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。 目前缺乏针对FX的靶向机制的有效治疗。 自闭症谱系障碍的原因，因此许多有FX的人表现出异常行为。 FX的个人也经常以异常的空间行为（例如，徘徊和和 迷路。 海马地区CA2和CA1分别对社会行为和空间记忆很重要 很少有研究发现CA2和CA1中神经粒细胞洛洛洛洛素机制中的干扰是否可以 基础是FX中的社会和空间认知功能。 通过研究亚细胞，细胞，电路和神经元种群机制的知识 在研究中，海马中的社会和空间记忆操作受损 将使用最新的体内和体外电生理技术。 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缺陷。 Ca2神经元中的固有特性改变的细胞机制改变了改变的内在特性和异常 CA1中的抑制作用。 使用，可以比较跨物种的FX病理生理学。 在FMR1 KO大鼠中，Ca2和主要输入之一CA3之间的神经元峰值活性比野生型弱 在探索社会刺激期间的大鼠。 直接从树突中包含录音 和小鼠对社会神经肽催产素的突触塑性和防御反应受损。 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是在FMR1 KO大鼠中进行的。 操作，因此被破坏的重播可能会导致FX重播中的空间认知和行为受损 CA1神经元尖峰序列的临时序列临时抑制作用。 中间神经元。 电路。特定目标4将使用CA1锥体神经元的整个细胞记录，CA1的特定类别 中间神经元和连接的CA1间神经元 - 锥体细胞细胞细胞对，以测试遗传回路的假设 在FX中被破坏。 FX中的基本异常的社会和空间认知和行为。 机制期望提出新的干预FX的目标。