Synaptic Plasticity within Neural Circuits Critical for Fear Memory Retrieval

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Project Summary / Abstract Memory formation, storage, and retrieval are critical components of healthy well-being, and dysfunction in these processes can lead to devastating health problems. The long-term goals of this project, which are in parallel with the training goals of this proposal, is to advance our understanding of the relationship between protein degradation through the ubiquitin-proteasome system (UPS) and the stability of memory and synaptic plasticity within specific brain circuits. The UPS is a major regulatory pathway that is responsible for the recognition and clearance of abnormal or damaged proteins, while memory destabilization (i.e. reconsolidation) refers to the process by which a previously consolidated memory can be destabilized by memory retrieval. In this proposal, we will identify how activity within select neural circuits affects both protein degradation and memory destabilization processes, as measured through quantification of α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor subunits, following fear conditioning (FC) memory retrieval. One neural circuit important for FC memory retrieval is the prelimbic (PL) cortex-lateral amygdala (LA) circuit. In Aim 1 (Experiment 1), we will determine if selective inhibition of PL-to-LA neuronal projections during fear memory retrieval is sufficient to affect behavior, UPS activity, AMPA receptor subunit expression, and other AMPA receptor-associated proteins at LA synapses. The goal of Aim 2 is to determine the functional role of the ventrolateral periaqueductal gray (vlPAG) in a larger vlPAG-PL-LA circuit, particularly at the level of LA synapses. In Exp. 2, we will test whether silencing vlPAG-to-PL projections is sufficient to affect behavior, UPS activity, AMPA receptor expression, and the expression of other proteins at LA synapses. Finally, in Exp. 3, we will test whether silencing PL-to-vlPAG projections is sufficient to affect these same measures. In all experiments we will also perform fluorescent in situ hybridization on tissue collected from the LA, PL, and vlPAG to characterize the cell types involved in these projections. In all three experiments we will use a dual-virus, Cre- dependent inhibitory optogenetic approach and silence these projections with a laser during FC memory retrieval, and brains will be collected for biochemical analysis of brain tissue. This approach will allow us to determine if silencing these projections is sufficient to affect behavioral performance, proteolytic activity, and memory destabilization processes. This work is innovative because little has been done to characterize the relationship between protein degradation and memory destabilization within select neural circuits essential for emotional memory functioning. Furthermore, little work has been done to determine the functional role of vlPAG feedback to cortical regions during the retrieval of a fear memory. Finally, this work is significant because these findings will advance the understanding of protein homeostasis, memory destabilization, and neural circuits, which will provide new directions for the treatment of debilitating memory-related mental health disorders.