Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

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Takashi eMaejima

2013-05-01

Full Text Available Serotonergic neurons project to virtually all regions of the CNS and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing and reproductive success. Therefore serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo.

Harmane inhibits serotonergic dorsal raphe neurons in the rat.

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Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

2005-11-01

Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

Tetracycline inducible gene manipulation in serotonergic neurons.

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Tillmann Weber

Full Text Available The serotonergic (5-HT neuronal system has important and diverse physiological functions throughout development and adulthood. Its dysregulation during development or later in adulthood has been implicated in many neuropsychiatric disorders. Transgenic animal models designed to study the contribution of serotonergic susceptibility genes to a pathological phenotype should ideally allow to study candidate gene overexpression or gene knockout selectively in serotonergic neurons at any desired time during life. For this purpose, conditional expression systems such as the tet-system are preferable. Here, we generated a transactivator (tTA mouse line (TPH2-tTA that allows temporal and spatial control of tetracycline (Ptet controlled transgene expression as well as gene deletion in 5-HT neurons. The tTA cDNA was inserted into a 196 kb PAC containing a genomic mouse Tph2 fragment (177 kb by homologous recombination in E. coli. For functional analysis of Ptet-controlled transgene expression, TPH2-tTA mice were crossed to a Ptet-regulated lacZ reporter line (Ptet-nLacZ. In adult double-transgenic TPH2-tTA/Ptet-nLacZ mice, TPH2-tTA founder line L62-20 showed strong serotonergic β-galactosidase expression which could be completely suppressed with doxycycline (Dox. Furthermore, Ptet-regulated gene expression could be reversibly activated or inactivated when Dox was either withdrawn or added to the system. For functional analysis of Ptet-controlled, Cre-mediated gene deletion, TPH2-tTA mice (L62-20 were crossed to double transgenic Ptet-Cre/R26R reporter mice to generate TPH2-tTA/Ptet-Cre/R26R mice. Without Dox, 5-HT specific recombination started at E12.5. With permanent Dox administration, Ptet-controlled Cre-mediated recombination was absent. Dox withdrawal either postnatally or during adulthood induced efficient recombination in serotonergic neurons of all raphe nuclei, respectively. In the enteric nervous system, recombination could not be detected. We

Characterization of Induced Pluripotent Stem Cell-derived Human Serotonergic Neurons

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Lining Cao

2017-05-01

Full Text Available In the brain, the serotonergic neurons located in the raphe nucleus are the unique resource of the neurotransmitter serotonin, which plays a pivotal role in the regulation of brain development and functions. Dysfunction of the serotonin system is present in many psychiatric disorders. Lack of in vitro functional human model limits the understanding of human central serotonergic system and its related diseases and clinical applications. Previously, we have developed a method generating human serotonergic neurons from induced pluripotent stem cells (iPSCs. In this study, we analyzed the features of these human iPSCs-derived serotonergic neurons both in vitro and in vivo. We found that these human serotonergic neurons are sensitive to the selective neurotoxin 5, 7-Dihydroxytryptamine (5,7-DHT in vitro. After being transplanted into newborn mice, the cells not only expressed their typical molecular markers, but also showed the migration and projection to the host’s cerebellum, hindbrain and spinal cord. The data demonstrate that these human iPSCs-derived neurons exhibit the typical features as the serotonergic neurons in the brain, which provides a solid foundation for studying on human serotonin system and its related disorders.

Why does serotonergic activity drastically decrease during REM sleep?

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Sato, Kohji

2013-10-01

Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep-wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation. Copyright © 2013. Published by Elsevier Ltd.

Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism.

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Lanteri, Christophe; Salomon, Lucas; Torrens, Yvette; Glowinski, Jacques; Tassin, Jean-Pol

2008-06-01

A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated d-amphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

Hypothesis: the regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia.

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Devereux, Diana; Ikomi-Kumm, Julie

2013-03-01

The regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia is a hypothesis, which proposes an inherent operative system in homo sapiens that allows central nervous system and endocrine-mediated vascular system adaption to variables in partial pressure of oxygen, pH and body composition, while maintaining sufficient oxygen saturation for the immune system and ensuring protection of major organs in hypoxic and suboptimal conditions. While acknowledging the importance of the Henderson-Hasselbalch equation in the regulation of acid base balance, the hypothesis seeks to define the specific neuroendocrine/vascular mechanisms at work in regulating acid base balance in hypoxia and infection. The SIA (serotonin-immune-adrenergic) system is proposed as a working model, which allows central nervous system and endocrine-mediated macro- and micro vascular 'fine tuning'. The neurotransmitter serotonin serves as a 'hypoxic sensor' in concert with other operators to orchestrate homeostatic balance in normal and pathological states. The SIA system finely regulates oxygen, fuel and metabolic buffering systems at local sites to ensure optimum conditions for the immune response. The SIA system is fragile and its operation may be affected by infection, stress, diet, environmental toxins and lack of exercise. The hypothesis provides new insight in the area of neuro-gastroenterology, and emphasizes the importance of diet and nutrition as a complement in the treatment of infection, as well as the normalization of intestinal flora following antibiotic therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Involvement of adrenergic and serotonergic nervous mechanisms in allethrin-induced tremors in mice.

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Nishimura, M; Obana, N; Yagasaki, O; Yanagiya, I

1984-05-01

Oral or intravenous administration of allethrin, a synthetic derivative of the pirethrin-based insecticides, produces neurotoxic symptoms consisting of mild salivation, hyperexcitability, tremors and convulsions which result in death. Intracerebroventricular injection of allethrin to mouse at about one-nineth the dose of intravenous administration, produced qualitatively identical but less prominent symptoms, indicating that at least some of the symptoms may be originated in the central nervous system. To investigate the mechanism of action of the compound, we studied the ability of agents which alter neurotransmission to prevent or potentiate the effect of convulsive doses of technical grade (15.5% cis, 84.5% trans) allethrin. Intraperitoneal pretreatment with drugs which block noradrenergic receptors or norepinephrine synthesis, such as pentobarbital, chlorpromazine, phentolamine, phenoxybenzamine and reserpine, depressed the tremor induced by allethrin. The inhibitory effect of reserpine was reversed by phenylephrine. Both the serotonergic blocker, methysergide, and the serotonin depletor, rho-chlorphenylalanine, potentiated the effect of allethrin. The potentiating effect of methysergide was antagonized by 5-hydroxytryptamine. However, intracerebroventricular administration of methysergide was ineffective in potentiating the effect of allethrin. alpha 2- and beta-adrenoceptor blockers, muscarinic antagonists, GABA mimenergics and morphine had no effect. These results suggest that allethrin produces its neurotoxic responses in mice by acting on the brain and spinal levels. Furthermore, adrenergic excitatory and serotonergic inhibitory mechanisms may be involved in the neural pathway through which the allethrin-induced tremor is evoked.

Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain.

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Carcagno, Abel L; Di Bella, Daniela J; Goulding, Martyn; Guillemot, Francois; Lanuza, Guillermo M

2014-11-12

The development of the nervous system is critically dependent on the production of functionally diverse neuronal cell types at their correct locations. In the embryonic neural tube, dorsoventral signaling has emerged as a fundamental mechanism for generating neuronal diversity. In contrast, far less is known about how different neuronal cell types are organized along the rostrocaudal axis. In the developing mouse and chick neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from ventral p3 progenitors, which possess a common transcriptional identity but are confined to distinct anterior-posterior territories. In this study, we show that the expression of the transcription factor Neurogenin3 (Neurog3) in the spinal cord controls the correct specification of p3-derived neurons. Gain- and loss-of-function manipulations in the chick and mouse embryo show that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program by repressing Ascl1 in spinal p3 progenitors through a mechanism dependent on Hes proteins. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by actively suppressing serotonergic specification in the spinal cord. These results explain how equivalent p3 progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types. Copyright © 2014 the authors 0270-6474/14/3415223-11$15.00/0.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus

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Li Zhou

2017-03-01

Full Text Available Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN.

Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

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Kathryn M. Buller

2012-01-01

Full Text Available Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

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Zhou, Li; Liu, Ming-Zhe; Li, Qing; Deng, Juan; Mu, Di; Sun, Yan-Gang

2017-03-21

Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Differential serotonergic innervation of the amygdala in bonobos and chimpanzees.

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Stimpson, Cheryl D; Barger, Nicole; Taglialatela, Jared P; Gendron-Fitzpatrick, Annette; Hof, Patrick R; Hopkins, William D; Sherwood, Chet C

2016-03-01

Humans' closest living relatives are bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), yet these great ape species differ considerably from each other in terms of social behavior. Bonobos are more tolerant of conspecifics in competitive contexts and often use sexual behavior to mediate social interactions. Chimpanzees more frequently employ aggression during conflicts and actively patrol territories between communities. Regulation of emotional responses is facilitated by the amygdala, which also modulates social decision-making, memory and attention. Amygdala responsiveness is further regulated by the neurotransmitter serotonin. We hypothesized that the amygdala of bonobos and chimpanzees would differ in its neuroanatomical organization and serotonergic innervation. We measured volumes of regions and the length density of serotonin transporter-containing axons in the whole amygdala and its lateral, basal, accessory basal and central nuclei. Results showed that accessory basal nucleus volume was larger in chimpanzees than in bonobos. Of particular note, the amygdala of bonobos had more than twice the density of serotonergic axons than chimpanzees, with the most pronounced differences in the basal and central nuclei. These findings suggest that variation in serotonergic innervation of the amygdala may contribute to mediating the remarkable differences in social behavior exhibited by bonobos and chimpanzees. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape.

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Lloret-Fernández, Carla; Maicas, Miren; Mora-Martínez, Carlos; Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter; Flames, Nuria

2018-03-22

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis -regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans . Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. © 2018, Lloret-Fernández et al.

The evolution of the serotonergic nervous system

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Hay-Schmidt, Anders

2000-01-01

Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion......Anatomy, serotonergic nervous system, neurons, invertebrates, phylogeny, development, apical ganglion...

Affective spectrum disorders and role of serotonergic system of the brain

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Timotijević Ivana P.

2014-01-01

Full Text Available Affective spectrum disorders include mood and anxiety disorders, whereas the term functional somatic syndromes describes disorders in which the main symptom is chronic pain, with no pathognomonic tissue damage, such as fibromyalgia, irritable colon, tension headache. Pain as a symptom is often present in patients with depression and anxiety, and similarly, depressed mood, anxiety and other psychiatric symptoms are common in patients with functional somatic syndromes. This explains attitudes that affective disorders and functional somatic syndromes should be found along the same spectrum, due to a similar neurobiochemicalmehanism and dysfunction of these CNS structures and neurotransmitter systems, which lead to similar symptoms in both groups. The symptoms of affective disorders, including somatic are associated with serotonin and serotonergic transmission in the CNS. The existence of depressive and anxiety disorders, such as fatigue, sleep disorders, cognitive disorders, depressed mood, anxiety, and functional somatic syndromes code indicate a similar mechanism of origin. Hypothesis of central neuropathic pain explains the possibility of the descending inhibitory pain mechanisms, including serotonergic and noradrenergic projections and their receptors. Central suprasegmental senzitization in nociceptive pathways, also at the level of the thalamus and the sensory cortex, trigered by an emotional stressors can cause painful symptoms in both groups of disorders. Serotonergic and noradrenergic pathways and voltage sensitive channels of their receptors are included in the mechanism. Modern psychopharmacology can no longer ignore the existence of painful symptoms in affective disorder or depressive and anxiety symptoms in functional somatic syndromes and their treatment can improve. Therapeutic effects of SSRI and SNRI antidepressants and alpha 2 delta ligands for all kinds of painful symptoms in affective disorders - serotonergic spectrum is

[Gradient of serotonergic innervation of internal organs].

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Lychkova, A E

2004-01-01

The unidirectional synergistic effect of the vegetative nervous system departments was studied at the regulation of the activity of internal organs. It was shown that the sympathetic nerve intensification of the vagal stimulation of EMA of stomach, urinary bladder, ureters, uteruss, fallopian tubes and deferent duct is realized by means of activation of serotonergic fibrae preganglionares that transmit the activation to 5-NTS,4 serotonin receptors of intramural ganglia that, in their turn, activate 5-NT1,2 serotonin receptors of effector cells.

Social isolation reduces serotonergic fiber density in the inferior colliculus of female, but not male, mice.

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Keesom, Sarah M; Morningstar, Mitchell D; Sandlain, Rebecca; Wise, Bradley M; Hurley, Laura M

2018-05-12

Early-life experiences, including maternal deprivation and social isolation during adolescence, have a profound influence on a range of adult social behaviors. Post-weaning social isolation in rodents influences behavior in part through the alteration of neuromodulatory systems, including the serotonergic system. Of significance to social behavior, the serotonergic system richly innervates brain areas involved in vocal communication, including the auditory system. However, the influence of isolation on serotonergic input to the auditory system remains underexplored. Here, we assess whether 4 weeks of post-weaning individual housing alters serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain nucleus in which serotonin alters auditory-evoked activity. Individually housed male and female mice were compared to conspecifics housed socially in groups of three. Serotonergic projections were subsequently visualized with an antibody to the serotonin transporter, which labels serotonergic fibers with relatively high selectivity. Fiber densities were estimated in the three major subregions of the IC using line-scan intensity analysis. Individually housed female mice showed a significantly reduced fiber density relative to socially housed females, which was accompanied by a lower body weight in individually housed females. In contrast, social isolation did not affect serotonergic fiber density in the IC of males. This finding suggests that sensitivity of the serotonergic system to social isolation is sex-dependent, which could be due to a sex difference in the effect of isolation on psychosocial stress. Since serotonin availability depends on social context, this finding further suggests that social isolation can alter the acute social regulation of auditory processing. Copyright © 2018. Published by Elsevier B.V.

Effect of diet on serotonergic neurotransmission in depression.

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Shabbir, Faisal; Patel, Akash; Mattison, Charles; Bose, Sumit; Krishnamohan, Raathathulaksi; Sweeney, Emily; Sandhu, Sarina; Nel, Wynand; Rais, Afsha; Sandhu, Ranbir; Ngu, Nguasaah; Sharma, Sushil

2013-02-01

Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy. Clinical and experimental evidence indicates that an appropriate diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B(6). Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavailability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these agents are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors. However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. This report highlights the clinical significance of tryptophan-rich diet and vitamin B(6) to boost serotonergic neurotransmission in

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek’s disease

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1. Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals and birds. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. 2. Our obje...

Brain Aromatase Modulates Serotonergic Neuron by Regulating Serotonin Levels in Zebrafish Embryos and Larvae

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Zulvikar Syambani Ulhaq

2018-05-01

Full Text Available Teleost fish are known to express two isoforms of P450 aromatase, a key enzyme for estrogen synthesis. One of the isoforms, brain aromatase (AroB, cyp19a1b, is highly expressed during early development of zebrafish, thereby suggesting its role in brain development. On the other hand, early development of serotonergic neuron, one of the major monoamine neurons, is considered to play an important role in neurogenesis. Therefore, in this study, we investigated the role of AroB in development of serotonergic neuron by testing the effects of (1 estradiol (E2 exposure and (2 morpholino (MO-mediated AroB knockdown. When embryos were exposed to E2, the effects were biphasic. The low dose of E2 (0.005 µM significantly increased serotonin (5-HT positive area at 48 hour post-fertilization (hpf detected by immunohistochemistry and relative mRNA levels of tryptophan hydroxylase isoforms (tph1a, tph1b, and tph2 at 96 hpf measured by semi-quantitative PCR. To test the effects on serotonin transmission, heart rate and thigmotaxis, an indicator of anxiety, were analyzed. The low dose also significantly increased heart rate at 48 hpf and decreased thigmotaxis. The high dose of E2 (1 µM exhibited opposite effects in all parameters. The effects of both low and high doses were reversed by addition of estrogen receptor (ER blocker, ICI 182,780, thereby suggesting that the effects were mediated through ER. When AroB MO was injected to fertilized eggs, 5-HT-positive area was significantly decreased, while the significant decrease in relative tph mRNA levels was found only with tph2 but not with two other isoforms. AroB MO also decreased heart rate and increased thigmotaxis. All the effects were rescued by co-injection with AroB mRNA and by exposure to E2. Taken together, this study demonstrates the role of brain aromatase in development of serotonergic neuron in zebrafish embryos and larvae, implying that brain-formed estrogen is an important factor to

Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification.

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Lise Gutknecht

Full Text Available Brain serotonin (5-HT is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2. Tph2 inactivation (Tph2-/- resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT(1A and 5-HT(1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

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Xi-Ling Jiang

2016-09-01

Full Text Available We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI, potentiates serotonin (5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88–0.496 µmol/L for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT–induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

Central serotonergic and noradrenergic receptors in functional dyspepsia

Institute of Scientific and Technical Information of China (English)

S O'Mahony; TG Dinan; PW Keeling; ASB Chua

2006-01-01

Functional dyspepsia is a symptom complex characterised by upper abdominal discomfort or pain, early satiety,motor abnormalities, abdominal bloating and nausea in the absence of organic disease. The central nervous system plays an important role in the conducting and processing of visceral signals. Alterations in brain processing of pain, perception and affective responses may be key factors in the pathogenesis of functional dyspepsia. Central serotonergic and noradrenergic receptor systems are involved in the processing of motor,sensory and secretory activities of the gastrointestinal tract. Visceral hypersensitivity is currently regarded as the mechanism responsible for both motor alterations and abdominal pain in functional dyspepsia. Some studies suggest that there are alterations in central serotonergic and noradrenergic systems which may partially explain some of the symptoms of functional dyspepsia. Alterations in the autonomic nervous system may be implicated in the motor abnormalities and increases in visceral sensitivity in these patients.Noradrenaline is the main neurotransmitter in the sympathetic nervous system and again alterations in the functioning of this system may lead to changes in motor function. Functional dyspepsia causes considerable burden on the patient and society. The pathophysiology of functional dyspepsia is not fully understood but alterations in central processing by the serotonergic and noradrenergic systems may provide plausible explanations for at least some of the symptoms and offer possible treatment targets for the future.

