Title: “Mechanistic study of hippocampal CA1 population dynamics during learning and memory using healthy and autism spectrum disorder mouse models”
Xue Han, PhD – BME (Advisor, Chair)
Kamal Sen, PhD – BME
Hengye Man, PhD – Biology
Ben Scott, PhD – Psychological & Brain Sciences
Michelle Sander, PhD – ECE
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. Here, we seek to understand how hippocampal neural dynamics participate in associative learning, assessed by trace conditioning and extinction learning, by utilizing single-cell resolution calcium and voltage imaging techniques in the CA1 of the hippocampus while mice perform these behavioral tasks. Calcium imaging enables us to observe of hundreds of neurons simultaneously over extended periods of time, allowing identification of the neural subpopulations within the hippocampus that contribute to trace conditioning and extinction learning. Complementarily, the novel genetically-encoded voltage sensor SomArchon can reliably measure 10-20 individual neurons with single-spike, single-cell resolution in awake, behaving mice, enabling us to investigate detailed temporal dynamics of hippocampal neurons during these tasks. Finally, 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). To probe the pathological hippocampal responses underlying intact trace conditioning but impaired extinction learning, we will perform calcium and voltage imaging in a mouse model of ASD. With these studies, 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 can be disordered 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.