The noradrenergic symptom cluster: clinical expression and neuropharmacology

Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT2A and 5-HT2C receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI

Effects of temperature on in vitro sediment reworking processes by a gallery biodiffusor, the polychaete Neanthes virens

Temperature-induced variations in bioturbation could affect sediment mixing processes in the marine benthic environment. In this study, sediment reworking by Neanthes virens (Sars), a widely distributed polychaete in muddy sand communities of northern temperate latitudes, was studied under different temperature conditions representing winter (1°C), spring and fall (6°C), summer(13°C), and tide pool (18°C) temperatures in the lower St. Lawrence Estuary, Québec, Canada. Sediment reworking was quantified using inert fluorescent particles (luminophores) deposited at the sediment surface. Based on the 1-D luminophore distributions obtained after 5 and 30 d, the use of the specific ‘gallery-biodiffusor’ model allowed us to quantify both biodiffusion (Db) and biotransport (Vb) due to the organisms. Our results showed temperature effects on sediment transport. The lowest biotransport and biodiffusion coefficients were measured at 1 and 6°C and did not change with time. The highest biodiffusion occurred at 13°C for both sampling periods. At 18°C, biodiffusion was intermediate while biotransport was maximal. Differences between the 13°C biodiffusive transport and the other temperatures increased with time. Low transport values at 1 and 6°C suggest that a quiescent stage exists for this species at these temperatures, with sediment mixing occurring mostly during burrow construction. On the other hand, sediment mixing resulted from both the burrow construction and maintenance phases at higher temperatures (13 and 18°C)

The longest-lived metazoan, Arctica islandica, exhibits high mitochondrial H2O2 removal capacities

A greater capacity of endogenous matrix antioxidants has recently been hypothesized to characterize mitochondria of long-lived species, curbing bursts of reactive oxygen species (ROS) generated in this organelle. Evidence for this has been obtained from studies comparing the long-lived naked mole rat to laboratory mice. We tested this hypothesis by comparing the longest-lived metazoan, the marine bivalve Arctica islandica (MLSP=507 y), with shorter-lived and evolutionarily related species. We used a recently developed fluorescent technique to assess mantle and gill tissue mitochondria’s capacity to consume hydrogen peroxide (H2O2) in multiple physiological states ex vivo. Depending on the type of respiratory substrate provided, mitochondria of Arctica islandica could consume between 3-14 times more H2O2 than shorter-lived species. These findings support the contention that a greater capacity for the elimination of ROS characterizes long-lived species, a novel property of mitochondria thus far demonstrated in two key biogerontological models from distant evolutionary lineages

The influence of gene-environment interactions on GHR and IGF-1 expression and their association with growth in brook charr, Salvelinus fontinalis (Mitchill)

<p>Abstract</p> <p>Background</p> <p>Quantitative reaction norm theory proposes that genotype-by-environment interaction (GxE) results from inter-individual differences of expression in adaptive suites of genes in distinct environments. However, environmental norms for actual gene suites are poorly documented. In this study, we investigated the effects of GxE interactions on levels of gene transcription and growth by documenting the impact of rearing environment (freshwater vs. saltwater), sex and genotypic (low vs. high estimated breeding value EBV) effects on the transcription level of insulin-like growth factor (IGF-1) and growth hormone receptor (GHR) in brook charr (<it>Salvelinus fontinalis</it>).</p> <p>Results</p> <p>Males grew faster than females (μ_♀= 1.20 ± 0.07 g·d^-1, μ_♂= 1.46 ± 0.06 g·d^-1) and high-EBV fish faster than low-EBV fish (μ_LOW= 0.97 ± 0.05 g·d^-1, μ_HIGH= 1.58 ± 0.07 g·d^-1; p < 0.05). However, growth was markedly lower in saltwater-reared fish than freshwater sibs (μ_FW= 1.52 ± 0.07 g·d^-1, μ_SW= 1.15 ± 0.06 g·d^-1), yet GHR mRNA transcription level was significantly higher in saltwater than in freshwater (μ_SW= 0.85 ± 0.05, μ_FW= 0.61 ± 0.05). The ratio of actual growth to units in assayed mRNA ('individual transcript efficiency', iTE; g·d^-1·u^-1) also differed among EBV groups (μ_LOW= 2.0 ± 0.24 g·d^-1·u^-1; μ_HIGH= 3.7 ± 0.24 g·d^-1·u^-1) and environments (μ_SW= 2.0 ± 0.25 g·d^-1·u^-1; μ_FW= 3.7 ± 0.25 g·d^-1·u^-1) for GHR. Males had a lower iTE for GHR than females (μ_♂= 2.4 ± 0.29 g·d^-1·u^-1; μ_♀= 3.1 ± 0.23 g·d^-1·u^-1). There was no difference in IGF-1 transcription level between environments (p > 0.7) or EBV groups (p > 0.15) but the level of IGF-1 was four times higher in males than females (μ_♂= 2.4 ± 0.11, μ_♀= 0.58 ± 0.09; p < 0.0001). We detected significant sexual differences in iTE (μ_♂= 1.3 ± 0.59 g·d^-1·u^-1; μ_♀= 3.9 ± 0.47 g·d^-1·u^-1), salinities (μ_SW= 2.3 ± 0.52 g·d^-1·u^-1; μ_FW= 3.7 ± 0.53 g·d^-1·u^-1) and EBV-groups (μ_LOW= 2.4 ± 0.49 g·d^-1·u^-1; μ_HIGH= 3.8 ± 0.49 g·d^-1·u^-1). Interaction between EBV-group and environment was detected for both GHR (p = 0.027) and IGF-1 (p = 0.019), and for iTE in the two genes (p < 0.0001; p < 0.05, respectively), where increased divergence in levels of GHR and IGF-1 transcription occurred among EBV-groups in the saltwater environment.</p> <p>Conclusion</p> <p>Our results show that both environment and sex have major impacts on the expression of mRNA for two key genes involved in the physiological pathway for growth. We also demonstrate for the first time, at least in fish, genotype-by-environment interaction at the level of individual gene transcription. This work contributes significantly to ongoing efforts towards documenting environmentally and sexually induced variance of gene activity and understanding the resulting phenotypes.</p