Distribution of serotonergic and dopaminergic nerve fibers in the salivary gland complex of the cockroach Periplaneta americana

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Kühnel Dana

2002-06-01

Full Text Available Abstract Background The cockroach salivary gland consists of secretory acini with peripheral ion-transporting cells and central protein-producing cells, an extensive duct system, and a pair of reservoirs. Salivation is controled by serotonergic and dopaminergic innervation. Serotonin stimulates the secretion of a protein-rich saliva, dopamine causes the production of a saliva without proteins. These findings suggest a model in which serotonin acts on the central cells and possibly other cell types, and dopamine acts selectively on the ion-transporting cells. To examine this model, we have analyzed the spatial relationship of dopaminergic and serotonergic nerve fibers to the various cell types. Results The acinar tissue is entangled in a meshwork of serotonergic and dopaminergic varicose fibers. Dopaminergic fibers reside only at the surface of the acini next to the peripheral cells. Serotonergic fibers invade the acini and form a dense network between central cells. Salivary duct segments close to the acini are locally associated with dopaminergic and serotonergic fibers, whereas duct segments further downstream have only dopaminergic fibers on their surface and within the epithelium. In addition, the reservoirs have both a dopaminergic and a serotonergic innervation. Conclusion Our results suggest that dopamine is released on the acinar surface, close to peripheral cells, and along the entire duct system. Serotonin is probably released close to peripheral and central cells, and at initial segments of the duct system. Moreover, the presence of serotonergic and dopaminergic fiber terminals on the reservoir indicates that the functions of this structure are also regulated by dopamine and serotonin.

The serotonergic system and cognitive function

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Švob Štrac Dubravka

2016-01-01

Full Text Available Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD. The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic system in cognitive function, particularly in AD and schizophrenia.

Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.

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Johnson, M D

1994-02-01

Serotonergic neurons are thought to play a role in depression and obsessive compulsive disorder. However, their functional transmitter repertoire is incompletely known. To investigate this repertoire, intracellular recordings were obtained from 132 cytochemically identified rat mesopontine serotonergic neurons that had re-established synapses in microcultures. Approximately 60% of the neurons evoked excitatory glutamatergic potentials in themselves or in target neurons. Glutamatergic transmission was frequently observed in microcultures containing a solitary serotonergic neuron. Evidence for co-release of serotonin and glutamate from single raphe neurons was also obtained. However, evidence for gamma-aminobutyric acid release by serotonergic neurons was observed in only two cases. These findings indicate that many cultured serotonergic neurons form glutamatergic synapses and may explain several observations in slices and in vivo.

Serotonergic neurons signal reward and punishment on multiple timescales

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Cohen, Jeremiah Y; Amoroso, Mackenzie W; Uchida, Naoshige

2015-01-01

Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We ‘tagged’ serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales. DOI: http://dx.doi.org/10.7554/eLife.06346.001 PMID:25714923

Assessment of serotonergic system in formation of memory and learning

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J. C. da Silva

2017-11-01

Full Text Available Abstract We evaluated the involvement of the serotonergic system on memory formation and learning processes in healthy adults Wistar rats. Fifty-seven rats of 5 groups had one serotonergic nuclei damaged by an electric current. Electrolytic lesion was carried out using a continuous current of 2mA during two seconds by stereotactic surgery. Animals were submitted to learning and memory tests. Rats presented different responses in the memory tests depending on the serotonergic nucleus involved. Both explicit and implicit memory may be affected after lesion although some groups showed significant difference and others did not. A damage in the serotonergic nucleus was able to cause impairment in the memory of Wistar. The formation of implicit and explicit memory is impaired after injury in some serotonergic nuclei.

Serotonergic neurotoxic metabolites of ecstasy identified in rat brain.

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Jones, Douglas C; Duvauchelle, Christine; Ikegami, Aiko; Olsen, Christopher M; Lau, Serrine S; de la Torre, Rafael; Monks, Terrence J

2005-04-01

The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell gamma-glutamyl transpeptidase (gamma-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of alpha-methyl dopamine (alpha-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of gamma-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-alpha-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA (and alpha-MeDA). The mechanisms by which such metabolites access the brain and produce selective

The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function.

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Annina Huser

Full Text Available The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naïve odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed.

Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

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Chowdhury, Srikanta; Yamanaka, Akihiro

2016-01-01

Orexin/hypocretin neurons play a crucial role in the regulation of sleep/wakefulness, primarily in the maintenance of wakefulness. These neurons innervate wide areas of the brain and receive diverse synaptic inputs including those from serotonergic (5-HT) neurons in the raphe nucleus. Previously we showed that pharmacological application of 5-HT directly inhibited orexin neurons via 5-HT1A receptors. However, it was still unclear how 5-HT neurons regulated orexin neurons since 5-HT neurons co...

Involvement of autophagy upregulation in 3,4-methylenedioxymethamphetamine ('ecstasy')-induced serotonergic neurotoxicity.

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Li, I-Hsun; Ma, Kuo-Hsing; Kao, Tzu-Jen; Lin, Yang-Yi; Weng, Shao-Ju; Yen, Ting-Yin; Chen, Lih-Chi; Huang, Yuahn-Sieh

2016-01-01

It has been suggested that autophagy plays pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug that causes long-term serotonergic neurotoxicity in the brain. Apoptosis and necrosis have been implicated in MDMA-induced neurotoxicity, but the role of autophagy in MDMA-elicited serotonergic toxicity has not been investigated. The present study aimed to examine the contribution of autophagy to neurotoxicity in serotonergic neurons in in vitro and in vivo animal models challenged with MDMA. Here, we demonstrated that in cultured rat serotonergic neurons, MDMA exposure induced LC3B-densely stained autophagosome formation, accompanying by a decrease in neurite outgrowth. Autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated MDMA-induced autophagosome accumulation, and ameliorated MDMA-triggered serotonergic neurite damage and neuron death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in serotonergic neurons and aggravated neurite degeneration. In addition, MDMA-induced autophagy activation in cultured serotonergic neurons might be mediated by serotonin transporter (SERT). In an in vivo animal model administered MDMA, neuroimaging showed that 3-MA protected the serotonin system against MDMA-induced downregulation of SERT evaluated by animal-PET with 4-[(18)F]-ADAM, a SERT radioligand. Taken together, our results demonstrated that MDMA triggers upregulation of autophagy in serotonergic neurons, which appears to be detrimental to neuronal growth. Copyright © 2015 Elsevier Inc. All rights reserved.

Serotonergic drugs in the treatment of depressive and anxiety disorders

NARCIS (Netherlands)

Den Boer, JA; Bosker, FJ; Slaap, BR

Serotonergic dysfunction has been implicated in the aetiology of several psychiatric conditions, including depressive and anxiety disorders. Much of the evidence for the role of serotonin (5-HT) in these disorders comes from treatment studies with serotonergic drugs, including selective serotonin

Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation : the involvement of the serotonergic system

NARCIS (Netherlands)

Waldinger, MD; Berendsen, HHG; Blok, BFM; Olivier, B; Holstege, G

Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying

Up-regulation of serotonergic binding sites labeled by (3H) WB4101 following fimbrial transection and 5,7-dihydroxytryptamine-induced lesions

International Nuclear Information System (INIS)

Morrow, A.L.; Norman, A.B.; Battaglia, G.; Loy, R.; Creese, I.

1985-01-01

Lesions of the serotonergic afferents to the hippocampus, by fimbrial transection or by 5,7-dihydroxytryptamine treatment, produce an increase in the Bmax of ( 3 H)WB4101 to its nanomolar affinity binding site, with no effect on its picomolar affinity binding site or on ( 3 H)prazosin binding. The nanomolar site is serotonergic as the serotonergic agonists, serotonin and 8-hydroxy-dipropylaminotetraline (8-OH-DPAT) have nanomolar affinity for ( 3 H)WB4101 binding when studied in the presence of a prazosin mask (30nM) of the alpha-1 component of ( 3 H)WB4101 binding. The serotonin receptor antagonists metergoline, lysergic acid diethylamide and lisuride also have high nanomolar affinities while ketanserin, yohimbine, prazosin and noradrenergic agonists have affinities in the micromolar range. Fimbrial transection or 5,7-dihydroxytryptamine injections produced 32% and 44% increases in the Bmax of ( 3 H)WB4101 binding in the presence of a prazosin mask. Serotonin competition for ( 3 H)WB4101 binding was identical in control and experimental tissues from each lesion experiment. Although specific binding of ( 3 H)WB4101 was increased, there was no change in the affinities or the percentages of the two binding components for serotonin competition with ( 3 H)WB4101. These data suggest that removal of the serotonergic input to the hippocampus produces an increase in the Bmax of serotonin receptor binding sites labeled by ( 3 H)WB4101. 33 references, 3 figures, 3 tables

Serotonergic synaptic input to facial motoneurons: localization by electron-microscopic autoradiography

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Aghajanian, G K; McCall, R B [Yale Univ., New Haven, CT (USA). School of Medicine

1980-12-01

Serotonergic nerve terminals in the facial motor nucleus were labelled with (/sup 3/H)5-hydroxytryptamine. When serotonergic nerve terminals were destroyed (by the selective neurotoxin 5,7-dihydroxytryptamine) the labelling was lost. By electron-microscopic autoradiography, labelled serotonergic terminals were found to make axo-dendritic or axo-somatic junctions with facial motor neurons. No axo-axonic junctions were observed. These morphological findings are consistent with physiological studies which indicate that 5-hydroxytryptamine facilitates the excitation of facial motoneurons through a direct postsynaptic action.

Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats.

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Lee, Ji-Hye; Li, Dong Xing; Yoon, Heera; Go, Donghyun; Quan, Fu Shi; Min, Byung-Il; Kim, Sun Kwang

2014-12-06

Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats. The behavioral signs of cold allodynia in Sprague-Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat's tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment. The serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 μg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 μg, i.t.) or

Transient electromyographic findings in serotonergic toxicity due to combination of essitalopram and isoniazid

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Çagdas Erdogan

2013-01-01

Full Text Available Here, we report a case of serotonergic toxicity due to combination of essitalopram and isoniazid, which was rarely reported before. Moreover, we observed transient neurogenic denervation potentials in needle electromyography, which disappeared with the treatment of serotonergic toxicity. As to our best knowledge, this is the first case, reporting transient electromyographic changes probably due to serotonergic toxicity.

Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism.

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Kroes, Marijn C W; van Wingen, Guido A; Wittwer, Jonas; Mohajeri, M Hasan; Kloek, Joris; Fernández, Guillén

2014-01-01

It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain-barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits. © 2013 Elsevier Inc. All rights reserved.

3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.

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Wermuth, C G; Schlewer, G; Bourguignon, J J; Maghioros, G; Bouchet, M J; Moire, C; Kan, J P; Worms, P; Biziere, K

1989-03-01

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.

Development of serotonergic and adrenergic receptors in the rat spinal cord: effects of neonatal chemical lesions and hyperthyroidism.

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Lau, C; Pylypiw, A; Ross, L L

1985-03-01

The sympathetic preganglionic neurons in the spinal cord receive dense serotonergic (5-HT) and catecholaminergic (CA) afferent inputs from the descending supraspinal pathways. In the rat spinal cord, the levels of these biogenic amines and their receptors are low at birth, but undergo rapid ontogenetic increases in the ensuing 2-3 postnatal weeks until the adult levels are reached. In many systems it has been shown that denervation of presynaptic neurons leads to an up-regulation of the number of postsynaptic receptors. To determine whether the 5-HT and CA receptors in the developing spinal cord are also subject to such transsynaptic regulation, we examined the ontogeny of serotonergic receptors and alpha- and beta-adrenergic receptors in thoracolumbar spinal cord of rats given neurotoxins which destroy serotonergic (5,7-dihydroxytryptamine (5,7-DHT)) or noradrenergic (6-hydroxydopamine (6-OHDA)) nerve terminals. Intracisternal administration of 5,7-DHT or 6-OHDA at 1 and 6 days of age prevented, respectively, the development of 5-HT and CA levels in the spinal cord. Rats lesioned with 5,7-DHT displayed a marked elevation of 5-HT receptors with a binding of 50% greater than controls at 1 week and a continuing increase to twice normal by 4 weeks. A similar pattern of up-regulation was also detected with the alpha-adrenergic receptor, as rats lesioned with 6-OHDA exhibited persistent increases in receptor concentration. However, in these same animals ontogeny of the beta-adrenergic receptor in the spinal cord remained virtually unaffected by the chemical lesion. In several other parts of the nervous system, it has been demonstrated that the beta-adrenergic sensitivity can be modulated by hormonal signals, particularly that of the thyroid hormones. This phenomenon was examined in the spinal cord and in confirmation with previous studies neonatal treatment of triiodothyronine (0.1 mg/kg, s.c. daily) was capable of evoking persistent increases in beta

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

NARCIS (Netherlands)

Rinne, T; Westenberg, HGM; den Boer, JA

2000-01-01

Background: Disturbances of affect, impulse regulation and autoaggressive behavior which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual

The use of serotonergic drugs to treat obesity – is there any hope?

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Nicholas T Bello

2011-02-01

Full Text Available Nicholas T Bello1, Nu-Chu Liang21Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USAAbstract: Surgical interventional strategies for the treatment of obesity are being implemented at an increasing rate. The safety and feasibility of these procedures are questionable for most overweight or obese individuals. The use of long-term pharmacotherapy options, on the other hand, can target a greater portion of the obese population and provide early intervention to help individuals maintain a healthy lifestyle to promote weight loss. Medications that act on the central serotonergic pathways have been a relative mainstay for the treatment of obesity for the last 35 years. The clinical efficacy of these drugs, however, has been encumbered by the potential for drug-associated complications. Two drugs that act, albeit by different mechanisms, on the central serotonergic system to reduce food intake and decrease body weight are sibutramine and lorcaserin. Sibutramine is a serotonin and norepinephrine reuptake inhibitor, whereas lorcaserin is a selective 5HT2C receptor agonist. The recent worldwide withdrawal of sibutramine and FDA rejection of lorcaserin has changed the landscape not only for serotonin-based therapeutics specifically, but for obesity pharmacotherapy in general. The purpose of this review is to focus on the importance of the serotonergic system in the control of feeding and its potential as a target for obesity pharmacotherapy. Advances in refining and screening more selective receptor agonists and a better understanding of the potential off-target effects of serotonergic drugs are needed to produce beneficial pharmacotherapy.Keywords: 5-hydroxytryptamine, serotonin 1B, fenfluramine, dexfenfluramine, satiety, dorsal raphe

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

NARCIS (Netherlands)

Rinne, T.; Westenberg, H. G.; den Boer, J. A.; van den Brink, W.

2000-01-01

Disturbances of affect, impulse regulation, and autoaggressive behavior, which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual abuse is

Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests.

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Inoue, Y; Terao, T; Iwata, N; Okamoto, K; Kojima, H; Okamoto, T; Yoshimura, R; Nakamura, J

2007-02-01

Premenstrual dysphoric disorder (PMDD) has been assumed to be a subtype of premenstrual syndrome (PMS) with depressive symptoms, such as depressive mood, tension, anxiety, and mood liability during luteal phase. At present, no conclusion has been established about serotonergic function in PMDD. The purpose of this study was to investigate the serotonergic function of PMDD subjects in comparison to PMS without PMDD subjects and normal controls via neuroendocrine challenge tests. Twenty-four women (seven with PMDD, eight with PMS without PMDD, and nine normal controls) were tested on three occasions (follicular phase, early luteal phase, and late luteal phase) receiving paroxetine 20 mg orally as a serotonergic probe at 8:00 A: .M: . Plasma ACTH and cortisol were measured prior to the administration and every hour for 6 h thereafter. As a whole, there were significant differences in serotonergic function measured by ACTH and cortisol responses to paroxetine challenge across these three groups. PMDD subjects showed higher serotonergic function in follicular phase but lower serotonergic function in luteal phase, compared with women with PMS without PMDD and normal controls. The present findings suggest that PMDD women have fluctuating serotonergic function across their menstrual cycles and that the pattern may be different from PMS without PMDD.

Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism

NARCIS (Netherlands)

Kroes, M.C.W.; Wingen, G.A. van; Wittwer, J.; Mohajeri, M.H.; Kloek, J.; Fernandez, G.S.E.

2014-01-01

It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport

Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism

NARCIS (Netherlands)

Kroes, Marijn C. W.; van Wingen, Guido A.; Wittwer, Jonas; Mohajeri, M. Hasan; Kloek, Joris; Fernández, Guillén

2014-01-01

It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, hyptophan competes with other long-neutral-amino-acids (LNAA) for transport across

Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders.

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Borrow, Amanda P; Cameron, Nicole M

2014-10-03

Clinical research has demonstrated a significant sex difference in the occurrence of depressive disorders. Beginning at pubertal onset, women report a higher incidence of depression than men. Women are also vulnerable to the development of depressive disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. These disorders are associated with reproductive stages involving changes in gonadal hormone levels. Specifically, female depression and female affective behaviors are influenced by estradiol levels. This review argues two major mechanisms by which estrogens influence depression and depressive-like behavior: through interactions with neurotrophic factors and through an influence on the serotonergic system. In particular, estradiol increases brain derived neurotrophic factor (BDNF) levels within the brain, and alters serotonergic expression in a receptor subtype-specific manner. We will take a regional approach, examining these effects of estrogens in the major brain areas implicated in depression. Finally, we will discuss the gaps in our current knowledge of the effects of estrogens on female depression, and the potential utility for estrogen receptor modulators in treatment for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

Serotonergic Drugs and Valvular Heart Disease

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Rothman, Richard B.; Baumann, Michael H.

2009-01-01

Background The serotonin (5-HT) releasers (±)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use due to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the “5-HT hypothesis”) suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease. Objective Here we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease. Methods Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations. Conclusions The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT2B receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT2B agonist activity. PMID:19505264

Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

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Cristina Miguelez

2017-09-01

Full Text Available The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA and the serotonergic (5-HT system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.

Hypocretin/Orexin Peptides Alter Spike Encoding by Serotonergic Dorsal Raphe Neurons through Two Distinct Mechanisms That Increase the Late Afterhyperpolarization.

