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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：
9885217
负责人：
GAVIN R RUMBAUGH
金额：
$ 55.3万
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/9885217
关键词：
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 Patients 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 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.

项目总结： -- 这一项目的总体目标是为了更好地了解ASD与遗传风险之间的潜在联系，并由此产生。分布式的大脑连通性和损伤，以及这一事件对与ASD相关的儿童行为的影响。我们将在2019年之前解决这一问题。在体内进行最先进的电生理学和研究，并在清醒行为的动物身上进行研究，这是一种新的单基因模型。这是ASD的一种形式。这个研究项目的结果是非常重要的，因为我们经常观察到大脑和连接能力的改变。然而，在ASD患者中，大脑的连通性和改变是如何导致异常的，仍然是未知的。行为与ASD相关。在我们的动物模型中，我们将重点关注能够优化其主动触觉的行为模式。这种方法是有效的，因为包括触觉在内的感觉功能的改变是ASD的一种核心表现形式。在ASD患者中，躯体运动和大脑区域显示的激活状态发生了变化。一个新兴的想法是，它改变了患者的功能。许多感觉神经系统会直接损害其他主要神经功能领域的功能，如认知功能和社交功能。系统。积极的身体触摸是通过快速的身体适应而产生的，在身体接触器官的动态过程中，通过对身体机能的反应而产生。与其他物体接触。这种行为方式的转变优化了与触觉相关的信息输入到大脑中，这是一种新的方式。紧急行为是由不同水平的感觉运动和整合导致的，在我们的神经系统中。因此，。我们通常会假设，导致ASD的基因变异可能会扰乱其在体内的功能和连接的关键关键点。人体运动控制系统反过来又会导致主动的触摸行为发生变化，从而导致公司对其收购行为发生变化。触觉信息。这个假设是非常重要的，因为它不能定义一个完整的神经过程(即，被改变的或分布的)。功能(连通性)解释了感官引导的适应性行为是如何受到基因变异的影响的。这可能会导致ASD。我们的大脑建模和研究也可能带来潜在的挑战，以更好地定义大脑和连接性的改变如何可能扰乱。相关的信息行为。我们将在第一个目标中通过记录整个过程中信息的流动来检验这一假设。这两个主要的领域包括建立非自闭症的躯体-运动控制系统，以及用于建立非自闭症的单一基因形式的小鼠模型。 VIVO记录的清醒行为的动物将不会利用最先进的硅和神经网络探针，这将使我们能够更好地研究。在不同的运动行为期间，包括在活动期间，测量不同神经元的局部功能和远程功能神经连接能力。触摸到许多物体。通过这些复杂的电路测量，将无法识别这些电路在运行过程中功能不佳。与ASD相关的行为。第二个目标是采取一种截然不同的、但互为补充的方法，由区域组织和组织实施。暂时干扰ASD基因的表达，然后观察这些干扰的主要影响。关于那些可以定义与病因相关的和主动的触摸的行为。我们预计他们会找到正确的ASD的表达方式。在发展躯体运动和皮质运动区的过程中，基因治疗是必需的，以促进正常和积极的触觉行为。这些相辅相成的方法的综合影响是，预计它们将无法定义它们所导致的主要电路。在智能鼠标模型中出现了异常的、活跃的和触摸相关的行为。因此，预计最新提出的智能研究模型将不再适用。推进我们对ASD主要风险基因如何扰乱其基础神经回路的正常连接能力的进一步理解。相关犯罪行为。