Cognitive Development and Brain Gray Matter Susceptibility to Prenatal Adversities: Moderation by the Prefrontal Cortex Brain-Derived Neurotrophic Factor Gene Co-expression Network.

Euclides José De Mendonça Filho,Denise Ruschel Bandeira,Michael J Meaney,Roberto Britto Sassi,Danusa Mar Arcego,Carla Dalmaz,Randriely Merscher Sobreira De Lima,Geoffrey B C Hall,Barbara Barth,Patricia Pelufo Silveira,Irina Pokhvisneva

doi:10.3389/fnins.2021.744743

Abstract

Background: Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density.Methods: We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales.Results: Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10).Conclusion: Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses.

Highlights

Brain-derived Neurotrophic Factor (BDNF) is a protein involved in several biological pathways – from neurogenesis, promotion of neuronal survival and differentiation, to modulation of synaptic plasticity – playing a central role in both the developing and adult nervous system (Hempstead, 2014)
We propose a novel genomics approach, using a biologically informed genetic score based on genes co-expressed with the BDNF gene in the prefrontal cortex (PFC) (BDNF ePRS) during the prenatal and early life periods to investigate the association with child cognitive development from 6 to 36 months of age
The final list consisted of 46 genes, with a 473 single nucleotide polymorphisms (SNPs) included in the BDNF ePRS

Summary

Introduction

Brain-derived Neurotrophic Factor (BDNF) is a protein involved in several biological pathways – from neurogenesis, promotion of neuronal survival and differentiation, to modulation of synaptic plasticity – playing a central role in both the developing and adult nervous system (Hempstead, 2014). Acting through its highaffinity tyrosine receptor kinase B (TrkB) receptor, it mediates neurite and spine outgrowth (Binder and Scharfman, 2004; Ji et al, 2005), and this signaling is important for synaptic plasticity (Ji et al, 2005; Lu et al, 2014), a phenomenon that enables the organism to change according to environmental stimuli, and makes possible learning and memory It controls short and long-lasting synaptic interactions in the hippocampus, and its expression mediates working memory processes in the prefrontal cortex (Gold et al, 2003; Xing et al, 2012; Kowianski et al, 2018). Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density

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