Early aversive events are known to increase the risk to develop psychiatric disorders later in life, although they rarely determine alone the nature and outcome of the psychopathology. However, it has been suggested that early life experiences could have negative consequences (vulnerability) or also confer adaptive value (resilience) in different individuals. We have recently demonstrated that Repeated Cross Fostered (RCF) pups by C57BL/6J (C57) strain show increased sensitivity to cocaine effects and, unexpectedly, increased resilience to depression-like behavior, two phenotypes related to the dopaminergic mesolimbic system function. This brain circuit includes the ventral tegmental area (VTA) and the Nucleus Accumbens (NAc) areas.
In addition, RCF animals also show altered DA release in NAC in response to different events (stress, cocaine) in adulthood.
All together, these data suggest that long-lasting effects induced by our early manipulation within VTA, the area from which this circuit arises, could explain the behavioral and neurochemical effects observed in RCF animals.
We have demonstrated a critical involvement of dopaminergic neurons of ventral tegmental area (VTA) in the phenotype observed. The goal of this project is to investigate if and how these neurons contribute to the resilience to depression-like phenotype induced by chronic stress (and, maybe, to increased cocaine sensitivity) by pharmacologically modulating their activity.
Recently, there is a growing interest in the concept of the ``susceptibility¿ and ``resilience¿ to depression induced by stress exposure. The main answer is: why do some people become depressed (i.e., susceptibility to depression), while others are not (i.e., resiliency to depression) following stressful life events? Resilience is in recent years considered to be a positive coping process from adverse stress instead of a lack of alterations.
Within this framework, the final goal of this project is to investigate the neurobiological basis of resilience to depression-like phenotype as well as the increased sensitivity (resilience) to cocaine effects observed in our animal model (RCF) following chronic stress exposure in adulthood. We would like to uncover new molecular targets in order, in the future, to set up a therapeutic strategy to rescue/prevent the propensity of some individuals exposed to early critical conditions, to develop an addiction-like phenotype when facing with adult stress events and, in addiction to actively promote resilience to stress-induced depression.
We will test the hypothesis that reduced ih current and firing observed in VTA DAergic neurons of RCF animals is responsible for both phenotypes. To test this hypothesis, Control animals will be subjected to chronic (4 days) intra-VTA infusion of ZD7288 to induce long-lasting changes of ih and firing in VTA DAergic neurons.
Although some really recent studies investigated the role of VTA DAergic neurons ih current and firing in depression-like phenotype induced by ¿contingent¿ stress exposure, our study is the first one evaluating the long-lasting effects of an early life manipulation of VTA DAergic neurons ih current and firing supposed to be involved in resilience to depression and sensitivity to cocaine.