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

• 批准号: 10303072
• 负责人: Darrin H Brager
• 金额: $ 58.97万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-16 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303072
• 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

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)是一种广泛存在的遗传性智力残疾。 目前缺乏针对外汇交易潜在机制的有效治疗方法。FX是最重要的单基因 自闭症谱系障碍的原因，因此许多FX患者表现出异常的社会行为。 患有FX的个体也经常从事异常的空间行为，如“私奔”、走失和 迷路了。海马体是一种特别容易受到FX影响的大脑结构。许多证据表明 海马区CA2和CA1分别对社会行为和空间记忆起重要作用。然而， 很少有研究调查社会和空间神经生理机制中的干扰 CA2和CA1的记忆功能是Fx社会行为和空间记忆损伤的基础。这 该项目的目标是通过调查亚细胞、细胞、电路、 啮齿动物海马区社会记忆和空间记忆操作的网络机制受损 外汇的模型。这些研究将采用最先进的体内和体外电生理技术。活体内 这些方法将被用来评估异常的细胞和网络机制是否与脑功能缺陷有关 社会探索和空间记忆。体外实验将揭示导致改变的细胞机制 CA2的固有特性和可塑性以及CA1的异常抑制。两个物种的外汇模型，特别是 将使用FMR1基因敲除(KO)大鼠和小鼠，允许跨物种比较FX病理生理学。 具体目标1将评估在探索社会刺激期间对CA2神经元的输入强度是否 Fmr1KO大鼠较野生型大鼠弱。该目标还将使用复杂的行为跟踪软件来 确定Fmr1 KO大鼠在社会探索过程中是否表现出异常行为模式。特定目标2将 采用全细胞和膜片钳记录，包括直接来自树突的记录 切片以测试Fmr1 KO大鼠和小鼠的CA2神经元是否表现出突触可塑性和反应受损 社会神经肽，催产素。特定目标3将测试来自 CA1神经元的集合被认为是空间记忆加工的重要网络机制 在执行空间记忆任务的Fmr1KO大鼠中受到干扰。跨组合的扣球的协调 海马神经元需要适当的时间激活特定的CA1中间神经元。因此，扰乱了 FX中CA1棘波序列的协调可能反映了CA1中间神经元的紊乱。具体目标4将 使用全细胞记录特定类别的CA1中间神经元和CA1锥体细胞的抑制性输入 以检验抑制回路在外汇中被破坏的假设。成功完成这些目标将提供 关于外汇市场中异常社会和空间行为背后的具体机制的新见解。获得了一个 对外汇机制的更深入理解有望为干预外汇提出新的目标。