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Ishibashi, Masaru; Gumenchuk, Iryna; Miyazaki, Kenichi; Inoue, Takafumi; Ross, William N; Leonard, Christopher S

2016-09-28

Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons. Intracellular phospholipase C inhibition (U73122) blocked the entire oeAHP, but neither component was sensitive to PKC inhibition or altered PKA signaling, unlike classical sAHPs. The enhanced SK current did not depend on IP3-mediated Ca(2+) release but resulted from A-current inhibition and the resultant spike broadening, which increased Ca(2+) influx and Ca(2+)-induced-Ca(2+) release, whereas the slower component was insensitive to these factors. Functionally, the oeAHP slowed and stabilized orexin-induced firing compared with firing produced by a virtual orexin conductance lacking the oeAHP. The oeAHP also reduced steady-state firing rate and firing fidelity in response to stimulation, without affecting the initial rate or fidelity. Collectively, these findings reveal a new orexin action in serotonergic raphe neurons and suggest that, when orexin is released during arousal and reward, it enhances the spike encoding of phasic over tonic inputs, such as those related to sensory, motor, and reward events. Orexin peptides are known to excite neurons via slow postsynaptic depolarizations. Here we elucidate a significant new orexin action that increases and prolongs the postspike

[Local GABA-ergic modulation of serotonergic neuron activity in the nucleus raphe magnus].

Science.gov (United States)

Iniushkin, A N; Merkulova, N A; Orlova, A O; Iniushkina, E M

2009-07-01

In voltage-clamp experimental on slices of the rat brainstem the effects of 5-HT and GABA on serotonergic neurons of nucleus raphe magnus were investigated. Local applications of 5-HT induced an increase in IPCSs frequency and amplitude in 45% of serotonergic cells. The effect suppressed by the blocker of fast sodium channels tetradotoxin. Antagonist of GABA receptor gabazine blocked IPSCs in neurons both sensitive and non-sensitive to 5-HT action. Applications of GABA induced a membrane current (I(GABA)), which was completely blocked by gabazine. The data suggest self-control of the activity of serotonergic neurons in nucleus raphe magnus by negative feedback loop via local GABAergic interneurons.

Different Serotonergic Expression in Nevomelanocytic Tumors

Energy Technology Data Exchange (ETDEWEB)

Naimi-Akbar, Clara; Ritter, Markus; Demel, Sasika; El-Nour, Husameldin; Hedblad, Mari-Anne [Dermatology and Venereology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Solna (Sweden); Azmitia, Efrain C. [Department of Biology and Psychiatry, New York University, NY (United States); Nordlind, Klas, E-mail: klas.nordlind@karolinska.se [Dermatology and Venereology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Solna (Sweden)

2010-06-07

The neuromediator serotonin (5-hydroxytryptamine; 5-HT) has been proposed to play a role in tumor progression. Thus, the aim of the present investigation was to determine whether alterations in the serotonergic system occur in nevomelanocytic tumors. For this purpose, paraffin-embedded biopsies of superficial spreading malignant melanoma (SSM), dysplastic compound nevi (DN) and benign compound nevi (BCN) were characterized with regard to their expression of 5-HT, the 5-HT1A and 5-HT2A receptors, and the serotonin transporter protein (SERT), by immunohistochemical analysis. Melanocytes in the region surrounding the tumor were found to express both the 5-HT1A and 5-HT2A receptors. Tumor cells that immunostained positively for the different serotonergic markers were observed in the suprabasal epidermis of DN tissue and, to an even greater extent, in the case of SSM. Furthermore, some of these latter cells expressed both 5-HT1AR and 5-HT2AR. The level of expression of 5-HT1AR at the junctional area was lower for SSM than for DN or BCN. As the degree of atypia increased, the intensity of tumor cell staining in the dermis for 5-HT1AR and SERT declined. Vessel immunoreactivity for 5-HT2A was more intense in SSM than in BCN tissue. Round-to-dendritic cells that expressed both SERT and 5-HT1AR were seen to infiltrate into the dermal region of the tumor, this infiltration being more evident in the case of DN and SSM. These latter cells were also tryptase-positive, indicating that they are mast cells. Thus, alterations in serotonergic system may be involved in nevomelanocytic tumors and mast cells may play an important role in this connection.

Iodine 125-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial cells

International Nuclear Information System (INIS)

Yagaloff, K.A.; Hartig, P.R.

1985-01-01

125 I-Lysergic acid diethylamide ( 125 I-LSD) binds with high affinity to serotonergic sites on rat choroid plexus. These sites were localized to choroid plexus epithelial cells by use of a novel high resolution stripping film technique for light microscopic autoradiography. In membrane preparations from rat choroid plexus, the serotonergic site density was 3100 fmol/mg of protein, which is 10-fold higher than the density of any other serotonergic site in brain homogenates. The choroid plexus site exhibits a novel pharmacology that does not match the properties of 5-hydroxytryptamine-1a (5-HT1a), 5-HT1b, or 5-HT2 serotonergic sites. 125 I-LSD binding to the choroid plexus site is potently inhibited by mianserin, serotonin, and (+)-LSD. Other serotonergic, dopaminergic, and adrenergic agonists and antagonists exhibit moderate to weak affinities for this site. The rat choroid plexus 125 I-LSD binding site appears to represent a new type of serotonergic site which is located on non-neuronal cells in this tissue

The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism

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Dietmar Fuchs

2010-08-01

Full Text Available Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC and the non-psychotropic cannabidiol (CBD modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC. The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO, suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.

Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus.

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Tuckwell, Henry C

2013-06-01

Serotonergic neurons of the dorsal raphe nuclei, with their extensive innervation of nearly the whole brain have important modulatory effects on many cognitive and physiological processes. They play important roles in clinical depression and other psychiatric disorders. In order to quantify the effects of serotonergic transmission on target cells it is desirable to construct computational models and to this end these it is necessary to have details of the biophysical and spike properties of the serotonergic neurons. Here several basic properties are reviewed with data from several studies since the 1960s to the present. The quantities included are input resistance, resting membrane potential, membrane time constant, firing rate, spike duration, spike and afterhyperpolarization (AHP) amplitude, spike threshold, cell capacitance, soma and somadendritic areas. The action potentials of these cells are normally triggered by a combination of sodium and calcium currents which may result in autonomous pacemaker activity. We here analyse the mechanisms of high-threshold calcium spikes which have been demonstrated in these cells the presence of TTX (tetrodotoxin). The parameters for calcium dynamics required to give calcium spikes are quite different from those for regular spiking which suggests the involvement of restricted parts of the soma-dendritic surface as has been found, for example, in hippocampal neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

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Nielsen, Kirsten; Brask, Dorthe; Knudsen, Gitte M.

2006-01-01

Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers...... and quantification of serotonin positive fibers has been widely used to detect changes in the serotonergic innervation. However, particularly in conditions with enhanced serotonin metabolism the detection level of serotonin may lead to an underestimation of the true number of serotonergic fibers. The serotonin...... immunostained for serotonin and SERT protein and colocalization was quantified in several brain areas by confocal microscopy. In comparison with untreated rats, MAO inhibitor treated rats had a significantly higher number (almost 200% increase) of serotonin immunopositive fibers whereas no difference...

A Subset of Serotonergic Neurons Evokes Hunger in Adult Drosophila.

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Albin, Stephanie D; Kaun, Karla R; Knapp, Jon-Michael; Chung, Phuong; Heberlein, Ulrike; Simpson, Julie H

2015-09-21

Hunger is a complex motivational state that drives multiple behaviors. The sensation of hunger is caused by an imbalance between energy intake and expenditure. One immediate response to hunger is increased food consumption. Hunger also modulates behaviors related to food seeking such as increased locomotion and enhanced sensory sensitivity in both insects and vertebrates. In addition, hunger can promote the expression of food-associated memory. Although progress is being made, how hunger is represented in the brain and how it coordinates these behavioral responses is not fully understood in any system. Here, we use Drosophila melanogaster to identify neurons encoding hunger. We found a small group of neurons that, when activated, induced a fed fly to eat as though it were starved, suggesting that these neurons are downstream of the metabolic regulation of hunger. Artificially activating these neurons also promotes appetitive memory performance in sated flies, indicating that these neurons are not simply feeding command neurons but likely play a more general role in encoding hunger. We determined that the neurons relevant for the feeding effect are serotonergic and project broadly within the brain, suggesting a possible mechanism for how various responses to hunger are coordinated. These findings extend our understanding of the neural circuitry that drives feeding and enable future exploration of how state influences neural activity within this circuit. Copyright © 2015 Elsevier Ltd. All rights reserved.

Serotonergic modulation of hippocampal pyramidal cells in euthermic, cold-acclimated, and hibernating hamsters

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Horrigan, D. J.; Horwitz, B. A.; Horowitz, J. M.

1997-01-01

Serotonergic fibers project to the hippocampus, a brain area previously shown to have distinctive changes in electroencephalograph (EEG) activity during entrance into and arousal from hibernation. The EEG activity is generated by pyramidal cells in both hibernating and nonhibernating species. Using the brain slice preparation, we characterized serotonergic responses of these CA1 pyramidal cells in euthermic, cold-acclimated, and hibernating Syrian hamsters. Stimulation of Shaffer-collateral/commissural fibers evoked fast synaptic excitation of CA1 pyramidal cells, a response monitored by recording population spikes (the synchronous generation of action potentials). Neuromodulation by serotonin (5-HT) decreased population spike amplitude by 54% in cold-acclimated animals, 80% in hibernating hamsters, and 63% in euthermic animals. The depression was significantly greater in slices from hibernators than from cold-acclimated animals. In slices from euthermic animals, changes in extracellular K+ concentration between 2.5 and 5.0 mM did not significantly alter serotonergic responses. The 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin mimicked serotonergic inhibition in euthermic hamsters. Results show that 5-HT is a robust neuromodulator not only in euthermic animals but also in cold-acclimated and hibernating hamsters.

Neuropeptides as endogenous neuronal growth regulatory factors on serotonergic maturation

International Nuclear Information System (INIS)

Davila-Garcia, M.I.

1989-01-01

Products of the proopiomelanocortin molecule as well as leu- and met-enkephalin were tested for their effects on serotonergic neuronal maturation. High affinity uptake of ( 3 H)5-HT and morphometrics using immunocytochemistry specific for serotonergic neurons were used to monitor neuronal maturation. Cultured brainstem raphe neurons from 14 day fetuses, in the presence or absence of target tissue, were administered neuropeptides at various concentrations for 1,3 or 5 days in culture. ACTH peptides stimulate neurite length and, with the endorphins, the expression of ( 3 H)5-HT uptake by serotonergic fetal neurons cultured alone but had no effect when these neurons were cocultured with hippocampal target cells. A daily dose of leu-enkephalin to these cells inhibited neuronal uptake after 5 days of exposure and decreased neurite cell length in 24 hr cultures. In contrast, a single dose of leu-enkephalin at plating stimulated uptake after 5 days while co-administration of bacitracin inhibited uptake expression. Naloxone reversed the opioid effect and stimulated uptake when administered alone. Desulfated-CCK, which resembles leu-enkephalin, was equally potent as leu-enkephalin in inhibiting uptake

Neuropeptides as endogenous neuronal growth regulatory factors on serotonergic maturation

Energy Technology Data Exchange (ETDEWEB)

Davila-Garcia, M.I.

1989-01-01

Products of the proopiomelanocortin molecule as well as leu- and met-enkephalin were tested for their effects on serotonergic neuronal maturation. High affinity uptake of ({sup 3}H)5-HT and morphometrics using immunocytochemistry specific for serotonergic neurons were used to monitor neuronal maturation. Cultured brainstem raphe neurons from 14 day fetuses, in the presence or absence of target tissue, were administered neuropeptides at various concentrations for 1,3 or 5 days in culture. ACTH peptides stimulate neurite length and, with the endorphins, the expression of ({sup 3}H)5-HT uptake by serotonergic fetal neurons cultured alone but had no effect when these neurons were cocultured with hippocampal target cells. A daily dose of leu-enkephalin to these cells inhibited neuronal uptake after 5 days of exposure and decreased neurite cell length in 24 hr cultures. In contrast, a single dose of leu-enkephalin at plating stimulated uptake after 5 days while co-administration of bacitracin inhibited uptake expression. Naloxone reversed the opioid effect and stimulated uptake when administered alone. Desulfated-CCK, which resembles leu-enkephalin, was equally potent as leu-enkephalin in inhibiting uptake.

A reassessment of the role of serotonergic system in the control of feeding behavior

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Medeiros Magda A.

2005-01-01

Full Text Available The role of serotonergic system in the feeding behaviorwas appraised by electrolytic lesions in the dorsal raphe nucleus (DRN and administration of para-chlorophenylalanine (PCPA, 3 mg/5 mul, icv. Chronic evaluations were accomplished through 120 and 360 days in PCPA-injected and DRN-lesioned rats, respectively. Acute food intake was evaluated in fasted rats and submitted to injection of PCPA and hydroxytryptophan (LHTP, 30 mg/kg, ip. DRN-lesioned rats exhibited 22-80% increase in food intake up to sixth month, whereas the obesity was evident and sustained by whole period. In PCPA-injected rats was observed an initial increase in the food intake followed by hypophagy from 25th to 30th day and a transitory increase of body weight from 5th to 60th day. In the acute study, the LHTP reverted partially the PCPA-induced increase in food intake of fasted rats suggesting a sustained capacity of decarboxylation of precursor by serotonergic neurons. Slow restoration of the levels of food intake in DRN-lesioned rats reveals a neuroplasticity in the systems that regulate feeding behavior. A plateau on the body weight curve in lesioned rats possibly represents the establishment of a new and higher set point of energetic balance.

Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphé neurones and cranial motoneurones.

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Norton, Will H; Mangoli, Maryam; Lele, Zsolt; Pogoda, Hans-Martin; Diamond, Brianne; Mercurio, Sara; Russell, Claire; Teraoka, Hiroki; Stickney, Heather L; Rauch, Gerd-Jörg; Heisenberg, Carl-Philipp; Houart, Corinne; Schilling, Thomas F; Frohnhoefer, Hans-Georg; Rastegar, Sepand; Neumann, Carl J; Gardiner, R Mark; Strähle, Uwe; Geisler, Robert; Rees, Michelle; Talbot, William S; Wilson, Stephen W

2005-02-01

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol-/- embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol-/- mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphenucleus and the trochlear motor nucleus are absent in mol-/- embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins.

Increased postpartum haemorrhage, the possible relation with serotonergic and other psychopharmacological drugs: a matched cohort study

NARCIS (Netherlands)

Heller, Hanna M.; Ravelli, Anita C. J.; Bruning, Andrea H. L.; de Groot, Christianne J. M.; Scheele, Fedde; van Pampus, Maria G.; Honig, Adriaan

2017-01-01

Postpartum haemorrhage is a major obstetric risk worldwide. Therefore risk factors need to be investigated to control for this serious complication. A recent systematic review and meta-analysis revealed that the use of both serotonergic and non-serotonergic antidepressants in pregnancy are

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

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Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex

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Daniel W. Sparks

2018-01-01

Full Text Available Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh and serotonin (5-HT have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex.

Science.gov (United States)

Sparks, Daniel W; Tian, Michael K; Sargin, Derya; Venkatesan, Sridevi; Intson, Katheron; Lambe, Evelyn K

2017-01-01

Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.

Frameworking memory and serotonergic markers.

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Meneses, Alfredo

2017-07-26

The evidence for neural markers and memory is continuously being revised, and as evidence continues to accumulate, herein, we frame earlier and new evidence. Hence, in this work, the aim is to provide an appropriate conceptual framework of serotonergic markers associated with neural activity and memory. Serotonin (5-hydroxytryptamine [5-HT]) has multiple pharmacological tools, well-characterized downstream signaling in mammals' species, and established 5-HT neural markers showing new insights about memory functions and dysfunctions, including receptors (5-HT1A/1B/1D, 5-HT2A/2B/2C, and 5-HT3-7), transporter (serotonin transporter [SERT]) and volume transmission present in brain areas involved in memory. Bidirectional influence occurs between 5-HT markers and memory/amnesia. A growing number of researchers report that memory, amnesia, or forgetting modifies neural markers. Diverse approaches support the translatability of using neural markers and cerebral functions/dysfunctions, including memory formation and amnesia. At least, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors and SERT seem to be useful neural markers and therapeutic targets. Hence, several mechanisms cooperate to achieve synaptic plasticity or memory, including changes in the expression of neurotransmitter receptors and transporters.

The role of the serotonergic system in suicidal behavior

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Sadkowski, Marta; Dennis, Brittany; Clayden, Robert C; ElSheikh, Wala; Rangarajan, Sumathy; DeJesus, Jane; Samaan, Zainab

2013-01-01

Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB); however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. PMID:24235834

A medicinal herb, Melissa officinalis L. ameliorates depressive-like behavior of rats in the forced swimming test via regulating the serotonergic neurotransmitter.

Science.gov (United States)

Lin, Shih-Hang; Chou, Mei-Ling; Chen, Wei-Cheng; Lai, Yi-Syuan; Lu, Kuan-Hung; Hao, Cherng-Wei; Sheen, Lee-Yan

2015-12-04

Depression is a serious psychological disorder that causes extreme economic loss and social problems. However, the conventional medications typically cause side effects that result in patients opting to out of therapy. Lemon balm (Melissa officinalis L., MO) is an old and particularly reliable medicinal herb for relieving feelings of melancholy, depression and anxiety. The present study aims to investigate the antidepressant-like activity of water extract of MO (WMO) by evaluating its influence on the behaviors and the relevant neurotransmitters of rats performed to forced swimming test. Two phases of the experiment were conducted. In the acute model, rats were administered ultrapure water (control), fluoxetine, WMO, or the indicated active compound (rosmarinic acid, RA) three times in one day. In the sub-acute model, rats were respectively administered ultrapure water (control), fluoxetine, or three dosages of WMO once a day for 10 days. Locomotor activity and depression-like behavior were examined using the open field test and the forced swimming test, respectively. The levels of relevant neurotransmitters and their metabolites in the frontal cortex, amygdala, hippocampus, and striatum were analyzed by high performance liquid chromatography. In the acute model, WMO and RA significantly reduced depressive-like behavior but the type of related neurotransmitter could not be determined. The results indicated that the effect of WMO administration on the reduction of immobility time was associated with an increase in swimming time of the rats, indicative of serotonergic neurotransmission modulation. Chromatography data validated that the activity of WMO was associated with a reduction in the serotonin turnover rate. The present study shows the serotonergic antidepressant-like activity of WMO. Hence, WMO may offer a serotonergic antidepressant activity to prevent depression and to assist in conventional therapies. Copyright © 2015. Published by Elsevier Ireland Ltd.

