Characterizing opposing BNST to VTA circuits that differentially regulate motivation and individual responses to stress

Descripción del proyecto

Nueva información biológica sobre la ansiedad relacionada con el estrés

El estrés cotidiano puede afectar de manera diferente a las personas, de forma que algunas presentan respuestas patológicas, como ansiedad y depresión. Es bien sabido que la ansiedad está correlacionada con la respuesta de las neuronas dopaminérgicas a la hormona de liberación de corticotropina inducida por el estrés. El proyecto financiado con fondos europeos MotiVTA trabajará en dos vías neuronales recién identificadas que también influyen en la ansiedad. El equilibrio entre estas dos vías parece afectar a la liberación de dopamina e incrementa la motivación como respuesta al estrés. Los investigadores del proyecto emplearán distintos métodos para observar y manipular estas vías y aclarar su implicación en la respuesta de ansiedad.

Objetivo

In our daily life, we face many challenges that create stressful situations. Some individuals experience stress as motivational drive, whereas in others, it can reduce motivation and trigger avoidance behavior. Pathological responses to stress, such as depression and anxiety, take an enormous toll on society. Despite the relevance of stress on mental health, little is understood about the neuronal circuit mechanisms that underlie the behavioral differences in stress responsivity and why some individuals are more resilient to the negative impact of stress than others. The mesolimbic dopamine system plays a major role in the stress response. Work in the host lab found that trait anxiety influences how an individual’s motivated behaviors change with stress and that the anxiety level correlates with differences in the response of dopamine neurons in the ventral tegmental area (VTA) to the stress-induced neuropeptide CRH. Recently, two parallel pathways from the basal nucleus of stria terminalis (BNST) to the VTA –one glutamatergic and the other GABAergic– have been identified and are thought to influence anxiety and motivated behaviors. However, solid evidence linking activity in these pathways to behavioral outcomes is lacking. The goal of this proposal is to monitor and manipulate the activity of these pathways using a combination of optogenetics, calcium imaging, and behavioral testing. I hypothesize that the glutamatergic and GABAergic BNST-VTA pathways are differentially engaged during stress. The balance between these pathways modulates dopamine release from the VTA, which then determines whether an individual would experience increased or decreased motivation in response to stress. I will first determine the natural activity pattern of VTA-projecting BNST neurons and then investigate the consequences of activation or inhibition of this circuit on motivated behaviors and the role of CRH in the modulation of this circuit using genetic tools and neuropharmacology.