Neural mechanisms of ASH1L in autism spectrum disorder

ASH1L 在自闭症谱系障碍中的神经机制

基本信息

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
项目类别：
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

项目摘要

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ASH1L的神经机制社会缺陷是自闭症谱系障碍儿童（ASD）的核心表型。一个重要的，但是未解决的问题是驱动社会缺陷的神经机制。人类遗传研究已经确定组蛋白甲基转移酶ASH1L作为ASD的高风险基因。我们发现ASH1L单倍弥补小鼠表现出社会缺陷，从而概括了ASD患者的核心症状。该提议的目标是为了确定驱动ASH1L单倍弥补相关的社会缺陷的神经回路。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至关重要的作用。胆碱能基础前脑（BF）中的神经元是向下游区域的主要乙酰胆碱输出前额叶皮层（PFC），这是参与社会行为的关键大脑区域，并在ASD儿童中受损。但是，尚不清楚的是，如果任何胆碱能预测在ASH1L单倍度不足 - 相关的社会缺陷。我们假设BF Drive社会缺陷中ASH1L的胆碱能电路受损单倍性小鼠。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）确定在BF驱动社会缺陷中胆碱能神经元活动减少的目标单倍性小鼠。大脑切片记录，体内多通道记录和化学遗传技术将用于检查BF在细胞和体内水平的BF中的胆碱能神经元活性。（2）确定来自BF的胆碱能神经回路介导了ASH1L单倍不足小鼠的社会缺陷。通过组合操纵胆碱能神经元活性的光遗传学和化学遗传学工具，我们将检查特定在电路水平的ASH1L单倍不足小鼠中，从BF到PFC的胆碱能传播。该提议将解决与ASD相关的社会缺陷的重要神经基础。这个项目的结果将提供一种新颖通过激活胆碱能系统为ASD儿童开发治疗性干预措施。