Clinical and preclinical studies have highlighted how exposure to aversive events during sensitive developmental periods increases the expression of several stress-related psychiatric disorders later in life, such as depression. However, fortunately only a limited proportion of people exposed to early life adversity develop depression, while other show potentiated resilience.
Why do some individuals become depressed when exposed to early stressful life events while others do not?
Critical early life experiences can have detrimental or beneficial effects on development depending on interaction between genetic and environmental factors.
Early experiences strongly impact the reward brain circuit, a system critically involved in processing of motivational stimuli. We have previously demonstrated that exposure to a postnatal stress (Repeated Cross Fostering (RCF)) induces in C57BL/6J (C57) female mice increased resilience to depression-like phenotype in adult life, as well as an altered response of the preFrontal Cortex-Nucleus Accumbens DA system (one of the most important targets of VTA DA neurons) to motivational stimuli.
Interestingly females of a different inbred strain, DBA2/J (DBA) show opposite behavioral and neurochemical patterns following RCF exposure, leading to increased vulnerability to depression in adults.
Our preliminary electrophysiological data show that resilience observed in RCF C57 animals is related to reduced neurons excitability of dopaminergic neurons in VTA. Based on these results, we predict to find an opposite electrophysiological profile (increased excitability) in VTA DA neurons of RCF DBA mice.
We will also use a pharmacological approach to revert the behavioral and electrophysiological phenotypes observed in both strains modulating excitability of dopaminergic VTA neurons.
The goal of this project is to investigate the role of VTA DA neurons in entering resilience or vulnerability to early stress-induced depression.
The main goal of this project is to investigate if and how VTA DA neurons contribute to resilience and vulnerability to depression-like phenotype in animals early exposed to aversive experiences.
We intend to reach this ambitious goal by investigating the neurobiological basis of the divergent modifications induced by instability of early environment (RCF) in two different inbred strains of mouse, thus investigating gene x environment interaction in depression.
Long-term effects of RCF will be evaluated in female mice 1) to investigate a gender often neglected in psychobiological studies, 2) based on significant incidence of gender differences in stress related disorders, 3) based on our previous data, 4) to support the Personalized Medicine approach of Horizon 2020.
Our preliminary electrophysiological data show reduced VTA DA neurons excitability in RCF C57 animals (characterized by increased depression resilience) compared to Control group, thus supporting long-lasting effects of early postnatal experience on this brain area.
Based on these observations, we next hypothesize that RCF induces an opposite effect on VTA DA neurons of RCF DBA animals showing increased depression susceptibility.
Moreover, we also hypothesize that electrophysiological patterns shown by C57 and DBA RCF animals contribute to their opposite behavioral phenotypes (resilience vs. vulnerability to depression). Using a pharmacological approach, we will reduce ih current and neuron excitability by local bilateral infusion of an ih inhibitor (ZD7288), into the VTA of DBA animals and, conversely, we will increase excitability of VTA DA neurons in C57 RCF animals. We expect that these treatments will be able to revert both electrophysiological VTA DA neurons activity and behavioral phenotype of both strains early exposed to RCF.
Early experiences influence developmental trajectories during maturation of the brain and can have a wide range of long-lasting effects (23,32,33). Notably, early life adversity can also confer resilience to cope with stressful adult events (21). However, mechanisms through which early life events affect the response to motivationally salient stimuli and promote vulnerability or resilience to psychopathological outcomes later in life are incompletely understood (2,21,22).
Animal models can be studied to identify factors of vulnerability and resilience to stress-induced psychopathologies, and rodents remain the gold-standard organism to uncover new disease mechanisms(2).
Recently, several evidences suggest neurophysiological adaptation in the brain¿s reward neural circuit as one of the mechanisms underlying susceptibility and resilience to depression (12-17). The VTA is one of the most important brain areas of motivation and reward circuitry. Since altered reward circuit function is theorized to underlie the loss of pleasure and ¿amotivational syndrome¿, two of the symptoms experienced by depressed patients, this brain region as well as its connectivity with other areas of the reward circuit, including the medial preFrontal Cortex and Nucleus Accumbens, have been deeply investigated in both animal models of depression-like behavior and in depressed patients (1,3).
Interestingly, altered VTA DA neuron firing has been suggested to be involved in both development of maladaptation leading to depressive-like phenotypes and in the adaptations leading to resilience (7,11, 13-17), supporting the notion that too much or too little VTA DA neurons activity contribute to depression phenotype and, most importantly, strongly suggesting resilience as an active neurophysiological process.
Accordingly, recent findings have proposed the reward circuitry as a target for antidepressants capacity to actively promote resilience (6) and, notably, it has been recently suggested that antidepressant efficacy may be related to its capacity to normalize VTA DA neurons activity in depressed individuals (3).
Overall, results from this project support the evidence that early experiences impact DA neurons excitability and functioning within VTA, the main node of reward brain circuit. This could strengthen the idea that altered VTA DA neurons represents the neurobiological substrate of resilience and vulnerability induced by early experiences.