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

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.