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Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.

ABSTRACT: Why individuals have negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted glucocorticoid response within the hypothalamic-pituitary-adrenal axis in both peripartum humans and mice. In mice, we examined puberty-stress reprogramming in the paraventricular nucleus (PVN) of the hypothalamus, which initiates the HPA axis response. We found that pubertal stress led to an upregulation of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. Here, we examined the response of the IEGs in the PVN to the primary disruption of pubertal stress in early adolescence and to the secondary disruption of increased allopregnanolone in pregnancy. We found that in adult female, but not male, mice previously stressed during puberty, intra-PVN allopregnanolone was sufficient to recapitulate the pubertal stress associated baseline IEG expression profile. We also examined baseline IEG expression during adolescence, where we found that IEGs have sex-specific developmental trajectories that were disrupted by pubertal stress. Altogether, these data establish that IEGs can act as a key molecular switch that leads to increased vulnerability to negative outcomes in adult, pubertally stressed animals. Understanding how the factors that produce vulnerability combine throughout the lifespan will further our understanding of the etiology of negative outcomes and will help guide both the nature and timing of potential treatments.

SUBMITTER: Gautier KN

PROVIDER: S-EPMC10592881 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.

Gautier Karissa N KN Higley Samantha L SL Mendoza John M JM Morrison Kathleen E KE

bioRxiv : the preprint server for biology 20240815

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in per ...[more]

PMID: 37873227

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Project description:BackgroundIdentifying stress vulnerability after antidepressant discontinuation may be useful in treating relapses in depression. Previous studies have suggested significant effects of the immune system as well as the central nervous system (CNS) on progression and induction of major depression. In the present study, we hypothesized that the factors that are not rescued by a tricyclic antidepressant imipramine may be associated with stress vulnerability and relapses in depression.MethodsTo address this issue, mice were exposed to 2 h of restraint stress for 21 consecutive days (chronic restraint stress (CRS)) with or without co-treatment of imipramine. These groups were exposed to an electronic foot shock (FS) as additional stress after imipramine washout. Main targets of stress and antidepressants were analyzed in the hippocampus, lymph node, and serum after a series of depression-like behavior analysis.ResultsIn this study, we found for the first time that mice exposed to CRS with a tricyclic antidepressant imipramine co-treatment, which did not show depressive-like behaviors, were vulnerable to subsequent stressful stimuli compared to the non-stressed mice after imipramine washout. CRS mice with imipramine co-treatment did not show any difference in BDNF, serotonin receptors, pro-inflammatory cytokines, or kynurenine pathway in the hippocampus compared to the controls. However, peripheral IL-4, IL-10, and alternatively activated microglial phenotypes in the hippocampus were not restored with sustained reduction in CRS mice despite chronic imipramine administration. Supplementing recombinant IL-4 and IL-10 in co-Imi+CRS mice prevented the stress vulnerability on additional stress and restored factors related to alternatively activated microglia (M2) in the hippocampus.ConclusionThus, our results suggest that the reduced IL-4 and IL-10 levels in serum with hippocampal M2 markers may be involved in the stress vulnerability after imipramine discontinuation, and the restoration and modulation of these factors may be useful to some forms of depression-associated conditions.

Dataset Information

Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.

Publications

The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.

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