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Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter.

ABSTRACT: Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naïve 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30?min/4?°C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress.

SUBMITTER: Marchette RCN

PROVIDER: S-EPMC6234269 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter.

Marchette Renata Cristina Nunes RCN Bicca Maíra Assunção MA Santos Evelyn Cristina da Silva ECDS de Lima Thereza Christina Monteiro TCM

Neurobiology of stress 20180816

Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naï ...[more]

PMID: 30450373

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Project description:Background Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). This condition has been associated with an increase of gamma-aminobutyric acid (GABA) neurotransmission and, consequently, an excitation/inhibition imbalance associated with autistic-like behavior in both human and animal models. Here, we explored the influence of biological sex in the GABAergic system and behavioral alterations induced by the Nf1+/− mutation in a murine model. Methods Juvenile male and female Nf1+/− mice and their wild-type (WT) littermates were used. Hippocampus size was assessed by conventional toluidine blue staining and structural magnetic resonance imaging (MRI). Hippocampal GABA and glutamate levels were determined by magnetic resonance spectroscopy (MRS), which was complemented by western blot for the GABA(A) receptor. Behavioral evaluation of on anxiety, memory, social communication, and repetitive behavior was performed. Results We found that juvenile female Nf1+/− mice exhibited increased hippocampal GABA levels. Moreover, mutant female displays a more prominent anxious-like behavior together with better memory performance and social behavior. On the other hand, juvenile Nf1+/− male mice showed increased hippocampal volume and thickness, with a decrease in GABA(A) receptor levels. We observed that mutant males had higher tendency for repetitive behavior. Conclusions Our results suggested a sexually dimorphic impact of Nf1+/− mutation in hippocampal neurochemistry, and autistic-like behaviors. For the first time, we identified a “camouflaging”-type behavior in females of an animal model of ASD, which masked their autistic traits. Accordingly, like observed in human disorder, in this animal model of ASD, females show larger anxiety levels but better executive functions and production of normative social patterns, together with an imbalance of inhibition/excitation ratio. Contrary, males have more externalizing disorders, such as hyperactivity and repetitive behaviors, with memory deficits. The ability of females to camouflage their autistic traits creates a phenotypic evaluation challenge that mimics the diagnosis difficulty observed in humans. Thus, we propose the study of the Nf1+/− mouse model to better understand the sexual dimorphisms of ASD phenotypes and to create better diagnostic tools. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-023-00509-8. Highlights Female Nf1+/− exhibit a “camouflaging”-type behavior mimicking autistic girls; Female Nf1+/− show a more anxious phenotype, but better social and memory performance; Female Nf1+/− display higher susceptibility to excitation/inhibition imbalance; Male Nf1+/− display repetitive behavior and develop cognitive deficits; Nf1+/− mouse model is a good candidate to study female camouflaging effects. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-023-00509-8.

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Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter.

Publications

Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter.

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