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The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accompanying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression associated with stress-related disorders in which there is evidence for KP activation.

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Background and Aim: Predisposing factors place certain individuals at higher risk for insomnia, especially in the presence of precipitating conditions such as stressful life events. Sleep spindles have been shown to play an important role in the preservation of sleep continuity. Lower spindle density might thus constitute an objective predisposing factor for sleep reactivity to stress. The aim of this study was therefore to evaluate the relationship between baseline sleep spindle density and the prospective change in insomnia symptoms in response to a standardized academic stressor.Methods: Twelve healthy students had a polysomnography recording during a period of lower stress at the beginning of the academic semester, along with an assessment of insomnia complaints using the insomnia severity index (ISI). They completed a second ISI assessment at the end of the semester, a period coinciding with the week prior to final examinations and thus higher stress. Spindle density, amplitude, duration, and frequency, as well as sigma power were computed from C4–O2 electroencephalography derivation during stages N2–N3 of non-rapid-eye-movement (NREM) sleep, across the whole night and for each NREM sleep period. To test for the relationship between spindle density and changes in insomnia symptoms in response to academic stress, spindle measurements at baseline were correlated with changes in ISI across the academic semester.Results: Spindle density (as well as spindle amplitude and sigma power), particularly during the first NREM sleep period, negatively correlated with changes in ISI (p < 0.05).Conclusion: Lower spindle activity, especially at the beginning of the night, prospectively predicted larger increases in insomnia symptoms in response to stress. This result indicates that individual differences in sleep spindle activity contribute to the differential vulnerability to sleep disturbances in the face of precipitating factors.

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These preliminary results suggest that inter-individual differences in sleep spindle density in insomnia may represent an endogenous biomarker predicting responsiveness to cognitive-behavioral therapy. Insomnia with altered spindle activity might constitute an insomnia subtype characterized by a neurophysiological vulnerability to sleep disruption associated with impaired responsiveness to cognitive-behavioral therapy.

Cross‐frequency coupling (CFC) between brain oscillations during non‐rapid‐eye‐movement (NREM) sleep (e.g. slow oscillations [SO] and spindles) may be a neural mechanism of overnight memory consolidation. Declines in CFC across the lifespan might accompany coinciding memory problems with ageing. However, there are few reports of CFC changes during sleep after learning in older adults, controlling for baseline effects. Our objective was to examine NREM CFC in healthy older adults, with an emphasis on spindle activity and SOs from frontal electroencephalogram (EEG), during a learning night after a declarative learning task, as compared to a baseline night without learning. Twenty‐five older adults (M [SD] age = 69.12 [5.53] years; 64% female) completed a two‐night study, with a pre‐ and post‐sleep word‐pair associates task completed on the second night. SO‐spindle coupling strength and a measure of coupling phase distance from the SO up‐state were both examined for between‐night differences and associations with memory consolidation. Coupling strength and phase distance from the up‐state peak were both stable between nights. Change in coupling strength between nights was not associated with memory consolidation, but a shift in coupling phase towards (vs. away from) the up‐state peak after learning predicted better memory consolidation. Also, an exploratory interaction model suggested that associations between coupling phase closer to the up‐state peak and memory consolidation may be moderated by higher (vs. lower) coupling strength. This study supports a role for NREM CFC in sleep‐related memory consolidation in older adults.