Clock Genes in Depression

Data demonstrate that abnormal regulation of the circadian system can result in cardiovascular disease, metabolic syndrome, obesity, immune dysfunction, increased risk for cancer, reproductive complications, etc. It is highly individual among depressed patients and may be expressed as a phase advance or phase delay of rhythms and/or increase or decrease in the amplitude. The stress-induced anhedonic-like state characterizes by hypothermia, hypercortisolemia, and hypermelatoninemia associated with disturbances in the circadian system. Mainly Per2 and Bmal1 demonstrate altered expression in the brain and liver: expression of Per2 is sensitive to stress and changes in Bmal1 mostly associated with depressive behavior. The Per1 expression is sustainable in maintaining the circadian rhythm. A normalization of the expression patterns is likely to be essential for the recovery from the pathological state. Depression is a high prevalent disorder. The number of incidents is rising due to changes in lifestyle. The symptomatology is inconsistent and it is difficult to agree on one hypothesis. The disturbances of the 24 h circadian rhythm may be a factor in the development of major depressive disorder. The molecular biology underlying a causal relationship between circadian rhythm and mood disorders is slowly being unraveled. However, many questions still need to be answered

Altered Expression Pattern of Clock Genes in a Rat Model of Depression

BACKGROUND: Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation of clock gene expression in depressive patients, many studies have reported single-nucleotide polymorphisms in clock genes in these patients. METHODS: In the present study we investigated whether a depression-like state in rats is associated with alternations of the diurnal expression of clock genes. The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes: period genes 1 and 2 (Per1 and Per2) and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at a 4h sampling interval within 24h. We quantified expression of clock genes on brain sections in the prefrontal cortex, nucleus accumbens, pineal gland, suprachiasmatic nucleus, substantia nigra, amygdala, ventral tegmental area, subfields of the hippocampus, and the lateral habenula using in situ hybridization histochemistry. Expression of clock genes in the liver was monitored by real-time quantitative polymerase chain reaction (PCR). RESULTS: We found that the effect of CMS on clock gene expression was selective and region specific. Per1 exhibits a robust diurnal rhythm in most regions of interest, whereas Bmal1 and in particular Per2 were susceptible to CMS. CONCLUSION: The present results suggest that altered expression of investigated clock genes is likely associated with the induction of a depression-like state in the CMS model

The importance of n-6/n-3 fatty acids ratio in the major depressive disorder

This review aims to clarify the relation between the ratio of omega-6 to omega-3 fatty acids and the development of depression. It is explained how these fatty acids are involved in the production of eicosanoids and how these fatty acids can affect the membrane fluidity, by their incorporation into membrane phospholipids. In addition, it is described how omega-3 derivatives are shown to regulate gene transcription. In view of the pathophysiology of depression, the mechanisms of how an altered ratio of omega-6 to omega-3 could be involved in depression are discussed. Possible mechanisms could include an increased production of pro-inflammatory cytokines, which can activate the HPA axis and a changed membrane fluidity, which potentially affects membrane bound enzymes, ion channels, receptor activity and neurotransmitter binding. In view of clinical trials, it is also discussed whether omega-3 supplementation could have a beneficial effect in the treatment of depressive patient. There are strong indications that an increased ratio of membrane omega-6 to omega-3 is involved in the pathogenesis of depression and so far, omega-3 supplementation has shown positive effects in clinical trials

Role of peripheral vascular resistance for the association between major depression and cardiovascular disease

Major depression and cardiovascular diseases are 2 of the most prevalent health problems in Western society, and an association between them is generally accepted. Although the specific mechanism behind this comorbidity remains to be elucidated, it is clear that it has a complex multifactorial character including a number of neuronal, humoral, immune, and circulatory pathways. Depression-associated cardiovascular abnormalities associate with cardiac dysfunctions and with changes in peripheral resistance. Although cardiac dysfunction in association with depression has been studied in detail, little attention was given to structural and functional changes in resistance arteries responsible for blood pressure control and tissue perfusion. This review discusses recent achievements in studies of depression-associated abnormalities in resistance arteries in humans and animal experimental models. The changes in arterial structure, contractile and relaxing functions associated with depression symptoms are discussed, and the role of these abnormalities for the pathology of major depression and cardiovascular diseases are suggested

