Abstract
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.
Highlights
Alterations in circadian rhythms are closely linked to psychiatric conditions, and disruption of rest/activity patterns in relation to the 24-h cycle are typically present in depressed patients[1,2]
DMI treatment restores circadian entrainment of spontaneous activity in DEX mice We investigated the circadian entrainment of spontaneous activity in response to a 6-h phase advance in the onset of dark (Fig. 1a)
Given that spontaneous activity is regulated by the suprachiasmatic nucleus (SCN), the expected response should be a gradual advance in onset of activity to match the LD cycle and presumably negligible alterations in intrinsic rhythmicity[36,38]
Summary
Alterations in circadian rhythms are closely linked to psychiatric conditions, and disruption of rest/activity patterns in relation to the 24-h cycle are typically present in depressed patients[1,2]. The core molecular clock machinery consists of a set of transcription factors (clock genes) engaged in interlocked feedback loops which generate self-sustained oscillations with a period ~24 h (i.e., circadian oscillations)[12,13]. The central clock is located in the anterior hypothalamus in the suprachiasmatic nucleus (SCN) and consists of several neuronal populations that display prominent spontaneous cyclic fluctuations in firing patterns and synchronized circadian oscillations in clock gene expression[13]. The oscillation in clock gene expression and neuronal activity in the SCN maintain synchronization even without external entrainment input[14,15]. Peripheral clocks are cell populations which express functional clock machinery, but require constant entrainment by the central clock[11]. The SCN regulates the activity of HPA axis by means of arginine-vasopressin (AVP) signaling in the paraventricular hypothalamic nucleus[18,19]
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