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.

项目概要/摘要 海马体是各种学习和记忆的关键大脑区域，也是一种强大的范例 研究海马在联想学习中的功能是追踪眨眼条件反射和消退学习。 在微量眨眼条件反射中，向受试者呈现中性条件刺激（CS），例如语气、 接下来是无声的跟踪间隔，然后是令人厌恶的无条件刺激（US），例如轻柔地吸一口 空气进入眼睛。受试者学会将 CS 和 US 联系起来，产生条件性眨眼反应 CS。通过删除美国来探索灭绝学习，使得CS不再预测美国， 受试者学会消除眨眼反应。对痕量条件反射的行为反应 消退学习已被充分记录，但尚不清楚海马体的持续实时活动是如何进行的 神经元有助于学习过程。此外，最近还观察到消退学习受损 患有精神疾病的患者，例如创伤后应激障碍（PTSD）、广泛性焦虑症和 自闭症谱系障碍（ASD）。该提案的目标是了解海马神经动力学如何 参与联想学习，通过痕量条件反射和消退学习来评估健康和 通过在 CA1 中利用单细胞分辨率钙和电压成像技术来观察病理状况 当小鼠执行这些行为任务时，海马体会产生变化。使用钙成像，我们最近完成了 野生型小鼠进行微量眨眼调节和消退时 CA1 神经元的群体分析 学习任务。此外，多项研究表明，患有 ASD 的人类患者和啮齿类动物 自闭症谱系障碍（ASD）模型可以获得与对照组相似的微量条件反射，但它们在消退学习方面受到损害； 即使CS无法预测美国，他们仍继续对CS做出反应。因此，要探查海马 网络反应是完整的痕迹调节但受损的消退学习的基础，我们将首先执行 ASD 小鼠模型中的钙成像（目标 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中，我们将使用一种新型基因编码的方法在 CA1 神经元中进行电压成像 电压传感器 SomArchon，可以通过单尖峰、单细胞可靠地测量多个单独的神经元 清醒、行为正常的小鼠的分辨率（目标 2）。最后，兴奋/抑制平衡的缺陷被认为是 ASD 表型的基础。为了研究这一假设（通过评估海马神经元之间的相关性） 对），我们将在目标 1（目标 3）中使用的相同 ASD 小鼠模型中进行电压成像。在 这项研究的结论，我们不仅希望更好地了解海马种群动态如何 有助于健康状况下的学习和记忆，而且还有助于这些海马体的反应 在 ASD 中发生改变。这种理解还可以为了解海马体如何被破坏提供有价值的见解。 人口动态可能会导致其他精神疾病的学习和记忆缺陷，例如创伤后应激障碍（PTSD）和 焦虑症，促进针对这些疾病患者的新疗法的开发。