Supercomplex Organization of the Electron Transfer System in Marine Bivalves, a Model of Extreme Longevity

The mitochondrial oxidative stress theory of aging suggests that the organelle’s decay contributes to the aging phenotype via exacerbated oxidative stress, loss of organ coordination and energetics, cellular integrity, and activity of the mitochondrial electron transfer system (ETS). Recent advances in understanding the structure of the ETS show that the enzymatic complexes responsible for oxidative phosphorylation are arranged in supramolecular structures called supercomplexes that lose organization during aging. Their exact role and universality among organisms are still under debate. Here, we take advantage of marine bivalves as an aging model to compare the structure of the ETS among species ranging from 28 to 507 years in maximal life span. Our results show that regardless of life span, the bivalve ETS is arrayed as a set of supercomplexes. However, bivalve species display varying degrees of ETS supramolecular organization with the highest supercomplex structures found in Arctica islandica, the longest-lived of the bivalve species under study. We discuss this comparative model in light of differences in the nature and stoichiometry of these complexes and highlight the potential link between the complexity of these superstructures and longer life spans

Leveraging Machine Learning Approaches for Predicting Antidepressant Treatment Response Using Electroencephalography (EEG) and Clinical Data

Background: Individuals with major depressive disorder (MDD) vary in their response to antidepressants. However, identifying objective biomarkers, prior to or early in the course of treatment that can predict antidepressant efficacy, remains a challenge.Methods: Individuals with MDD participated in a 12-week antidepressant pharmacotherapy trial. Electroencephalographic (EEG) data was collected before and 1 week post-treatment initiation in 51 patients. Response status at week 12 was established with the Montgomery-Asberg Depression Scale (MADRS), with a ≥50% decrease characterizing responders (N = 27/24 responders/non-responders). We used a machine learning (ML)-approach for predicting response status. We focused on Random Forests, though other ML methods were compared. First, we used a tree-based estimator to select a relatively small number of significant features from: (a) demographic/clinical data (age, sex, individual item/total MADRS scores at baseline, week 1, change scores); (b) scalp-level EEG power; (c) source-localized current density (via exact low-resolution electromagnetic tomography [eLORETA] software). Second, we applied kernel principal component analysis to reduce and map important features. Third, a set of ML models were constructed to classify response outcome based on mapped features. For each dataset, predictive features were extracted, followed by a model of all predictive features, and finally by a model of the most predictive features.Results: Fifty eLORETA features were predictive of response (across bands, both time-points); alpha1/theta eLORETA features showed the highest predictive value. Eighty-eight scalp EEG features were predictive of response (across bands, both time-points), with theta/alpha2 being most predictive. Clinical/demographic data consisted of 31 features, with the most important being week 1 “concentration difficulty” scores. When all features were included into one model, its predictive utility was high (88% accuracy). When the most important features were extracted in the final model, 12 predictive features emerged (78% accuracy), including baseline scalp-EEG frontopolar theta, parietal alpha2 and frontopolar alpha1.Conclusions: These findings suggest that ML models of pre- and early treatment-emergent EEG profiles and clinical features can serve as tools for predicting antidepressant response. While this must be replicated using large independent samples, it lays the groundwork for research on personalized, “biomarker”-based treatment approaches

