Effects of early life stress on biochemical indicators of the dopaminergic system: A 3 level meta-analysis of rodent studies

Abstract

Adverse early life events are a well-established risk factor for the precipitation of behavioral disorders characterized by anomalies in the dopaminergic system, such as schizophrenia and addiction. The correlation between early life conditions and the dopaminergic system has been causally investigated in more than 90 rodent publications. Here, we tested the validity of the hypothesis that early life stress (ELS) alters dopamine signaling by performing an extensive 3-level mixed effect meta-analysis. We included several ELS models and biochemical indicators of the dopaminergic system in a variety of brain areas, for a total of 1009 comparisons. Contrary to our expectations, only a few comparisons displayed a significant effect. Specifically, the striatal area was the most vulnerable, displaying decreased dopamine precursor and increased metabolites after ELS. To make all data openly accessible, we created MaDEapp (https://osf.io/w25m4/), a tool to explore data of the meta-analysis with the intent to guide future (pre)clinical research and allow power calculations. All in all, ELS induces a few yet robust changes on biochemical indicators of the dopaminergic system.

The behavioral phenotype of early life adversity: a 3-level meta-analysis of preclinical studies

“…The lack of sufficient power to detect experimental effects is an emerging issue in preclinical literature (22,30) that seriously hampers research interpretation (22). As a consequence, results from singlestudies are useful for hypotheses generation but do require replication.…”

“…In this project, we intertwine this concept with state-of the-art statistical methodology, adopting an approach never used in preclinical studies. Firstly, our meta-analysis was built with a 3-level model (32), which allows for a more robust estimation of the effects by accounting for the dependency of same-animal's data (30,50). Secondly, a leading strength of preclinical meta-analyses is the systematic exploration of heterogeneity (49).…”

“…S1.6 details the extraction of statistical information as well as handling of missing values. We estimated the summary statistics of data presented only graphically with Ruler for Windows (https://a-ruler-for-windows.en.softonic.com/), of which we previously validated the accuracy (30). If the data was not reported in any format (or other crucial information was missing e.g.…”

“…In our experimental design, the 3 levels correspond to variance of effect size between 1) animals, 2) outcomes and 3) experiments. This approach accounts for the violation of the assumption of independency when the data is collected from the same animals (30)(31)(32), thereby improving the robustness of the conclusions drawn. We included "domains" and "hits" as moderators in order to address the following two research question: 1) what are the effects of ELA on each behavioral domain?…”

Vulnerable and resilient cognitive performance related to early life stress: The potential mediating role of dopaminergic receptors in the medial prefrontal cortex of adult mice

“…Despite the significant data suggesting that ELS experiences lead to behavioral and cognitive dysfunctions in consequence of the abnormal neurodevelopment trajectory, it is difficult to infer a deterministic prediction. Inconsistent data among preclinical studies (Bonapersona, Joels, & Sarabdjitsingh, ; Molet, Maras, Avishai‐Eliner, & Baram, ; Nylander & Roman, ; Tractenberg et al, ), and the lack of knowledge regarding why some stressed individuals are susceptible to the negative consequences of early life experiences, while others seem to be “unaffected” or resilient seem to contribute to these mixed findings (Miller, Chen, & Parker, ; Silk et al, ; Yehuda, Flory, Southwick, & Charney, ). Some efforts have been made in this direction, particularly when distinct expression patterns of specific target genes related to cognitive dysfunctions seen among subgroups of stressed animals were investigated.…”