Early weaning increases anxiety via brain-derived neurotrophic factor signaling in the mouse prefrontal cortex

Takefumi Kikusui,Kuriko Mitsuyama,Mariya Ozaki,Kumiko Ida,Mika Tokita,Nozomi Hirayama,Miho Nagasawa,Miki Yoshida,Naho Tanabe,Hatsuki Abe,Kazutaka Mogi,Natsumi Kanbara

doi:10.1038/s41598-019-40530-9

Takefumi Kikusui, Kuriko Mitsuyama + Show 10 more

Open Access

https://doi.org/10.1038/s41598-019-40530-9

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Journal: Scientific Reports	Publication Date: Mar 8, 2019
Citations: 15	License type: open-access

Affiliation: Azabu University

Abstract

Deprivation of maternal care during early development markedly affects emotional development, but the underlying neuromolecular mechanisms are not fully understood. In a mouse model of disrupted mother-infant relationship, early weaning causes long-term impacts on pups to exhibit increased corticosterone secretion, anxiety, and stress responses in their adulthood. Revealing the molecular mechanisms behind it would beneficial to ameliorating mental problems caused by abuse in childhood. We report that normalizing circulating corticosterone in early-weaned mice, either in adulthood or soon after weaning, ameliorated anxiety levels assessed in the plus maze test. Administering a glucocorticoid receptor antagonist into the prefrontal cortex (PFC) reversed the effects of early weaning, whereas administering corticosterone increased anxiety levels, suggesting that the PFC is corticosterone’s target brain region. In the PFCs of early-weaned mice, we observed prolonged reductions in the expression of brain-derived neurotrophic factor (BDNF) and associated mRNAs. Anxiety in early-weaned mice was ameliorated by pretreatment with BDNF or a BDNF receptor agonist. In summary, early weaning increased anxiety levels by modulating glucocorticoid and BDNF signaling in the PFC.

Highlights

Mammalian infants heavily depend on their mothers, and mother-infant interactions greatly influence neurobehavioral development
We have demonstrated that early weaning causes precocious myelination in the basolateral amygdala[15] and decreased neural connectivity between the prefrontal cortex (PFC) and basolateral amygdala[16]
To determine whether elevated circulating corticosterone caused increased anxiety in the early-weaned mice, adrenalectomies were conducted on postnatal days 42–44 (PD42-44), and their behaviors were measured on PD56 (Fig. 1a)

Summary

Introduction

Mammalian infants heavily depend on their mothers, and mother-infant interactions greatly influence neurobehavioral development. Early-weaned mice exhibit heightened hypothalamic–pituitary–adrenal axis (HPA) activity, a marker of physiological stress, in response to mild stressors[13] and novel environments[14] These results indicate that the developing brain in late suckling is vulnerable to stress and shaped by the social environment, that these juvenile social experiences are encoded in the brain, and that these experiences have enduring behavioral effects. EW Sham EW CBX NW Sham childhood in humans, such as anxiety, post-traumatic stress disorder and depression To elucidate these mechanisms, we tested for a causal relation between heightened HPA axis activity and heightened anxiety behavior in early-weaned mice and aimed to identify the molecules and brain regions responsible for early weaning’s neural and behavioral effects. We hypothesized that BDNF in mPFC is involved in early weaning-induced behavioral changes

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