Anti-inflammatory properties of natural ingredients used in combinations on adjuvant induced arthritis in rats

Background: Rheumatoid arthritis has seen a significant increase in both incidence and prevalence and its treatments show limited efficiency due to their undesirable effects on patient health. Therefore, major interests lie in the development of treatments with drugs derived from plants or other natural sources with little adverse effects as an alternative to current treatments. Hypothesis/Purpose: The present study evaluates the therapeutic effects of glucosamine against rheumatoid arthritis in combination with hyaluronic acid, resin extract of Boswellia serrata or a bark extract of Salix alba on an animal model. We suggest that combinations with plants could improve the attenuation of arthritis symptoms and articular inflammation. Study design: We used Freund’s complete adjuvant on rats as models of rheumatoid arthritis. Individuals were separated into eight experimental groups: a control group without arthritis, one with arthritis and without treatment, and six other groups receiving a daily therapeutic treatment from days 14 to 29. Methods: Hind-paw thickness and arthritis scores were measured at days 0, 3, 6 and 9 post-induction, and then every day from days 12 to 29 with a digital caliper and a score system respectively. At the end of the treatment, the mRNA content of three pro-inflammatory cytokines from cartilage was measured using real-time PCR. The total antioxidant activity was evaluated with an Antioxidant Assay Kit. Results: Treatments with Boswellia serrata and Salix alba (Glu+Hyal A+Bosw, Glu+Bosw+Sal, Glu+Bosw and Glu+Hyal A+Sal) saw significant reductions in hind-paw thickness and arthritis scores at the end of the experiment when compared to the untreated group. Expression of pro-inflammatory gene IL 17A was also reduced, but only the Glu+Hyal A+Sal combination significantly decreased the expression of IL-1β and TNF-α. The total antioxidant activity in blood plasma significantly increased in groups treated with plant extracts. Conclusion: The addition of Boswellia serrata and/or Salix alba attenuates clinical signs of rheumatoid arthritis in Freund’s complete adjuvant-induced arthritis in rats likely due to both their anti-inflammatory and antioxidant properties

Responsiveness of 5-HT1A and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition

Background: The only antidepressant drugs that are effective in the treatment of obsessive-compulsive disorder (OCD) are those that effectively block the reuptake of serotonin (5-hydroxytryptamine; 5-HT). In humans, positron emission tomography studies have implicated the orbitofrontal cortex (OFC) in the mediation of OCD symptoms. In animals, administration of selective serotonin reuptake inhibitors (SSRIs) for 8 weeks (but not 3 weeks) led to increased release of 5-HT in the OFC, because of desensitization of the terminal 5-HT autoreceptors. However, the increase in synaptic levels of 5-HT in the OFC after long-term administration of SSRIs might be cancelled out by desensitization of postsynaptic 5-HT receptors. This study was undertaken to investigate if these OFC receptors adapt under such conditions. Methods: In vivo electrophysiologic techniques were used in this animal study. Male Sprague-Dawley rats received the SSRI paroxetine or vehicle control, delivered by implanted osmotic minipumps, for 3 or 8 weeks. With the rats under anesthesia, neuronal responsiveness to the microiontophoretic application of various drugs was assessed by determining the number of spikes suppressed per nanoampere of ejection current. Results: After administration of paroxetine for either 3 weeks or 8 weeks, there was no modification in the inhibitory effect of 5-HT, the preferential 5-HT 2A receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) or the preferential 5-HT 2C receptor agonist 3-chlorophenyl piperazine dihydrochloride (mCPP). In contrast, the inhibitory effect of the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT) was attenuated in the OFC after both 3 and 8 weeks of paroxetine administration. Conclusion: These results indicate a desensitization of postsynaptic 5-HT 1A receptors in the OFC but a lack of compensatory adaptation of the 5-HT receptor(s) mediating the main effect of 5-HT in this brain region. These observations imply that the activation of normosensitive postsynaptic 5-HT 2 -like receptors may mediate the effect of enhanced 5-HT release in the OFC. Contexte : Seuls les antidépresseurs qui parviennent à bloquer le recaptage de la sérotonine (5-HT) sont efficaces dans le traitement du trouble obsessionnel compulsif (TOC). Chez l&apos;humain, les études fondées sur la tomographie par émission de positrons ont lié le cortex orbitofrontal (COF) avec la médiation des symptômes du TOC. Chez l&apos;animal, l&apos;administration d&apos;inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) pendant huit semaines (plutôt que trois semaines) a conduit à une libération accrue de 5-HT dans le COF, en raison de l&apos;hyposensibilisation des autorécepteurs terminaux de la 5-HT. L&apos;hyposensibilisation des récepteurs post-synaptiques de la 5-HT pourrait toutefois neutraliser l&apos;accroissement des taux synaptiques de 5-HT dans le COF suite à un traitement de longue durée faisant appel aux ISRS. Cette étude visait à étudier la question de savoir si ces récepteurs du COF s&apos;adaptent dans ces conditions. Méthodes : Des techniques in vivo en électrophysiologie ont été appliqués dans cette étude chez l&apos;animal. Pendant trois ou huit semaines, on a administré à des rats mâles de Sprague-Dawley soit de la paroxétine, un ISRS, soit un véhicule de contrôle, au moyen de minipompes osmotiques implantées. Chez les rats sous anesthésie, la réponse neuronale à l&apos;application microiontophorétique de diverses substances a été évaluée par la détermination du nombre de potentiels d&apos;action supprimés par nanoampère de courant éjecté. Résultats : Suite à l&apos;administration de paroxétine pendant trois ou huit semaines, il n&apos;y a pas eu de modification de l&apos;effet d&apos;inhibition de la 5-HT, du chlorhy

