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.

项目概要/摘要 ASH1L 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。一个重要但尚未解决的问题是导致社会缺陷的神经机制。人类遗传学研究发现组蛋白甲基转移酶 ASH1L 是 ASD 的高危基因。我们发现 Ash1l 单倍体不足小鼠表现出社交缺陷，这概括了自闭症谱系障碍患者的核心症状。本提案的目标的目的是确定驱动 ASH1L 单倍体不足相关社交缺陷的神经回路。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方面发挥着重要作用。胆碱能基底前脑 (BF) 中的神经元是向下游区域（例如，前额皮质 (PFC) 是参与社交行为的关键大脑区域，在自闭症谱系障碍 (ASD) 儿童中受到损害。然而，尚不清楚哪种胆碱能投射在 ASH1L 单倍体不足中起因果作用。相关的社会缺陷。我们假设 BF 导致的胆碱能回路受损会导致 Ash1l 的社交缺陷单倍体不足的小鼠。为了测试这一点，我们将结合使用尖端技术来解决两个特定问题目的：(1) 确定 BF 中胆碱能神经元活动的减少导致 Ash1l 的社交缺陷单倍体不足的小鼠。脑切片记录、体内多通道记录和化学遗传学技术将用于检查 BF 中细胞和体内水平的胆碱能神经元活动。 (2) 确定 BF 的胆碱能神经回路介导 Ash1l 单倍剂量不足小鼠的社交缺陷。通过结合光遗传学和化学遗传学工具来操纵胆碱能神经元活动，我们将检查特定的 Ash1l 单倍体不足小鼠中，电路水平上从 BF 到 PFC 的胆碱能传递。该提案将解决与自闭症谱系障碍相关的社会缺陷的重要神经基础。该项目的结果将提供一种新颖的胆碱能回路驱动 ASH1L 单倍体不足相关的社会缺陷，并为研究提供新的线索通过激活胆碱能系统开发针对 ASD 儿童的治疗干预措施。