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

项目摘要/摘要 海马体是各种类型学习和记忆的关键大脑区域，也是一个强大的范例 探讨海马区在联想学习中的作用是示踪、眨眼、条件反射和消退学习。 在示踪眨眼条件反射中，向受试者呈现中性条件刺激(CS)，例如音调， 然后是一个无声的轨迹间隔，然后是一个令人厌恶的无条件刺激(US)，比如轻轻地喷一口 空气直射眼睛。受试者学习将CS和US联系起来，产生条件性眨眼反应 政务司司长。灭绝学习是通过删除美国来探索的，这样CS就不再是美国的预测， 受试者学会了消除眨眼反应。对示踪条件反射的行为反应 灭绝学习已经得到了很好的记录，但还不清楚海马体的实时活动是如何进行的。 神经元对学习过程有贡献。此外，最近还观察到灭绝学习受损。 在患有精神障碍的患者中，如创伤后应激障碍(PTSD)、广泛性焦虑和 自闭症谱系障碍(ASD)。这项提议的目标是了解海马神经动力学 参与联想学习，通过跟踪条件反射和消退学习对健康和健康儿童进行评估 病理条件下，通过利用单细胞分辨钙和电压成像技术在CA1 当小鼠执行这些行为任务时，海马体。使用钙成像，我们最近完成了 野生型小鼠进行示踪眨眼条件反射和消退时CA1神经元的群体分析 学习任务。此外，几项研究表明，患有自闭症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到损害； 他们继续对政务司司长做出回应，即使政务司司长对美国没有预测性。因此，要探测海马体 追踪条件反射完好但消亡学习受损的网络反应，我们将首先进行 ASD小鼠模型的钙成像(目标1)。检验海马神经元对之间的相关性 在这些任务中，我们将用一种新的基因编码的CA1神经元进行电压成像 电压传感器SomArchon，可以可靠地测量单尖峰、单细胞的多个单个神经元 清醒的、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。为了研究这一假说(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小鼠模型上进行电压成像。在 总结这项研究，我们希望不仅能更好地了解海马区的种群动态 在健康的状态下有助于学习和记忆，但这些海马体如何反应 在ASD中会发生改变。这一理解还可以为我们提供有价值的洞察，了解海马体是如何受到破坏的 人口动态可以在其他精神疾病中造成学习和记忆障碍，如创伤后应激障碍和 焦虑，促进为这些疾病患者开发新的治疗方法。

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.