Can trans-generational experiments be used to enhance species resilience to ocean warming and acidification?

Human-assisted, trans-generational exposure to ocean warming and acidification has been proposed as a conservation and/or restoration tool to produce resilient offspring. To improve our understanding of the need for and the efficacy of this approach, we characterized life-history and physiological responses in offspring of the marine polychaete Ophryotrocha labronica exposed to predicted ocean warming (OW: + 3 degrees C), ocean acidification (OA: pH -0.5) and their combination (OWA: + 3 degrees C, pH -0.5), following the exposure of their parents to either control conditions (within-generational exposure) or the same conditions (trans-generational exposure). Trans-generational exposure to OW fully alleviated the negative effects of within-generational exposure to OW on fecundity and egg volume and was accompanied by increased metabolic activity. While within-generational exposure to OA reduced juvenile growth rates and egg volume, trans-generational exposure alleviated the former but could not restore the latter. Surprisingly, exposure to OWA had no negative impacts within-or trans-generationally. Our results highlight the potential for trans-generational laboratory experiments in producing offspring that are resilient to OW and OA. However, trans-generational exposure does not always appear to improve traits and therefore may not be a universally useful tool for all species in the face of global change

Mitochondrial phylogenomics of the Bivalvia (Mollusca): searching for the origin and mitogenomic correlates of doubly uniparental inheritance of mtDNA

<p>Abstract</p> <p>Background</p> <p>Doubly uniparental inheritance (DUI) is an atypical system of animal mtDNA inheritance found only in some bivalves. Under DUI, maternally (F genome) and paternally (M genome) transmitted mtDNAs yield two distinct gender-associated mtDNA lineages. The oldest distinct M and F genomes are found in freshwater mussels (order Unionoida). Comparative analyses of unionoid mitochondrial genomes and a robust phylogenetic framework are necessary to elucidate the origin, function and molecular evolutionary consequences of DUI. Herein, F and M genomes from three unionoid species, <it>Venustaconcha ellipsiformis, Pyganodon grandis </it>and <it>Quadrula quadrula </it>have been sequenced. Comparative genomic analyses were carried out on these six genomes along with two F and one M unionoid genomes from GenBank (F and M genomes of <it>Inversidens japanensis </it>and F genome of <it>Lampsilis ornata</it>).</p> <p>Results</p> <p>Compared to their unionoid F counterparts, the M genomes contain some unique features including a novel localization of the <it>trnH </it>gene, an inversion of the <it>atp8-trnD </it>genes and a unique 3'coding extension of the cytochrome <it>c </it>oxidase subunit II gene. One or more of these unique M genome features could be causally associated with paternal transmission. Unionoid bivalves are characterized by extreme intraspecific sequence divergences between gender-associated mtDNAs with an average of 50% for <it>V. ellipsiformis</it>, 50% for <it>I. japanensis</it>, 51% for <it>P. grandis </it>and 52% for <it>Q. quadrula </it>(uncorrected amino acid p-distances). Phylogenetic analyses of 12 protein-coding genes from 29 bivalve and five outgroup mt genomes robustly indicate bivalve monophyly and the following branching order within the autolamellibranch bivalves: ((Pteriomorphia, Veneroida) Unionoida).</p> <p>Conclusion</p> <p>The basal nature of the Unionoida within the autolamellibranch bivalves and the previously hypothesized single origin of DUI suggest that (1) DUI arose in the ancestral autolamellibranch bivalve lineage and was subsequently lost in multiple descendant lineages and (2) the mitochondrial genome characteristics observed in unionoid bivalves could more closely resemble the DUI ancestral condition. Descriptions and comparisons presented in this paper are fundamental to a more complete understanding regarding the origins and consequences of DUI.</p