Early weaning impairs fear extinction and decreases brain‐derived neurotrophic factor expression in the prefrontal cortex of adult male C57BL/6 mice

Mogi, Kazutaka; Ishida, Yuiko; Nagasawa, Miho; Kikusui, Takefumi

doi:10.1002/dev.21437

Cited by 16 publications

(20 citation statements)

References 61 publications

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“…The procedure to obtain EW mice (F1) was similar to our previous study [45]. Briefly, pregnant female mice were checked daily every morning until parturition.…”

Section: Animal Preparation and Proceduresmentioning

confidence: 99%

Low maternal licking/grooming stimulation increases pain sensitivity in male mouse offspring

et al. 2021

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Deprivation of maternal care has been associated with higher pain sensitivity in offspring. In the present study, we hypothesized that the maternal licking/grooming behavior was an important factor for the development of the pain regulatory system. To test this hypothesis, we used male F2 offspring of early-weaned (EW) F1 mother mice that exhibit lower frequency of licking/grooming behavior. The formalin test revealed that F2 offspring of EW F1 dams showed significantly higher pain behavior than F2 offspring of normally-weaned (NW) F1 dams. We found that the mRNA levels of transient receptor potential vanilloid 1 (TRPV1), a nociceptor, were higher in the lumbosacral dorsal root ganglion (DRG) of F2 offspring of EW F1 dams than those of F2 offspring of NW F1 dams, suggesting that the higher pain sensitivity may be attributed to low licking/grooming, which may result in developmental changes in nociceptive neurons. In the DRG, mRNA levels of Mas-related G-protein coupled receptor B4 (MrgprB4), a marker of sensory neurons that detect gentle stroking, was also up-regulated in the F2 offspring of EW F1 dams. Considering that gentle touch alleviates pain, Mrgprb4 up-regulation may reflect a compensatory change. The present findings indicate important implications of maternal licking/grooming behavior in the development of the pain regulatory system.

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“…The procedure to obtain EW mice (F1) was similar to our previous study [45]. Briefly, pregnant female mice were checked daily every morning until parturition.…”

Section: Animal Preparation and Proceduresmentioning

confidence: 99%

Low maternal licking/grooming stimulation increases pain sensitivity in male mouse offspring

et al. 2021

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“…In contrast, all studies that observed age differences in relapse following extinction of conditioned fear involved P16–P28 rodents that remained in litters together with the dam throughout experimentation (Gogolla et al, ; Kim & Richardson, ,), to reduce any potential confounding effects of weaning. While the detrimental effects of premature weaning (i.e., before P20) on the brain has been established (Kikusui, Ichikawa, & Mori, ; Mogi, Ishida, Nagasawa, & Kikusui, ), how weaning at P21 may change contextual conditioned fear has never been explicitly tested. Given that the hippocampus undergoes significant development until 4 weeks of age in rodents (Semple, Blomgren, Gimlin, Ferriero, & Noble‐Haeusslein, ), it is possible that weaning rodents at P21 may accelerate contextual fear learning and memory.…”

Section: Introductionmentioning

confidence: 99%

A dissociation between renewal and contextual fear conditioning in juvenile rats

Park

Ganella

Kim

2017

Developmental Psychobiology

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We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning.

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“…In identifying the brain region responsible for early weaning-induced anxiety, we considered the PFC a candidate because BDNF expression is correlated with fear-related memory in early-weaned mice 11 . This indicates that early-weaned mice have greater PFC corticosterone activity than normally weaned mice do.…”

Section: Resultsmentioning

confidence: 99%

“…Early separation from the dam in late-suckling rats and mice also negatively affects neurobehavioral development 6,7 . Early weaning consistently produces adult mice with increased anxiety-like behaviors and aggression 8–10 , delayed conditioned-fear extinction 11 , and decreased empathy 12 . Early-weaned mice also exhibit heightened hypothalamic–pituitary–adrenal axis (HPA) activity, a marker of physiological stress, in response to mild stressors 13 and novel environments 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the central nervous system and regulates anxiety and fear extinction in the medial PFC (mPFC) 17–20 . Early-weaned mice exhibit decreased BDNF levels in the hippocampus 21 and PFC and decreased BDNF exon III mRNA 11 , which may affect social cognition and emotional expression in both humans and rodents 22,23 . Therefore, BDNF signaling might be responsible for early weaning-induced neural dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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

Kikusui

Kanbara

Ozaki

et al. 2019

Sci Rep

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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.

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Early weaning impairs fear extinction and decreases brain‐derived neurotrophic factor expression in the prefrontal cortex of adult male C57BL/6 mice

Cited by 16 publications

References 61 publications

Low maternal licking/grooming stimulation increases pain sensitivity in male mouse offspring

Low maternal licking/grooming stimulation increases pain sensitivity in male mouse offspring

A dissociation between renewal and contextual fear conditioning in juvenile rats

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

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