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice.

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Mariana G Fronza

Full Text Available A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT and dopamine transporter (DAT by docking molecular. 5-(4methoxyphenyl-1-(2-(phenylselanylphenyl-1H-1,2,3-triazole-4-carbonitrile (SeTACN exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g. was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist, ketanserin (a 5HT2a/c antagonist and ondansetron (a selective 5ht3 antagonist, PCPA (an inhibitor of serotonin synthesis but not with SCH23390 (dopaminergic D1 antagonist and sulpiride (D2 antagonist. Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT. These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

[Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges].

Science.gov (United States)

Majić, Tomislav; Jungaberle, Henrik; Schmidt, Timo T; Zeuch, Andrea; Hermle, Leo; Gallinat, Jürgen

2017-07-01

Background  Recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (LSD) and entactogens like 3,4-methylendioxymethamphetamine (MDMA) within the framework of psychotherapy has resumed. The present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances. Method  A selective search was carried out in the PubMed and Cochrane Library including studies investigating the clinical use of serotonergic psychoactive substances since 2000. Results  Studies were found investigating the following indications: alcohol (LSD and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (LSD and psilocybin), obsessive-compulsive disorder (OCD) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (PTSD) (MDMA). Discussion  Substance use disorders, PTSD and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. To date, studies indicate efficacy and relatively good tolerability. Further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future. © Georg Thieme Verlag KG Stuttgart · New York.

Serotonergic modulation of reward and punishment

DEFF Research Database (Denmark)

Macoveanu, Julian

2014-01-01

Until recently, the bulk of research on the human reward system was focused on studying the dopaminergic and opioid neurotransmitter systems. However, extending the initial data from animal studies on reward, recent pharmacological brain imaging studies on human participants bring a new line......-related processing and may also provide a neural correlated for the emotional blunting observed in the clinical treatment of psychiatric disorders with selective serotonin reuptake inhibitors. Given the unique profile of action of each serotonergic receptor subtype, future pharmacological studies may favor receptor...

Serotonergic modulation of reward and punishment: evidence from pharmacological fMRI studies.

Science.gov (United States)

Macoveanu, Julian

2014-03-27

Until recently, the bulk of research on the human reward system was focused on studying the dopaminergic and opioid neurotransmitter systems. However, extending the initial data from animal studies on reward, recent pharmacological brain imaging studies on human participants bring a new line of evidence on the key role serotonin plays in reward processing. The reviewed research has revealed how central serotonin availability and receptor specific transmission modulates the neural response to both appetitive (rewarding) and aversive (punishing) stimuli in putative reward-related brain regions. Thus, serotonin is suggested to be involved in behavioral control when there is a prospect of reward or punishment. The new findings may have implications in understanding psychiatric disorders such as major depression which is characterized by abnormal serotonergic function and reward-related processing and may also provide a neural correlated for the emotional blunting observed in the clinical treatment of psychiatric disorders with selective serotonin reuptake inhibitors. Given the unique profile of action of each serotonergic receptor subtype, future pharmacological studies may favor receptor specific investigations to complement present research mainly focused on global serotonergic manipulations. Copyright © 2014 Elsevier B.V. All rights reserved.

Generation of Pet1210-Cre Transgenic Mouse Line Reveals Non-Serotonergic Expression Domains of Pet1 Both in CNS and Periphery

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Pelosi, Barbara; Migliarini, Sara; Pacini, Giulia; Pratelli, Marta; Pasqualetti, Massimo

2014-01-01

Neurons producing serotonin (5-hydroxytryptamine, 5-HT) constitute one of the most widely distributed neuronal networks in the mammalian central nervous system (CNS) and exhibit a profuse innervation throughout the CNS already at early stages of development. Serotonergic neuron specification is controlled by a combination of secreted molecules and transcription factors such as Shh, Fgf4/8, Nkx2.2, Lmx1b and Pet1. In the mouse, Pet1 mRNA expression appears between 10 and 11 days post coitum (dpc) in serotonergic post-mitotic precursors and persists in serotonergic neurons up to adulthood, where it promotes the expression of genes defining the mature serotonergic phenotype such as tryptophan hydroxylase 2 (Tph2) and serotonin transporter (SERT). Hence, the generation of genetic tools based on Pet1 specific expression represents a valuable approach to study the development and function of the serotonergic system. Here, we report the generation of a Pet1210-Cre transgenic mouse line in which the Cre recombinase is expressed under the control of a 210 kb fragment from the Pet1 genetic locus to ensure a reliable and faithful control of somatic recombination in Pet1 cell lineage. Besides Cre-mediated recombination accurately occurred in the serotonergic system as expected and according to previous studies, Pet1210-Cre transgenic mouse line allowed us to identify novel, so far uncharacterized, Pet1 expression domains. Indeed, we showed that in the raphe Pet1 is expressed also in a non-serotonergic neuronal population intermingled with Tph2-expressing cells and mostly localized in the B8 and B9 nuclei. Moreover, we detected Cre-mediated recombination also in the developing pancreas and in the ureteric bud derivatives of the kidney, where it reflected a specific Pet1 expression. Thus, Pet1210-Cre transgenic mouse line faithfully drives Cre-mediated recombination in all Pet1 expression domains representing a valuable tool to genetically manipulate serotonergic and non-serotonergic

Adenoviral vectors for highly selective gene expression in central serotonergic neurons reveal quantal characteristics of serotonin release in the rat brain

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Teschemacher Anja G

2009-03-01

Full Text Available Abstract Background 5-hydroxytryptamine (5 HT, serotonin is one of the key neuromodulators in mammalian brain, but many fundamental properties of serotonergic neurones and 5 HT release remain unknown. The objective of this study was to generate an adenoviral vector system for selective targeting of serotonergic neurones and apply it to study quantal characteristics of 5 HT release in the rat brain. Results We have generated adenoviral vectors which incorporate a 3.6 kb fragment of the rat tryptophan hydroxylase-2 (TPH-2 gene which selectively (97% co-localisation with TPH-2 target raphe serotonergic neurones. In order to enhance the level of expression a two-step transcriptional amplification strategy was employed. This allowed direct visualization of serotonergic neurones by EGFP fluorescence. Using these vectors we have performed initial characterization of EGFP-expressing serotonergic neurones in rat organotypic brain slice cultures. Fluorescent serotonergic neurones were identified and studied using patch clamp and confocal Ca2+ imaging and had features consistent with those previously reported using post-hoc identification approaches. Fine processes of serotonergic neurones could also be visualized in un-fixed tissue and morphometric analysis suggested two putative types of axonal varicosities. We used micro-amperometry to analyse the quantal characteristics of 5 HT release and found that central 5 HT exocytosis occurs predominantly in quanta of ~28000 molecules from varicosities and ~34000 molecules from cell bodies. In addition, in somata, we observed a minority of large release events discharging on average ~800000 molecules. Conclusion For the first time quantal release of 5 HT from somato-dendritic compartments and axonal varicosities in mammalian brain has been demonstrated directly and characterised. Release from somato-dendritic and axonal compartments might have different physiological functions. Novel vectors generated in this

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems.

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Brüning, César Augusto; Souza, Ana Cristina Guerra; Gai, Bibiana Mozzaquatro; Zeni, Gilson; Nogueira, Cristina Wayne

2011-05-11

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems. Copyright © 2011 Elsevier B.V. All rights reserved.

The association between concomitant use of serotonergic antidepressants and lithium-induced polyuria. A multicenter medical chart review study.

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Wilting, I; Egberts, A C G; Movig, K L L; Laarhoven, J H M van; Heerdink, E R; Nolen, W A

2008-07-01

A previous study aimed at revealing the prevalence and determinants of lithium induced polyuria suggested an increased risk of polyuria (urine volume > or =3 L/24 h) in those using serotonergic antidepressants next to lithium. The objective of our study was to re-evaluate this secondary finding in another study population. We performed a multicenter medical chart review study in patients using lithium in whom a 24-hour urine volume had been determined. We included 116 patients, twelve (26%)of the 46 patients with polyuria used serotonergic antidepressants compared to ten (14%) of the 70 patients without polyuria. We found an increased risk of polyuria in lithium users concurrently using serotonergic antidepressants (oddsratio 2.86; 95% confidence interval 1.00-8.21), adjusted for age, gender, use of antiepileptics and thyreomimetics. Our results confirm the previous secondary finding of an increased risk of polyuria in patients using serotonergic antidepressants next to lithium. Physicians should take this into account when evaluating polyuria in patients using lithium and when choosing an antidepressant in patients using lithium.

Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs

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Abrams, J K; Johnson, P L; Hay-Schmidt, Anders

2005-01-01

Serotonergic systems play important roles in modulating behavioral arousal, including behavioral arousal and vigilance associated with anxiety states. To further our understanding of the neural systems associated with increases in anxiety states, we investigated the effects of multiple anxiogenic...... and vigilance behaviors consistent with an increase in anxiety state. In addition, these anxiogenic drugs, excluding yohimbine, had convergent actions on an anatomically-defined subset of serotonergic neurons within the middle and caudal, dorsal subdivision of the DR. High resolution topographical analysis...... nucleus, a forebrain structure important for emotional appraisal and modulation of anxiety-related physiological and behavioral responses. Together these findings support the hypothesis that there is a functional topographical organization in the DR and are consistent with the hypothesis that anxiogenic...

Serotonergic neurotransmission in emotional processing

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Laursen, Helle Ruff; Henningsson, Susanne; Macoveanu, Julian

2016-01-01

,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational...... ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex...... judgement on each face stimulus. Positron emission tomography with (11)C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets...

Valproic acid silencing of ascl1b/Ascl1 results in the failure of serotonergic differentiation in a zebrafish model of fetal valproate syndrome

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John Jacob

2014-01-01

Full Text Available Fetal valproate syndrome (FVS is caused by in utero exposure to the drug sodium valproate. Valproate is used worldwide for the treatment of epilepsy, as a mood stabiliser and for its pain-relieving properties. In addition to birth defects, FVS is associated with an increased risk of autism spectrum disorder (ASD, which is characterised by abnormal behaviours. Valproate perturbs multiple biochemical pathways and alters gene expression through its inhibition of histone deacetylases. Which, if any, of these mechanisms is relevant to the genesis of its behavioural side effects is unclear. Neuroanatomical changes associated with FVS have been reported and, among these, altered serotonergic neuronal differentiation is a consistent finding. Altered serotonin homeostasis is also associated with autism. Here we have used a chemical-genetics approach to investigate the underlying molecular defect in a zebrafish FVS model. Valproate causes the selective failure of zebrafish central serotonin expression. It does so by downregulating the proneural gene ascl1b, an ortholog of mammalian Ascl1, which is a known determinant of serotonergic identity in the mammalian brainstem. ascl1b is sufficient to rescue serotonin expression in valproate-treated embryos. Chemical and genetic blockade of the histone deacetylase Hdac1 downregulates ascl1b, consistent with the Hdac1-mediated silencing of ascl1b expression by valproate. Moreover, tonic Notch signalling is crucial for ascl1b repression by valproate. Concomitant blockade of Notch signalling restores ascl1b expression and serotonin expression in both valproate-exposed and hdac1 mutant embryos. Together, these data provide a molecular explanation for serotonergic defects in FVS and highlight an epigenetic mechanism for genome-environment interaction in disease.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

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Dolphin Annette C

2009-08-01

descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in α2δ-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

Genetic and biochemical changes of the serotonergic system in migraine pathobiology.

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Gasparini, Claudia Francesca; Smith, Robert Anthony; Griffiths, Lyn Robyn

2017-12-01

Migraine is a brain disorder characterized by a piercing headache which affects one side of the head, located mainly at the temples and in the area around the eye. Migraine imparts substantial suffering to the family in addition to the sufferer, particularly as it affects three times more women than men and is most prevalent between the ages of 25 and 45, the years of child rearing. Migraine typically occurs in individuals with a genetic predisposition and is aggravated by specific environmental triggers. Attempts to study the biochemistry of migraine began as early as the 1960s and were primarily directed at serotonin metabolism after an increase of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin was observed in urine of migraineurs. Genetic and biochemical studies have primarily focused on the neurotransmitter serotonin, considering receptor binding, transport and synthesis of serotonin and have investigated serotonergic mediators including enzymes, receptors as well as intermediary metabolites. These studies have been mainly assayed in blood, CSF and urine as the most accessible fluids. More recently PET imaging technology integrated with a metabolomics and a systems biology platform are being applied to study serotonergic biology. The general trend observed is that migraine patients have alterations of neurotransmitter metabolism detected in biological fluids with different biochemistry from controls, however the interpretation of the biological significance of these peripheral changes is unresolved. In this review we present the biology of the serotonergic system and metabolic routes for serotonin and discuss results of biochemical studies with regard to alterations in serotonin in brain, cerebrospinal fluid, saliva, platelets, plasma and urine of migraine patients.

Botanical modulation of menopausal symptoms: Mechanisms of action?

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Hajirahimkhan, Atieh; Dietz, Birgit M.; Bolton, Judy L.

2013-01-01

Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats which can affect quality of life. Although hormone therapy (HT) has been the treatment of choice for relieving these symptoms, HT has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief, have been controversial and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-HT7 ligands or inhibit serotonin re-uptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for women’s health, could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future. PMID:23408273

Genistein alleviates anxiety-like behaviors in post-traumatic stress disorder model through enhancing serotonergic transmission in the amygdala.

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Wu, Zhong-Min; Ni, Gui-Lian; Shao, Ai-Min; Cui, Rong

2017-09-01

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder, characterized by intense fear, and increased arousal and avoidance of traumatic events. The current available treatments for PTSD have limited therapeutic value. Genistein, a natural isoflavone, modulates a variety of cell functions. In this study, we tested anti-anxiety activity and underlying mechanisms of genistein in a PTSD rat model. The rats were trained to associate a tone with foot shock delivery on day 0, then fear conditioning was performed on day 7, 14 and 21. Genistein (2-8mg/kg) was injected intraperitoneally daily for 7 days. The anti-anxiety effects of genistein were measured by contextual freezing behavior and elevated plus maze. By the end of the experiments, the amygdala was extracted and subject to neurochemistry analysis. Genistein alleviated contextual freezing behavior and improved performance in elevated plus maze dose-dependently in PTSD rats. Furthermore, in these rats, genistein enhanced serotonergic transmission in the amygdala, including upregulation of tryptophan hydroxylase, serotonin, and phosphorylated (p)-CaMKII and p-CREB, as well. Genistein exerts anti-anxiety effects on a PTSD model probably through enhancing serotonergic system and CaMKII/CREB signaling pathway in the amygdala. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Is a serotonergic mechanism involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the Sprague-Dawley rat

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Rozman, K. (Kansas Univ., Kansas City, KS (USA). Dept. of Pharmacology, Toxicology and Therapeutics Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen (GSF), Neuherberg (Germany, F.R.). Inst. fuer Toxikologie); Pfeifer, B.; Kerecsen, L.; Alper, R.H. (Kansas Univ., Kansas City, KS (USA). Dept. of Pharmacology, Toxicology and Therapeutics)

1991-02-01

The major cause of TCDD-induced death in rats is a progressive voluntary feed refusal which has been correlated with reduced gluconeogenesis. Since centrally administered TCDD does not cause death or decreased feed intake in rats, the ability of TCDD to suppress appetite via peripheral mechanisms acting on the central nervous system was examined in two experimental models. First, it was found that the feed intake of rats on scheduled feeding cycles was not decreased by blood transfused from rats with TCDD-induced appetite suppression (8 days after a lethal dose of TCDD, i.p.). In contrast, a similar transfusion from normal, satiated rats did reduce feed intake of recipient rats by approximately 40%, suggesting that TCDD-treated rats are not satiated but rather that they are not hunggy. In the second study tryptophan (the amino acid precursor of the neutrotransmitter serotonin) was measured in the plasma and tryptophan, serotonin, norepinephrine and dopamine in the hypothalamus as well as dopamine and its metabolites in the striatum 4, 8, and 16 days after TCDD dosage (125 {mu}g/kg, i.p.). Progressive time-dependent increases in tryptophan levels in plasma and brain were paralleled by increases in brain serotonin and 5-hydroxyindoleacetic acid (the primary metabolite of serotonin) in TCDD-treated rats. No changes were observed regarding the other biogenic amines. It is suggested based on these data and on substantial evidence from the published literature that a serotonergic mechanism may be involved in TCDD-induced feed intake reduction. (orig.).

Studies on the characterization and regulation of alpha-1 adrenergic receptors and [3H]WB4101 binding sites in the central nervous system

International Nuclear Information System (INIS)

Morrow, A.L.

1985-01-01

The purpose of these studies has been to resolve the anomalous binding characteristics of two alpha adrenergic receptor ligands, [ 3 H]WB4101 and [ 3 H]prazosin and to study the regulation of the receptors labeled by these compounds after surgical denervation and chronic drug treatments. Preliminary studies indicated that [ 3 H]WB4101 binding sites, which were believed to represent alpha-1 adrenergic receptors, were increased in number following removal of the fimbrial afferents to the hippocampus. This increase was not due to removal of the adrenergic input into this structure since destruction of the locus coeruleus or the dorsal noradrenergic bundle did not produce the up-regulation. Characterization of alpha-1 adrenergic receptors using [ 3 H]prazosin and [ 3 H]WB4101 revealed evidence for subtypes of alpha-1 receptors designated alpha-1A and alpha-1B. The nanomolar affinity component of [ 3 H]WB4101 binding is not adrenergic but serotonergic. The serotonergic agonists, serotonin and 8-hydroxy-dipropylaminotetraline have affinities of 1.5 and 3.0 nM for this site, when studied in the presence of a 30 nM prazosin mask of the alpha-1 component of [ 3 H]WB4101 binding. Fimbria transection or 5,7 dihydroxytryptamine injections produced increases in the Bmax of the nanomolar affinity component of [ 3 H]WB4101 binding in the presence of a prazosin mask. The up-regulated site showed identical serotonergic pharmacology compared to control tissue. Thus, the author concluded that serotonergic denervation of the hippocampus produces the increase in serotonergic binding sites labeled by [ 3 H]WB4101

The role of the serotonergic system in suicidal behavior

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Sadkowski M

2013-11-01

Full Text Available Marta Sadkowski,1,* Brittany Dennis,2–4,* Robert C Clayden,2 Wala ElSheikh,5 Sumathy Rangarajan,5 Jane DeJesus,5 Zainab Samaan3–6 1Arts and Sciences Program, 2Faculty of Health Sciences, 3Department of Clinical Epidemiology and Biostatistics, 4Population Genomics Program, McMaster University, Hamilton, ON, Canada; 5Population Health Research Institute, Hamilton, ON, Canada; 6Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada *These authors contributed equally to this work Abstract: Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB; however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. Keywords: serotonin, suicide, genetic

Phrenic motoneuron expression of serotonergic and glutamatergic receptors following upper cervical spinal cord injury

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Mantilla, Carlos B.; Bailey, Jeffrey P.; Zhan, Wen-Zhi; Sieck, Gary C.

