Molecular Pathways of Disturbed Sleep and Depression : Studies on Adenosine and Gene Expression Patterns

Background: Adenosine is a potent sleep-promoting substance, and one of its targets is the basal forebrain. Fairly little is known about its mechanism of action in the basal forebrain and about the receptor subtype mediating its regulating effects on sleep homeostasis. Homeostatic deficiency might be one of the causes of the profoundly disturbed sleep pattern in major depressive disorder, which could explain the reduced amounts of delta-activity-rich stages 3 and 4. Since major depression has a relatively high heritability, and on the other hand adenosine regulates sleep homeostasis and might also be involved in mood modulation, adenosine-related genes should be considered for their possible contribution to a predisposition for depression and disturbed sleep in humans. Depression is a complex disorder likely involving the abnormal functioning of several genes. Novel target genes which could serve as the possible common substrates for depression and comorbid disturbed sleep should be identified. In this way specific brain areas related to sleep regulation should be studied by using animal model of depression which represents more homogenous phenotype as compared to humans. It is also important to study these brain areas during the development of depressive-like features to understand how early changes could facilitate pathophysiological changes in depression. Aims and methods: We aimed to find out whether, in the basal forebrain, adenosine induces recovery non-rapid eye movement (NREM) sleep after prolonged waking through the A1 or/and A2A receptor subtype. A1 and A2A receptor antagonists were perfused into the rat basal forebrain during 3 h of sleep deprivation, and the amount of NREM sleep and delta power during recovery NREM sleep were analyzed. We then explored whether polymorphisms in genes related to the metabolism, transport and signaling of adenosine could predispose to depression accompanied by signs of disturbed sleep. DNA from 1423 individuals representative of the Finnish population and including controls and cases with depression, depression accompanied by early morning awakenings and depression accompanied by fatigue, was used in the study to investigate the possible association between polymorphisms from adenosine-related genes and cases. Finally to find common molecular substrates of depression and disturbed sleep, gene expression changes were investigated in specific brain areas in the rat clomipramine model of depression. We focused on the basal forebrain of 3-week old clomipramine-treated rats which develop depressive-like symptoms later in adulthood and on the hypothalamus of adult female clomipramine-treated rats. Results: Blocking of the A1 receptor during sleep deprivation resulted in a reduction of the recovery NREM sleep amount and delta power, whereas A2A receptor antagonism had no effect. Polymorphisms in adenosine-related genes SLC29A3 (equilibrative nucleoside transporter type 3) in women and SLC28A1 (concentrative nucleoside transporter type 1) in men associated with depression alone as well as when accompanied by early morning awakenings and fatigue. In Study III the basal forebrain of postnatal rats treated with clomipramine displayed disturbances in gamma-aminobutyric acid (GABA) receptor type A signaling, in synaptic transmission and possible epigenetic changes. CREB1 was identified as a common transcription denominator which also mediates epigenetic regulation. In the hypothalamus the major changes included the expression of genes in GABA-A receptor pathway, K+ channel-related, glutamatergic and mitochondrial genes, as well as an overexpression of genes related to RNA and mRNA processing. Conclusions: Adenosine plays an important role in sleep homeostasis by promoting recovery NREM sleep via the A1 receptor subtype in the basal forebrain. Also adenosine levels might contribute to the risk of depression with disturbed sleep, since the genes encoding nucleoside transporters showed the strongest associations with depression alone and when accompanied by signs of disturbed sleep in both women and men. Sleep and mood abnormalities in major depressive disorder could be a consequence of multiple changes at the transcriptional level, GABA-A receptor signaling and synaptic transmission in sleep-related basal forebrain and the hypothalamus.Depressiolla ja unella tiedetään olevan useita liittymäkohtia, ja depressiopotilaiden uni on lähes aina häiriintynyt. Unelle on tyypillistä homeostaattinen säätely, mikä tarkoittaa unen pitenemistä ja syvenemistä pitkittyneen valvejakson jälkeen. Unen homeostaasin häiriintyminen saattaa olla yhtenä syynä depressiossa ilmeneviin unihäiriöihin. Adenosiini on unen homeostaasia säätelevä molekyyli, joka vaikuttaa etuaivojen pohjaosassa. Tässä yössä tutkimme unen homeostaattisen säätelyn, adenosiinin ja depression yhteyksiä käyttäen sekä ihmistuloksia että eläinmalleja. Havaitsimme, että adenosiini edistää NREM unta adenosiini A1 mutta ei A2 reseptoreiden kautta rotan etuaivojen pohjaosassa. Seuraavaksi tutkimme mitkä adenosiinin aineenvaihduntaan liittyvät geenit ihmisillä liittyivät depressioalttiuteen ja huonounisuuteen. Polymorfismit geeneissä SLC29A3 (tasapainottava adenosiinikuletusmolekyyli tyyppi 3) naisilla ja SLC28A1 (konsentroiva kuljetusmolekyyli tyyppi 1) miehillä assosioituivat sekä depressioon sinänsä että depressioon, jossa lisäoireina olivat aikaiset aamuheräämiset ja voimattomuuden tunne. Tutkimus tehtiin suomalaisesta koko väestön kattavasta aineistosta. Käyttäen depression eläinmallia (varhaisiän klomipramiinikäsittely) etsimme yhteisiä geenejä, jotka voisivat liittyä sekä depression että unihäiriöiden syntyyn. Tutkimme geenien ilmentymistä etuvaivojen pohjaosassa 3 viikon ikäisillä rotanpoikasilla sekä aikuisten rottien hypotalamusta klomipramiinikäsitellyillä eläimillä ja vertasimme tuloksia käsittelemättömiin rottiin. Havaitsimme, että poikasilla häiriöitä gamma-aminovoihapon (GABA) reseptori A viestinvälityksessä sekä mahdollisesti epigeneettiseen säätelyyn liittyviä muutoksia. Myös CREB1 geenin ilmentyminen oli muuttunut. Aikuisena GABA-A reseptorin ja K-kanavan toimintaa säätelevien geenien ilmentyminen oli muuttunut, samoin kuin glutamaatin ja mitokondrioiden toimintaan liittyvien geenien ilmentyminenkin. Löydökset viittaavat siihen, että depressiolla on geneettinen tausta, jossa tärkeinä geeneinä ovat useat neurotransmitterit, mukaanlukien adenosiini

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Interactive tool to create adjustable anatomical atlases for mouse brain imaging

Objective!#!Brain atlases are important research tools enabling researchers to focus their investigations on specific anatomically defined brain regions and are used in many MRI applications, e.g. in fMRI, morphometry, whole brain spectroscopy, et cetera. Despite their extensive use and numerous versions they usually consist of predefined rigid brain regions with a given level of detail often degrading them to a non-ideal tool in special research topics.!##!Result!#!To overcome this intrinsic weakness we present a graphical user interface application which allows researchers to easily create mouse brain atlases with an adjustable user-defined level of detail and coverage to match specific research questions

Evaluation of Large-Scale Parameters in Urban Microcells at 3.8 GHz

This paper evaluates MIMO radio channel measurements at 3.8 GHz, conducted in various urban microcell environments in Louvain-la-Neuve. Large-scale parameters, such as shadow fading, delay and angular spreads, are extracted and compared with values provided by existing models (COST 273, COST 2100 and 3GPP- 3D)