Exposure to highly stressful life-threatening events that elicit an intense response of fear and helplessness causes in some individuals an enduring reaction known as post-traumatic stress disorder (PTSD). Although PTSD is one of the few mental disorders whose triggering cause is known, we have a very limited knowledge of the biological mechanisms underlying its development, and what differentiates resilient and susceptible individuals. As a result, no clearly effective pharmacological treatment, nor preventive strategy, or reliable biological markers are currently available. Increasing evidence links the cerebellum to depression e PTSD. Recently, structural and functional alterations have been reported in the cerebellum of PTSD patients. This structure is well known for its role in the control of movements and motor learning, but it is often overlooked by the literature on the neural basis of stress response.
The main objective of this project is to investigate cerebellar contribution to traumatic stress response by analyzing long-term molecular, structural and functional changes in the cerebellum of stress-resilient and stress susceptible individuals, in a preclinical model of PTSD. Using a multidisciplinary approach, we propose 1) To determine whether exposure to a traumatic stress induces long-lasting alterations in stress response pathways and gene expression in the cerebellum; 2) To study stress-induced morphological and functional remodeling of cerebellar neural circuits, including expression of synaptic cell-adhesion proteins.
Exposure to traumatic events such as a natural disaster, a serious car accident or a sexual or physical assault, can be associated with the development of PTSD, a clinical syndrome characterized by persistent and exaggerated stress-related reactions. People with PTSD also manifest other problems including feelings of hopelessness, depression or anxiety, physical symptoms and chronic pain, relationship and employment difficulties, and often turn to drinking or drug abuse. Together, these symptoms constitute a complex syndrome that severely jeopardizes daily life of affected subjects and turns into elevated costs for the national health system.
Recently, the European Commission estimated the total cost of brain disorders in the Union at EUR 800 billion and recognized mental health disorders as one of the major causes of disability, ill-health and premature death in the Union. Although mental health is of great importance to individuals and societies, our little basic understanding of the biological basis for normal and pathological mental functions makes it difficult to adopt rational strategies to improve mental health.
PTSD symptoms may appear even months or years after a traumatic event, but importantly not all people exposed to a trauma develop PTSD over time. The reason for this dichotomy is still unclear, but it may be linked to external factors such as intensity and duration of the traumatic event, as well as to differences in individual's responses. Available treatments for PTSD include psychotherapy, antidepressant medications or a combination of the two. Although helpful in many cases, these treatments target the clinical symptoms rather than the processes leading to PTSD development. For example, cognitive behavioral therapy is being widely used in the clinics to treat PTSD, but it has been shown to be effective only in 60% of PTSD-affected veterans. There is a critical lack of deeper understanding of PTSD etiology, which is essential to aid the identification of novel and effective pharmacological targets. The understanding of factors contributing to individual responses becomes then of pivotal importance for the development of novel therapeutic approaches to PTSD.
Using a multidisciplinary systems approach, this project aims to advance our knowledge of the biological basis of the response to traumatic stress bringing together two key elements: i) analysis of stress-induced changes in the cerebellum, a region often overlooked by stress-related literature, but with an emerging role in PTSD; and ii) evaluation of long-lasting individual differences in the response to traumatic stress. The results of the experiments described in this proposal could be significant for informing future human studies, providing novel candidate targets for the prevention or clinical treatment of the disease.