Investigating mechanisms underlying impaired social and spatial cognition in rodent models of Fragile X syndrome

研究脆性 X 综合征啮齿动物模型社会和空间认知受损的机制

• 批准号: 10675050
• 负责人: Darrin H Brager
• 金额: $ 76.49万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675050
• 关键词: Address; Affect; Area; Behavior; Biochemical; Brain; Brain region; Cells; Code; Cognition; Data; Defect; Dendrites; Electrophysiology (science); Environment; Event; Exhibits; FMR1; Feedback; Fire - disasters; Fragile X Syndrome; Functional disorder; Goals; Hippocampus; Impaired cognition; Impairment; In Vitro; Individual; Inherited; Intellectual functioning disability; Interneurons; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Learning Disabilities; Location; Long-Term Potentiation; Measures; Memory; Memory impairment; Modeling; Mus; Neocortex; Neurons; Neuropeptides; Output; Oxytocin; Pattern; Physiology; Play; Population; Property; Pyramidal Cells; Rattus; Regulation; Rest; Rodent Model; Role; Sleep; Slice; Social Behavior; Social Phobia; Spatial Behavior; Stimulus; Structure; Symptoms; Synapses; Synaptic plasticity; Techniques; Testing; Time; Whole-Cell Recordings; autism spectrum disorder; cognitive function; effective therapy; experience; experimental study; hippocampal pyramidal neuron; in vivo; insight; multisensory; neocortical; neuromechanism; neurophysiology; non rapid eye movement; novel; operation; patch clamp; pharmacologic; place fields; response; sensory stimulus; social; spatial memory; tool; transmission process

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 in CA2 and CA1 could underlie impaired social and spatial cognitive functioning in FX. This project’s goal is to address this gap in knowledge by investigating the extent to which subcellular, cellular, circuit, and neuronal population 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 impairments in cellular responses in CA2 and coordinated neuronal population activity in CA1 could explain deficits in social and spatial cognition in FX. In vitro experiments will be conducted to uncover cellular mechanisms underlying altered intrinsic properties of and plasticity in CA2 neurons and aberrant inhibitory circuits 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 correlated neuronal spiking activity between CA2 and one of its major inputs, CA3, is weaker in Fmr1 KO rats than wildtype rats during exploration of social stimuli. 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 deficient responses to the social neuropeptide, oxytocin. Specific Aim 3 will test whether reactivation, or “replay”, of spike sequences from populations of CA1 neurons that code for previously learned spatial trajectories is disrupted in Fmr1 KO rats. Replay is critical for spatial memory operations, and thus disrupted replay could contribute to impaired spatial cognition and behavior in FX. Replay of CA1 neuronal spike sequences is temporally coordinated by properly timed activation of specific CA1 inhibitory interneurons. Thus, disrupted replay of CA1 spike sequences in FX may reflect disturbances in CA1 inhibitory circuits. Specific Aim 4 will employ whole cell recordings from CA1 pyramidal neurons, specific classes of CA1 interneurons, and connected CA1 interneuron-pyramidal cell pairs 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 cognition and 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。脆弱的X综合征（FX）是遗传智障的一种宽度类型。 目前缺乏针对FX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，因此许多患有FX暴露异常社会行为的人。 具有FX的人也经常从事异常的空间行为，例如“私奔”，徘徊和 迷路。海马是一种特别容易受到FX的大脑结构。许多证据表明 海马区CA2和CA1分别对于社会行为和空间记忆很重要。然而， 很少有研究研究CA2和CA1中神经生理机制中的灾难是否可以 FX中的社会和空间认知功能受损的基础。这个项目的目标是解决这个差距 通过研究亚细胞，细胞，电路和神经元种群机制的知识 在FX的啮齿动物模型中，海马中的社会和空间记忆操作受损。研究 将采用最先进的体内和体外电生理技术。体内方法将使用 评估CA2和CA1中协调神经元人群活性中细胞反应的损害是否损害 可以解释FX中社会和空间认知的定义。将进行体外实验以发现 Ca2神经元中的内在特性和可塑性的内在特性和异常 CA1中的抑制回路。 FX模型在两个物种中，特别是FMR1敲除（KO）大鼠和小鼠的模型，将是 使用，可以比较跨规范的FX病理生理学。具体目标1将评估是否相关 在FMR1 KO大鼠中，Ca2和其主要输入之一CA3之间的神经元峰值活性比野生型弱弱 在探索社会刺激期间的大鼠。特定的AIM 2将采用整个单元格和斑块夹记录， 在海马切片中直接包括从树突中的录音，以测试FMR1 KO大鼠中的Ca2神经元是否 小鼠表现出对社会神经肽氧加毒素的合成可塑性受损和反应不足。具体的 AIM 3将测试CA1神经元群体的尖峰序列的重新激活或“重播” 对于以前学习的空间轨迹，在FMR1 KO大鼠中被禁用。重播对于空间记忆至关重要 操作以及因此被破坏的重播可能导致FX中的空间认知和行为受损。重播 通过特定的Ca1抑制作用的适当时间激活，CA1神经元尖峰序列暂时协调 中间神经元。这是FX中CA1尖峰序列的破坏重播可能反映了CA1抑制性的干扰 电路。特定目标4将采用CA1锥体神经元的全细胞记录，CA1的特定类别 中间神经元和连接的CA1间神经元 - 锥体细胞对，以测试抑制回路的假设 在FX中被破坏。这些目标的成功完成将提供有关特定机制的新见解 FX中的基本异常社会和空间认知和行为。对FX有更深入的了解 预计机制将暗示用于干预FX的新目标。