Causal Interactions between genetic risk, precise cortical connectivity, and autism-associated behaviors

遗传风险、精确皮质连接和自闭症相关行为之间的因果相互作用

基本信息

批准号：
10063962
负责人：
GAVIN R RUMBAUGH
金额：
$ 52.52万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063962
关键词：
ASD patient Adaptive Behaviors Air Animal Model Animals Area Behavior Behavioral Biological Brain Brain region Cognitive Disease Echolocation Electrophysiology (science)Emotions Environment Epilepsy Esthesia Etiology Fingers Generations Genes Genetic Risk Goals Head Heterozygote Impairment Individual Intervention Link Location Measurement Measures Mendelian disorder Modeling Motor Motor Cortex Motor output Movement Mus Mutant Strains Mice Nervous system structure Neurons Organ Population Process Research Research Project Grants Risk Factors Running Saccades Scanning Sensory Silicon Somatosensory Cortex Source Structure Structure of trigeminal ganglion Study models System Tactile Telephone Testing Thalamic structure Thinking Time Touch sensation Vibrissae Visual Fields autism spectrum disorder awake behavioral impairment behavioral phenotyping brain abnormalities experience functional disability genetic variant in vivo individuals with autism spectrum disorder insight mouse model neural circuit neural network novel physical model relating to nervous system response risk variant sensory input sensory processing disorder sensory system social

项目摘要

PROJECT SUMMARY The overarching goal of this project is to better understand the links between ASD genetic risk, resulting distributed brain connectivity impairments, and the impact of this on ASD-relevant behaviors. We will do this by performing state-of-the art in vivo electrophysiology studies in awake-behaving animals that model a monogenic form of ASD. This research project is significant because altered brain connectivity is routinely observed in ASD patients, though it remains unknown how brain connectivity alterations cause abnormal behaviors relevant to ASD. In the animal model, we will focus on behaviors that optimize active touch. This is approach is valid because altered sensory function, including touch, is a core manifestation of ASD and somatomotor brain areas display altered activation in ASD patients. An emerging idea is that altered functioning of sensory systems directly impairs the functions of other major neural domains, such as cognitive and social systems. Active touch arises through rapid adaptions in the dynamics of touch organs in response to physical contact with objects. This behavioral transformation optimizes touch-related input into the brain and is an emergent behavior resulting from sensorimotor integration at various levels in the nervous system. Therefore, we generally hypothesize that genetic variants that cause ASD disrupt key points of functional connectivity within the somatomotor system, which in turn causes altered active touch behaviors, leading to altered acquisition of tactile information. This hypothesis is significant because it could define a neural process (i.e. altered distributed functional connectivity) that explains how sensory-guided adaptive behaviors are impaired by genetic variants that cause ASD. Our modeling studies also have the potential to define how altered brain connectivity can disrupt relevant behaviors. We will test this hypothesis in the first aim by recording the flow of information throughout the major areas of the somato-motor system in a mouse model for a monogenic form of ASD. The proposed in vivo recordings in awake-behaving animals will utilize state-of-art silicon neural probes that will enable us to measure local and long-range functional connectivity of neurons during distinct behaviors, including during active touches of objects. These sophisticated measurements will identify circuits that are functionally impaired during ASD-relevant behaviors. The second aim takes a distinct, but complementary approach by regionally and temporally disrupting expression of the causal ASD gene and then observing the impact of these perturbations on behaviors that define etiologically-relevant active touch. We expect to find that proper expression of the ASD gene is required in developing somatomotor cortical areas to promote normal active touch behaviors. The combined impact of these complementary approaches is that they are expected to define the circuits that cause abnormal active touch-related behaviors in the mouse model. Thus, the proposed research is expected to advance our understanding of how major ASD risk genes disrupt the connectivity of neural circuits that underlie relevant behaviors.

项目摘要时间的总体目标分布式大脑连通性障碍以及这对ASD相关行为的影响。在醒着的动物中进行最先进的体内电生理学研究，以建模单基因 ASD的形式是严重的vecaused脑连接性在ASD患者中，尽管尚不清楚大脑连接如何改变异常与ASD相关的行为，我们将专注于优化主动触摸的行为。方法是有效的有效阀门改变的感觉函数，包括触摸，是ASD和和和体育体脑区域显示ASD特定性的激活改变。感觉系统的直接损害其他主要神经领域的功能，例如认知和社会系统通过快速适应触摸器官的动力学而造成的系统。与对象接触。神经系统中各个级别的感觉运动整合产生的紧急行为。我们通常假设导致ASD的遗传变异破坏了功能连接的关键点躯体运动系统又导致主动触摸行为改变，导致对触觉信息。功能连通性）解释了感官引导的自适应行为如何受到遗传变异的损害 ASD的原因。我们的建模研究也有可能定义大脑连接相关行为。我们将通过记录信息流来检验这一假设小鼠模型中的somotor系统的主要区域，用于ASD的单基因使用最先进的硅神经探针在清醒的动物中的体内录音也使我们也使我们测量神经元在不同行为时的局部和远程功能连接连接，包括在活动期间这些复杂测量的对象将确定在功能上受损的电路与ASD相关的行为。在时间上破坏因果ASD基因的表达，然后观察这些扰动关于定义病因与主动触摸的行为。基因在开发躯体运动区域以促进正常的活动触摸行为评论方法的综合影响是预期定义引起的电路小鼠模型中的主动触摸相关行为异常。促进我们对主要ASD风险基因的理解，主要要求基因破坏基于核心的神经Ciral Ciral Ciratuts的联系相关行为。