为的关键大脑区域，在ASD儿童中受损。 然而，目前尚不清楚是否有任何胆碱能投射在Ash1单倍体功能不全中起到了因果作用。 相关的社会赤字。我们假设来自BF的胆碱能环路受损会导致Ash1的社会缺陷。 单倍体功能不全小鼠。为了测试这一点，我们将使用尖端技术的组合来解决两个特定的 目的：(1)确定BF导致社会缺陷的胆碱能神经元活性降低。 单倍体功能不全小鼠。脑片记录、活体多道记录与化学发生技术 将被用来在细胞和体内水平上检测BF中胆碱能神经元的活动。(二)确定 来自BF的胆碱能神经回路调节Ash11单倍体功能不全小鼠的社会缺陷。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 Ash11单倍体功能不全小鼠胆碱能从BF到PFC的电路水平传递。这项提议将 解决与ASD相关的社会缺陷的重要神经基础。这个项目的结果将是 提供一种新的胆碱能回路，驱动Ash1单倍体功能不全相关的社会缺陷，并为 激活胆碱能系统治疗儿童自闭症的研究进展