2012-01-01

Following cervical spinal cord injury at C2 (SH hemisection model) there is progressive recovery of phrenic activity. Neuroplasticity in the postsynaptic expression of neurotransmitter receptors may contribute to functional recovery. Phrenic motoneurons express multiple serotonergic (5-HTR) and glutamatergic (GluR) receptors, but the timing and possible role of these different neurotransmitter receptor subtypes in the neuroplasticity following SH are not clear. The current study was designed to test the hypothesis that there is an increased expression of serotonergic and glutamatergic neurotransmitter receptors within phrenic motoneurons after SH. In adult male rats, phrenic motoneurons were labeled retrogradely by intrapleural injection of Alexa 488-conjugated cholera toxin B. In thin (10 μm) frozen sections of the spinal cord, fluorescently-labeled phrenic motoneurons were visualized for laser capture microdissection (LCM). Using quantitative real-time RT-PCR in LCM samples, the time course of changes in 5-HTR and GluR mRNA expression was determined in phrenic motoneurons up to 21 days post-SH. Expression of 5-HTR subtypes 1b, 2a and 2c and GluR subtypes AMPA, NMDA, mGluR1 and mGluR5 was evident in phrenic motoneurons from control and SH rats. Phrenic motoneuron expression of 5-HTR2a increased ~8-fold (relative to control) at 14 days post-SH, whereas NMDA expression increased ~16-fold by 21-days post-SH. There were no other significant changes in receptor expression at any time post-SH. This is the first study to systematically document changes in motoneuron expression of multiple neurotransmitter receptors involved in regulation of motoneuron excitability. By providing information on the neuroplasticity of receptors expressed in a motoneuron pool that is inactivated by a higher-level spinal cord injury, appropriate pharmacological targets can be identified to alter motoneuron excitability. PMID:22227062

Influence of early stress on social abilities and serotonergic functions across generations in mice.

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Tamara B Franklin

Full Text Available Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

Perinatal serotonergic activity: A decisive factor in the control of food intake

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Isabeli Lins PINHEIRO

Full Text Available ABSTRACT The serotoninergic system controls key events related to proper nervous system development. The neurotransmitter serotonin and the serotonin transporter are critical for this control. Availability of these components is minutely regulated during the development period, and the environment may affect their action on the nervous system. Environmental factors such as undernutrition and selective serotonin reuptake inhibitors may increase the availability of serotonin in the synaptic cleft and change its anorectic action. The physiological responses promoted by serotonin on intake control decrease when requested by acute stimuli or stress, demonstrating that animals or individuals develop adaptations in response to the environmental insults they experience during the development period. Diseases, such as anxiety and obesity, appear to be associated with the body’s response to stress or stimulus, and require greater serotonergic system action. These findings demonstrate the importance of the level of serotonin in the perinatal period to the development of molecular and morphological aspects of food intake control, and its decisive role in understanding the possible environmental factors that cause diseases in adulthood.

Feeding motivation as a personality trait in Nile tilapia (Oreochromis niloticus): role of serotonergic neurotransmission

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Silva, P.I.M.; Martins, C.I.M.; Höglund, Erik

2014-01-01

Consistent individual variation in behaviour and physiology (i.e. animal personality or coping style) has emerged as a central topic in many biological disciplines. Yet, underlying mechanisms of crucial personality traits like feeding behaviour in novel environments remain unclear. Comparative...... to determine to what degree brain 5-hydroxytryptamine (5-HT, serotonin) activity pertains to this aspect of animal personality, as a correlate to feed anticipatory behaviour and recovery of feed intake after transfer to a novel environment. Crucial to the definition of animal personality, a strong degree...... of individual consistency in different measures of feeding behaviour (feeding latency and feeding score), was demonstrated. Furthermore, low serotonergic activity in the hypothalamus was highly correlated with a personality characterized by high feeding motivation, with feeding motivation represented...

Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals.

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Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; DeBerry, Jennifer J; Gu, Jianguo G

2016-09-13

The evolution of sensory systems has let mammals develop complicated tactile end organs to enable sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. The Merkel disc, a main type of tactile end organ consisting of Merkel cells (MCs) and Aβ-afferent endings, are highly abundant in fingertips, touch domes, and whisker hair follicles of mammals. The Merkel disc has high tactile acuity for an object's physical features, such as texture, shape, and edges. Mechanisms underlying the tactile function of Merkel discs are obscured as to how MCs transmit tactile signals to Aβ-afferent endings leading to tactile sensations. Using mouse whisker hair follicles, we show herein that tactile stimuli are transduced by MCs into excitatory signals that trigger vesicular serotonin release from MCs. We identify that both ionotropic and metabotropic 5-hydroxytryptamine (5-HT) receptors are expressed on whisker Aβ-afferent endings and that their activation by serotonin released from MCs initiates Aβ-afferent impulses. Moreover, we demonstrate that these ionotropic and metabotropic 5-HT receptors have a synergistic effect that is critical to both electrophysiological and behavioral tactile responses. These findings elucidate that the Merkel disc is a unique serotonergic synapse located in the epidermis and plays a key role in tactile transmission. The epidermal serotonergic synapse may have important clinical implications in sensory dysfunctions, such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes, inflammatory diseases, and undergo chemotherapy. It may also have implications in the exaggerated tactile sensations induced by recreational drugs that act on serotoninergic synapses.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology.

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De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-11-23

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

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John D. Chan

2016-12-01

Full Text Available 5-hydroxytryptamine (5-HT is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL, prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users.

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Parrott, Andrew C

2013-09-01

Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component. Copyright © 2013 Elsevier Ltd. All rights reserved.

The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms?

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Goodman, Neil

2002-01-01

This article aims to explore, through established scientific research and documented accounts of personal experience, the similarities between religious mystical experiences and some effects of D-lysergic diethylamide or LSD. LSD predominantly works upon the serotonergic (serotonin-using neurons) diffuse neuromodulatory system, which projects its axons to virtually all areas of the brain including the neocortex. By its normal action it modulates awareness of the environmental surroundings and filters a high proportion of this information before it can be processed, thereby only allowing the amount of information that is necessary for survival. LSD works to open this filter, and so an increased amount of somatosensory data is processed with a corresponding increase in what is deemed important. This article describes the effects and actions of LSD, and due to the similarities with the nondrug-induced mystical experience the author proposes that the two could have common modes of action upon the brain. This could lead to avenues of research into mysticism and a wealth of knowledge on consciousness and how we perceive the universe.

Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children.

Science.gov (United States)

Brown, Hilary K; Ray, Joel G; Wilton, Andrew S; Lunsky, Yona; Gomes, Tara; Vigod, Simone N

2017-04-18

Previous observations of a higher risk of child autism spectrum disorder with serotonergic antidepressant exposure during pregnancy may have been confounded. To evaluate the association between serotonergic antidepressant exposure during pregnancy and child autism spectrum disorder. Retrospective cohort study. Health administrative data sets were used to study children born to mothers who were receiving public prescription drug coverage during pregnancy in Ontario, Canada, from 2002-2010, reflecting 4.2% of births. Children were followed up until March 31, 2014. Serotonergic antidepressant exposure was defined as 2 or more consecutive maternal prescriptions for a selective serotonin or serotonin-norepinephrine reuptake inhibitor between conception and delivery. Child autism spectrum disorder identified after the age of 2 years. Exposure group differences were addressed by inverse probability of treatment weighting based on derived high-dimensional propensity scores (computerized algorithm used to select a large number of potential confounders) and by comparing exposed children with unexposed siblings. There were 35 906 singleton births at a mean gestational age of 38.7 weeks (50.4% were male, mean maternal age was 26.7 years, and mean duration of follow-up was 4.95 years). In the 2837 pregnancies (7.9%) exposed to antidepressants, 2.0% (95% CI, 1.6%-2.6%) of children were diagnosed with autism spectrum disorder. The incidence of autism spectrum disorder was 4.51 per 1000 person-years among children exposed to antidepressants vs 2.03 per 1000 person-years among unexposed children (between-group difference, 2.48 [95% CI, 2.33-2.62] per 1000 person-years; hazard ratio [HR], 2.16 [95% CI, 1.64-2.86]; adjusted HR, 1.59 [95% CI, 1.17-2.17]). After inverse probability of treatment weighting based on the high-dimensional propensity score, the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]). The association was also not significant when exposed children

Serotonin-induced down-regulation of cell surface serotonin transporter

DEFF Research Database (Denmark)

Jørgensen, Trine Nygaard; Christensen, Peter Møller; Gether, Ulrik

2014-01-01

The serotonin transporter (SERT) terminates serotonergic signaling and enables refilling of synaptic vesicles by mediating reuptake of serotonin (5-HT) released into the synaptic cleft. The molecular and cellular mechanisms controlling SERT activity and surface expression are not fully understood...

d-Lysergic Acid Diethylamide (LSD as a Model of Psychosis: Mechanism of Action and Pharmacology

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Danilo De Gregorio

2016-11-01

Full Text Available d-Lysergic Acid Diethylamide (LSD is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1 and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA mechanism or acting on TAAR1 receptors.

Serotonergic neurotransmission in emotional processing: New evidence from long-term recreational poly-drug ecstasy use.

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Laursen, Helle Ruff; Henningsson, Susanne; Macoveanu, Julian; Jernigan, Terry L; Siebner, Hartwig R; Holst, Klaus K; Skimminge, Arnold; Knudsen, Gitte M; Ramsoy, Thomas Z; Erritzoe, David

2016-12-01

The brain's serotonergic system plays a crucial role in the processing of emotional stimuli, and several studies have shown that a reduced serotonergic neurotransmission is associated with an increase in amygdala activity during emotional face processing. Prolonged recreational use of ecstasy (3,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex judgement on each face stimulus. Positron emission tomography with 11 C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets was associated with an increase in amygdala activity during angry face processing. Conversely, time since the last ecstasy intake was associated with a trend toward a decrease in amygdala activity during angry and sad face processing. These results indicate that the effects of long-term serotonin depletion resulting from ecstasy use are dose-dependent, affecting the functional neural basis of emotional face processing. © The Author(s) 2016.

Acute restriction impairs memory in the elevated T-maze (ETM) and modifies serotonergic activity in the dorsolateral striatum.

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Cruz-Morales, Sara Eugenia; García-Saldívar, Norma Laura; González-López, María Reyes; Castillo-Roberto, Georgina; Monroy, Juana; Domínguez, Roberto

2008-12-16

Serotonin (5-HT) is involved in behaviors such as sleep, eating, memory, in mental disorders like anxiety and depression and plays an important role in the modulation of stress. On the other hand, exposure to stress influence learning as well as declarative and non-declarative memory. These effects are dependent on the type of stressor, their magnitude, and the type of memory. The striatum has been associated with non-declarative procedural memory, while the information about stress effects on procedural memory and their relation with striatal serotonin is scarce. The objective of this study was to evaluate the effects of stress on the modifications of the striatal serotonergic system. In Experiment 1, the effects of either 60 min of restraint (R) or exposure to the elevated T-maze (ETM) was assessed. Exposure to ETM decreased 5-HT concentration and to R increased 5-HT activity ([metabolite]/[neurotransmitter]). In Experiment 2, we evaluated the effects of restraint on ETM trained immediately, 24 or 48 h after restraint. No effects were detected in acquisition or escape latencies, while retention latencies were lower in all groups compared with the non-restrained group, although significant effects were detected immediately and 24h after restraint. The memory impairment seems to be associated with changes in striatal serotonergic system, given that 5-HT concentration increased, while serotonergic activity decreased. The differences in the activity of 5-HT detected in each experiment could be explained by the effects of different stressors on the serotonergic neurons ability to synthesize the neurotransmitter. Thus, we suggest that exposure to stress impairs procedural memory and that striatal serotonin modulates this effect.

Early-life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

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Tomoko eSoga

2015-11-01

Full Text Available Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinising hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP-tagged GnIH-transgenic rats. Socially isolated rats were observed for anxious and depressive behaviours. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group -housing. We also inspected serotonergic fibre juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviours. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fibre juxtapositions on EGFP–GnIH neurons was also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat

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Asante, Curtis O.; Dickenson, Anthony H.

2010-01-01

We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states. PMID:20709148

Serotonergic outcome, stress and sexual steroid hormones, and growth in a South American cichlid fish fed with an L-tryptophan enriched diet.

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Morandini, Leonel; Ramallo, Martín Roberto; Moreira, Renata Guimarães; Höcht, Christian; Somoza, Gustavo Manuel; Silva, Ana; Pandolfi, Matías

2015-11-01

Reared animals for edible or ornamental purposes are frequently exposed to high aggression and stressful situations. These factors generally arise from conspecifics in densely breeding conditions. In vertebrates, serotonin (5-HT) has been postulated as a key neuromodulator and neurotransmitter involved in aggression and stress. The essential amino acid L-tryptophan (trp) is crucial for the synthesis of 5-HT, and so, leaves a gateway for indirectly augmenting brain 5-HT levels by means of a trp-enriched diet. The cichlid fish Cichlasoma dimerus, locally known as chanchita, is an autochthonous, potentially ornamental species and a fruitful laboratory model which behavior and reproduction has been studied over the last 15years. It presents complex social hierarchies, and great asymmetries between subordinate and dominant animals in respect to aggression, stress, and reproductive chance. The first aim of this work was to perform a morphological description of chanchita's brain serotonergic system, in both males and females. Then, we evaluated the effects of a trp-supplemented diet, given during 4weeks, on brain serotonergic activity, stress and sexual steroid hormones, and growth in isolated specimens. Results showed that chanchita's brain serotonergic system is composed of several populations of neurons located in three main areas: pretectum, hypothalamus and raphe, with no clear differences between males and females at a morphological level. Animals fed with trp-enriched diets exhibited higher forebrain serotonergic activity and a significant reduction in their relative cortisol levels, with no effects on sexual steroid plasma levels or growth parameters. Thus, this study points to food trp enrichment as a "neurodietary'' method for elevating brain serotonergic activity and decreasing stress, without affecting growth or sex steroid hormone levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease

DEFF Research Database (Denmark)

Marner, Lisbeth; Frøkjær, Vibe; Kalbitzer, Jan

2012-01-01

and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C...

Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

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Berit eBrogaard

2013-10-01

Full Text Available Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia.

Science.gov (United States)

Brogaard, Berit

2013-01-01

Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

Mechanism of economic regulation of land relations

OpenAIRE

Mykhaylo Stupen'; Svitlana Rogach; Ivan Riy

2015-01-01

In the article the mechanism of economic regulation of land relations is revealed. The main functions of the economic evaluation of land resources are: registration of land resources and environment; choices of resources and conditions usage. The author proves that the proper economic regulation needs governmental support which is to preserve the land as a natural resource.

The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test.

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Vega-Rivera, N M; López-Rubalcava, C; Estrada-Camarena, E

2013-10-10

17α-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 μg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 μg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and subjected to the FST. In addition, the participation of α2-adrenergic receptors in the antidepressant-like action of EE2 was explored using the selective α2-receptor antagonist idazoxan (0.25, 0.5 and 1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Putaminal serotonergic innervation: monitoring dyskinesia risk in Parkinson disease.

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Lee, Jee-Young; Seo, Seongho; Lee, Jae Sung; Kim, Han-Joon; Kim, Yu Kyeong; Jeon, Beom S

2015-09-08

To explore serotonergic innervation in the basal ganglia in relation to levodopa-induced dyskinesia in patients with Parkinson disease (PD). A total of 30 patients with PD without dementia or depression were divided into 3 matched groups (dyskinetic, nondyskinetic, and drug-naive) for this study. We acquired 2 PET scans and 3T MRI for each patient using [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ((11)C-DASB) and N-(3-[(18)F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane ((18)F-FP-CIT). Then we analyzed binding potentials of the 2 radiotracers at basal ganglia structures and correlations with clinical variables. We observed no difference in (18)F-FP-CIT binding between dyskinetic and nondyskinetic patients, whereas there were differences in (11)C-DASB binding for the caudate and putamen. Binding potential ratios ((11)C-DASB/(18)F-FP-CIT) at the putamen, which indicate serotoninergic fiber innervation relative to dopaminergic fiber availability, were highest in the dyskinetic group, followed by the nondyskinetic and drug-naive PD groups. (11)C-DASB/(18)F-FP-CIT ratios at the putamen and pallidum correlated positively with Unified Parkinson's Disease Rating Scale (UPDRS) total scores and duration of PD, and pallidal binding ratio also correlated with the UPDRS motor scores. Ratios were not dependent on dopaminergic medication dosages for any of the regions studied. Relative serotonergic innervation of the putamen and pallidum increased with clinical PD progression and was highest in patients with established dyskinesia. The serotonin/dopamine transporter ratio might be a potential marker of disease progression and an indicator of risk for levodopa-induced dyskinesia in PD. A prospective evaluation is warranted in the future. © 2015 American Academy of Neurology.

A happy valve in a happy patient? Serotonergic antidepressants and the risk of valvular heart disease (SERVAL). A case-control study.

