The role of puberty on physical and brain development: A longitudinal study in male Rhesus Macaques

Abstract

This study examined the role of male pubertal maturation on physical growth and development of neurocircuits that regulate stress, emotional and cognitive control using a translational nonhuman primate model. We collected longitudinal data from male macaques between pre- and peri-puberty, including measures of physical growth, pubertal maturation (testicular volume, blood testosterone -T- concentrations) and brain structural and resting-state functional MRI scans to examine developmental changes in amygdala (AMY), hippocampus (HIPPO), prefrontal cortex (PFC), as well as functional connectivity (FC) between those regions. Physical growth and pubertal measures increased from pre- to peri-puberty. The indexes of pubertal maturation -testicular size and T- were correlated at peri-puberty, but not at pre-puberty (23 months). Our findings also showed ICV, AMY, HIPPO and total PFC volumetric growth, but with region-specific changes in PFC. Surprisingly, FC in these neural circuits only showed developmental changes from pre- to peri-puberty for HIPPO-orbitofrontal FC. Finally, testicular size was a better predictor of brain structural maturation than T levels -suggesting gonadal hormones-independent mechanisms-, whereas T was a strong predictor of functional connectivity development. We expect that these neural circuits will show more drastic pubertal-dependent maturation, including stronger associations with pubertal measures later, during and after male puberty.

Keywords: Adolescence; Amygdala; Hippocampus; MRI; Prefrontal cortex; Testosterone.

Fig. 1

Prefrontal cortex (PFC) brain ROIs. (Left) Sagittal view of ROIs location in the rhesus brain MRI image. (Right) External view of ROIs location in the 3D rhesus brain MRI image. Structural MRI (sMRI) and resting state fMRI (rs-fMRI) data were analyzed in the following PFC areas: mPFC areas 14, 24, 25, and 32; dlPFC areas 9 and 46; vlPFC area 47/12; and OFC areas 11 and 13.

Fig. 2

Pubertal and physical measures from pre- to peri-puberty. (A) Testicular volume; (B) blood testosterone -T- concentrations; (C) body weight; (D) height; (E) waist circumference. Gray lines indicate individual data measured from 23 to 37 months of age; black lines represent mean±SEM (individual data with <4 timepoints was dropped from the RM ANOVA of testicular volume, body weight, height and waist circumference).

Fig. 3

Correlation between pubertal measures. Testicular volume and testosterone -T- levels were not correlated at pre-puberty (A), but they were positively correlated at peri-puberty (B).

Fig. 4

Volumetric brain developmental changes using sMRI. (A) Intracranial volume -ICV-; (B) total prefrontal cortex (PFC) volume; (C) hippocampal volume; (D) amygdala volume; (E) area 25 vol; (F) area 32 vol; (G) area 9 vol (extreme outlier removed). Gray lines represent individual data; bar charts represent mean ± SEM ICV or ROI volumes per AGE and HEMISPHERE.

Fig. 5

Significant regression models. (Top: A) Table shows R² changes for significant associations between pubertal measures and volumetric or FC. (Bottom: B-E) Scatterplots show significant associations between testicular volume measured during pre-puberty and dlPFC area 9 vol measured at pre- and peri-puberty (B, C) and testosterone T- levels measured during pre-puberty and HIPPO-OFC area 11 FC measured during peri-puberty in both the left and right hemispheres (D, E). Black dots represent individual data (n = 10). Uncorrected p values (none of the significant regression results reported here or in Supplemental Table 1 survived Bonferroni correction for multiple comparisons -corrected p value=0.05/12 =0.0041-).

Fig. 6

Functional connectivity (FC) developmental changes using rs-fMRI. (Top) Significant AGE by HEMISPHERE interaction effect for HIPPO-OFC area 11 FC; gray lines represent individual data, bar charts represent mean±SEM FC per AGE and HEMISPHERE. (Bottom) HIPPO-OFC area 11 average FC map in the rhesus brain MRI atlas image; colored squares represent FC (r values) between HIPPO and each voxel in the OFC area 11.