Inter-Regional Variations in Gene Expression and Age-Related Cortical Thinning in the Adolescent Brain

Abstract

Age-related decreases in cortical thickness observed during adolescence may be related to fluctuations in sex and stress hormones. We examine this possibility by relating inter-regional variations in age-related cortical thinning (data from the Saguenay Youth Study) to inter-regional variations in expression levels of relevant genes (data from the Allen Human Brain Atlas); we focus on genes coding for glucocorticoid receptor (NR3C1), androgen receptor (AR), progesterone receptor (PGR), and estrogen receptors (ESR1 and ESR2). Across 34 cortical regions (Desikan-Killiany parcellation), age-related cortical thinning varied as a function of mRNA expression levels of NR3C1 in males (R2 = 0.46) and females (R2 = 0.30) and AR in males only (R2 = 0.25). Cortical thinning did not vary as a function of expression levels of PGR, ESR1, or ESR2 in either sex; this might be due to the observed low consistency of expression profiles of these 3 genes across donors. Inter-regional levels of the NR3C1 and AR expression interacted with each other vis-à-vis cortical thinning: age-related cortical thinning varied as a function of NR3C1 mRNA expression in brain regions with low (males: R2 = 0.64; females: R2 = 0.58) but not high (males: R2 = 0.0045; females: R2 = 0.15) levels of AR mRNA expression. These results suggest that glucocorticoid and androgen receptors contribute to cortical maturation during adolescence.

Figure 1.

The mRNA expression levels for the NR3C1, AR, PGR, ESR1, and ESR2 genes. Note: Relative to each specific gene, red regions represent regions with the highest expression levels and blue regions represent regions with the lowest expression levels.

Figure 2.

Inter-regional age-related cortical thinning as a function of inter-regional mRNA expression levels of NR3C1, AR, PGR, ESR1, and ESR2 genes. The relationship between cortical thickness and age varied negatively as a function of NR3C1 mRNA expression levels in both males and females (A). The relationship between cortical thickness and age varied negatively as a function of AR mRNA expression levels in males only (B). The relationship between cortical thickness and age did not vary as a function of PGR, ESR1, nor ESR2 mRNA expression levels (C, D, and E, respectively). Note: within each subfigure, each point represents 1 of the 34 cortical regions.

Figure 3.

The interaction of NR3C1 and AR mRNA expression levels. There was a significant NR3C1 and AR interaction in males and in females. In both males and females, inter-regional age-related cortical thinning varied as a function of inter-regional NR3C1 mRNA expression levels in the low AR mRNA expression group, but not the high AR mRNA expression group. Note: within each subfigure, each point represents 1 of the 34 cortical regions.