Introduction Electroconvulsive therapy (ECT) is one of the most efficient treatments of major depressive disorder (MDD), although the underlying neurobiology remains poorly understood. There is evidence that ECT and MDD exert opposing effects on the hippocampal formation with respect to volume and number of neurons. However, there has been a paucity of quantitative data in experimental models of ECT and MDD. Methods Using design‐based stereology, we have measured the effects of a stress‐induced depression model (chronic restraint stress, CRS) and ECS on the morphology of the hippocampus by estimating the volume and total number of neurons in the hilus, CA1, and CA2/3, as well as in the entire hippocampus. Results We find that CRS induces a significant decrease in volume exclusively of the hilus and that ECS (CRS + ECS) blocks this reduction. Furthermore, ECS alone does not change the volume or total number of neurons in the entire hippocampus or any hippocampal subdivision in our rat model.

Objective measures, such as activity monitoring, can potentially complement clinical assessment for psychiatric patients. Alterations in rest–activity patterns are commonly encountered in patients with major depressive disorder. The aim of this study was to investigate whether features of activity patterns correlate with severity of depression symptoms (evaluated by Montgomery–Åsberg Rating Scale (MADRS) for depression). We used actigraphy recordings collected during ongoing major depressive episodes from patients not undergoing any antidepressant treatment. The recordings were acquired from two independent studies using different actigraphy systems. Data was quality-controlled and pre-processed for feature extraction following uniform procedures. We trained multiple regression models to predict MADRS score from features of activity patterns using brute-force and semi-supervised machine learning algorithms. The models were filtered based on the precision and the accuracy of fitting on training dataset before undergoing external validation on an independent dataset. The features enriched in the models surviving external validation point to high depressive symptom severity being associated with less complex activity patterns and stronger coupling to external circadian entrainers. Our results bring proof-of-concept evidence that activity patterns correlate with severity of depressive symptoms and suggest that actigraphy recordings may be a useful tool for individual evaluation of patients with major depressive disorder.

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.

Exposure to prenatal insults, such as excess glucocorticoids (GC), may lead to pathological outcomes, including neuropsychiatric disorders. The aim of the present study was to investigate the long-term effects of in utero exposure to the synthetic GC analog dexamethasone (Dex) in adult female offspring. We monitored spontaneous activity in the home cage under a constant 12 h/12 h light/dark cycle, as well as the changes following a 6-h advance of dark onset (phase shift). For comparison, we re-analysed data previously recorded in males. Dex-exposed females were spontaneously more active, and the activity onset re-entrained slower than in controls. In contrast, Dex-exposed males were less active, and the activity onset re-entrained faster than in controls. Following the phase shift, control females displayed a transient reorganisation of behaviour in light and virtually no change in dark, while Dex-exposed females showed limited variations from baseline in both light and dark, suggesting weaker photic entrainment. Next, we ran bulk RNA-sequencing in the suprachiasmatic nucleus (SCN) of Dex and control females. SPIA pathway analysis of ~ 2300 differentially expressed genes identified significantly downregulated dopamine signalling, and upregulated glutamate and GABA signalling. We selected a set of candidate genes matching the behaviour alterations and found consistent differential regulation for ~ 73% of tested genes in SCN and hippocampus tissue samples. Taken together, our data highlight sex differences in the outcome of prenatal exposure to excess GC in adult mice: in contrast to depression-like behaviour in males, the phenotype in females, defined by behaviour and differential gene expression, is consistent with ADHD models.