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Dissecting the Central Stress Response: Bridging the Genotype-Phenotype Gap

Final Report Summary - EURO-NEUROSTRESS (Dissecting the Central Stress Response: Bridging the Genotype-Phenotype Gap)

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 not completely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is substantial 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, depression and metabolic-related disorders. 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.
During the last 5 years since receiving the ERC kind support, we have been using advanced mouse genetics and viral tools to “dissect” the contribution of different members of the corticotropin-releasing factor (CRF)/ Urocortin family of peptides and receptors, expressed at different brain nuclei and cell types, to the complex regulation of the central and neuroendocrine stress response. In a series of studies, we demonstrated novel and deeper mechanistic insights into the central role of selected CRF/ Urocortin family members in mediating variety of normal and abnormal behaviors and physiological changes, including anxiety / posttraumatic stress disorder (PTSD)-like behavior, social approach and avoidance behaviors and metabolic/energy expenditure changes, in response to different stressful challenges. In addition to manipulating the levels of these family members in specific brain nuclei or neurons-types, our more recent studies also involve the use of optogenetics and chemogenetics approaches that significantly add to our understanding of the importance of these neurons’ activity in mediating the behavioral and physiological responses to stressful challenges.
Most psychiatric disorders display a strong genetic component, but heritability by itself can only partially explain an individual’s risk to develop a mental disorder. Environmental factors — mainly exposure to psychological or physiological stressors — have been associated in epidemiological studies with psychiatric morbidity. Thus, a complex interaction between genetic predisposition and environmental factors is suggested to be at the root of mental illness. Environmental factors can, through epigenetic mechanisms, induce changes in gene expression levels that might mediate the onset of a disease without altering the DNA sequence. In a series of recent and detailed studies, we demonstrated the importance and involvement of several miRNAs in the regulation of the central stress response and stress-linked psychiatric disorders. Elucidating the role of epigenetic processes in mediating central nervous system functions may promote a better understanding of the pathophysiology and neurobiology of psychiatric disorders and could thereby promote the much needed breakthroughs in the development of new drug targets and biomarkers for these illnesses.