Post-Traumatic Stress Disorder (PTSD) is a severe and debilitating disturbance with a lifetime prevalence estimate of 0.3% to 6.1%. Although it is amongst the very few mental diseases with a recognized pathogen -the experience of an extreme stressful event- the psychobiological processes leading to PTSD are still poorly understood. The search for intermediate phenotypes (IPs) -specific brain-based pathophysiological mechanisms leading to altered brain function and specific symptoms- has been recently proposed as a promising strategy. The proposed research is aimed at identifying IPs underlying persistent relapses of trauma-related memories in PTDS using a translational approach.
The first year of this 3-years project will be dedicated to the development of an animal model of a recognized PTDS pathogenic trajectory in mice. The pathogenic trajectory to be modeled is based on clinical and preclinical evidences supporting an interaction between sex, early childhood adversities, and proximal trauma in the development of severe re-experiencing symptoms and higher levels of physiological reactivity to trauma recalling. The model is based on preliminary results indicating that the experience of an unstable maternal environment (repeated cross-fostering [RCF]) moderates stress-induced neuroplasticity within the medial pre-Frontal Cortex (mpFC) of adult C57BL/6 mice sex-dependently. Indeed, learning- induced plasticity in mpFC is involved in acquisition and extinction of fear-related memories in either human or non-human animals.
In the first year we plan to perform the following experiments: 1. Test the effects of a proximal acute stress on acquisition and extinction of conditioned fear in RCF adult male and female mice; 2. Test the hypothesis of a parallel influence of estrogens on behavioral and neuroplastic effects of stress in RCF adult female mice.
Although PTSD is a diffuse and debilitating mental disease fostered by traumatic experiences, its psychobiological determinants are still poorly understood. One way to identify these mechanisms is to search for translationally meaningful IPs -intermediate phenotypes measurable in animal models as well as in human subjects- that are associated with specific behavioral and neural outcomes of adaptation to a severe stressful experience.
We propose a fully translational research project aimed at testing a candidate IP.
Indeed, the project is based on an animal model that reproduces a PTSD pathogenic pathway strongly supported by the clinical findings, i.e. sex-specific influences of early adverse experiences on adaptation to a severe stressful experience in adulthood. Preliminary data collected in this model point to mpFC-amygdala connectivity as the main target of the pathogenic pathway and this phenotype is certainly translationally meaningful because of its implication in emotional regulation in both human and non-human animals.
The project research plan proposes an approach in two steps that will lead to testing candidate IPs identified in the animal model in human subjects. A first step will identify the pattern of functional and structural connectivity associated with severe impairment of long-term extinction of conditioned fear in male and female mice. The second step will identify cognitive phenotypes capable of predicting the development of this dysfunctional neuroadaptation to stress challenge. We will search for cognitive phenotypes associated with frontocortical functioning because stability of acquired extinction, frontocortical functioning, and mpFC-amygdala connectivity are characterized by parallel maturational windows during early postnatal and late adolescence in different mammalian species. Moreover, cognitive phenotypes can be used to evaluate functional and structural connectivity in human subjects allowing for successful translation of the neurobiological findings from the animal model.