Exposure to aversive events during the postnatal period increases vulnerability to a variety of psychopathologies. Unpredictability of the early environment (repeated cross-fostering, RCF) has been used in mice as postnatal manipulation to model human early environmental instability. However, it is now clear that the same early life events can produce very different long-term consequences depending on both the genetic make-up and the adult experiences.
Inbred strains of mice provide valuable models for studying the interaction between genetic and environmental factors, and we have previously demonstrated that individuals belonging to DBA2/J (DBA) strain, that appear to be resilient to develop an addiction-like behavioral phenotype, showed an increased sensitivity to anhedonic-like phenotype, thus suggesting an altered response to successive stressful experiences in adulthood, while an opposite phenotype was evident in C57BL/6J (C57) strain mice.
However, the mechanism by which RCF modifies adult phenotype in a genotype-dependent manner is currently unknown.
Based on these data, here we suggest that RCF makes DBA mice more prone to develop a depression-like phenotype when exposed to chronic mild stress in adulthood affecting genes expression in the NAc. The main goal of this project will be to directly investigate the role of two candidate genes (Xlr4a and Xlr4b) in the depression-like phenotype shown by RCF DBA. These target genes were up-regulated in our RCF model of ¿instability of the early environment¿ in DBA mice, and we plan, through an innovative technique based on adeno-associated virus gene therapy, to restore control levels of these genes¿ mRNA and check subsequent effects on the depression-like phenotype. Moreover, an environmental treatment will be tested during development in order to prevent deleterious effects of RCF experience in adulthood. This project represents a first step to explore the translational nature of our results.
The final goal of this project is to set up a therapeutic, environmental strategy to prevent the propensity of some individuals to develop a depression-like phenotype when they have been exposed to early adverse conditions. We intend to reach this ambitious goal by investigating expression and transcription of two genes supposed to be responsible for the long-term behavioral, morphological and neurochemical modifications induced in the mouse, by instability of early environment.
Long term effects of RCF will be evaluated in female mice 1) to stress gender differences, usually neglected in pharmacological studies, 2) based on significant incidence of gender differences in stress related disorders, 3) based on our previous data, 4) to evaluate the transmission of the behavioral phenotype to the next generation, 5) to support the Personalized Medicine approach of Horizon 2020.
Although their influence may be strong and pervasive, early experiences rarely determine the nature and outcome of the psychopathology. Indeed large individual differences exist, probably depending on the genetic make-up, in susceptibility to the impact of early life events on health.
Our preliminary data and the present project aim to extend previous findings suggesting that the interplay between genetic background and early events is not sufficient to forecast direction of behavioral output; we suggest that other factors such as the features of adult events and genes expression modifications should be also taken in account, thus shedding new light on a so complex phenomena such as development/expression of stress-induced psychopathologies. All together, these factors may account for the great variability of behavioral outputs reported in human subjects.
Preclinical studies can shed light on molecular mechanisms responsible for 1) risky genotypes, 2) vulnerability to adverse conditions, 3) characteristics of adversities responsible for the long-term effects.
We initially aim to focus on two candidate genes that are up regulated in our RCF model of ¿instability of the early environment¿ in DBA mice. Through an innovative technique based on adeno-associated virus (AAV) gene therapy, we plan to restore control mRNA levels of these genes and check subsequent effects on the depression-like phenotype.
In addition, the application of an environmental enrichment during development represents a potential rescue treatment, easily valuable in the mouse. This innovative treatment (father presence) is proposed based on really recent evidence indicating that paternal behavior can strongly affects development and produce long-term effects in different species (23). Whether the stable presence of other conspecifics during the cross-fostering period could prevent up regulation of Xlrs expression, a simpler and preventing strategy could be suggested to reduce the expression of depression phenotype in adulthood. This ¿environmental treatment¿ is not far from ¿psychological therapies¿ conducted during adolescence in children exposed to unstable environments. Moreover, collection of changes in genes expression data would give the possibility to have an additional molecular parameter to monitor risky period in infancy. This could allow to predict the efficacy of the ¿psychological therapy¿ and, maybe, to select the right one, able to change gene expression. We are not aware of which stimuli of the social environmental enrichment have exerted positive effects in our previous studies (24) (surplus of olfactory/visual/tactile stimulation received by pups, the greater thermoregulatory component, reduced stress condition of the dam). Whatever the mechanism, the possibility to evaluate the role of the father (or of the second female) on mother-pups bond instability could help to focalize on relevant factors reducing the instability of the early environment.
Depression is a major contributor to the global burden of disease and disability. According to the World Health Organization survey, the relatively high lifetime prevalence of depression ranges from 2% to 15% around the world. It costs $150 billion per year, according to the latest survey in the United States. Several physiological systems are involved in the pathophysiology of depression, such as the alteration of monoamine system, dysregulation of the hypothalamus pituitary adrenal (HPA) axis, and imbalanced cytokine system (17). The comprehension of mechanisms behind depression-like phenotype in animal models could represent a first step explore the translational nature of our results. The possibility to increase welfare as well as reduce costs and dangers for the entire society should represent the final goal of each preclinical research.