Investigating the effects of chronic stress on hippocampal representations, synaptic connectivity and learning.

压力是造成抑郁症、精神分裂症、焦虑症和创伤后应激障碍等精神疾病的病理生理的最突出的环境因素。压力对认知的有害影响包括学习和记忆的失调。与此一致的是，在人类和小鼠中，压力会改变海马体的结构和生理机能，海马体是情景记忆的关键大脑区域。虽然应激会引起海马结构的深刻变化，但目前还不清楚这些变化对海马神经元网络学习和回忆信息的能力有何影响。这主要是因为，到目前为止，它一直是不可能的跟踪神经元的活动在相同的主题在典型的持续时间的慢性压力和研究神经元结构纵向海马。为了克服这些障碍，我建议使用头戴式宽场光学成像跟踪活动的数千个CA1海马锥体神经元在自由行为的小鼠和研究慢性应激的空间表示。这将使我们能够纵向研究相同动物中应激诱导的空间编码变化和学习记忆障碍。此外，我计划将联合收割机头戴式宽场与双光子光学成像相结合，以跟踪相同海马CA1锥体神经元中的细胞活动和突触连接数周。这将使我们第一次研究神经元连接和活动之间的关系，在基线和压力条件下。通过研究压力如何改变海马体代表空间的方式，该项目将揭示学习和记忆的基本机制，这不仅对基础科学而且对转化科学都很重要。

Stress is the most prominent environmental factor contributing to the pathophysiology of psychiatric diseases such as depression, schizophrenia, anxiety and post traumatic stress disorder. The detrimental effects of stress on cognition include dysregulation of learning and memory. Consistently with this, in humans and mice, stress alters the structure and physiology of the hippocampus, which is a brain region key for episodic memory. Although stress induces profound structural changes in the hippocampus, it still is unclear what are the effects of such changes on the ability of hippocampal neuronal networks to learn and recall information. This is mainly because, until now, it has been impossible to track neuronal activity in the same subjects over the typical durations of chronic stress and to investigate neuronal structure longitudinally in the hippocampus. To overcome these obstacles, I propose to use head mounted wide field optical imaging to track activity of thousands of CA1 hippocampal pyramidal neurons in freely behaving mice and to study spatial representations upon chronic stress. This will enable us to investigate stress-induced changes in spatial codes and impairment in learning and memory in the same animals longitudinally. Moreover, I plan to combine head mounted wide field with two-photon optical imaging to track cellular activity and synaptic connectivity in the same hippocampal CA1 pyramidal neurons over weeks. This will enable us for the first time to study the relationship between neuronal connectivity and activity under baseline and stressful conditions. By investigating how stress changes the way in which the hippocampus represents space this project will shed light on the fundamental mechanisms of learning and memory which will be important not only for basic but also for translational science.