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.

项目概要/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FX潜在机制的有效治疗方法。外汇是最重要的单基因 自闭症谱系障碍的原因，因此许多个体与FX表现出异常的社会行为。 具有FX的个体也经常从事异常的空间行为，如“私奔”，游荡， 迷路了海马体是一种特别容易受到FX影响的大脑结构。很多证据表明 海马CA 2和CA 1区分别对社会行为和空间记忆很重要。然而， 少数研究调查了CA 2和CA 1的神经生理机制紊乱是否可以 是FX中社会和空间认知功能受损的基础。该项目的目标是解决这一差距， 通过研究亚细胞，细胞，电路和神经元群体机制的程度来了解知识 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。将使用体内方法 评估CA 2中细胞反应的损伤和CA 1中协调的神经元群体活动是否 可以解释FX的社交和空间认知缺陷。将进行体外实验， CA 2神经元的内在特性和可塑性改变的细胞机制以及异常的 CA 1的抑制回路。将在两个物种，特别是Fmr 1敲除（KO）大鼠和小鼠中建立FX模型， 使用，允许跨物种比较FX病理生理学。具体目标1将评估是否相关 与野生型相比，Fmr 1基因敲除大鼠中CA 2和其主要输入之一CA 3之间的神经元尖峰活动较弱 在探索社会刺激的过程中。具体目标2将采用全细胞和膜片钳记录， 包括直接来自树突的记录，以测试Fmr 1基因敲除大鼠中的CA 2神经元是否 而小鼠表现出受损的突触可塑性和对社会神经肽催产素的反应不足。具体 Aim 3将测试来自CA 1神经元群体的锋电位序列的重新激活或“重放”， 先前学习的空间轨迹在Fmr 1 KO大鼠中被破坏。回放对空间记忆至关重要 操作，从而中断重放可能有助于受损的空间认知和行为的外汇。重放 的CA 1神经元锋电位序列的时间协调适当定时激活特定的CA 1抑制 中间神经元因此，FX中CA 1峰电位序列的中断重放可能反映了CA 1抑制性细胞内的干扰。 电路.具体目标4将采用来自CA 1锥体神经元的全细胞记录，特定类别的CA 1 中间神经元，并连接CA 1中间神经元-锥体细胞对，以检验抑制回路 在FX中被破坏。这些目标的成功完成将提供关于具体机制的新见解 潜在的异常社会和空间认知和行为的外汇。深入了解FX 机制，预计提出新的目标，干预外汇。