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

S Spulber,S Ceccatelli,C Dupont,N Onishchenko,M Raciti,M Conti,R Bose

doi:10.1038/tp.2015.94

S Spulber, S Ceccatelli + Show 5 more

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https://doi.org/10.1038/tp.2015.94

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Journal: Translational Psychiatry	Publication Date: Jul 1, 2015
Citations: 22	License type: CC BY 4.0

Affiliation: Karolinska Institutet

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.

Highlights

IntroductionMajor depressive disorder is a major cause of disability, and has high economical and personal costs. Apparently easy to recognize, major depressive disorder is a clinical entity with multiple endophenotypes and multifactorial etiology. Environmental factors, such as childhood abuse/neglect or exposure to food contaminants, can cause epigenetic changes in early life, which may lead to mood disorders in adults, as shown in humans and rodents. Recent epidemiological studies point to a correlation between intrauterine growth retardation and depression. animal models have shown that prenatal stress, glucocorticoid (GC) exposure and inhibition of 11βhydroxysteroid dehydrogenase type 2 (the placental enzyme that inactivates maternal GC) reduce birth body weight and increase the occurrence of pathological conditions in adults, including dysregulation of the hypothalamic–pituitary–adrenal axis with subsequent alterations in circadian rhythms and anxiety-related behaviors.8Neurotransmitters imbalance is believed to have a major role in the etiology of depression (monoamine hypothesis; see Nutt)
The difference was consistent until weaning (PND21), but disappeared soon thereafter
We investigated neurogenesis at 12 mo of age and observed that DEX-exposed mice had a lower number of EdU-positive cells in the subgranular zone (Figure 2a) and less DCX-positive cells in the granular layer of the dentate gyrus (DG) (Figure 2b)

Summary

Introduction

Major depressive disorder is a major cause of disability, and has high economical and personal costs. Apparently easy to recognize, major depressive disorder is a clinical entity with multiple endophenotypes and multifactorial etiology. Environmental factors, such as childhood abuse/neglect or exposure to food contaminants, can cause epigenetic changes in early life, which may lead to mood disorders in adults, as shown in humans and rodents. Recent epidemiological studies point to a correlation between intrauterine growth retardation and depression. animal models have shown that prenatal stress, glucocorticoid (GC) exposure and inhibition of 11βhydroxysteroid dehydrogenase type 2 (the placental enzyme that inactivates maternal GC) reduce birth body weight and increase the occurrence of pathological conditions in adults, including dysregulation of the hypothalamic–pituitary–adrenal axis with subsequent alterations in circadian rhythms and anxiety-related behaviors.8Neurotransmitters imbalance is believed to have a major role in the etiology of depression (monoamine hypothesis; see Nutt). Major depressive disorder is a major cause of disability, and has high economical and personal costs.. Easy to recognize, major depressive disorder is a clinical entity with multiple endophenotypes and multifactorial etiology.. Easy to recognize, major depressive disorder is a clinical entity with multiple endophenotypes and multifactorial etiology.2,3 Environmental factors, such as childhood abuse/neglect or exposure to food contaminants, can cause epigenetic changes in early life, which may lead to mood disorders in adults, as shown in humans and rodents.. Recent epidemiological studies point to a correlation between intrauterine growth retardation and depression.. Neurotransmitters imbalance is believed to have a major role in the etiology of depression (monoamine hypothesis; see Nutt9)

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