Although early aversive postnatal events are known to increase the risk to develop psychiatric disorders later in life, rarely they determine alone the nature and outcome of the psychopathology, indicating that interaction with genetic factors is crucial for expression of psychopathologies in adulthood. We have recently showed that Repeated Cross Fostering (RCF, Fig 1) experienced by pups affected the response to a negative experience in adulthood in opposite direction in two genotypes leading DBA2/J, but not C57BL/6J (C57) mice, toward an "anhedonic-like" phenotype. In contrast, individuals belonging to C57 strain, that appear to be resilient to develop an anhedonic-like behavioral phenotype, showed an increased sensitivity for a natural reinforcing stimulus, thus suggesting an enhanced response of the reward system to pharmacological stimuli (drugs of abuse).
Based on strong preliminary data, here we suggest that RCF makes C57 mice more prone to develop an addiction-like phenotype in adulthood by affecting genes expression in the NAc.
The main goal of this project will be to directly investigate the role of candidate genes in the addiction-like phenotype shown by RCF C57. We have till now selected two target genes, down regulated in our RCF model of "instability of the early environment" in C57 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 addiction-like phenotype. Moreover, pharmacological treatments will be tested to counteract deleterious effects of RCF experience in adulthood. Understanding and rescuing the mechanisms responsible for early stress-induced drug addiction-like phenotype in our RCF mouse model, could represent a first step to investigate other forms of addiction and explore the translational nature of our results.
Several studies have reported the effects of early postnatal experiences on increased sensitivity to drugs of abuse later in life (10,32-34), probably affecting catecholaminergic cortical-accumbal system (35-38).
Preliminary data suggest that adult mice previously exposed to RCF experience show a greater sensitivity to cocaine than their Controls (CPP results) (Fig 2) suggesting that RCF mice could show an addiction-like phenotype when exposed to drugs of abuse in adult life.
The main goal of this project will be to investigate the role of two candidate genes (Xlr4a and Xlr4b) on postnatal stress-induced addiction-like phenotype in order to set up a therapeutic strategy to rescue the propensity of some individuals to develop an addiction-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 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 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 down regulated in our RCF model of "instability of the early environment" in C57 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 addiction-like phenotype. The results of the systemic AAV treatment could provide a strong translational value to this project whether stable molecular, morphological and behavioral data would confirm results obtained by in situ (intra-NAc) treatment.
The comprehension of mechanisms behind addiction-like phenotype is important because of the implication of drug addiction in our society that not only affects physical health, but also induces problems related to criminality, education and others. Moreover, because the malfunctioning of the motivational system resulting in addiction like-phenotypes may be the same whatever the reward stimulus is involved (food, alcohol, sex, gambling...), understanding and rescuing the mechanisms responsible for early stress-induced drug addiction-like phenotype in our RCF mouse model, could represent a first step to investigate other forms of addiction in the animal models and to 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.
26 Cubelos B, Nieto M 2010 Com Integr Biol 3:483-6
27 Graham DL et al., 2007 Nat Neurosci 10:1029-37
28 Lo Iacono L et al, 2015 Transl Psych 5:e629
29 Truchet B et al, 2012 Learn Mem 19:282-93
30 Andolina D et al, 2016 Neuropharm 107:305-16
31 Weinberg MS et al., 2013 Neuropharm 69:82-8
32 Kosten TA et al. 2003 Brain Res Dev 141:109-116
33 Meaney MJ et al, 2002 Psychoneuroendocrin 27:127-38
34 Zhang XY al, 2005 Psychopharmacol 177:391-99
35 Brake WG et al, 2004 Eur J Neurosci 19:1863-74
36 Gatzke-Kopp LM 2011 Neurosci Biobehav Rev 35:794-803
37 Moffett MC et al, 2007 Biochem Pharmacol 73:321-30
38 Romano-López QF et al, Dev Neurobiol 76:819-31