Physiological mechanisms underlying disrupted hippocampal function in Fragile X syndrome

脆性 X 综合征海马功能破坏的生理机制

基本信息

批准号：
10296758
负责人：
Darrin H Brager
金额：
$ 58.42万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2020-11-16 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10296758
关键词：
Address Affect Animals Area Behavior Behavioral Biochemical Brain Brain region Cells Computer software Data Defect Dendrites Electrophysiology (science)Environment Exhibits FMR1 Feedback Fire - disasters Fragile X Syndrome Functional disorder Goals Hippocampus (Brain)Impaired cognition Impairment In Vitro Individual Inherited Intellectual functioning disability Interneuron function Interneurons Intervention Knock-out Knockout Mice Knowledge Lead Learning Learning Disabilities Link Location Long-Term Potentiation Measures Memory Memory impairment Metabotropic Glutamate Receptors Modeling Mus Neurons Neuropeptides Output Oxytocin Pattern Periodicity Pharmacology Physiological Physiology Play Property Pyramidal Cells Rattus Receptor Activation Regulation Rewards Rodent Model Role Slice Social Behavior Social Phobia Spatial Behavior Stimulus Structure Symptoms Synapses Synaptic plasticity Techniques Testing Theta Rhythm Time Whole-Cell Recordings autism spectrum disorder behavioral impairment effective therapy experience experimental study hippocampal pyramidal neuron in vivo insight memory process multisensory neuromechanism neurophysiology novel operation patch clamp place fields response sensory stimulus social spatial memory tool

项目摘要

Project Summary/Abstract. Fragile X syndrome (FX) is a widespread type of inherited intellectual disability. Effective treatments that target mechanisms underlying FX are currently lacking. FX is the foremost monogenic cause of autism spectrum disorders, and thus many individuals with FX exhibit abnormal social behaviors. Individuals with FX also often engage in aberrant spatial behaviors such as “elopement”, wandering off and getting lost. The hippocampus is a brain structure that is particularly vulnerable to FX. Much evidence suggests that hippocampal areas CA2 and CA1 are important for social behaviors and spatial memory, respectively. Yet, few studies have investigated whether disturbances in neurophysiological mechanisms of social and spatial memory functions in CA2 and CA1 underlie social behavioral and spatial memory impairments in FX. This project’s goal is to address this gap in knowledge by investigating the extent to which subcellular, cellular, circuit, and network mechanisms of social and spatial memory operations in the hippocampus are impaired in rodent models of FX. The studies will employ state-of-the-art in vivo and in vitro electrophysiological techniques. In vivo approaches will be used to assess whether aberrant cellular and network mechanisms are related to deficits in social exploration and spatial memory. In vitro experiments will uncover cellular mechanisms underlying altered intrinsic properties and plasticity in CA2 and aberrant inhibition in CA1. Models of FX in two species, specifically Fmr1 knockout (KO) rats and mice, will be used, allowing comparison of FX pathophysiology across species. Specific Aim 1 will assess whether the strength of inputs to CA2 neurons during exploration of social stimuli is weaker in Fmr1 KO rats than wildtype rats. This Aim will also use sophisticated behavioral tracking software to determine whether Fmr1 KO rats show aberrant behavioral patterns during social exploration. Specific Aim 2 will employ whole cell and patch clamp recordings, including recordings directly from dendrites, in hippocampal slices to test whether CA2 neurons in Fmr1 KO rats and mice show impaired synaptic plasticity and responses to the social neuropeptide, oxytocin. Specific Aim 3 will test whether coordination of spike sequences from ensembles of CA1 neurons, believed to be an important network mechanism of spatial memory processing, is disrupted in Fmr1 KO rats performing spatial memory tasks. Coordination of spiking across ensembles of hippocampal neurons requires properly timed activation of specific CA1 interneurons. Thus, disrupted coordination of CA1 spike sequences in FX may reflect disturbances in CA1 interneurons. Specific Aim 4 will employ whole cell recordings of specific classes of CA1 interneurons and inhibitory inputs to CA1 pyramidal cells to test the hypothesis that inhibitory circuits are disrupted in FX. Successful completion of these Aims will provide novel insights about specific mechanisms underlying aberrant social and spatial behaviors in FX. Gaining a deeper understanding of FX mechanisms is expected to suggest novel targets for intervention in FX.

项目摘要/摘要。脆性 X 综合征 (FX) 是一种普遍存在的遗传性智力障碍。目前缺乏针对 FX 潜在机制的有效治疗方法是最重要的单基因治疗。 FX 是自闭症谱系障碍的病因，因此许多患有 FX 的人表现出异常的社会行为。患有 FX 的人还经常从事异常的空间行为，例如“私奔”、流浪和许多证据表明，海马体是一个特别容易受到FX影响的大脑结构。海马区 CA2 和 CA1 分别对社会行为和空间记忆很重要很少有研究调查社会和空间的神经生理机制是否受到干扰 CA2 和 CA1 的记忆功能是 FX 社会行为和空间记忆障碍的基础。该项目的目标是通过研究亚细胞、细胞、电路、啮齿类动物海马体的社会和空间记忆运作网络机制受损这些研究将采用最先进的体内和体外电生理技术。方法将用于评估异常的细胞和网络机制是否与缺陷有关社会探索和空间记忆的体外实验将揭示改变背后的细胞机制。 CA2 的内在特性和可塑性以及 CA1 的异常抑制模型，特别是两个物种。将使用 Fmr1 敲除 (KO) 大鼠和小鼠，以便比较不同物种的 FX 病理生理学。具体目标 1 将评估在探索社会刺激期间 CA2 神经元的输入强度是否为 Fmr1 KO 大鼠比野生型大鼠弱。该目标还将使用复杂的行为跟踪软件来检测。确定 Fmr1 KO 大鼠在社会探索期间是否会表现出异常行为模式。在海马中使用全细胞和膜片钳记录，包括直接来自树突的记录切片测试 Fmr1 KO 大鼠和小鼠的 CA2 神经元是否表现出受损的突触可塑性和反应特定目标 3 将测试社会神经肽催产素是否协调。 CA1神经元的集合被认为是空间记忆处理的重要网络机制 Fmr1 KO 大鼠执行空间记忆任务时，各组间的放电协调受到干扰。海马神经元需要适当定时激活特定的 CA1 中间神经元，因此会受到干扰。 FX 中 CA1 尖峰序列的协调可能反映 CA1 中间神经元的干扰。具体目标 4 将。采用特定类别 CA1 中间神经元的全细胞记录和 CA1 锥体细胞的抑制输入测试 FX 中抑制电路被破坏的假设，成功完成这些目标将提供。关于外汇异常社会和空间行为背后的特定机制的新颖见解。对外汇机制的更深入了解预计将为外汇干预提出新的目标。