Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies

Implementation of Scheduled Maintenance in Companies with Support of Computer Programs

Import 05/08/2014Tato bakalářská práce se zabývá zavedením plánované údržby v závodě Dolu Karviná, implementací programu SAP (Systémy, Aplikace, Produkty) do údržby a vytvořením nového kontrolního úseku zabývajícím se plánováním, řízením, kontrolováním a vyhodnocováním údržby ve výrobním procesu.This thesis deals with the introduction of scheduled maintenance in the plant Karvina Mine, implementations program SAP (Systeme, Anwendungen, Produkte) in the maintenance and creation of new control section dealing with planning, managing, controlling and evaluating maintenance in the manufacturing process.340 - Katedra výrobních strojů a konstruovánídobř

Issue of Mine Water Pumping

Import 02/11/2016Diplomová práce se zabývá problematikou čerpání důlních vod. V teoretické části diplomové práce jsou popsány používané typy čerpadel, jejich parametry a použití. Dále byly popsány druhy poruchových stavů při čerpání důlních vod. V praktické části jsem aplikoval vibrodiagnostiku na zjištění technického stavu čerpadel. Dále je aplikováno ustavování hřídele do osy na důlním čerpadle pomocí laserového přístroje a následná aplikace diagnostiky, konkrétně vibrodiagnostiky, tribodiagnostiky a termodiagnostiky.The thesis deals with the issue of mine water pumping. The theoretical part of thesis describes common types of pumps, their characteristics and applications. It also describes kinds of fault conditions in the mine water pumping. In the practical part I have applied vibrodiagnostics on the findings of the technical condition of the pumps. Next is also applied shaft alignment to amine pump axis using a laser device and subsequent application of diagnostics, specifically vibrodiagnostics, trobodiagnostics and thermodiagnostics.340 - Katedra výrobních strojů a konstruovánívýborn

Murine Warriors or Worriers: The Saga of Comt1, B2 SINE Elements, and the Future of Translational Genetics

Catechol-O-methyltransferase (COMT) is an extremely well characterized enzyme that degrades catecholamines. A common coding polymorphism (rs4680; Val158Met) in the human COMT gene has been associated with a diverse array of phenotypes including personality, cognition, pain sensitivity, and risk for psychiatric disorders (Tunbridg

Editorial: Why should we read Dalit literature?

<p>(A) BDNF and (B) NCAM1 expression in the VTA of mice exposed to ABA conditions. Insets indicate mean BDNF and NCAM1 expression during restriction for the independent measure depicted. Results expressed as mean log2(RQ) ± S.E.M. p<0.05. STV, starved mice exposed to food restriction and house without a wheel; RUN, mice exposed to wheel running; ABA, mice exposed to ABA conditions; W, wheel; FR, food restriction.</p

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Modulation of Tcf7l2 Expression Alters Behavior in Mice

The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether Tcf7l2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of Tcf7l2 or overexpressing Tcf7l2. We identified a role for Tcf7l2 in anxiety-like behavior and a dose-dependent effect of Tcf7l2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that Tcf7l2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further

The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.

Major depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1(-/-) mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1(-/-) mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant-like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1(-/-) mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment-resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development