Introduction
The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression.
Understanding the neurobiology of stress by focusing on the specific genes and brain circuits, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. Our laboratory focuses on integrated multidisciplinary projects from gene to behavior using state-of-the-art mouse genetics and animal models. We are employing integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.
Long-term research objectives and expected significance: The long-term goal of our research is to elucidate the pathways by which stress is perceived, processed, and transduced into neuroendocrine and behavioral responses. We are currently studying the CRF/Urocortin family of peptides and receptors as the research model system and examining the hypothesis that this family plays important roles in the modulation of neuroendocrine and behavioral responses to challenge.
Using genetic manipulation in vivo, we recently generated a variety of specific transgenic mice models and viral tools that can be use to generate brain nuclei specific genetic modifications (knockdown, knockout or over-expression of the gene of interest), allowing us to “dissect” the contribution, of each member of this family of stress-related peptides and receptors, to the initiation, maintenance and termination of the central stress response. Molecular, biochemical and morphological analysis of these mice models is followed by stress-linked physiological and behavioral studies
Furthermore, combining the data obtained from these studies with: 1) Gene regulation and gene network studies, aim to explore the molecular mechanisms mediating the effects of CRF/Urocortins receptors activation on downstream genes and proteins, and to elucidate the emerging role of microRNA’s in the regulation of the central stress response; 2) Studying the interactions between the CRF/Urocortin system and the monoaminergic system, especially with the serotonergic system, known to be directly involved in modulating the central stress response; and 3) Elucidating the functional properties of the CRF/Urocortin circuitry, will provide a better understanding of the specific genes and circuitry that involved in initiation or termination the central stress response.
