Transient inactivation of hypothalamic hormone release to prevent post-traumatic stress sensitization

Introduction

Stress is the foremost consequence of human life and has become a pressing societal burden through the many sensory and societal pressures that have evolved during the past decades. Severe stress induces maladaptive changes in the brain that clinically manifest as post-traumatic stress disorder (PTSD).

Prevalence and Current Treatments

Despite approximately 4% of the population presenting PTSD, only symptomatic therapies are available.

Research Overview

In the SECRET-CELLS ERC award, we have identified a multimodal neurocircuit that induces brain-wide sensitization to stress through the sequential recruitment of hypothalamic, midbrain, and then cortical neuronal circuits.

Protein Targets

Particularly, we identified protein targets that can simultaneously affect hormone and neurotransmitter release within this circuit, and whose knock-out makes mice stress resilient.

Methodology

1. Proteomics: We used unbiased proteomics to select protein interactors that participate in the related signaling cascades.
2. Biochemical Parameters: We determined the biochemical parameters of any such interaction and the X-ray structures of the relevant protein complexes.
3. High-Throughput Screening: A high-throughput screen was established to identify inhibitors.

Application of Knowledge

Here, we will apply this knowledge to use interacting proteins as templates for small-molecule inhibitor discovery and hit optimization.

Pharmacological Profiling

Subsequently, we will profile the pharmacology and cytotoxicity of the candidates in vitro.

Conclusion

Thus, we will take critical steps towards developing a circuit breaker that can inactivate the neuronal contingents that are causal to the development of PTSD. Thereby, we will offer a fundamentally novel framework for pharmacotherapy.