Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress

Abstract

The prefrontal cortex (PFC) undergoes dramatic, sex-specific maturation during adolescence. Adolescence is a vulnerable window for developing mental illnesses that show significant sexual dimorphisms. Gestational stress is associated with increased risk for both schizophrenia, which is more common among men, and cognitive deficits. We have shown that male, but not female, rats exposed to prenatal stress develop postpubertal deficits in cognitive behaviors supported by the prefrontal cortex. Here we tested the hypothesis that repeated variable prenatal stress during the third week of rat gestation disrupts periadolescent development of prefrontal neurons in a sex-specific fashion. Using Golgi-Cox stained tissue, we compared dendritic arborization and spine density of prelimbic layer III neurons in prenatally stressed and control animals at juvenile (day 20), prepubertal (day 30), postpubertal (day 56), and adult (day 90) ages (N = 115). Dendritic ramification followed a sex-specific pattern that was disrupted during adolescence in prenatally stressed males, but not in females. In contrast, the impact of prenatal stress on the female PFC was not evident until adulthood. Prenatal stress also caused reductions in brain and body weights, and the latter effect was more pronounced among males. Additionally, there was a trend toward reduced testosterone levels for adult prenatally stressed males. Our findings indicate that, similarly to humans, the rat PFC undergoes sex-specific development during adolescence and furthermore that this process is disrupted by prenatal stress. These findings may be relevant to both the development of normal sex differences in cognition as well as differential male-female vulnerability to psychiatric conditions.

Figure 1

A Golgi Cox stained pyramidal neuron in the medial PFC, showing multiple dendritic branches (scale bar = 50μm) and dendritic spines (B; scale bar = 5μm).

Figure 2

Reconstructions of Golgi-impregnated pyramidal neurons in layer III of the medial PFC (A), and images showing dendritic spines on segments located on the apical tree of these neurons (B), taken from each of the four Control male age groups. Scale bar = 50μm (A) or =5μm (B).

Figure 3

Peri-adolescent maturation of apical dendritic complexity on layer III pyramidal neurons in the medial PFC follows a sex-specific pattern in control (C) animals that is disrupted by prenatal stress (PS) (**treatment by sex by age interaction, p<0.01). Mean number of Sholl ring intersections for each group ± standard errors of the mean are shown. Lines indicate significant age-related changes. *day 30 Control males < Control females (p<0.053) and < PS males (p<0.02). #day 90 PS females < Control females (p<0.01) and < PS males (p<0.03).

Figure 4

Apical dendritic ramification according to dendritic location relative to the soma: proximal (20–120μm), middle (140–240μm), and distal (>260μm)) in control (A,B) and prenatal stress (PS) (C,D) animals of both sexes. Mean number of Sholl ring intersections for each group ± standard errors of the mean are shown. Lines indicate significant age-related changes. *day 30 Control females > Control males (p<0.03). # day 56 PS males < Control males (p<0.05). & day 90 PS females < Control females (p<0.05).

Figure 5

Peri-adolescent maturation of basilar dendritic complexity on layer III pyramidal neurons in the medial PFC follows a sex-specific pattern in control (C) and prenatally stress (PS) animals. Mean number of Sholl ring intersections for each group ± standard errors of the mean are shown. (A) total intersections, (B) intersections by dendritic location: proximal (20–60μm), middle (80–120μm), distal (>140μm). For (B), data from all four sex/treatment groups were collapsed for best presentation of the age x location interaction. Lines indicate significant age-related changes.

Figure 6

Peri-adolescent maturation of dendritic spine density on the apical (A) and basilar (B) dendritic trees of layer III pyramidal neurons in the medial PFC takes place primarily during early adolescence. Group means ± standard errors of the mean are shown. Lines indicate significant age-related changes. Only females show post-adolescent spine pruning, resulting in an adult sex difference in spine density (*day 56 females < males (p<0.02)).