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Author Spotlight: Exploring Microglial Interactions with Stress-Response Circuitry Using the Limited Bedding and Nesting Model
Published on: July 12, 2024
Postpartum scarcity-adversity inflicts sex-specific cerebellar adaptations and reward behaviors in adolescence
Malabika Maulik1, Kassandra Looschen2, Colton Smith2
1Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
Insights
Early life adversity, like limited nesting materials, causes sex-specific behavioral changes in adolescent mice. This adversity impacts social behavior and drug preference, linked to cerebellar gene changes.
Area of Science:
- Neuroscience
- Developmental Psychology
- Genetics
Background:
- Early life adversity, particularly poor postnatal care, significantly impacts long-term neurobehavioral outcomes.
- Limited bedding and nesting (LBN) materials during early development are known stressors that induce behavioral deficits.
- Adolescence is a critical period for brain development and vulnerability to psychiatric disorders, including substance use disorder.
Purpose of the Study:
- To investigate the sex-specific effects of limited bedding and nesting (LBN) on adolescent mouse behavior.
- To explore the molecular mechanisms, including gene expression and extracellular matrix changes, underlying these behavioral adaptations.
- To understand how early life stress influences the developing cerebellum and its role in psychiatric vulnerability.
Main Methods:
- Adolescent male and female C57BL/6 mice were exposed to limited bedding and nesting (LBN) or standard conditions.
- A battery of behavioral tests was employed: open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference.
- Quantitative real-time PCR was used to measure Klf9 and Bmal1 mRNA levels in the deep cerebellar nuclei (DCN).
- Immunohistochemistry was performed to assess perineuronal nets (PNN) in the DCN.
Main Results:
- Male mice exposed to LBN exhibited a significant deficit in social preference compared to controls.
- Both male and female LBN mice showed an increased preference for the drug-paired chamber in the conditioned place preference test.
- LBN exposure led to sex-specific increases in Klf9 mRNA and decreases in Bmal1 mRNA in the DCN of males.
- Depleted perineuronal nets (PNN) were observed in the DCN of male LBN mice, but not in females.
Conclusions:
- Postpartum adversity through LBN disrupts cerebellar extracellular matrix homeostasis in a sex-specific manner.
- This disruption is potentially mediated by Klf9-induced alterations in the circadian gene Bmal1 within the deep cerebellar nuclei.
- These molecular changes may underlie sex-specific behavioral adaptations during adolescence, potentially increasing vulnerability to psychiatric disorders.
Abstract:
Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.
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