Science.gov (United States)

De Backer, Tine; Petrovic, Mirko; Audenaert, Kurt; Coeman, Mathieu; De Bacquer, Dirk

2016-02-01

The objective was to investigate the risk of valvular heart disease in humans in relation to the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors. A case-control study. We conducted a case-control study within this cohort in which patients with newly diagnosed cardiac valve regurgitation were age-matched to controls. Patient demographics, their cardiovascular risk factors and medication use were extracted in both series. Use of SSRIs, serotonin and noradreline reuptake inhibitors (SNRIs) and other pro-serotonergic agents, their dose and treatment duration were recorded. Logistic regression analysis was used to establish the strength of the association between SSRI/SNRI use and valvular heart disease. Outpatient clinic of the cardiology department at the Ghent University Hospital, East-Flanders in Belgium. Total of 2911 persons 21-58 years of age who had undergone an echocardiogram in the period 2006-2010 and had no known cardiovascular disease or previous cardiac intervention. Two hundred and six echocardiographically proven cases of valvular regurgitation and 195 matched controls. Odd ratio of valvular disease associated with intake of serotonergic drugs. Of the 206 patients with newly diagnosed cardiac valve regurgitation, 11.6% were exposed to serotonergic agents compared to 4.1% in the 195 control patients, leading to an odds ratio of 3.08 (95% confidence interval [CI] 1.35-7.04). The analysis of doses and treatment durations revealed a dose-relationship pattern between SSRI/SNRI use and prevalent valvular heart disease. In this study, use of serotonergic antidepressants was associated with an increased rate of valvular regurgitation in humans.

Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents.

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Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; Gu, Jianguo G

2017-05-01

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In this study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, γ-aminobutyric acid (GABA), and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (I h ), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of I h currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. © 2017 International Society for Neurochemistry.

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

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Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

The anatomy of the serotonergic nervous system of an entoproct creeping-type larva and its phylogenetic implications

DEFF Research Database (Denmark)

Wanninger, Andreas Wilhelm Georg; Fuchs, Judith; Haszprunar, Gerhard

2007-01-01

the anatomy of the serotonergic nervous system of the creeping-type larva of Loxosomella murmanica. The apical organ is very complex and comprises six to eight centrally positioned flask cells and eight bipolar peripheral cells. In addition, a prototroch nerve ring, an anterior nerve loop, a paired buccal...... molluscs and may be diagnostic for a mollusc-entoproct clade. In addition, the larva of Loxosomella expresses a mosaic of certain neural features that are also found in other larval or adult Spiralia, e.g., a prototroch nerve ring, an anterior nerve loop, and a buccal nervous system....... ones, are found along the anterior-posterior axis. The combination of a complex larval serotonergic apical organ and (adult) tetraneury, comprising one pair of ventral and one pair of more dorsally situated lateral longitudinal nerve cords without ganglia, has so far only been reported for basal...

Mindful Emotion Regulation: Exploring the Neurocognitive Mechanisms behind Mindfulness

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Alessandro Grecucci

2015-01-01

Full Text Available The purpose of this paper is to review some of the psychological and neural mechanisms behind mindfulness practice in order to explore the unique factors that account for its positive impact on emotional regulation and health. After reviewing the mechanisms of mindfulness and its effects on clinical populations we will consider how the practice of mindfulness contributes to the regulation of emotions. We argue that mindfulness has achieved effective outcomes in the treatment of anxiety, depression, and other psychopathologies through the contribution of mindfulness to emotional regulation. We consider the unique factors that mindfulness meditation brings to the process of emotion regulation that may account for its effectiveness. We review experimental evidence that points towards the unique effects of mindfulness specifically operating over and above the regulatory effects of cognitive reappraisal mechanisms. A neuroanatomical circuit that leads to mindful emotion regulation is also suggested. This paper thereby aims to contribute to proposed models of mindfulness for research and theory building by proposing a specific model for the unique psychological and neural processes involved in mindful detachment that account for the effects of mindfulness over and above the effects accounted for by other well-established emotional regulation processes such as cognitive reappraisal.

Quantitative accuracy of serotonergic neurotransmission imaging with high-resolution 123I SPECT

International Nuclear Information System (INIS)

Kuikka, J.T.

2004-01-01

Aim: Serotonin transporter (SERT) imaging can be used to study the role of regional abnormalities of neurotransmitter release in various mental disorders and to study the mechanism of action of therapeutic drugs or drugs' abuse. We examine the quantitative accuracy and reproducibility that can be achieved with high-resolution SPECT of serotonergic neurotransmission. Method: Binding potential (BP) of 123 I labeled tracer specific for midbrain SERT was assessed in 20 healthy persons. The effects of scatter, attenuation, partial volume, misregistration and statistical noise were estimated using phantom and human studies. Results: Without any correction, BP was underestimated by 73%. The partial volume error was the major component in this underestimation whereas the most critical error for the reproducibility was misplacement of region of interest (ROI). Conclusion: The proper ROI registration, the use of the multiple head gamma camera with transmission based scatter correction introduce more relevant results. However, due to the small dimensions of the midbrain SERT structures and poor spatial resolution of SPECT, the improvement without the partial volume correction is not great enough to restore the estimate of BP to that of the true one. (orig.) [de

The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response

DEFF Research Database (Denmark)

Frederiksen, Kristian Steen; Oranje, Bob; Wienberg, Malene

2007-01-01

Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic...

Characterization of the serotonin transporter knockout rat : A selective change in the functioning of the serotonergic system

NARCIS (Netherlands)

Homberg, J. R.; Olivier, J.D.A.; Smits, B. M. G.; Mul, J. D.; Mudde, J.; Verheul, M.; Nieuwenhuizen, O. F. M.; Cools, A. R.; Ronken, E; Cremers, Thomas; Schoffelmeere, A. N. M.; Ellenbroeik, B. A.; Cuppen, E.

2007-01-01

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by

Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system.

NARCIS (Netherlands)

Homberg, J.R.; Olivier, J.D.A.; Smits, B.M.; Mul, J.D.; Mudde, J.; Verheul, M.; Nieuwenhuizen, O.F.; Cools, A.R.; Ronken, E.; Cremers, T.; Schoffelmeer, A.N.; Ellenbroek, B.A.; Cuppen, E.

2007-01-01

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by

Mechanisms regulating skin immunity and inflammation.

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Pasparakis, Manolis; Haase, Ingo; Nestle, Frank O

2014-05-01

Immune responses in the skin are important for host defence against pathogenic microorganisms. However, dysregulated immune reactions can cause chronic inflammatory skin diseases. Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease. In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

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Brezo, J; Bureau, A; Mérette, C; Jomphe, V; Barker, E D; Vitaro, F; Hébert, M; Carbonneau, R; Tremblay, R E; Turecki, G

2010-08-01

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts

An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.

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Jason E Shoemaker

2015-06-01

Full Text Available Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases.

Immunomodulatory Effects Mediated by Serotonin

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Rodrigo Arreola

2015-01-01

Full Text Available Serotonin (5-HT induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b downstream signaling transduction proteins; and (c enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases.

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice.

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Otsuka, Tsuyoshi; Kawai, Misato; Togo, Yuki; Goda, Ryosei; Kawase, Takahiro; Matsuo, Haruka; Iwamoto, Ayaka; Nagasawa, Mao; Furuse, Mitsuhiro; Yasuo, Shinobu

2014-02-01

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. Copyright © 2013 Elsevier Ltd. All rights reserved.

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

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Peiyan eWong

2015-04-01

Full Text Available Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT mice and mice with deficient tryptophan hydroxylase 2 (TPH2 function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI mice. Whereas, maternal separation (MS stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A. The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex, will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive

Early Family Relationships Predict Children’s Emotion Regulation and Defense Mechanisms

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Jallu Lindblom

2016-12-01

Full Text Available Early family relationships have been suggested to influence the development of children’s affect regulation, involving both emotion regulation and defense mechanisms. However, we lack research on the specific family predictors for these two forms of affect regulation, which have been conceptualized to differ in their functions and accessibility to consciousness. Accordingly, we examine how the (a quality and (b timing of family relationships during infancy predict child’s later emotion regulation and defense mechanisms. Parents (N = 703 reported autonomy and intimacy in marital and parenting relationships at the child’s ages of 2 and 12 months, and the child’s use of emotion regulation and immature and neurotic defenses at 7 to 8 years. As hypothesized, the results showed that functional early family relationships predicted children’s efficient emotion regulation, whereas dysfunctional relationships predicted reliance on defense mechanisms in middle childhood. Further, results showed a timing effect for neurotic defenses, partially confirming our hypothesis of early infancy being an especially important period for the development of defense mechanisms. The findings are discussed from the viewpoints of attachment and family dynamics, emotional self-awareness, and sense of security.

Intraspinal serotonergic neurons consist of two, temporally distinct populations in developing zebrafish.

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Montgomery, Jacob E; Wiggin, Timothy D; Rivera-Perez, Luis M; Lillesaar, Christina; Masino, Mark A

2016-06-01

Zebrafish intraspinal serotonergic neuron (ISN) morphology and distribution have been examined in detail at different ages; however, some aspects of the development of these cells remain unclear. Although antibodies to serotonin (5-HT) have detected ISNs in the ventral spinal cord of embryos, larvae, and adults, the only tryptophan hydroxylase (tph) transcript that has been described in the spinal cord is tph1a. Paradoxically, spinal tph1a is only expressed transiently in embryos, which brings the source of 5-HT in the ISNs of larvae and adults into question. Because the pet1 and tph2 promoters drive transgene expression in the spinal cord, we hypothesized that tph2 is expressed in spinal cords of zebrafish larvae. We confirmed this hypothesis through in situ hybridization. Next, we used 5-HT antibody labeling and transgenic markers of tph2-expressing neurons to identify a transient population of ISNs in embryos that was distinct from ISNs that appeared later in development. The existence of separate ISN populations may not have been recognized previously due to their shared location in the ventral spinal cord. Finally, we used transgenic markers and immunohistochemical labeling to identify the transient ISN population as GABAergic Kolmer-Agduhr double-prime (KA″) neurons. Altogether, this study revealed a novel developmental paradigm in which KA″ neurons are transiently serotonergic before the appearance of a stable population of tph2-expressing ISNs. © 2015 Wiley Periodicals, Inc.

Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections

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Antonietta Messina

2018-02-01

Full Text Available IntroductionSleep and migraine share a common pathophysiological substrate, although the underlying mechanisms are unknown. The serotonergic and orexinergic systems are both involved in the regulation of sleep/wake cycle, and numerous studies show that both are involved in the migraine etiopathogenesis. These two systems are anatomically and functionally interconnected. Our hypothesis is that in migraine a dysfunction of orexinergic projections on the median raphe (MR nuclei, interfering with serotonergic regulation, may cause Non-Rapid Eye Movement parasomnias, such as somnambulism.Hypothesis/theoryActing on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would lead to a higher release of serotonin. The activation of serotonergic receptors located on the walls of large cerebral vessels would lead to abnormal vasodilatation and consequently increase transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. As a consequence, there is activation of sensory nerve endings at the level of hard vessels in the meninges, with release of pro-inflammatory peptides (e.g., substance P and CGRP. Within this hypothetical frame, the released serotonin could also interact with trigeminovascular afferents to activate and/or facilitate the release of the neuropeptide at the level of the trigeminal ganglion. The dysregulation of the physiological negative feedback of serotonin on the orexinergic neurons, in turn, would contribute to an alteration of the whole system, altering the sleep–wake cycle.ConclusionSerotonergic neurons of the MR nuclei receive an excitatory input from hypothalamic orexin/hypocretin neurons and reciprocally inhibit orexin/hypocretin neurons through the serotonin 1A receptor (or 5-HT1A receptor. Considering this complex system, if there is an alteration it may facilitate the pathophysiological mechanisms involved in the migraine, while it may produce

Localization of serotonin and ultrastructure of serotonergic neutrons in the nervous system of fasciola hepatica

International Nuclear Information System (INIS)

Huang Shile; Cheng Bing; Rong Yaofang

1993-01-01

Rabbits antisera were raised against an antigen prepared by coupling 5-HT to bovine serum albumin (BSA) using formaldehyde as a coupling reagent. The fresh adult Fasciola hepatica were fixed with 4% formaldehyde and sectioned on a cryostat. The sections were stained by indirect immunofluorescence technique. Abundant immunofluorescence specific for 5-HT was observed in ganglion cell bodies and their processes, the transverse commissure that connects two ganglia and longitudinal axes extending from the ganglia. Immuno-reactivity to 5-HT was also found in the nerve fibre innervating tegument, gut wall, the epithelium of testes or ovary, the musculature of uterus and ootype, etc. The ultrastructure of serotonergic neurons was visualized. As in other invertebrates, the serotonergic neutrons of Fasciola hepatica consisted of cell bodies, axons, synapses, herring bodies and neuromuscular junctions. The nerve cell bodies were aggregatively located in ganglia and many dispersed spherical granular vesicles were present in cytoplasm. The nerve axons branched out to the muscles forming synapses, where synaptic vesicles contained 5-HT dense-core granules were found. The distribution of 5-HT within the neurons strongly suggested that 5-HT was functioning as a neurotrasmitter in Fasciola hepatica

Molecular Mechanisms of Appetite Regulation

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Ji Hee Yu

2012-12-01

Full Text Available The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity.

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Gazea, Mary; Patchev, Alexandre V; Anderzhanova, Elmira; Leidmaa, Este; Pissioti, Anna; Flachskamm, Cornelia; Almeida, Osborne F X; Kimura, Mayumi

2018-01-10

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep. SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY 3-36 can reverse this neurochemical imbalance and

The Effect of Tongue Exercise on Serotonergic Input to the Hypoglossal Nucleus in Young and Old Rats

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Behan, Mary; Moeser, Adam E.; Thomas, Cathy F.; Russell, John A.; Wang, Hao; Leverson, Glen E.; Connor, Nadine P.

2012-01-01

Purpose: Breathing and swallowing problems affect elderly people and may be related to age-associated tongue dysfunction. Hypoglossal motoneurons that innervate the tongue receive a robust, excitatory serotonergic (5HT) input and may be affected by aging. We used a rat model of aging and progressive resistance tongue exercise to determine whether…

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens.

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Halberstadt, Adam L

2015-01-15

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. Copyright © 2014 Elsevier B.V. All rights reserved.

The association between concomitant use of serotonergic antidepressants and lithium-induced polyuria. A multicenter medical chart review study

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Wilting, I.; Egberts, A. C. G.; Movig, K. L. L.; van Laarhoven, J. H. M.; Heerdink, E. R.; Nolen, W. A.

Background: A previous Study aimed at revealing the prevalence and determinants Of lithium induced polyuria Suggested an increased risk of polyuria (urine volume >= 3L/24h) in those using serotonergic antidepressants next to lithium. Objective: The objective of our study was to re-evaluate this

Mechanical homeostasis regulating adipose tissue volume

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Svedman Paul

2007-09-01

Full Text Available Abstract Background The total body adipose tissue volume is regulated by hormonal, nutritional, paracrine, neuronal and genetic control signals, as well as components of cell-cell or cell-matrix interactions. There are no known locally acting homeostatic mechanisms by which growing adipose tissue might adapt its volume. Presentation of the hypothesis Mechanosensitivity has been demonstrated by mesenchymal cells in tissue culture. Adipocyte differentiation has been shown to be inhibited by stretching in vitro, and a pathway for the response has been elucidated. In humans, intermittent stretching of skin for reconstructional purposes leads to thinning of adipose tissue and thickening of epidermis – findings matching those observed in vitro in response to mechanical stimuli. Furthermore, protracted suspension of one leg increases the intermuscular adipose tissue volume of the limb. These findings may indicate a local homeostatic adipose tissue volume-regulating mechanism based on movement-induced reduction of adipocyte differentiation. This function might, during evolution, have been of importance in confined spaces, where overgrowth of adipose tissue could lead to functional disturbance, as for instance in the turtle. In humans, adipose tissue near muscle might in particular be affected, for instance intermuscularly, extraperitoneally and epicardially. Mechanical homeostasis might also contribute to protracted maintainment of soft tissue shape in the face and neck region. Testing of the hypothesis Assessment of messenger RNA-expression of human adipocytes following activity in adjacent muscle is planned, and study of biochemical and volumetric adipose tissue changes in man are proposed. Implications of the hypothesis The interpretation of metabolic disturbances by means of adipose tissue might be influenced. Possible applications in the head and neck were discussed.

Regulation Mechanism of HBV cccDNA

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Cheng Jun

2012-06-01

Full Text Available Covalently closed circular (ccc DNA of hepatitis B virus (HBV existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathematic model. Viral protein feedback regulation in HBV life cycle to maintain vital viral replication is an important mechanism. Interleukin-6, epithelial growth factor, heme oxygenase-1, histones, and hepatocyte nuclear factors are demonstrated as the key regulators for HBV life cycle. CpG island structure and methylation status are involved in the regulation of HBV DNA replication. Nucleos(tide analogues are widely used in the clinical practice for the treatment of chronic hepatitis B patients, although no evidence indicating a direct inhibiton of HBV cccDNA. In the future, along with the study of HBV life cycle, new drugs including RNA interference technique, will pave the way to eliminate the HBV cccDNA from infected hepatocytes resulting final cure of chronic hepatitis B.

The role of focal adhesion kinase in the regulation of cellular mechanical properties

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Mierke, Claudia Tanja

2013-01-01

The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation. (paper)

The role of focal adhesion kinase in the regulation of cellular mechanical properties

Science.gov (United States)

Mierke, Claudia Tanja

2013-12-01

The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation.

Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.

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Baratta, Michael V; Kodandaramaiah, Suhasa B; Monahan, Patrick E; Yao, Junmei; Weber, Michael D; Lin, Pei-Ann; Gisabella, Barbara; Petrossian, Natalie; Amat, Jose; Kim, Kyungman; Yang, Aimei; Forest, Craig R; Boyden, Edward S; Goosens, Ki A

2016-05-15

Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Mediation by the serotonergic system of U-50,488H-induced antinociception and tolerance

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Ho, Begonia Yeeman.

