Mechanistic study of the role of autism spectrum disorder risk genes in hippocampal CA1 population dynamics during learning and memory

自闭症谱系障碍危险基因在学习记忆过程中海马CA1群动态中作用的机制研究

• 批准号: 10542789
• 负责人: Rebecca Mount
• 金额: $ 1.04万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542789
• 关键词: Action Potentials; Air; Animal Model; Anxiety; Association Learning; Behavior; Behavioral; Blinking; Brain Diseases; Brain region; Calcium; Cells; Complex; Conditioned Reflex; Conditioned Stimulus; Development; Disease; Disease model; Episodic memory; Equilibrium; Exhibits; Extinction; Eye; Functional disorder; Genes; Genetic; Goals; Hippocampus; Human; Image; Imaging Techniques; Impairment; Individual; Intervention; Knock-out; Knockout Mice; Learning; Lesion; Link; Measures; Membrane; Memory; Memory Loss; Memory impairment; Mental disorders; Mus; Neurons; Pathogenesis; Pathologic; Pathway Analysis; Patients; Phenotype; Population; Population Analysis; Population Dynamics; Post-Traumatic Stress Disorders; Process; Psychiatric therapeutic procedure; Pyramidal Cells; Reporting; Resolution; Rodent Model; Role; Stimulus; Synapses; Time; Wild Type Mouse; anxiety spectrum disorders; autism spectrum disorder; awake; behavioral response; conditioning; eyeblink conditioning; generalized anxiety; imaging study; improved; insight; learning extinction; male; membrane activity; mouse model; neural; novel; novel therapeutics; recruit; response; risk variant; sensor; voltage

PROJECT SUMMARY/ABSTRACT The hippocampus is a critical brain region for various types of learning and memory, and one powerful paradigm to investigate hippocampal function in associative learning is trace eye-blink conditioning and extinction learning. In trace eye-blink conditioning, subjects are presented with a neutral conditioned stimulus (CS), such as tone, followed by a silent trace interval, followed by an aversive unconditioned stimulus (US), such as a gentle puff of air to the eye. The subject learns to associate the CS and US, generating a conditioned eye-blink response to the CS. Extinction learning is probed by removing the US, such that the CS is no longer predictive of the US, and the subject learns to extinguish the eye-blink response. The behavioral responses to trace conditioning and extinction learning have been well-documented, but it is unclear how ongoing, real-time activities of hippocampal neurons contribute to the learning process. Additionally, impaired extinction learning has recently been observed in patients with psychiatric disorders such as post-traumatic stress disorder (PTSD), generalized anxiety, and autism spectrum disorder (ASD). The goal of this proposal is to understand how hippocampal neural dynamics participate in associative learning, assessed by trace conditioning and extinction learning in both healthy and pathological conditions, by utilizing single-cell resolution calcium and voltage imaging techniques in the CA1 of the hippocampus while mice perform these behavioral tasks. Using calcium imaging, we recently completed population analysis of CA1 neurons while wild-type mice perform a trace eye-blink conditioning and extinction learning task. Additionally, several studies have demonstrated that both human patients with ASD and rodent models of ASD can acquire trace conditioning similarly to controls, but they are impaired in extinction learning; they continue to respond to the CS even after it is non-predictive of the US. Thus, to probe the hippocampal network responses underlying intact trace conditioning but impaired extinction learning, we will first perform calcium imaging in a mouse model of ASD (Aim 1). To examine correlation between hippocampal neuron pairs’ activity during these tasks, we will perform voltage imaging in CA1 neurons with a novel genetically-encoded voltage sensor, SomArchon, that can reliably measure multiple individual neurons with single-spike, single-cell resolution in awake, behaving mice (Aim 2). Finally, deficits in excitatory/inhibitory balance are thought to underlie ASD phenotype. To investigate this hypothesis (via assessing correlation between hippocampal neuron pairs), we will perform voltage imaging in the same mouse model of ASD utilized in Aim 1 (Aim 3). At the conclusion of this study, we hope to better understand not only how hippocampal population dynamics contribute to learning and memory in a healthy condition, but also how these hippocampal responses are altered in ASD. This understanding could also provide valuable insight into how disrupted hippocampal population dynamics can create learning and memory deficits in other psychiatric conditions, such as PTSD and anxiety, facilitating the development of new therapies for patients with these disorders.

项目摘要/摘要 海马是各种学习和记忆的关键大脑区域，也是一个强大的范式 在关联学习中研究海马功能是痕量眼光调节和扩展学习。 在痕量眼光调节中，对受试者进行了中性条件刺激（CS），例如音调， 其次是无声的痕量间隔，然后进行厌恶的无条件刺激（美国），例如轻柔的泡沫 空气到眼睛。该主题学会将CS和我们关联，从 CS。通过删除美国来探测灭绝学习，使得CS不再预测美国， 主题学会了扑灭眼睛的反应。对跟踪条件的行为反应和 扩展学习已经有充分的文献记录，但是目前尚不清楚海马的实时活动如何 神经元有助于学习过程。此外，最近已经观察到扩展学习受损 在患有精神疾病的患者中，例如创伤后应激障碍（PTSD），广义动画和 自闭症谱系障碍（ASD）。该提议的目的是了解海马神经动态如何 参加社会学习，通过痕量调理和健康和扩展学习评估 病理条件，通过在CA1中使用单细胞分辨率钙和电压成像技术 使用钙成像，我们最近完成了 CA1神经元的人口分析，而野生型小鼠进行痕量眼光调节和延伸 学习任务。此外，几项研究表明，ASD和啮齿动物的人类患者均可 ASD的模型可以与对照相似，但在扩展学习中会受到损害。 即使在美国对CS的预测之后，他们仍会继续对CS做出回应。那是为了探测海马 网络响应完整的痕量条件，但扩展学习受损，我们将首先执行 ASD小鼠模型中的钙成像（AIM 1）。检查海马神经元对之间的相关性 在这些任务期间的活动，我们将在具有新的遗传编码的CA1神经元中执行电压成像 电压传感器，Somarchon，可以可靠地测量具有单个尖峰，单细胞的多个单独的神经元 清醒中的解决方案，行为小鼠（AIM 2）。最后，认为在兴奋/抑制平衡中定义为 基础ASD表型。研究这一假设（通过评估海马神经元之间的相关性 对），我们将在AIM 1中使用的同一鼠标模型中执行电压成像（AIM 3）。 这项研究的结论，我们希望不仅能更好地了解海马人口动态 在健康状况下有助于学习和记忆，也有助于这些海马反应 在ASD中改变。这种理解还可以提供宝贵的洞察力，了解海马的干扰 人口动态可以创建学习和记忆在其他精神病疾病（例如PTSD和 焦虑，支持为这些疾病患者开发新疗法。