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Circuit Disruptions Underlying Atypical Sensory Processing in Fragile X Syndrome

脆性 X 综合征中非典型感觉处理背后的电路中断

基本信息

批准号：
10033726
负责人：
Craig Erickson
金额：
$ 47.63万
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：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10033726
关键词：
Address Adult Affect Anxiety Arousal Attentional deficit Auditory Behavioral Biological Brain Cells Characteristics Clinic Clinical Research Clinical Trials Collaborations Coupling Cre-LoxP Data Defect Discrimination Down-Regulation Electroencephalography Engineering Epilepsy Exhibits Experimental Designs FMR1 Fragile X Syndrome Frequencies Functional disorder Future Genes Genetic Goals Human Hypersensitivity Imaging Techniques Impairment Individual Inherited Intellectual functioning disability Interneurons Investigation Knockout Mice Knowledge Laboratories Lead Learning Link Methodology Molecular Morphology Mus Nature Neurodevelopmental Disorder Neurons Neurosciences Output Paper Participant Parvalbumins Pathogenesis Pathway interactions Performance Phase Population Dynamics Publishing Quality of life Reporting Research Research Personnel Role Running Sensory Silicon Stimulus Symptoms Synapses Tactile Task Performances Techniques Testing Time Universities Vasoactive Intestinal Peptide Visual Visual impairment area striata autism spectrum disorder awake base behavioral impairment behavioral phenotyping cell type designer receptors exclusively activated by designer drugs distraction experimental study hippocampal pyramidal neuron human subject improved outcome in vivo calcium imaging in vivo imaging inhibitory neuron innovation insight migration mouse model neuroregulation novel novel strategies relating to nervous system sensory discrimination sensory input sex translational approach translational study

项目摘要

SUMMARY The underlying brain defects in Fragile X Syndrome (FXS) are not well understood. We have been investigating the specific circuit alterations that lead to a variety of symptoms in FXS, including attention deficit, anxiety, hyperarousal, sensory hypersensitivity and delayed learning. We focus on FXS, the most common inherited cause of autism and intellectual disability, because most investigators use the same Fmr1 knockout mouse model to investigate it, and because it lacks neuropathological features that often confound investigations in other neurodevelopmental disorders (e.g., severe epilepsy, neuronal migration defects, etc.). We strive to overcome limitations of previous studies by comparing the performance of humans and mice with FXS on analogous behavioral tasks. Our goal is to identify shared deficits in sensory processing and learning across both species that will hopefully improve outcomes of future clinical trials in FXS. Here, we will determine the impact of sensory distractors on behavioral performance in both humans and mice using a visual discrimination task. We will also identify specific alterations in population dynamics of pyramidal neurons and different subtypes of inhibitory interneurons that are responsible for deficits in sensory discrimination in Fmr1 knockout mice. Building on our recently published study in Nature Neuroscience (Goel et al., 2018), we will address the following important questions: 1. Does distraction worsen performance in a sensory discrimination task in Fmr1 knockout mice and in adult subjects with FXS? (Aim 1)? 2. Is the firing of parvalbumin (PV)- and vasoactive intestinal polypeptide (VIP)-expressing interneurons disrupted in Fmr1 knockout mice during the sensory discrimination task, especially in the presence of sensory distractors? (Aim 2A)? 3. Can silencing VIP interneurons (or exciting PV neurons) with DREADDs rescue behavioral performance in Fmr1 knockout mice? (Aim 2B)? 4. Do mice and humans with FXS share similar deficits in neural oscillations (Aim 3)? The mouse studies will be performed in the laboratory of established FXS investigator Carlos Portera-Cailliau (PI) at UCLA. Craig Erickson (co-I), who runs the world’s 3rd largest FXS clinic at the University of Cincinnati, will conduct the human studies. The experimental design exploits cutting edge in vivo imaging techniques (e.g., chemogenetics, in vivo two-photon calcium imaging, Cre-Lox genetics, silicon probe recordings, phase- amplitude coupling analysis of EEG) and seeks to address important knowledge gaps in ASD pathogenesis.

总结