Skeletal Muscle Na,K-ATPase as a Target for Circulating Ouabain

While the role of circulating ouabain-like compounds in the cardiovascular and central nervous systems, kidney and other tissues in health and disease is well documented, little is known about its effects in skeletal muscle. In this study, rats were intraperitoneally injected with ouabain (0.1–10 µg/kg for 4 days) alone or with subsequent injections of lipopolysaccharide (1 mg/kg). Some rats were also subjected to disuse for 6 h by hindlimb suspension. In the diaphragm muscle, chronic ouabain (1 µg/kg) hyperpolarized resting potential of extrajunctional membrane due to specific increase in electrogenic transport activity of the α2 Na,K-ATPase isozyme and without changes in α1 and α2 Na,K-ATPase protein content. Ouabain (10–20 nM), acutely applied to isolated intact diaphragm muscle from not injected rats, hyperpolarized the membrane to a similar extent. Chronic ouabain administration prevented lipopolysaccharide-induced (diaphragm muscle) or disuse-induced (soleus muscle) depolarization of the extrajunctional membrane. No stimulation of the α1 Na,K-ATPase activity in human red blood cells, purified lamb kidney and Torpedo membrane preparations by low ouabain concentrations was observed. Our results suggest that skeletal muscle electrogenesis is subjected to regulation by circulating ouabain via the α2 Na,K-ATPase isozyme that could be important for adaptation of this tissue to functional impairment

Evaluation of Divers’ Neuropsychometric Effectiveness and High-Pressure Neurological Syndrome via Computerized Test Battery Package and Questionnaires in Operational Setting

Introduction: When divers are compressed to water depths deeper than 150 meter sea water (msw), symptoms of high-pressure neurological syndrome (HPNS) might appear due to rapid increase in pressure on the central nervous system during compression. The aim of this study was to first operate a new computerized tool, designed to monitor divers’ wellbeing and cognitive function, and to record the results. The second aim was to evaluate the feasibility and validity of the Physiopad software and HPNS questionnaires as a new tool for monitoring divers wellbeing in an operational setting, including sensible visualization and presentation of results. Methods: The Physiopad was operated onboard Deep Arctic (TechnipFMC Diving Support Vessel). The diving work was performed between 180 and 207 msw. The data from 46 divers were collected from the HPNS questionnaires, Hand dynamometry test, Critical Flicker Fusion Frequency test (CFFF), Adaptive Visual Analog Scale (AVAS), Simple Math Process (MathProc test), Perceptual Vigilance Task (PVT), and Time Estimation Task (time-wall). Result: Diver’s subjective evaluation revealed different symptoms, possibly also HPNS related, which lasted from 1 to 5 days in storage, with the common duration being 1 day. The results from Physiopad battery testing showed no signs of significant neurological alteration. Conclusion: The present study showed that there was no association between subjective measurements of HPNS and neuropsychometric test results. We also confirmed the feasibility of using the computerized test battery to monitor saturation divers at work. The HPNS battery and Physiopad software could be an important tool for monitoring diver’s health in the future. This tool was not used during the Bahr Essalam project to operationally evaluate any HPNS effect on divers as data analysis was performed post-project

Molecular Profiling of the Lateral Habenula in a Rat Model of Depression

<div><p>Objective</p><p>This study systematically investigated the effect of chronic mild stress and response to antidepressant treatment in the lateral habenula at the whole genome level.</p><p>Methods</p><p>Rat whole genome expression chips (Affymetrix) were used to detect gene expression regulations in the lateral habenula of rats subjected to chronic mild stress (mild stressors exchanged twice a day for 8 weeks). Some rats received antidepressant treatment during fifth to eights week of CMS. The lateral habenula gene expression profile was studied through the gene ontology and signal pathway analyses using bioinformatics. Real-time quantitative polymerase chain reaction (RT-PCR) was used to verify the microarray results and determine the expression of the <i>Fcrla, Eif3k, Sec3l1, Ubr5, Abca8a, Ankrd49, Cyp2j10, Frs3, Syn2, and Znf503</i> genes in the lateral habenula tissue.</p><p>Results</p><p>In particular we found that stress and antidepressant treatment affected intracellular cascades like growth factor receptor signaling, G-protein-coupled receptor signaling, and Wnt signaling – processes involved in the neuroplastic changes observed during the progression of depression and antidepressant treatment.</p><p>Conclusion</p><p>The present study suggests an important role of the lateral habenula in the development of depression-like conditions and correlates to previous studies demonstrating a significant role of the lateral habenula in depressive-like conditions and antidepressant treatment.</p></div

Relationships between groups built up for PANTHER analysis.

<p>Statistical enrichment of biological pathways was assessed by binomial statistics within the PANTHER system. (A and B) Relationships for classification of pathways implicated in depression and recovery; (C and D) Relationships for classification of pathways implicated in treatment response. Dashed lines indicate significant differences in pathways between groups (<i>p</i><0.05), regular lines indicate no differences in pathways between groups. U-V, unchallenged control rats; CMS-V, CMS vehicle; Esc-R, CMS escitalopram responders; Esc-NR, CMS escitalopram non-responders.</p