Exposure to early life stress (ELS) can alter trajectories of brain maturation and induce susceptibility to develop substance use disorder. ELS produces dysfunction in the dopamine (DA) system, which is involved in the responses to drugs of abuse. More recently, it has been shown that ELS has strong effects on the immune system, including activation of microglial cells. Microglia, the immune cells of the brain, play a major role in shaping and refinement of circuits during development. Recent evidences demonstrated that microglia directly contribute to the correct development of the DA system and DA-dependent behavior.
Given this, I hypothesized that ELS-induced immune responses underlie an altered development of the DA system. This may be the mechanism which confers susceptibility towards the effects of addictive drugs later in life.
To test this hypothesis, I will use a murine model of early life social stress (SS), characterized by increased microglial reactivity in pups and sensitivity to cocaine in adulthood. I will perform experiments at two different time points: 1. after the stress, to evaluate what happens in the DA system when microglia are particularly reactive and 2. early adulthood, to evaluate the adaptive consequences of the stress on the brain. First, I will explore differences between SS and control mice by gene expression analysis of mediators of DAergic transmission, such as metabolic and catabolic enzymes, DA receptors and transporter in key areas of the mesocorticolimbic system. Then I will compare expression analyses in SS mice treated with minocycline, an inhibitor of microglial/immune activation, to explore whether gene expression changes are dependent on SS-induced microglial activation. Finally, I will evaluate differences on a protein level by performing immunofluorescence and confocal microscopy analyses with targeted antibodies on brain sections.
CM is one of the leading causes of the susceptibility to develop SUD later in life (Dube et al., Pediatrics, 2003). Both human and animal studies have shown that early childhood adversities induce alterations in the formation of the DA system, which is a prime candidate to explain ELS-induced SUD. However, the causal mechanisms of these alterations are still not clear. Existing theoretical frameworks have suggested that ELS directly acts on DA networks, which respond in a dynamic and interactive way and undergo adaptive molecular and functional changes that may increase the vulnerability of the individual to psychopathologies (Gatzke-Kopp, Neurosci. Biobehav. Rev. 2011). Nevertheless, in this framework much remains to be elucidated with regard to what specifically affects functional variation in receptor subtypes, reuptake mechanisms, and receptor sensitivity, and how changes in these processes influence developmental trajectories within the mesolimbic system. It is of paramount importance to establish who are the actors in this situation; this would not only provide crucial information on the etiology of psychopathological risk following childhood adversities, but also give insight in brain development pure research.
In this project, based on literature evidences and preclinical data recently acquired from our group of research, I propose the immune system, and in particular microglia, as the mediator of ELS-induced altered development of the DA system. To my knowledge, this is an innovative, new hypothesis that has not been explored yet. Indeed, existing research has focused on the effects of ELS on these two systems separately, without investigating the interactions between them.
Results from this project will advance knowledge on the role of the immune system in abnormal development of the brain following early adverse environmental conditions. Moreover, they would provide further information to understand mechanisms of altered brain maturation in the context of ELS with the long-term aim of discovering possible therapeutic targets for children/adolescents with a history of maltreatment. Finally, these data will be a starting point to further explore the role of ELS-induced susceptibility towards the effects of addictive drugs.