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Mothers do it differently: reproductive experience alters fear extinction in female rats and women.

ABSTRACT: Fear extinction is the laboratory basis of exposure therapy for anxiety disorders. Recent findings have revealed that estradiol is necessary to the consolidation of extinction memories in females. These findings are based on studies conducted using virgin rats and young women whose reproductive history is unknown. We hypothesized that motherhood, which results in extensive endocrinological, neurobiological and behavioral changes, may lead to alterations in fear extinction in females. We used a cross-species translational approach to investigate the impact of reproductive experience on fear extinction and fear relapse in female rats (n=116) and women (n=64). Although freezing during extinction recall was associated with estrous cycle phase during extinction training in virgin rats, this association was mitigated in age-matched reproductively experienced rats, even when fear extinction occurred 3 months after pups had been weaned, and even though reproductively experienced rats exhibited attenuated serum estradiol levels. In addition, although serum estradiol levels predicted extinction recall in human women with no prior reproductive experience, no such association was found in women with children. Finally, although virgin rats displayed both renewal and reinstatement after fear extinction, these common relapse phenomena were absent in rats with reproductive experience. Together, these findings suggest that reproductive experience alters the endocrine and behavioral features of fear extinction in females long after the hormonal surges of pregnancy and lactation have diminished. These results highlight the need to incorporate both hormonal and reproductive status as important factors in current models of fear extinction in females.

SUBMITTER: Milligan-Saville JS

PROVIDER: S-EPMC5290346 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Mothers do it differently: reproductive experience alters fear extinction in female rats and women.

Milligan-Saville J S JS Graham B M BM

Translational psychiatry 20161025 10

Fear extinction is the laboratory basis of exposure therapy for anxiety disorders. Recent findings have revealed that estradiol is necessary to the consolidation of extinction memories in females. These findings are based on studies conducted using virgin rats and young women whose reproductive history is unknown. We hypothesized that motherhood, which results in extensive endocrinological, neurobiological and behavioral changes, may lead to alterations in fear extinction in females. We used a c ...[more]

PMID: 27779622

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Project description:BACKGROUND:Kisspeptins bind to the G-protein-coupled receptor (GPR54) to activate hypothalamic luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. Alcohol (ALC) causes depressed prepubertal LHRH release, resulting in depressed luteinizing hormone (LH) secretion and delayed puberty. Because KiSS-1 and GPR54 are important to the onset of puberty, we assessed the effects of chronic ALC administration on basal expression of these puberty-related genes within the reproductive hypothalamus, as well as hormones and transduction signaling pathways contributing to their activity. METHODS:Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Controls received either companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Blood was collected for the assessment of serum hormone levels. Brain tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were obtained for assessing expression of specific puberty-related genes and proteins. RESULTS:KiSS-1 mRNA levels in the AVPV and ARC nuclei were suppressed (p < 0.001) in the ALC-treated rats. GPR54 gene and protein expressions were both modestly increased (p < 0.05) in AVPV nucleus, but not in ARC nucleus. Alcohol exposure also resulted in suppressed serum levels of insulin-like growth factor-1 (IGF-1), LH, and estradiol (E(2)). As IGF-1, in the presence of E(2), can induce expression of the KiSS-1 gene, we assessed the potential for ALC to alter IGF-1 signaling in the reproductive hypothalamus. IGF-1 receptor gene and protein expressions were not altered. However, protein expression of phosphorylated Akt, a transduction signal used by IGF-1, was suppressed in the AVPV (p < 0.05) and ARC (p < 0.01) nuclei. CONCLUSIONS:Alcohol causes suppressed KiSS-1 gene expression in the reproductive hypothalamus; hence, contributing to this drug's ability to cause suppressed LHRH secretion and disruption of the pubertal process. We suggest that this action, at least in part, is through altered IGF-1 signaling.

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Mothers do it differently: reproductive experience alters fear extinction in female rats and women.

Publications

Mothers do it differently: reproductive experience alters fear extinction in female rats and women.

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