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

 脆性X综合征（FXS）是自闭症和精神障碍最常见的单基因原因，影响多达1/2500的儿童。患有FXS的儿童患有各种认知和行为障碍，包括对感官刺激的超敏反应。在FXS的完善的Fmr1敲除（KO）小鼠模型中，已经发现了各种神经元缺陷，从突触可塑性和树突棘稳定性异常到皮质回路水平的改变。Recet研究已经确定，神经元过度兴奋导致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实验室发现，处理胡须输入的桶皮质中的神经元在自发活动期间显示出异常升高的放电，并且在出生后早期大脑发育的关键时期显示出高度的网络同步。目前尚不清楚感觉刺激是否也可能引发Fmr1基因敲除小鼠的过度神经反应，这可能会改变感觉知觉。因此，目的1中的实验将测试两个初始假设：首先，在发育和成年年龄的Fmr1 KO小鼠中，桶皮质中的神经元显示响应于须刺激的过度放电，以及宽调谐（即，给定桶中的神经元对多个胡须作出反应）和对持续刺激的适应受损;第二，突变小鼠在感觉处理中具有行为缺陷，这损害了它们在胡须辨别任务中的决策。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。乙酰胆碱可以调节注意力和神经元集合对感觉输入的反应，有证据表明，Fmr1 KO小鼠表现出过量的毒蕈碱乙酰胆碱受体（mAChR）信号，但胆碱能神经张力改变对感觉回路活动的实际影响尚不清楚。因此，目的2中的实验还将检验以下假设：过量的胆碱能紧张性可以解释KO小鼠中感觉回路的病理性过度兴奋性。目的2也将检查是否药理学管理的胆碱能拮抗剂可以纠正异常的感觉诱发的反应和救援的知觉缺陷的Fmr1基因敲除小鼠。这项拟议的研究将使用尖端的体内双光子钙成像和遗传编码的钙指示剂GCaMP 6s来记录执行Go/No-go胡须辨别任务的清醒、行为小鼠中桶状皮质中大量皮质神经元的网络活动。这些研究将首次在神经发育障碍模型中， 具有特定行为改变的缺陷。

 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.