The impact of chronic stress on the rat brain lipidome

Abstract

Chronic stress is a major risk factor for several human disorders that affect modern societies. The brain is a key target of chronic stress. In fact, there is growing evidence indicating that exposure to stress affects learning and memory, decision making and emotional responses, and may even predispose for pathological processes, such as Alzheimer’s disease (AD) and depression. Lipids are a major constituent of the brain, and specifically signaling lipids have been shown to regulate brain function. Here, we used a mass spectrometry-based lipidomic approach to evaluate the impact of a chronic unpredictable stress paradigm on the rat brain in a region-specific manner. We found that the prefrontal cortex (PFC) was the area with the highest degree of changes induced by chronic stress. Although the hippocampus presented relevant lipidomic changes, the amygdala and to a more extent, the cerebellum, presented few lipid changes upon chronic stress exposure. The sphingolipid and phospholipid metabolism were profoundly affected, showing an increase in ceramide and a decrease in sphingomyelin and dihydrosphingomyelin levels, and decreased phosphatidylethanolamine and ether phosphatidylcholine and increased lysophosphatidylethanolamine levels, respectively. Furthermore, the fatty acyl profile of phospholipids and diacylglycerol revealed that chronic stressed rats had higher 38 carbon(38C)-lipid levels in the hippocampus and a decrease in 36C-lipid levels in the PFC. Finally, lysophosphatidylcholine levels in the PFC were found to be correlated with blood corticosterone levels. In summary, lipidomic profiling of the effect of chronic stress allowed for the identification of dysregulated lipid pathways, revealing putative targets for pharmacological intervention that may potentially be used to modulate stress-induced deficits.

A sphingolipid mechanism for behavioral extinction

“…; Oliveira et al . ). Here we provide, to our knowledge, first evidence for a role of ASM–Cer in the learning processes involved in coping with the absence of expected reward.…”

“…Both components are marked by different behaviors. The ASM-Cer system has been suggested to play an important role in genetically induced and stress-induced depression in rodent models (Gulbins et al 2013;Oliveira et al 2016). Here we provide, to our knowledge, first evidence for a role of ASM-Cer in the learning processes involved in coping with the absence of expected reward.…”

“…These findings suggested a role of the ASM-Cer pathway in genetically induced depression (Kornhuber et al 2014;M€ uller et al 2015). Recently, evidence was reported for a role of Cer in stress-induced depression, as various inescapable stressors were shown to enhance ASM activity and/or Cer levels in the brain (Gulbins et al 2013;Oliveira et al 2016). Also, genetic manipulations of ceramide species by knock out of ceramide synthase 1 and 6 have shown evidence for altered emotionality (Ginkel et al 2012;Ebel et al 2013).…”

The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk

“…Numerous studies have highlighted an association between MDD and the lipidome (32, 34, 35), indeed it has been previously shown that reductions phosphatidylcholine (and sphingomyelin) concentrations are associated with symptoms of depression (33). However, previous research has not shown whether the lipid alterations observed in MDD are secondary to the manifestation of the illness or its treatment, or whether lipid concentrations are related to the genetic predisposition for depression.…”

Inverse changes in L1 retrotransposons between blood and brain in major depressive disorder

“…We found a decreased L1 copy number in PFC, but there was no change in other regions due to a mild CUMS given in our study. Previous studies demonstrated that there was the highest extent of changes induced by chronic stress in PFC51. Studies of post-mortem brain and imaging revealed that the volume of prefrontal cortex was decreased in MDD, consistent with a reduction in the size and density of neurons5253.…”