Linking defects in cortical network activity with altered sensory perception in Fragile X mice

将脆性 X 小鼠的皮质网络活动缺陷与感官知觉改变联系起来

基本信息

批准号：
9101817
负责人：
Cynthia He
金额：
$ 3.58万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101817
关键词：
Accounting Acetylcholine Acute Adult Affect Age Anti-Cholinergics Attention Autistic Disorder Behavior Behavioral Brain Calcium Child Cholinergic Antagonists Decision Making Defect Dendritic Spines Development Disease Exhibits FMR1 Fragile X Syndrome Functional disorder Genes Hypersensitivity Image Impaired cognition Impairment Individual Knockout Mice Lead Link Modeling Mus Muscarinic Acetylcholine Receptor Muscarinic Antagonists Mutant Strains Mice Neurodevelopmental Disorder Neurons Neurotransmitters Parietal Lobe Perception Performance Pharmaceutical Preparations Pharmacological Treatment Play Population Process Psyche structure Receptor Signaling Research Role Scopolamine Sensory Sensory Process Signal Transduction Symptoms Synaptic plasticity Testing Therapeutic Therapeutic Effect Time Vibrissae Wild Type Mouse acetylcholine transporter awake barrel cortex behavioral impairment calcium indicator cholinergic critical period hippocampal pyramidal neuron improved in vivo mouse model optogenetics postnatal public health relevance ranpirnase receptive field relating to nervous system research study response sensory discrimination sensory input sensory stimulus therapeutic target two-photon whisker discrimination

项目摘要

DESCRIPTION (provided by applicant): Fragile X Syndrome (FXS) is the most common single-gene cause of autism and mental impairment, affecting as many as 1 in 2500 children. Children with FXS suffer from a variety of cognitive and behavioral impairments, including hypersensitivity to sensory stimuli. In the well-established Fmr1 knockout (KO) mouse model of FXS, a variety of neuronal defects have been discovered, ranging from abnormalities in synaptic plasticity and dendritic spine stabilization to alterations at the level of cortical circuits. Recet studies have established that neuronal hyperexcitability contributes to circuit dysfunction in Fmr1 KO mice and could lead to sensory hypersensitivity in FXS. Using Fmr1 KO mice, the Portera-Cailliau lab has found that neurons in the barrel cortex, which processes whisker inputs, show abnormally elevated firing during spontaneous activity and high network synchrony during a critical period of early postnatal brain development. It remains unknown whether sensory stimulation might also trigger exaggerated neural responses in Fmr1 KO mice, which could conceivably alter sensory perception. Therefore, the experiments in Aim 1 will test two initial hypotheses: First, in Fmr1 KO mice at both developmental and adult ages, neurons in barrel cortex show excessive firing in response to whisker stimulation, as well as broad tuning (i.e., neurons in a given barrel respond to multiple whiskers) and impaired adaptation to persistent stimulation; and second, the mutant mice have behavioral deficits in sensory processing that impair their decision-making in a whisker discrimination task. Additionally, a growing body of work indicates that dysregulated signaling of the excitatory neurotransmitter acetylcholine (ACh) plays a role in FXS pathophysiology. ACh can modulate attention and the response of neuronal ensembles to sensory input, and there is evidence that the Fmr1 KO mouse exhibits excessive muscarinic ACh receptor (mAChR) signaling, but the actual impact of altered cholinergic tone on the activity of sensory circuits is unknown. Accordingly, the experiments in Aim 2 will also test the hypothesis that an excess of cholinergic tone could account for the pathological hyperexcitability of sensory circuits in the KO mice. Aim 2 will also examine whether pharmacological administration of a cholinergic antagonist can correct the abnormal sensory-evoked responses and rescue the perceptual deficits of Fmr1 KO mice. The proposed research will use cutting-edge in vivo two-photon calcium imaging with the genetically encoded calcium indicator GCaMP6s to record network activity in large ensembles of cortical neurons in barrel cortex, in awake, behaving mice performing a Go/No-go whisker discrimination task. These studies will link, for the first time in a model of a neurodevelopmental disorder, cortical network defects with specific behavioral alterations.

描述（由应用程序提供）：脆弱的X综合征（FXS）是自闭症和心理障碍的最常见的单基因原因，影响了2500名儿童中多达1个。 FXS儿童患有多种认知和行为障碍，包括对感觉刺激的超敏反应。在良好的FMR1敲除（KO）小鼠FXS模型中，已经发现了多种神经元缺陷，从突触可塑性的异常和树突状棘突稳定到皮质回路水平的改变。 Recet研究已经确定，神经元过度兴奋性有助于FMR1 KO小鼠的电路功能障碍，并可能导致FXS的感觉超敏反应。使用FMR1 KO小鼠，Portera-Cailliau Lab发现，处理晶须输入的枪管皮层中的神经元在出现活动期间的发射和高网络同步期间在出生后早期脑发育的关键时期显示出绝对升高的射击。在FMR1 KO小鼠中，感觉刺激是否也可能引发夸张的神经元反应，这可能会改变感觉知觉。因此，AIM 1中的实验将检验两个最初的假设：首先，在发育和成人年龄的FMR1 KO小鼠中，枪管皮层中的神经元在响应晶须刺激以及广泛的调节（即给定桶中的神经元对多种晶须的神经元）和对多种晶粒的良性适应性刺激症状的神经元表现出过度的射击，并且对抑制作用的刺激性刺激了;其次，突变小鼠在感觉处理中具有行为缺陷，在晶须歧视任务中损害了他们的决策。此外，越来越多的工作表明兴奋性神经递质乙酰胆碱（ACH）的信号失调在FXS病理生理学中起作用。 ACH可以调节注意力和神经元合奏对感觉输入的反应，并且有证据表明FMR1 KO小鼠表现出过多的毒蕈碱ACH受体（MACHR）信号传导，但是胆碱能音调对感觉循环活性的实际影响是未知的。彼此之间，AIM 2中的实验还将检验以下假设：过量的胆碱能音调可以解释KO小鼠中感觉电路的病理过度兴奋性。 AIM 2还将检查胆碱能拮抗剂的药物给药是否可以纠正异常的感官诱发反应并挽救FMR1 KO小鼠的感知定义。拟议的研究将使用一般编码的钙指示剂GCAMP6使用尖端的体内两光子钙成像，以记录桶形皮质的大型皮质神经元集团中的网络活动，在醒来中，行为执行GO/No-Gog go/dog go-Goger晶须歧视任务。这些研究将首次通过神经发育障碍，皮质网络建立联系具有特定行为改变的缺陷。