Attenuation of ethological traumatic memories

Introduction

Traumatic experiences generate among the strongest memories that can result in trauma-related disorders. Despite the high prevalence of these disorders, effective treatment options are scarce, calling for a deterministic understanding of the neuronal mechanisms underlying traumatic memory attenuation.

Current Research Methods

For this, rodent studies classically use fear extinction paradigms where aversive experiences are modeled with the exposure to an electrical foot shock. However, the simple nature of this stimulus does not mirror the complexity of traumatic events in humans, which is likely to be processed by equally complex networks.

Proposed Investigation

Here, I propose to investigate for the first time the neural circuits underlying the extinction of traumatic memories induced by exposure to naturalistic threats, namely, predators and aggressive conspecifics.

Research Objectives

1. Comprehensive Atlas Creation
   First, we will compile a comprehensive atlas of brain activity underlying the extinction of these ethological traumas and generate network organization models, which will be causally probed by pathway-specific chemogenetic manipulations.

2. Connectome Characterization
   Second, we will characterize the functional input-output connectome of ethological extinction centers using a combination of viral tracing, neuronal activity, and optogenetically assisted circuit mapping.

3. Mechanism Analysis
   This set of data will, third, provide the substrate for the study of the neurophysiological and molecular mechanisms underlying efficient extinction of ethological traumas, which will be analyzed by:

   • Pathway-specific in-vivo Ca2+ imaging
   • Closed-loop optogenetics
   • Ex-vivo electrophysiology
   • RNA sequencing

4. Investigation of Extinction Deficits
   Lastly, we will investigate whether impairments at the level of these newly identified networks underlie extinction deficits at the basis of trauma-related disorders.

Conclusion

Together, these results will pave the way for the identification of novel therapeutic targets for trauma-related disorders and shed light on how the brain can flexibly update complex memories.