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

项目总结/摘要 海马体是一个重要的大脑区域，对各种类型的学习和记忆，和一个强大的范式 研究海马在联想学习中的作用是跟踪眨眼条件化和消退学习。 在跟踪眨眼条件反射中，受试者呈现中性条件刺激（CS），如音调， 接着是一个无声的跟踪间隔，然后是一个令人厌恶的无条件刺激（US），如一个温和的喷烟， 空气对眼睛。受试者学会将CS和US相关联，产生条件性眨眼反应， CS。灭绝学习是通过去除US来探索的，使得CS不再预测US， 受试者学会了消除眨眼反应。对痕迹条件反射的行为反应 灭绝学习已经有了很好的记录，但目前还不清楚海马神经元的持续实时活动是如何进行的。 神经元参与学习过程。此外，最近还观察到， 在患有精神疾病的患者中，如创伤后应激障碍（PTSD），广泛性焦虑症， 自闭症谱系障碍（ASD）。这项提议的目的是了解海马神经动力学是如何 参与联想学习，通过跟踪条件反射和消退学习评估健康和 病理条件下，通过利用单细胞分辨率钙和电压成像技术在CA 1的 海马体，而小鼠执行这些行为任务。利用钙成像，我们最近完成了 当野生型小鼠进行微量眨眼条件反射和消退时，CA 1神经元的群体分析 学习任务。此外，几项研究表明，患有ASD的人类患者和啮齿动物 ASD模型可以获得与对照组相似的痕迹条件反射，但它们在消退学习中受损; 他们继续对CS做出反应，即使在CS对美国没有预测性之后。因此，为了探测海马 网络反应的基础完整的痕迹条件反射，但受损的灭绝学习，我们将首先执行 ASD小鼠模型中的钙成像（目的1）。为了检验海马神经元对之间的相关性， 在这些任务中的活动，我们将在CA 1神经元中进行电压成像， 电压传感器，SomArchon，可以可靠地测量多个单独的神经元与单尖峰，单细胞 在清醒的行为小鼠中的分辨率（目的2）。最后，兴奋/抑制平衡的缺陷被认为是 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Aim 1（Aim 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，我们希望更好地了解不仅海马种群动态 有助于健康条件下的学习和记忆，而且这些海马反应如何 在ASD中发生了改变这种理解也可以提供有价值的见解，以了解如何破坏海马 人口动态可以在其他精神疾病中产生学习和记忆缺陷，如创伤后应激障碍和 焦虑症，促进了对这些疾病患者的新疗法的开发。

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.