Dataset Information

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

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.

SUBMITTER: Holder MK

PROVIDER: S-EPMC5291383 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Holder Mary K MK Blaustein Jeffrey D JD

PloS one 20170203 2

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 respo ...[more]

PMID: 28158270

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Project description:Plasma GH profiles regulate the sexually dimorphic expression of cytochromes P450 and many other genes in rat and mouse liver; however, the proximal transcriptional regulators of these genes are unknown. Presently, we characterize three liver transcription factors that are expressed in adult female rat and mouse liver at levels up to 16-fold [thymus high-mobility group box protein (Tox)], 73-fold [tripartite motif-containing 24 (Trim24)/transcription initiation factor-1alpha (TIF1alpha)], and 125-fold [cut-like 2 (Cutl2)/cut homeobox 2 (Cux2)] higher than in adult males, depending on the strain and species, with Tox expression only detected in mice. In rats, these sex differences first emerged at puberty, when the high prepubertal expression of Cutl2 and Trim24 was extinguished in males but was further increased in females. Rat hepatic expression of Cutl2 and Trim24 was abolished by hypophysectomy and, in the case of Cutl2, was restored to near-female levels by continuous GH replacement. Cutl2 and Trim24 were increased to female-like levels in livers of intact male rats and mice treated with GH continuously (female GH pattern), whereas Tox expression reached only about 40% of adult female levels. Expression of all three genes was also elevated to normal female levels or higher in male mice whose plasma GH profile was feminized secondary to somatostatin gene disruption. Cutl2 and Trim24 both responded to GH infusion in mice within 10-24 h and Tox within 4 d, as compared with at least 4-7 d required for the induced expression of several continuous GH-regulated cytochromes P450 and other female-specific hepatic genes. Cutl2, Trim24, and Tox were substantially up-regulated in livers of male mice deficient in either of two transcription factors implicated in GH regulation of liver sex specificity, namely, signal transducer and activator of transcription 5b (STAT5b) and hepatocyte nuclear factor 4alpha (HNF4alpha), with sex-specific expression being substantially reduced or lost in mice deficient in either nuclear factor. Cutl2 and Trim24 both display transcriptional repressor activity and could thus contribute to the loss of GH-regulated, male-specific liver gene expression seen in male mice deficient in STAT5b or HNF4alpha. Binding sites for Cutl1, whose DNA-binding specificity is close to that of Cutl2, were statistically overrepresented in STAT5b-dependent male-specific mouse genes, lending support to this hypothesis.

Project description:BackgroundMicroarray experiments enable simultaneous measurement of the expression levels of virtually all transcripts present in cells, thereby providing a 'molecular picture' of the cell state. On the other hand, the genomic responses to a pharmacological or hormonal stimulus are dynamic molecular processes, where time influences gene activity and expression. The potential use of the statistical analysis of microarray data in time series has not been fully exploited so far, due to the fact that only few methods are available which take into proper account temporal relationships between samples.ResultsWe compared here four different methods to analyze data derived from a time course mRNA expression profiling experiment which consisted in the study of the effects of estrogen on hormone-responsive human breast cancer cells. Gene expression was monitored with the innovative Illumina BeadArray platform, which includes an average of 30-40 replicates for each probe sequence randomly distributed on the chip surface. We present and discuss the results obtained by applying to these datasets different statistical methods for serial gene expression analysis. The influence of the normalization algorithm applied on data and of different parameter or threshold choices for the selection of differentially expressed transcripts has also been evaluated. In most cases, the selection was found fairly robust with respect to changes in parameters and type of normalization. We then identified which genes showed an expression profile significantly affected by the hormonal treatment over time. The final list of differentially expressed genes underwent cluster analysis of functional type, to identify groups of genes with similar regulation dynamics.ConclusionsSeveral methods for processing time series gene expression data are presented, including evaluation of benefits and drawbacks of the different methods applied. The resulting protocol for data analysis was applied to characterization of the gene expression changes induced by estrogen in human breast cancer ZR-75.1 cells over an entire cell cycle.

Dataset Information

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

Publications

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

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