Developmental time course and effects of immunostressors that alter hormone-responsive behavior on microglia in the peripubertal and adult female mouse brain.

Mary K Holder,Jeffrey D Blaustein,Giuseppe Biagini

doi:10.1371/journal.pone.0171381

Abstract

In female mice, the experience of being shipped from the breeder facility or a single injection of the bacterial endotoxin, lipopolysaccharide (LPS), during pubertal development alters the behavioral response to estradiol in adulthood as demonstrated by perturbations of estradiol’s effects on sexual behavior, cognitive function, as well as its anxiolytic and anti-depressive properties. Microglia, the primary type of immunocompetent cell within the brain, contribute to brain development and respond to stressors with marked and long-lasting morphological and functional changes. Here, we describe the morphology of microglia and their response to shipping and LPS in peripubertal and adult female mice. Peripubertal mice have more microglia with long, thick processes in the hippocampus, amygdala and hypothalamus as compared with adult mice in the absence of an immune challenge. An immune challenge also increases immunoreactivity (IR) of ionized calcium binding adaptor molecule 1 (Iba1), which is constitutively expressed in microglia. In the hippocampus, the age of animal was without effect on the increase in Iba1- IR following shipping from the breeder facility or LPS exposure. In the amygdala, we observed more Iba1-IR following shipping or LPS treatment in peripubertal mice, compared to adult mice. In the hypothalamus, there was a disassociation of the effects of shipping and LPS treatment as LPS treatment, but not shipping, induced an increase in Iba1-IR. Taken together these data indicate that microglial morphologies differ between pubertal and adult mice; moreover, the microglial response to complex stressors is greater in pubertal mice as compared to adult mice.

Highlights

Puberty, the transition into a reproductively competent adult, and adolescence are developmental periods of great physiological, psychosocial, and cultural changes [1]
There was a significant interaction of the age of the animal and the microglial morphology [F(3,24) = 22.15, p
While more microglia display the long, thin morphology compared to round/amoeboid microglia (p

Summary

Introduction

The transition into a reproductively competent adult, and adolescence are developmental periods of great physiological, psychosocial, and cultural changes [1]. The brain’s resident immune cells, play a critical role in brain development such as neurogenesis, migration, differentiation, synapse formation and neural plasticity [20,21,22,23] Based on their role as the brain’s immune cells and in the normal neurodevelopmental processes, we postulate that microglia mediate the vulnerability of the pubertal brain to the effects of an immune challenge on long-terms changes in estradiol-regulated behaviors. In support of this idea, a bacterial infection in male rat pups, but not juvenile male rats, leads to long-term microglial activation, increased brain cytokine levels, and behavioral changes in adulthood [24, 25]. These stressors were chosen because they result in enduring changes in behavioral responses to estradiol [8,9,10, 18, 19, 32]

Material and methods

Results

Discussion