Therapeutic methods designed to attenuate maladaptive emotional memories are not satisfactorily effective. Disruption of the reconsolidation process has been proposed to be a powerful method to attenuate strong memories in psychopathologies such as PTSD, but numerous studies indicate that strong memories are resistant to becoming destabilized following reactivation. Because of this, viable treatments to therapeutically attenuate maladaptive memories by taking advantage of the phenomenon of reconsolidation updating have yet to be fully developed. Here, we present preliminary data detailing the ability of the FDA-approved drug simvastatin (SV) to enhance the retrieval-dependent destabilization of a strong fear memory. Our proposed experiments will investigate the potential clinical utility of SV, as well as determine the mechanism of action by which SV renders typically modification-resistant circuits modifiable. This work has broad applicability because it investigates both the mechanisms gating induction of plasticity in difficult-to-modify circuits and potential therapeutic methods to intervene on these states.
Aim 1 : Our preliminary data indicate that 5 days of SV treatment prior to fear memory retrieval enhances destabilization of a strong fear memory. Therefore, we propose to assess the ability of SV to enhance destabilization of a strong fear memory by using an animal model of PTSD in conjunction with FDA- approved reconsolidation disruptors.
Aim 2 : SV has been reported to enhance GluN2B surface localization via inhibition of its phosphorylation-driven endocytosis. To determine if inhibition of this process is sufficient to enhance destabilization of a strong fear memory, we generated lenti viruses to express GluN2B(E1479Q) within ?-CaMKII positive BLA neurons in a doxycycline-dependent manner. This allows us to increase surface expression of GluN2B after the memory has consolidated by manipulating the same phosphorylation-driven endocytosis pathway that SV is reported to affect. We show that expression of GluN2B(E1479Q) in the mouse BLA is sufficient to enhance destabilization of a strong fear memory, supporting the hypothesis that SV enhances plasticity by enhancing synaptic localization of GluN2B. Therefore, we propose a suite of biochemical and electrophysiological analyses to determine precisely how SV alters BLA GluN2B trafficking, neurotransmission, and plasticity.
Aim 3 : In this aim, we will determine whether SV exerts its mechanism of action through inhibition of HMG-CoA reductase (HMGCR) pharmacologically by utilizing other statins, and genetically by conditionally and acutely knocking out HMGCR in Floxed-HMGCR mice. Investigating the mechanism of action of SV may lead to discoveries that not only have the potential to affect current therapeutic practice for PTSD, but also for other disorders for which their etiologies involve modification-resistant neuronal circuits (e.g., depression and chronic pain). By advancing our understanding of circuit stability and our ability to modify previously modification- resistant traces, our proposed experiments may lead to the development of novel therapeutic strategies to attenuate pathological symptoms and improve the health of patients suffering from a variety of disorders.

Public Health Relevance

Dysregulation of the fear system is associated with many psychiatric disorders underscoring the need for developing better treatments for pathological fear. This project aims to identify the mechanisms that contribute to the maintenance of pathological fear and provide the basis of a strategy for attenuating maladaptive fear memories.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH120302-02
Application #
9963361
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Driscoll, Jamie
Project Start
2019-07-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas-Dallas
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800188161
City
Richardson
State
TX
Country
United States
Zip Code
75080