Dysregulation of learning and memory processes is often a core and disabling clinical component of a broad variety of neuropsychiatric disorders. For example, the healthy brain continuously links discontiguous, sequential experiences across time. However, in patients who have developed PTSD, a neutral cue may trigger severe symptoms if previous exposure to a similar cue had been temporally followed by, and became mnemonically associated with, a traumatic event. Such temporal association memories can be studied with ?trace? fear conditioning paradigms that require selective hippocampal (HPC) circuitry and may also engage distributed prefrontal-thalamo-hippocampal circuits. However, the neural circuit activity mechanisms underlying the key processes of mnemonic temporal association and fear regulation remain largely unclear. This project studies circuit activity mechanisms for these systems level mental processes using current state-of-the-art techniques for combined neural circuit activity monitoring and perturbation. Thus, 2-photon activity imaging of circuit dynamics, opto- and pharmacogenetic manipulations, multi-site electrophysiological recordings of neural activity, and computational analyses, will all be applied to study learning and memory processes in awake, behaving mice. First, the dynamic HPC output activity mechanisms associated with ?trace? fear memory will be identified using 2-photon imaging of cellular network activity during learning (Aim 1). Next, the role of long-range thalamo-hippocampal inputs in potentially regulating ?trace? fear memories through this HPC circuit output (Aim 2) will be tested using a combination of presynaptic activity imaging, circuit perturbation, and imaging of postsynaptic output activity. Finally, the hypothesis that coordination between prefrontal-thalamo-hippocampal systems is important for ?trace? fear memories will be tested (Aim 3) using simultaneous recordings of neural activity from distant brain regions and optogenetic inhibition of circuit elements. The project builds directly from the PI?s prior studies in synaptic physiology, plasticity, and microcircuit dynamics underlying learning and memory in the HPC and leverages previous experience with some of the techniques applied here. The award proposes a program for expanded training with established basic and translational science experts in circuit, systems, computational, and behavioral neurosciences, to facilitate the PI?s development into an independent physician-scientist investigator focusing on memory dysregulation in neuropsychiatric disorders.
Dysregulation of memory function is often a disabling component of a number of neurological and psychiatric disorders. For example, in patients with PTSD, an innocuous cue might trigger severe symptoms if previous exposure to even a similar cue had been followed some time later by a traumatic event such that the experiences became associated in memory. This project aims to uncover brain circuit activity mechanisms underlying such temporal association fear memories, with the long-term goal of identifying targets for treatment and prevention of psychopathology caused by the dysregulation of fearful memories.
