Targeting Dentate Gyrus to Disrupt Fentanyl-Linked Context Memories

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Addiction is a chronic, relapsing disorder, characterized by persistent drug-taking behavior despite negative consequences. New therapies are needed that prevent relapse.One trigger for relapse is the context where drug use previously occurred. When a rewarding drug is taken in a particular context, a “reward-context memory” can be formed. Reward-context memories are powerful; placing a human or rodent back into a reward-linked context can provoke drug craving. Disruption of reward-context memories is thought to prevent addiction. However, to disrupt reward-context memories, we have to first understand their neural basis.The neural basis of reward-context memories can be informed by literature on fear-context memories. Fear-context memories are reliant on the hippocampal dentate gyrus (DG) and a discrete population of DG context memory cells—termed an “engram”. Inhibition of DG fear-context memory engrams disrupts fear memory recall. It is unknown whether the DG is a site of reward-context engrams or if inhibition of the DG disrupts reward-context memory recall. Stimulation of the DG prior to context-fear memory encoding enhances fear-context memory. It is unknown if stimulation of the DG prior to reward-context memory enhances reward-context memory recall. My objective is to assess if DG reward-context memories can be manipulated, with the long-term goal of diminishing the salience of context cues and preventing relapse. The Aims of this proposal are to 1) test if DG neurons active during reward-context memory encoding can be inhibited during re-exposure to the reward-context, reducing or inhibiting drug-linked context memory recall and 2) determine if stimulation of DG neurons during reward-context memory encoding improves drug-linked context memory recall. When completed in two years, these experiments will determine whether or not the DG can serve a novel therapeutic target for diminishing the salience of drug-context memories. Further, regardless of experimental outcome, we will be able to elucidate novel properties of reward linked memories. Starting my postdoc during Covid-19 and moving into a new field (from context fear memory to addiction), it took time for me to establish a baseline knowledge and generate pilot data in order to develop these aims. Through this fellowship, I will accomplish defined Training Goals: learn hippocampal circuit manipulation, develop expertise in the field of substance abuse in the context of disordered learning/memory, use machine learning for the characterization for reward behaviors, and gain further professional development skills including project and personnel management. I have a supportive and ideal mentoring team (Drs. Amelia Eisch and Julie Blendy) to guide my training of both conceptual and technical skills. At the Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, I have exceptional resources and a stimulating environment in which to accomplish these goals.The completion of these Aims, and the training provided within, will provide the foundation for my path to becoming an independent investigator at an academic institution.