Specific Metabolomics Adaptations Define a Differential Regional Vulnerability in the Adult Human Cerebral Cortex.

Rosanna Cabré,Rebeca Berdun,Victoria Ayala,Maria P Gil-Villar,Alba Naudí,Gerard Piñol-Ripoll,Natalia Mota-Martorell,Mariona Jové,Manuel Portero-Otin,Mayelin Dominguez-Gonzalez,Èlia Obis,Reinald Pamplona,Isidre Ferrer

doi:10.3389/fnmol.2016.00138

Abstract

Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions—entorhinal cortex, hippocampus, and frontal cortex—using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex. These findings, along with the better antioxidant capacity and lower mTOR signaling also seen in frontal cortex, suggest that this brain region is especially resistant to stress compared to the entorhinal cortex and hippocampus, which are more vulnerable regions. Globally, our results show the presence of specific metabolomics adaptations in three mature, healthy human brain regions, confirming the existence of cross-regional differences in cell vulnerability in the human cerebral cortex.

Highlights

Human evolution is associated with rapid expansion of brain size and complexity, a prerequisite for the emergence of cognitive functions
We have extended this idea to three different regions of the adult human brain cerebral cortex to evaluate possible differences in the density of glial cells relative to neurons, as an indirect indication of region-specific adaptation to neuronal metabolic demands
Our results demonstrate that frontal cortex shows an increased density of neurons along with a concomitant decrease in glial cells compared to entorhinal cortex (p < 0.01 and p < 0.05, respectively) and hippocampus (p < 0.05 and p < 0.01, respectively) (Figure 1), suggesting lower neuronal metabolic demands in frontal cortex

Summary

Introduction

Human evolution is associated with rapid expansion of brain size and complexity, a prerequisite for the emergence of cognitive functions. Neurons in the human nervous system can perform a wide array of motor, sensory, regulatory, behavioral, and cognitive functions This functional diversity is expressed in the central nervous system (CNS) by a complex organization in different regions that groups neuronal populations with a diversity of neural cells. The morphological and functional diversity among neurons suggests that each neuron type, and by extension each brain region, has its own genomic expression profile in addition to the ‘housekeeping’ genes necessary for the basal function of all cells, which are Metabolomics of Human Cerebral Cortex essentially related to cellular metabolism (Lein et al, 2007; Hawrylycz et al, 2012). Because each level of organization of the ‘-omics’ depends on the other, and a perturbation in one network can affect another, the phenotypic properties of different brain regions are the product of distinctive combinations of expressed gene products and their regulation, resulting in the metabolome as the informative modality to define cellular diversity in the CNS

Results

Discussion

Conclusion