Early Institutional Care Predicts Pro-inflammatory Gene Expression and Diminished Brain Connectivity in Adolescence

• In Event: 1-015 - Translational Perspectives on the Role of Inflammation in Brain Development and Function

Integrative Statement

Relative to other systems such as the hypothalamic pituitary adrenal axis, the immune system has been largely overlooked as a potential mediator between early life stress (ELS) exposure and neurodevelopment. Accumulating evidence from animal models and adult human research have independently linked ELS exposure to inflammation, an immune response, and inflammation to altered prefrontal-subcortical function (Ganguly & Brenhouse, 2015; Muscatell et al., 2015). Although influential theories posit that ELS exposure increases inflammation and in turn alters the course of prefrontal-subcortical development (Nusslock & Miller, 2016), no prior work has tested this chain of events in humans. The present study sought to fill these gaps in the literature by assessing pro-inflammatory gene expression and prefrontal-subcortical connectivity during self-regulation in a group of adolescents who experienced early institutional care before being adopted. The present study represents an interdisciplinary attempt to bring a multi-system (immune system and brain circuits) perspective to the study of ELS.

In the ongoing present study, previously institutionalized (PI) and comparison (never-institutionalized) adolescents are recruited to participate in a laboratory and neuroimaging testing session. During the laboratory session, participants completed questionnaires and provided blood samples for inflammation testing. At the neuroimaging testing session, participants completed a self-regulation task that involved using a cognitive distancing strategy to attenuate affective responses to threatening images (i.e., scenes depicting bullying, aggression or rejection). At the time of submission, 66 participants had completed the lab session (33 PI, 33 comparison; 37 female; mean age=16.27 years, S.D.=3.69) and 41 participants had completed fMRI scanning (20 PI, 21 comparison; 23 female; mean age=16.51, S.D.=3.50).

Pro-inflammatory gene expression techniques were used to assess participants’ pro-inflammatory phenotypes. Preliminary results suggest that PI adolescents show elevated expression of genes regulated by the pro-inflammatory transcription factor NF-kB (1.8-fold greater prevalence in genes showing > 1.5-fold up-regulation in PI group vs. comparisons; mean log2 ratio=.86±SE .28; p=.002; Figure 1A) and increased activation of monocytes (cell type diagnosticity score: .17±.06, p=.001; Figure 1B), a type of pro-inflammatory immune cell. These data tentatively support the hypothesis that PI adolescents are more likely to exhibit a pro-inflammatory phenotype than comparison adolescents.

We used psychophysiological interaction analyses to examine whether early institutionalization disrupts connectivity between the amygdala and ventrolateral prefrontal cortex in the context of self-regulation (Silvers, Shu, Hubbard, Weber, & Ochsner, 2015). Consistent with hypotheses, preliminary neuroimaging data suggest that comparison adolescents have stronger negative connectivity between the vlPFC and the amygdala relative to PI adolescents during self-regulation (Figure 2; p<.01, uncorrected).

The present, ongoing study presents a novel attempt to use a combination of pro-inflammatory gene expression and neuroimaging techniques to understand how ELS contributes to adolescent phenotypes. Analyses are planned to examine interactions between inflammation and brain connectivity at the time of the conference. Our preliminary findings and planned work have implications for basic models of neurodevelopment as well as for future intervention work seeking to ameliorate negative effects of ELS on subsequent development.

Authors

• Jennifer Silvers, UCLA
  Presenting Author

• Steve Cole, University of California, Los Angeles
  Non-Presenting Author

• Joao Guassi Moreira, University of California, Los Angeles
  Non-Presenting Author

• Emilia Ninova, University of California, Los Angeles
  Non-Presenting Author

• Yael Waizman, University of California, Los Angeles
  Non-Presenting Author