Neuroanatomical and functional consequences of oxytocin treatment at birth in prairie voles

Abstract

Birth is a critical period for the developing brain, a time when surging hormone levels help prepare the fetal brain for the tremendous physiological changes it must accomplish upon entry into the 'extrauterine world'. A number of obstetrical conditions warrant manipulations of these hormones at the time of birth, but we know little of their possible consequences on the developing brain. One of the most notable birth signaling hormones is oxytocin, which is administered to roughly 50% of laboring women in the United States prior to / during delivery. Previously, we found evidence for behavioral, epigenetic, and neuroendocrine consequences in adult prairie vole offspring following maternal oxytocin treatment immediately prior to birth. Here, we examined the neurodevelopmental consequences in adult prairie vole offspring following maternal oxytocin treatment prior to birth. Control prairie voles and those exposed to 0.25 mg/kg oxytocin were scanned as adults using anatomical and functional MRI, with neuroanatomy and brain function analyzed as voxel-based morphometry and resting state functional connectivity, respectively. Overall, anatomical differences brought on by oxytocin treatment, while widespread, were generally small, while differences in functional connectivity, particularly among oxytocin-exposed males, were larger. Analyses of functional connectivity based in graph theory revealed that oxytocin-exposed males in particular showed markedly increased connectivity throughout the brain and across several parameters, including closeness and degree. These results are interpreted in the context of the organizational effects of oxytocin exposure in early life and these findings add to a growing literature on how the perinatal brain is sensitive to hormonal manipulations at birth.

Keywords: Birth; Brain; Development; Oxytocin; Prairie vole.

Figure 1.

A 3D color coded reconstructions summarizing the significantly different brain areas with volumetric changes for each experimental condition. Details of these differences can be found in tables 1–3.

Figure 2.

(A) Voxel-based morphometry (VBM) measures from 111 brain regions were loaded into a principal component analysis. The overall explanatory value of dimensions 1 and 2 was 29.4% and 15.9%, respectively. (B) Both male sex and OXT treatment lead to greater values in dimension 1 (p < 0.029 for both comparisons). Post-hoc analyses revealed OXT-exposed males had significantly greater dimension 1 scores than Control males (* p = 0.017), while OXT-exposed females tended to be greater than Control females (# p = 0.079). (C) There were no effects in dimension 2.

Figure 3.

Diffusion-weighted imaging (DWI) measures for fractional anisotropy (FA, panels A and B) and apparent diffusion coefficient (ADC, panels C and D) from 111 brain regions were loaded into a principal component analysis. (B) There were no significant differences in FA. (D) Control males had greater dimension 1 scores than OXT-exposed males (* p = 0.026) and OXT-exposed females (* p = 0.042). in terms of ADC.

Figure 4.

Resting-state functional connectivity from 111 brain regions. (A) Both OXT treatment and male sex increased functional connectivity, meaning OXT-exposed males had the greatest proportion of region-region pairs significantly functionally connected for both positive (dark fill) and negative (light fill) correlations. Significant group differences are indicated with different letters over top the bars. (B) The average strength of correlation among region-region pairs whose activity was significantly correlated. Both OXT treatment and male sex increased the strength of connectivity for positive connections (dark fill). There were no significant differences among negative connections (light fill). (C) Both OXT treatment and male sex increased the strength of connectivity among both intra- and inter-cluster, though intra-cluster connectivity was more sensitive to these effects. Significant group differences are indicated with different letters over top the bars. In panels (D) and (E), connectivity from males and females respectively, 111x111 cell matrices show the strength of connectivity for all possible pairs of brain regions. Reflected across the diagonal are opposing treatment conditions, with OXT on top and Control on bottom. Region-region pairs whose connectivity Z score was less than |2.3| were excluded.

Figure 5.

A map of the strength of connectivity (i.e. correlations’ z-scores) averaged over regional clusters by group. For example, the ‘Hippocampus’ cluster includes the: CA1, CA3, Dentate gyrus, Subiculum and Parasubiculum. * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 6.

A map of betweenness averaged over regional clusters by group. For example, the ‘Hippocampus’ cluster includes the: CA1, CA3, Dentate gyrus, Subiculum and Parasubiculum. * p < 0.0332, ** p < 0.0021, *** p < 0.0002, **** p <0.0001.

Figure 7.

A map of closeness averaged over regional clusters by group. Both OXT treatment and male sex increased closeness throughout the brain, with effects most apparent in OXT-exposed males. * p < 0.0332, ** p < 0.0021, *** p < 0.0002, **** p <0.0001.

Figure 8.

A map of degree averaged over regional clusters by group. Both OXT treatment and male sex increased closeness throughout the brain, with effects most apparent in OXT-exposed males. * p < 0.0332, ** p < 0.0021, *** p < 0.0002, **** p <0.0001.