1989-01-01

The antinociceptive action of U-50,488H, a selective {kappa}-opioid receptor agonist, was attenuated by serotonergic but not by noradrenergic receptor antagonists. Intracerebroventricularly (i.c.v.) administered U-50,488H was antagonized by more than two fold by i.c.v. administered pindolol, methysergide, mianserin, ketanserin, pirenperone or ICS-205,930. A similar degree of antagonism of U-50,488H (i.c.v.) was found after intrathecal (i.t.) treatments with pindolol, methysergide or ICS-205,930 but not with mianserin, ketanserin or pirenperone. When U-50,488H and the antagonists were both given i.t., its antinociceptive action was attenuated by pindolol or methysergide, potentiated by mianserin, ketanserin or pirenperone and not affected by ICS-205,930. The release of serotonin was further studied directly by using a superfusion system. A naloxone reversible, concentration- and Ca{sup 2+}- dependent enhancement of release of ({sup 3}H)serotonin by U-50,488H was observed in spinal and brain tissues. Tolerance to the antinociceptive action of U-50,488H was induced in mice using slow release preparations of U-50,488H. Serotonergic receptor antagonists (pindolol or ketanserin) were co-administered with U-50,488H to test for their effects on the development of tolerance to U-50,488H.

Orexin receptor activation generates gamma band input to cholinergic and serotonergic arousal system neurons and drives an intrinsic Ca2+-dependent resonance in LDT and PPT cholinergic neurons.

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Masaru eIshibashi

2015-06-01

Full Text Available A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT and pedunculopontine (PPT tegmental neurons and serotonergic dorsal raphe (DR neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4 - 14 Hz and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep and intracortical

GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon

DEFF Research Database (Denmark)

Ducray, Angélique; Krebs, Sandra H:; Schaller, Benoft

2006-01-01

Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), known as the GDNF family ligands (GFLs), influence the development, survival and differentiation of cultured dopaminergic neurons from ventral mesencephalon (VM). Detailed knowledge about...... factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development....

Serotonergic dysfunctions and abnormal iron metabolism: Relevant to mental fatigue of Parkinson disease.

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Zuo, Li-Jun; Yu, Shu-Yang; Hu, Yang; Wang, Fang; Piao, Ying-Shan; Lian, Teng-Hong; Yu, Qiu-Jin; Wang, Rui-Dan; Li, Li-Xia; Guo, Peng; Du, Yang; Zhu, Rong-Yan; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

2016-12-21

Fatigue is a very common non-motor symptom in Parkinson disease (PD) patients. It included physical fatigue and mental fatigue. The potential mechanisms of mental fatigue involving serotonergic dysfunction and abnormal iron metabolism are still unknown. Therefore, we evaluated the fatigue symptoms, classified PD patients into fatigue group and non-fatigue group, and detected the levels of serotonin, iron and related proteins in CSF and serum. In CSF, 5-HT level is significantly decreased and the levels of iron and transferrin are dramatically increased in fatigue group. In fatigue group, mental fatigue score is negatively correlated with 5-HT level in CSF, and positively correlated with the scores of depression and excessive daytime sleepiness, and disease duration, also, mental fatigue is positively correlated with the levels of iron and transferrin in CSF. Transferrin level is negatively correlated with 5-HT level in CSF. In serum, the levels of 5-HT and transferrin are markedly decreased in fatigue group; mental fatigue score exhibits a negative correlation with 5-HT level. Thus serotonin dysfunction in both central and peripheral systems may be correlated with mental fatigue through abnormal iron metabolism. Depression, excessive daytime sleepiness and disease duration were the risk factors for mental fatigue of PD.

Requirement for tyrosine phosphatase during serotonergic neuromodulation by protein kinase C.

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Catarsi, S; Drapeau, P

1997-08-01

Tyrosine kinases and phosphatases are abundant in the nervous system, where they signal cellular differentiation, mediate the responses to growth factors, and direct neurite outgrowth during development. Tyrosine phosphorylation can also alter ion channel activity, but its physiological significance remains unclear. In an identified leech mechanosensory neuron, the ubiquitous neuromodulator serotonin increases the activity of a cation channel by activating protein kinase C (PKC), resulting in membrane depolarization and modulation of the receptive field properties. We observed that the effects on isolated neurons and channels were blocked by inhibiting tyrosine phosphatases. Serotonergic stimulation of PKC thus activates a tyrosine phosphatase activity associated with the channels, which reverses their constitutive inhibition by tyrosine phosphorylation, representing a novel form of neuromodulation.

The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

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Kinney, Hannah C; Broadbelt, Kevin G; Haynes, Robin L; Rognum, Ingvar J; Paterson, David S

2011-07-01

The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain. Copyright © 2011 Elsevier B.V. All rights reserved.

Cholinergic and serotonergic modulation of visual information processing in monkey V1.

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Shimegi, Satoshi; Kimura, Akihiro; Sato, Akinori; Aoyama, Chisa; Mizuyama, Ryo; Tsunoda, Keisuke; Ueda, Fuyuki; Araki, Sera; Goya, Ryoma; Sato, Hiromichi

2016-09-01

The brain dynamically changes its input-output relationship depending on the behavioral state and context in order to optimize information processing. At the molecular level, cholinergic/monoaminergic transmitters have been extensively studied as key players for the state/context-dependent modulation of brain function. In this paper, we review how cortical visual information processing in the primary visual cortex (V1) of macaque monkey, which has a highly differentiated laminar structure, is optimized by serotonergic and cholinergic systems by examining anatomical and in vivo electrophysiological aspects to highlight their similarities and distinctions. We show that these two systems have a similar layer bias for axonal fiber innervation and receptor distribution. The common target sites are the geniculorecipient layers and geniculocortical fibers, where the appropriate gain control is established through a geniculocortical signal transformation. Both systems exert activity-dependent response gain control across layers, but in a manner consistent with the receptor subtype. The serotonergic receptors 5-HT1B and 5HT2A modulate the contrast-response curve in a manner consistent with bi-directional response gain control, where the sign (facilitation/suppression) is switched according to the firing rate and is complementary to the other. On the other hand, cholinergic nicotinic/muscarinic receptors exert mono-directional response gain control without a sign reversal. Nicotinic receptors increase the response magnitude in a multiplicative manner, while muscarinic receptors exert both suppressive and facilitative effects. We discuss the implications of the two neuromodulator systems in hierarchical visual signal processing in V1 on the basis of the developed laminar structure. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Role and mechanism of arsenic in regulating angiogenesis.

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Ling-Zhi Liu

Full Text Available Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1 and vascular endothelial growth factor (VEGF. Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.

Gene Expression of Serotonin and Dopamine Receptors and Monoamine Oxidase-A in the Brain of Dominant and Subordinate Pubertal Pigs Fed a ß-Adrenoreceptor Agonist

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Aggression is a major source of social stress and injuries, negatively affecting the health and well-being of those involved in the fight. The serotonergic and dopaminergic systems are widely implicated in aggression regulation in several animal species, but information on molecular mechanisms media...

The signaling lipid sphingosine 1-phosphate regulates mechanical pain

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Hill, Rose Z; Hoffman, Benjamin U; Morita, Takeshi; Campos, Stephanie M; Lumpkin, Ellen A; Brem, Rachel B

2018-01-01

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds. PMID:29561262

Effect Mechanism of Penstock on Stability and Regulation Quality of Turbine Regulating System

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Wencheng Guo

2014-01-01

Full Text Available This paper studies the effect mechanism of water inertia and head loss of penstock on stability and regulation quality of turbine regulating system with surge tank or not and proposes the construction method of equivalent model of regulating system. Firstly, the complete linear mathematical model of regulating system is established. Then, the free oscillation equation and time response of the frequency that describe stability and regulation quality, respectively, are obtained. Finally, the effects of penstock are analysed by using stability region and response curves. The results indicate that the stability and regulation quality of system without surge tank are determined by time response of frequency which only depends on water hammer wave in penstock, while, for system with surge tank, the time response of frequency depending on water hammer wave in penstock and water-level fluctuation in surge tank jointly determines the stability and regulation quality. Water inertia of penstock mainly affects the stability and time response of frequency of system without surge tank as well as the stability and head wave of time response of frequency with surge tank. Head loss of penstock mainly affects the stability and tail wave of time response of frequency with surge tank.

Genetic polymorphisms in the serotonergic system are associated with circadian manifestations of bruxism.

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Oporto, G H; Bornhardt, T; Iturriaga, V; Salazar, L A

2016-11-01

Bruxism (BRX) is a condition of great interest for researchers and clinicians in dental and medical areas. BRX has two circadian manifestations; it can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, WB). However, it can be suffered together. Recent investigations suggest that central nervous system neurotransmitters and their genes could be involved in the genesis of BRX. Serotonin is responsible for the circadian rhythm, maintaining arousal, regulating stress response, muscle tone and breathing. Thus, serotonin could be associated with BRX pathogenesis. The aim of this work was to evaluate the frequency of genetic polymorphisms in the genes HTR1A (rs6295), HTR2A (rs1923884, rs4941573, rs6313, rs2770304), HTR2C (rs17260565) and SLC6A4 (rs63749047) in subjects undergoing BRX treatment. Patients included were classified according to their diagnosis in awake bruxism (61 patients), sleep bruxism (26 patients) and both (43 patients). The control group included 59 healthy patients with no signs of BRX. Data showed significant differences in allelic frequencies for the HTR2A rs2770304 polymorphism, where the C allele was associated with increased risk of SB (odds ratio = 2·13, 95% confidence interval: 1·08-4·21, P = 0·03). Our results suggest that polymorphisms in serotonergic pathways are involved in sleep bruxism. Further research is needed to clarify and increase the current understanding of BRX physiopathology. © 2016 John Wiley & Sons Ltd.

Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

International Nuclear Information System (INIS)

Jung, T.

2000-01-01

The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

Mechanisms Down-Regulating Sprouty1, a Growth Inhibitor in Prostate Cancer

National Research Council Canada - National Science Library

Kwabi-Addo, Bernard

2006-01-01

.... I have demonstrated that Sprouty1 is down-regulated in human prostate cancer (PCa). The purpose of the present study is to characterize the molecular mechanisms regulating Sprouty1 expression in the human PCa. Results...

Osmosensory mechanisms in cellular and systemic volume regulation

DEFF Research Database (Denmark)

Pedersen, Stine Helene Falsig; Kapus, András; Hoffmann, Else K

2011-01-01

Perturbations of cellular and systemic osmolarity severely challenge the function of all organisms and are consequently regulated very tightly. Here we outline current evidence on how cells sense volume perturbations, with particular focus on mechanisms relevant to the kidneys and to extracellular...

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making.

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Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha; Zhou, Xiaolin

2017-09-01

The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. © The Author (2017). Published by Oxford University Press.

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making

Science.gov (United States)

Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha

2017-01-01

Abstract The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. PMID:28431168

An overview on benzylisoquinoline derivatives with dopaminergic and serotonergic activities.

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Cabedo, N; Berenguer, I; Figadère, B; Cortes, D

2009-01-01

Dopamine and serotonin are important neurotransmitters in the mammalian central nervous system (CNS) involved in numerous physiological and behavioural disorders such as schizophrenia, major depression, anxiety, Parkinson's and Huntington's diseases, and attention deficit hyperactivity disorder. Several natural and synthetic benzylisoquinoline derivatives have displayed affinity for dopamine and serotonin receptors in nanomolar or micromolar ranges. This review covers the last three decades of dopaminergic and serotonergic activities, and especially focuses on structure-activity relationships of natural and synthetic benzylisoquinoline derivatives. We have included aporphines, 1-benzyltetrahydroisoquinolines, bis-benzylisoquinolines, protoberberines, cularines and other structural analogues. Further molecular modelling calculations have been considered as important tools to not only obtain structural information of both neurotransmitter receptors, but to also identify their pharmacophore features. The development of selective potential ligands like benzylisoquinoline derivatives may help in the therapy of diseases related to CNS dysfunction.

Advance in the Study of the Mechanisms Regulated by Sphingosine-1-Phosphate

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Ye, Fei; Kong, Xiangqian; Luo, Cheng

2010-09-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid messenger in the cells that regulate gene expression and NF-KB signal pathway through unknown mechanisms. Recently, Cheng Luo, associate professor of DDDC in Shanghai Institute of Materia Medica, whose project was funded by the National Natural Science Foundation of China, joined in a research team led by Professor Sarah Spiegel of Virginia Commonwealth University. The team continuously made significant breakthroughs in understanding the regulation mechanism of Sphingosine-1-Phosphate. In September 2009, in a paper published on SCIENCE magazine (Science 2009, 325: 1254-7), they firstly demonstrated that S1P is a physiologically important regulator of histone deacetylases (HDACs), HDACs are direct intracellular targets of S1P. Furthermore, they identified the mechanism that S1P regulates gene expression through regulating the activity of HDACs. In June 24th, 2010, in another paper to be published on NATURE magazine (Nature 2010, June 24th, advance online publication) which reports the regulation of NF-KB signaling pathway by S1P. They demonstrate that S1P is the missing cofactor for TRAF2 (tumour-necrosis factor receptor-associated factor 2) and indicate a new paradigm for the regulation of lysine-63-linked poly-ubiquitination. The study also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-KB activation pathway, and then play crucial role in inflammatory, antiapoptotic and immune processes. The identification of new mechanisms by which S1P regulates gene expression and TNF and NF-KB signaling pathway will light up the road to develop novel inhibitors that might be useful for treatment of cancer and inflammatory diseases.

Serotonergic and dopaminergic modulation of attentional processes.

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Boulougouris, Vasileios; Tsaltas, Eleftheria

2008-01-01

Disturbances in attentional processes are a common feature of several psychiatric disorders such as schizophrenia, attention deficit/hyperactivity disorder and Huntington's disease. The use of animal models has been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic and vice-versa. In this chapter, a comparative and integrated account is provided on the neuroanatomical and neurochemical modulation of basic behavioural operations such as selective attention, vigilance, set-shifting and executive control focusing on the comparative functions of the serotonin and dopamine systems in the cognitive control exerted by the prefrontal cortex. Specifically, we have reviewed evidence emerging from several behavioural paradigms in experimental animals and humans each of which centres on a different aspect of the attentional function. These paradigms offering both human and animal variants include the five-choice serial reaction time task (5CSRTT), attentional set-shifting and stop-signal reaction time task. In each case, the types of operation that are measured by the given paradigm and their neural correlates are defined. Then, the role of the ascending dopaminergic and serotonergic systems in the neurochemical modulation of its behavioural output are examined, and reference is made to clinical implications for neurological and neuropsychiatric disorders which exhibit deficits in these cognitive tests.

The loudness dependence of auditory evoked potentials (LDAEP as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms.

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Christine Wyss

Full Text Available Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP. The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.

Central analgesic activity of the aqueous and ethanolic extracts of the leaves of Albizia lebbeck: role of the GABAergic and serotonergic pathways.

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Meshram, Girish G; Kumar, Anil; Rizvi, Waseem; Tripathi, C D; Khan, R A

2015-01-01

Albizia lebbeck Benth. is extensively used in Indian traditional medicine for treating several painful and inflammatory disorders. The possible central analgesic activity and the underlying mechanism of action of the aqueous (AE) and ethanolic extracts (EE) of the leaves of A. lebbeck were investigated in Wistar rats using Eddy's hot plate and the tail flick tests. In order to investigate the underlying mechanism of action, rats were pretreated with naloxone, bicuculline or methysergide and then were administered a per os (p.o.) dose of AE or EE. AE and EE caused a significant (p<0.05) elevation in the mean basal reaction time in the hot plate method and an increase in the latency time in the tail flick method. In rats pretreated with bicuculline and methysergide, a significant (p<0.05) reduction in the analgesic activity was observed in comparison to AE and EE. Thus, AE and EE exhibited significant central analgesic activity and act possibly via the GABAergic and serotonergic pathways. The flavonoids and saponins found in the leaves could be responsible for the observed effect.

Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain.

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Komorowski, A; James, G M; Philippe, C; Gryglewski, G; Bauer, A; Hienert, M; Spies, M; Kautzky, A; Vanicek, T; Hahn, A; Traub-Weidinger, T; Winkler, D; Wadsak, W; Mitterhauser, M; Hacker, M; Kasper, S; Lanzenberger, R

2017-01-01

Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post-mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5-HT1A) and excitatory (5-HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase-A (MAO-A), using Spearman's correlation coefficients (rs) in a voxel-wise and region-wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5-HT1A (voxel-wise rs = 0.71; region-wise rs = 0.93) and the 5-HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO-A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region-wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5-HT1Ars = 0.82; 5-HT2Ars = 0.88; MAO-A rs = 0.50; SERT rs = -0.01). The SERT and MAO-A appear to be regulated in a region-specific manner across the whole brain. In contrast, the serotonin-1A and -2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins. © The Author 2016. Published by Oxford University Press.

Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression.

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Thibault Renoir

Full Text Available Depression is the most common psychiatric disorder in Huntington's disease (HD patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT and the forced-swimming test (FST. The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2 mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

Concomitant use of opioid medications with triptans or serotonergic antidepressants in US office-based physician visits.

