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Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.

ABSTRACT: Growing evidence links adverse prenatal conditions to mood disorders. We investigated the long-term behavioral alterations induced by prenatal exposure to excess glucocorticoids (dexamethasone--DEX). At 12 months, but not earlier, DEX-exposed mice displayed depression-like behavior and impaired hippocampal neurogenesis, not reversible by the antidepressant fluoxetine (FLX). Concomitantly, we observed arrhythmic glucocorticoid secretion and absent circadian oscillations in hippocampal clock gene expression. Analysis of spontaneous activity showed progressive alterations in circadian entrainment preceding depression. Circadian oscillations in clock gene expression (measured by means of quantitative PCR) were also attenuated in skin fibroblasts before the appearance of depression. Interestingly, circadian entrainment is not altered in a model of depression (induced by methylmercury prenatal exposure) that responds to FLX. Altogether, our results suggest that alterations in circadian entrainment of spontaneous activity, and possibly clock gene expression in fibroblasts, may predict the onset of depression and the response to FLX in patients.

SUBMITTER: Spulber S

PROVIDER: S-EPMC5068723 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.

Spulber S S Conti M M DuPont C C Raciti M M Bose R R Onishchenko N N Ceccatelli S S

Translational psychiatry 20150714

Growing evidence links adverse prenatal conditions to mood disorders. We investigated the long-term behavioral alterations induced by prenatal exposure to excess glucocorticoids (dexamethasone--DEX). At 12 months, but not earlier, DEX-exposed mice displayed depression-like behavior and impaired hippocampal neurogenesis, not reversible by the antidepressant fluoxetine (FLX). Concomitantly, we observed arrhythmic glucocorticoid secretion and absent circadian oscillations in hippocampal clock gene ...[more]

PMID: 26171984

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Project description:Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of perturbed emotionality following fluoxetine exposure in early life.

Project description:Alterations in circadian rhythms are closely linked to depression, and we have shown earlier that progressive alterations in circadian entrainment precede the onset of depression in mice exposed in utero to excess glucocorticoids. The aim of this study was to investigate whether treatment with the noradrenaline reuptake inhibitor desipramine (DMI) could restore the alterations in circadian entrainment and prevent the onset of depression-like behavior. C57Bl/6 mice were exposed to dexamethasone (DEX-synthetic glucocorticoid analog, 0.05 mg/kg/day) between gestational day 14 and delivery. Male offspring aged 6 months (mo) were treated with DMI (10 mg/kg/day in drinking water) for at least 21 days before behavioral testing. We recorded spontaneous activity using the TraffiCage™ system and found that DEX mice re-entrained faster than controls after an abrupt advance in light-dark cycle by 6 h, while DMI treatment significantly delayed re-entrainment. Next we assessed the synchronization of peripheral oscillators with the central clock (located in the suprachiasmatic nucleus-SCN), as well as the mechanisms required for entrainment. We found that photic entrainment of the SCN was apparently preserved in DEX mice, but the expression of clock genes in the hippocampus was not synchronized with the light-dark cycle. This was associated with downregulated mRNA expression for arginine vasopressin (AVP; the main molecular output entraining peripheral clocks) in the SCN, and for glucocorticoid receptor (GR; required for the negative feedback loop regulating glucocorticoid secretion) in the hippocampus. DMI treatment restored the mRNA expression of AVP in the SCN and enhanced GR-mediated signaling by upregulating GR expression and nuclear translocation in the hippocampus. Furthermore, DMI treatment at 6 mo prevented the onset of depression-like behavior and the associated alterations in neurogenesis in 12-mo-old DEX mice. Taken together, our data indicate that DMI treatment enhances GR-mediated signaling and restores the synchronization of peripheral clocks with the SCN and support the hypothesis that altered circadian entrainment is a modifiable risk factor for depression.

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Project description:ObjectiveAntiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis.MethodsMitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-β2 -glycoprotein I (anti-β2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control.ResultsMitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-β2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-β2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice.ConclusionIn lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.

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Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.

Publications

Alterations in circadian entrainment precede the onset of depression-like behavior that does not respond to fluoxetine.

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