Role of NT3/TrkC in the regulation of fear

Overview

Project Summary

Promotion of mental health and well-being is one of the goals within the 2030 global development agenda. Fear is a defense response essential for survival making per se fundamental research aimed at elucidating the underlying physiological mechanisms a priority. Moreover, fear is disturbed in anxiety disorders - the most prevalent mental disorders, especially in Western societies such as the European. In my previous studies, I found that neurotrofin 3 (NT3) and its receptor TrkC play a role in the regulation of fear in a pathological context (in disease), however their role in normality was never investigated. This project aims to study the role of NT3 and TrkC in the formation and extinction of fear, under physiological conditions, and investigate the underlying cellular and molecular mechanisms. Our hypothesis is that proper activation of specific fear circuits in the brain, by means of contextual fear conditioning and fear extinction paradigms, demands for NT3 and TrkC supplies in specific brain regions. Moreover, we hypothesize that NT3/TrkC duo regulate fear memory and extinction by signaling through pathways known for their role in learning and memory, such as the ERK/MAPK pathway. This research project is fundamental by nature. Linking NT3/TrkC with key molecules in learning and memory and specific fear memory processes will put forward a new pathway to be exploited in the future in the promotion of mental health, but also might impart resilience in disorders of disturbed fear, such as posttraumatic stress disorder, panic disorder and a wide spectrum of other anxiety disorders.

Main Goals

This project aims at studying the implications of NT3 and its receptor TrkC in the formation and extinction of fear memory, in physiological conditions, and investigate the underlying cellular and molecular mechanisms. Our hypothesis is that proper activation of specific fear circuits in the brain, by means of contextual fear conditioning and fear extinction paradigms, demands for NT3 and TrkC supplies in specific brain regions. Moreover, we hypothesize that NT3/TrkC duo regulate fear memory and extinction by signaling through pathways known for its role in learning and memory, such as the ERK/MAPK pathway. To address this hypothesis, we propose the following specific objectives:

AIM 1. Monitor the levels of NT3 and TrkC in brain regions of the fear circuit at different phases of fear learning and memory formation, using the contextual fear conditioning and extinction paradigms as classical models to study learning and memory;

AIM 2. Combine rodent behavior with state-of-the-art genetic tools to identify the source of NT3 needed in fear regulation;

AIM 3. Combine rodent behavior with state-of-the-art genetic tools to prove that TrkC is necessary for NT3-induced actions in the regulation of fear;

AIM 4. Perform a MAPK phospho-antibody array to study NT3/TrkC intracellular signaling in the formation of a fear memory.

Project Details