Fatty acid dysregulation in the anterior cingulate cortex of depressed suicides with a history of child abuse

Kelly Perlman,Giulia Cisbani,Richard P Bazinet,Naguib Mechawar,Raphaël Chouinard-Watkins,Massimiliano Orri,Gustavo Turecki,Arnaud Tanti

doi:10.1038/s41398-021-01657-4

Abstract

Child abuse (CA) strongly increases the lifetime risk of suffering from major depression and predicts an unfavorable course for the illness. Severe CA has been associated with a specific dysregulation of oligodendrocyte function and thinner myelin sheaths in the human anterior cingulate cortex (ACC) white matter. Given that myelin is extremely lipid-rich, it is plausible that these findings may be accompanied by a disruption of the lipid profile that composes the myelin sheath. This is important to explore since the composition of fatty acids (FA) in myelin phospholipids can influence its stability, permeability, and compactness. Therefore, the objective of this study was to quantify and compare FA concentrations in postmortem ACC white matter in the choline glycerophospholipid pool (ChoGpl), a key myelin phospholipid pool, between adult depressed suicides with a history of CA (DS-CA) matched depressed suicides without CA (DS) and healthy non-psychiatric controls (CTRL). Total lipids were extracted from 101 subjects according to the Folch method and separated into respective classes using thin-layer chromatography. FA methyl esters from the ChoGpl fraction were quantified using gas chromatography. Our analysis revealed specific effects of CA in FAs from the arachidonic acid synthesis pathway, which was further validated with RNA-sequencing data. Furthermore, the concentration of most FAs was found to decrease with age. By extending the previous molecular level findings linking CA with altered myelination in the ACC, these results provide further insights regarding white matter alterations associated with early-life adversity.

Highlights

Child abuse (CA) is a major public health problem
As can be seen on the principal component analysis plot for concentration (Supplementary Figure 1), this sample is separated from all others across PC1, which clearly makes it an extreme outlier
In this study of the quantification of choline glycerophospholipid pool (ChoGpl) fatty acids (FA) in human anterior cingulate cortex (ACC), our key findings are that (1) the concentration of key FAs are dysregulated between depressed suicides with a history of CA (DS-CA), depressed suicides without CA (DS), and CTRL groups; (2) the concentration of most FAs as well as the total FA concentration tends to decrease with age; and (3) concentration appears to be a more robust metric as compared to relative percentage for this type of research

Summary

Introduction

Child abuse (CA) is a major public health problem. In 2016, it was estimated that, worldwide, one billion children between 2 and 17 years of age experienced maltreatment in the previous year [1]. CA strongly increases the lifetime risk of suffering from major depressive disorder (MDD) and predicts an unfavorable course for the illness as well as poorer response to treatment [3]. It has been posited that the experience of CA modifies neural development such that the brain becomes more susceptible to the psychopathology of MDD and suicide [5], making it such a potent risk factor. Converging evidence in both animal and human studies suggests that the process of myelination contributes to this CA-induced vulnerability [5, 6]

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