Gene X Stress Interaction: Epigenetic Mechanisms

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. Only a few specific gene mutations have been directly linked to increased susceptibility for mental illness. Environmental factors — mainly exposure to psychological or physiological stressors — have been associated in epidemiological studies with psychiatric morbidity. For example, stress in utero or during early-life may program brain vulnerability to particular psychiatric disorders, while stress in adolescence or later in adulthood may trigger the onset of such disorders. 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. These mechanisms include histone modification, DNA methylation/ demethylation, and post-transcriptional regulation by non-coding RNAs such as miRNAs and RNA methylation/ demethylation, which are the focus of several ongoing projects in our group. 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.

Stress Linked Psychopathologies

Dysregulation of the behavioral and neuroendocrine responses to stressors can have severe psychological and physiological consequences. A wealth of evidence suggests 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. Current research in the lab focuses on studying the central pathways and molecular mechanisms mediating the stress response and the related psychopathologies. Defining the contribution of known and novel gene products to the maintenance of stress-linked homeostasis could improve our ability to design therapeutic interventions for stress-related psychiatric disorders.

Metabolism and Eating Disorders

Maintaining energy homeostasis in the presence of real or perceived challenges is a complex task, reliant on multiple adaptations in the neuroendocrine and central nervous systems. Energy homeostasis is ultimately governed by the brain, where a variety of incoming signals about the organism’s nutritional state and its external environment are integrated, in order to modulate pathways that control feeding behavior and energy expenditure. Ongoing projects in the lab aim to determine the role of components of the stress system – such as corticotropin releasing factor (CRF) and its two receptors – in such processes, under normal and stressful conditions. Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis could improve our ability to design therapeutic interventions for metabolic disorders and related behavioral disorders.

Complex Behavior

The behavior of an organism is determined by both its genetic makeup and environmental influences. Neurobiological processes play a central role in translating genetic predispositions into complex behavioral traits, as well as in modulating behavior under a variety of conditions. However, these processes are still only partially understood, and bridging the gap between genotype and behavior is one of the foremost challenges in the field of neuroscience. Current research in the lab puts focus on complex social behavior, observing and tracking multiple behavioral readouts in groups of normal or mutant mice under various conditions. This approach allows us to obtain and analyze large amounts of behavioral data in high spatial and temporal resolution. Improving knowledge of the subtle ways in which genes and pathways influence group behavior could lead to better understanding and treatment of disorders affecting social behavior, such as social anxiety disorder and autism.

Early Life Stress

Early life environmental factors affect developing systems and may permanently alter organ structure and function throughout life. The central and peripheral organs that play pivotal roles in the body’s response to stress and the maintenance of homeostasis are key targets for such effects. Substantial evidence links early life stress to the etiology and pathophysiology of anxiety disorders, depression and cognitive dysfunction later in life; for instance, low birth weight that is still within the normal range is associated with a 2-3-fold increase in the prevalence of depression both in childhood and adulthood. Nevertheless, the pathways by which the brain is programmed to translate stressful stimuli into the final, integrated biological response are incompletely understood. Current research in the lab focuses on the brain circuits and genes which are associated with, or altered by, prenatal and perinatal stress, aiming to better understand the brain mechanisms by which early life stress affects psychological and neuroendocrine disorders.

Stress Circuitry and Regulation

The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This complex 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 areas involved in sensory, motor, autonomic, neuroendocrine, cognitive and emotional functions in order to adapt to the demand. At present, the details of the pathways by which the brain translates stressful stimuli into an integrated biological response are only partially understood. We study specific genes and brain circuits which are associated with, or altered by, the stress response, in order to gain a better and broader understanding of the neurobiology of stress. These studies could provide important insights into the way stress affects physiological and psychological disorders.

Weizmann Institute Branch
Arison Neurobiology Building
Room 312, 7610001
Rehovot, Israel
Max Planck Institute of Psychiatry Branch
2-10, 80804.
München, Germany