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Molina, Kyle C; Fairman, Kathleen A; Sclar, David A

2018-01-01

Opioids are not recommended for routine treatment of migraine because their benefits are outweighed by risks of medication overuse headache and abuse/dependence. A March 2016 US Food and Drug Administration (FDA) safety communication warned of the risk of serotonin syndrome from using opioids concomitantly with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Epidemiological information about co-prescribing of these medications is limited. The objective of this study was to estimate the nationwide prevalence of co-prescribing of an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by 1) all patients and 2) patients diagnosed with migraine. National Ambulatory Medical Care Survey (NAMCS) data were obtained for 2013 and 2014. Physician office visits that included the new or continued prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI were identified. Co-prescribed opioids were stratified by agent to determine the proportion of co-prescriptions with opioids posing a higher risk of serotonergic agonism (meperidine, tapentadol, and tramadol). Of an annualized mean 903.6 million office-based physician visits in 2013-2014, 17.7 million (2.0% of all US visits) resulted in the prescribing of ≥1 opioid medication with a triptan or an SSRI/SNRI. Opioid-SSRI/SNRI was co-prescribed in 16,044,721 visits, while opioid-triptan was co-prescribed in 1,622,827 visits. One-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol (18.6% of opioid-SSRI/SNRI, 21.8% of opioid-triptan). Of 7,672,193 visits for patients diagnosed with migraine, 16.3% included opioid prescribing and 2.0% included co-prescribed opioid-triptan. During a period approximately 2 years prior to an FDA warning about the risk of serotonin syndrome from opioid-SSRI/SNRI or

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

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Narasimamurthy, Rajesh; Virshup, David M

2017-01-01

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

Directory of Open Access Journals (Sweden)

David M. Virshup

2017-04-01

Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Science.gov (United States)

Croonenberghs, J; Delmeire, L; Verkerk, R; Lin, A H; Meskal, A; Neels, H; Van der Planken, M; Scharpe, S; Deboutte, D; Pison, G; Maes, M

2000-03-01

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

Acute Exposure to Fluoxetine Alters Aggressive Behavior of Zebrafish and Expression of Genes Involved in Serotonergic System Regulation

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Michail Pavlidis

2017-04-01

Full Text Available Zebrafish, Danio rerio, is an emerging model organism in stress and neurobehavioral studies. In nature, the species forms shoals, yet when kept in pairs it exhibits an agonistic and anxiety-like behavior that leads to the establishment of dominant-subordinate relationships. Fluoxetine, a selective serotonin reuptake inhibitor, is used as an anxiolytic tool to alter aggressive behavior in several vertebrates and as an antidepressant drug in humans. Pairs of male zebrafish were held overnight to develop dominant—subordinate behavior, either treated or non-treated for 2 h with fluoxetine (5 mg L−1, and allowed to interact once more for 1 h. Behavior was recorded both prior and after fluoxetine administration. At the end of the experiment, trunk and brain samples were also taken for cortisol determination and mRNA expression studies, respectively. Fluoxetine treatment significantly affected zebrafish behavior and the expression levels of several genes, by decreasing offensive aggression in dominants and by eliminating freezing in the subordinates. There was no statistically significant difference in whole-trunk cortisol concentrations between dominant and subordinate fish, while fluoxetine treatment resulted in higher (P = 0.004 cortisol concentrations in both groups. There were statistically significant differences between dominant and subordinate fish in brain mRNA expression levels of genes involved in stress axis (gr, mr, neural activity (bdnf, c-fos, and the serotonergic system (htr2b, slc6a4b. The significant decrease in the offensive and defensive aggression following fluoxetine treatment was concomitant with a reversed pattern in c-fos expression levels. Overall, an acute administration of a selective serotonin reuptake inhibitor alters aggressive behavior in male zebrafish in association with changes in the neuroendocrine mediators of coping styles.

Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals.

Science.gov (United States)

Challet, E; Turek, F W; Laute, M; Van Reeth, O

2001-08-03

The circadian pacemaker in the suprachiasmatic nuclei is primarily synchronized to the daily light-dark cycle. The phase-shifting and synchronizing effects of light can be modulated by non-photic factors, such as behavioral, metabolic or serotonergic cues. The present experiments examine the effects of sleep deprivation on the response of the circadian pacemaker to light and test the possible involvement of serotonergic and/or metabolic cues in mediating the effects of sleep deprivation. Photic phase-shifting of the locomotor activity rhythm was analyzed in mice transferred from a light-dark cycle to constant darkness, and sleep-deprived for 8 h from Zeitgeber Time 6 to Zeitgeber Time 14. Phase-delays in response to a 10-min light pulse at Zeitgeber Time 14 were reduced by 30% in sleep-deprived mice compared to control mice, while sleep deprivation without light exposure induced no significant phase-shifts. Stimulation of serotonin neurotransmission by fluoxetine (10 mg/kg), a serotonin reuptake inhibitor that decreases light-induced phase-delays in non-deprived mice, did not further reduce light-induced phase-delays in sleep-deprived mice. Impairment of serotonin neurotransmission with p-chloroamphetamine (three injections of 10 mg/kg), which did not increase light-induced phase-delays in non-deprived mice significantly, partially normalized light-induced phase-delays in sleep-deprived mice. Injections of glucose increased light-induced phase-delays in control and sleep-deprived mice. Chemical damage of the ventromedial hypothalamus by gold-thioglucose (600 mg/kg) prevented the reduction of light-induced phase-delays in sleep-deprived mice, without altering phase-delays in control mice. Taken together, the present results indicate that sleep deprivation can reduce the light-induced phase-shifts of the mouse suprachiasmatic pacemaker, due to serotonergic and metabolic changes associated with the loss of sleep.

Mechanisms involved in regulation of osteoclastic differentiation by mechanical stress-loaded osteoblasts

International Nuclear Information System (INIS)

Kaneuji, Takeshi; Ariyoshi, Wataru; Okinaga, Toshinori; Toshinaga, Akihiro; Takahashi, Tetsu; Nishihara, Tatsuji

2011-01-01

Highlights: → Effect of compressive force on osteoblasts were examined. → Compressive force induced OPG expression and suppressed osteoclastogenesis. → This enhancement of OPG is dependent on Wnt/Ca2+ signal pathway. -- Abstract: Mechanical stress is known to be important for regulation of bone turnover, though the detailed mechanisms are not fully understood. In the present study, we examined the effect of mechanical stress on osteoblasts using a novel compression model. Mouse osteoblastic MC3T3-E1 cells were embedded in three-dimensional (3D) gels and cultured with continuous compressive force (0-10.0 g/cm 2 ) for 48 h, and the conditioned medium were collected. RAW264.7 cells were then incubated with the conditioned medium for various times in the presence of receptor activator of nuclear factor-κB ligand (RANKL). Conditioned medium was found to inhibit the differentiation of RAW264.7 cells into osteoclasts induced by RANKL via down-regulation of the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of IκBα, and nuclear translocation of p50 and p65. Interestingly, the conditioned medium also had a high level of binding activity to RANKL and blocked the binding of RANK to RANKL. Furthermore, the binding activity of conditioned medium to RANKL was reduced when the 3D gel was supplemented with KN-93, an inhibitor of non-canonical Wnt/Ca 2+ pathway. In addition, expression level of osteoprotegerin (OPG) mRNA was increased in time- and force-dependent manners, and remarkably suppressed by KN-93. These results indicate that osteoblastic cells subjected to mechanical stress produce OPG, which binds to RANKL. Furthermore, this binding activity strongly inhibited osteoclastogenesis through suppression of TRAF6 and the nuclear factor-kappa B (NF-κB) signaling pathway, suggesting that enhancement of OPG expression induced by mechanical stress is dependent on non-canonical Wnt/Ca 2+ pathway.

Mechanisms involved in regulation of osteoclastic differentiation by mechanical stress-loaded osteoblasts

Energy Technology Data Exchange (ETDEWEB)

Kaneuji, Takeshi [Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Ariyoshi, Wataru; Okinaga, Toshinori; Toshinaga, Akihiro [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Takahashi, Tetsu [Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Nishihara, Tatsuji, E-mail: tatsujin@kyu-dent.ac.jp [Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan); Oral Bioresearch Center, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580 (Japan)

2011-04-29

Highlights: {yields} Effect of compressive force on osteoblasts were examined. {yields} Compressive force induced OPG expression and suppressed osteoclastogenesis. {yields} This enhancement of OPG is dependent on Wnt/Ca2+ signal pathway. -- Abstract: Mechanical stress is known to be important for regulation of bone turnover, though the detailed mechanisms are not fully understood. In the present study, we examined the effect of mechanical stress on osteoblasts using a novel compression model. Mouse osteoblastic MC3T3-E1 cells were embedded in three-dimensional (3D) gels and cultured with continuous compressive force (0-10.0 g/cm{sup 2}) for 48 h, and the conditioned medium were collected. RAW264.7 cells were then incubated with the conditioned medium for various times in the presence of receptor activator of nuclear factor-{kappa}B ligand (RANKL). Conditioned medium was found to inhibit the differentiation of RAW264.7 cells into osteoclasts induced by RANKL via down-regulation of the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of I{kappa}B{alpha}, and nuclear translocation of p50 and p65. Interestingly, the conditioned medium also had a high level of binding activity to RANKL and blocked the binding of RANK to RANKL. Furthermore, the binding activity of conditioned medium to RANKL was reduced when the 3D gel was supplemented with KN-93, an inhibitor of non-canonical Wnt/Ca{sup 2+} pathway. In addition, expression level of osteoprotegerin (OPG) mRNA was increased in time- and force-dependent manners, and remarkably suppressed by KN-93. These results indicate that osteoblastic cells subjected to mechanical stress produce OPG, which binds to RANKL. Furthermore, this binding activity strongly inhibited osteoclastogenesis through suppression of TRAF6 and the nuclear factor-kappa B (NF-{kappa}B) signaling pathway, suggesting that enhancement of OPG expression induced by mechanical stress is dependent on non-canonical Wnt

Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms.

Science.gov (United States)

DePina, Ana S; Iser, Wendy B; Park, Sung-Soo; Maudsley, Stuart; Wilson, Mark A; Wolkow, Catherine A

2011-07-12

Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms

Directory of Open Access Journals (Sweden)

Wilson Mark A

2011-07-01

Full Text Available Abstract Background Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. Results In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS. We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+ sperm. However, yolk protein (YP levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. Conclusions C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.

The heart as a self-regulating system: integration of homeodynamic mechanisms.

Science.gov (United States)

Kresh, J Y; Armour, J A

1997-04-01

In the past the study of mechanical and electrical properties of the heart has been disjointed with minimal overlap and unification. The fact remains that these features are tightly coupled and central to the functioning heart. The maintenance of adequate cardiac output relies upon the highly integrated autoregulatory mechanisms and modulation of cardiac myocyte function. Regional ventricular mechanics and energetics are dependent upon muscle fiber stress-strain rate, the passive properties of myocardial collagen matrix, adequate vascular perfusion, transcapillary transport and electrical activation pattern. Intramural hydraulic "loading" is regulated by coronary arterial and venous dynamics. All of these components are under the constant influence of intrinsic cardiac and extracardiac autonomic neurons, as well as circulating hormones. A brief overview of the putative regulation of these various components is presented in this paper.

Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers.

Science.gov (United States)

Tanimoto, Ryuta; Lu, Kuojung G; Xu, Shi-Qiong; Buraschi, Simone; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2016-01-01

The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

DEFF Research Database (Denmark)

Fisher, Patrick M; Hariri, Ahmad R

2013-01-01

. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment...

Altered brain serotonergic neurotransmission following caffeine withdrawal produces behavioral deficits in rats.

Science.gov (United States)

Khaliq, Saima; Haider, Saida; Naqvi, Faizan; Perveen, Tahira; Saleem, Sadia; Haleem, Darakhshan Jabeen

2012-01-01

Caffeine administration has been shown to enhance performance and memory in rodents and humans while its withdrawal on the other hand produces neurobehavioral deficits which are thought to be mediated by alterations in monoamines neurotransmission. A role of decreased brain 5-HT (5-hydroxytryptamine, serotonin) levels has been implicated in impaired cognitive performance and depression. Memory functions of rats were assessed by Water Maze (WM) and immobility time by Forced Swim Test (FST). The results of this study showed that repeated caffeine administration for 6 days at 30 mg/kg dose significantly increases brain 5-HT (pcaffeine. Withdrawal of caffeine however produced memory deficits and significantly increases the immobility time of rats in FST. The results of this study are linked with caffeine induced alterations in serotonergic neurotransmission and its role in memory and depression.

Molecular mechanisms of platelet P2Y(12) receptor regulation.

Science.gov (United States)

Cunningham, Margaret R; Nisar, Shaista P; Mundell, Stuart J

2013-02-01

Platelets are critical for haemostasis, however inappropriate activation can lead to the development of arterial thrombosis, which can result in heart attack and stroke. ADP is a key platelet agonist that exerts its actions via stimulation of two surface GPCRs (G-protein-coupled receptors), P2Y(1) and P2Y(12). Similar to most GPCRs, P2Y receptor activity is tightly regulated by a number of complex mechanisms including receptor desensitization, internalization and recycling. In the present article, we review the molecular mechanisms that underlie P2Y(1) and P2Y(12) receptor regulation, with particular emphasis on the structural motifs within the P2Y(12) receptor, which are required to maintain regulatory protein interaction. The implications of these findings for platelet responsiveness are also discussed.

Anxiogenic drug administration and elevated plus-maze exposure in rats activate populations of relaxin-3 neurons in the nucleus incertus and serotonergic neurons in the dorsal raphe nucleus.

Science.gov (United States)

Lawther, A J; Clissold, M L; Ma, S; Kent, S; Lowry, C A; Gundlach, A L; Hale, M W

2015-09-10

Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioral symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behavior via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the Gi/o-protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behavior in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30 min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behavior. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Neural mechanisms of emotional regulation and decision making

OpenAIRE

Gospic, Katarina

2011-01-01

Emotions influence our perception and decision making. It is of great importance to understand the neurophysiology behind these processes as they influence human core functions. Moreover, knowledge within this field is required in order to develop new medical therapies for pathological conditions that involve dysregulation of emotions. In this thesis the neural mechanisms of emotional regulation and decision making were investigated using different pharmacological manipul...

Mechanism for automatic regulation of combustion. Regolazione automatica della combustione

Energy Technology Data Exchange (ETDEWEB)

Borelli, L.; Tagliaferro, B.; Cossalter, V.; Da Lio, M. (Padua Univ. (Italy))

1993-09-01

The article describes an original application of a mechanism for the automatic regulation of burners. The aim is to maintain a constant air-fuel ratio even with variations occurring in ambient temperature and fuel supply. To obtain the correct mixture, the air damper is opened with a double mechanism by an ambient temperature transducer and by a screw for the setting up of the rate of fuel supply.

Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

Science.gov (United States)

Tanaka, Leonardo Y; Laurindo, Francisco R M

2017-08-01

Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases. Copyright © 2017 Elsevier Inc. All

Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers

Directory of Open Access Journals (Sweden)

Ryuta Tanimoto

2016-07-01

Full Text Available The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells.In this review we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors.

AGC kinases, mechanisms of regulation ‎and innovative drug development.

Science.gov (United States)

Leroux, Alejandro E; Schulze, Jörg O; Biondi, Ricardo M

2018-02-01

The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

DEFF Research Database (Denmark)

Manna, Moutusi; Niemelä, Miia; Tynkkynen, Joona

2016-01-01

) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates b2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located...... near the transmembrane helices 5-7 of the receptor. The alternative mechanism, where the β2AR conformation would be modulated by membrane-mediated interactions, plays only a minor role. Cholesterol analogues also bind to cholesterol binding sites and impede the structural flexibility of β2AR, however...... cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions....

Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

Science.gov (United States)

Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2016-09-01

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. © The Author(s) 2016.

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men.

NARCIS (Netherlands)

Agorastos, A.; Kellner, M.; Stiedl, O.; Muhtz, C.; Demiralay, C.

2015-01-01

Background: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However,

Roles of Transcriptional and Translational Control Mechanisms in Regulation of Ribosomal Protein Synthesis in Escherichia coli.

Science.gov (United States)

Burgos, Hector L; O'Connor, Kevin; Sanchez-Vazquez, Patricia; Gourse, Richard L

2017-11-01

Bacterial ribosome biogenesis is tightly regulated to match nutritional conditions and to prevent formation of defective ribosomal particles. In Escherichia coli , most ribosomal protein (r-protein) synthesis is coordinated with rRNA synthesis by a translational feedback mechanism: when r-proteins exceed rRNAs, specific r-proteins bind to their own mRNAs and inhibit expression of the operon. It was recently discovered that the second messenger nucleotide guanosine tetra and pentaphosphate (ppGpp), which directly regulates rRNA promoters, is also capable of regulating many r-protein promoters. To examine the relative contributions of the translational and transcriptional control mechanisms to the regulation of r-protein synthesis, we devised a reporter system that enabled us to genetically separate the cis -acting sequences responsible for the two mechanisms and to quantify their relative contributions to regulation under the same conditions. We show that the synthesis of r-proteins from the S20 and S10 operons is regulated by ppGpp following shifts in nutritional conditions, but most of the effect of ppGpp required the 5' region of the r-protein mRNA containing the target site for translational feedback regulation and not the promoter. These results suggest that most regulation of the S20 and S10 operons by ppGpp following nutritional shifts is indirect and occurs in response to changes in rRNA synthesis. In contrast, we found that the promoters for the S20 operon were regulated during outgrowth, likely in response to increasing nucleoside triphosphate (NTP) levels. Thus, r-protein synthesis is dynamic, with different mechanisms acting at different times. IMPORTANCE Bacterial cells have evolved complex and seemingly redundant strategies to regulate many high-energy-consuming processes. In E. coli , synthesis of ribosomal components is tightly regulated with respect to nutritional conditions by mechanisms that act at both the transcription and translation steps. In

Somatic influences on subjective well-being and affective disorders: the convergence of thermosensory and central serotonergic systems

Directory of Open Access Journals (Sweden)

Charles L Raison

2015-01-01

Full Text Available Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinical studies suggesting that afferent thermosensory signals contribute to well-being and depression. Although thermoregulatory systems have traditionally been conceptualized as serving primarily homeostatic functions, increasing evidence suggests neural pathways responsible for regulating body temperature may be linked more closely with emotional states than previously recognized, an affective warmth hypothesis. Human studies indicate that increasing physical warmth activates brain circuits associated with cognitive and affective functions, promotes interpersonal warmth and prosocial behaviour, and has antidepressant effects. Consistent with these effects, preclinical studies in rodents demonstrate that physical warmth activates brain serotonergic neurons implicated in antidepressant-like effects. Together, these studies suggest that 1 thermosensory pathways interact with brain systems that control affective function, 2 these pathways are dysregulated in affective disorders, and 3 activating warm thermosensory pathways promotes a sense of well-being and has therapeutic potential in the treatment of affective disorders.

Regulation of gene expression and pain states by epigenetic mechanisms.

Science.gov (United States)

Géranton, Sandrine M; Tochiki, Keri K

2015-01-01

The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signaling events which lead to changes in gene expression. These changes ultimately cause alterations in macromolecular synthesis, synaptic transmission, and structural architecture which support central sensitization, a process required for the establishment of long-term pain states. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression. This is because epigenetic modifications are known to regulate gene transcription by aiding the physical relaxation or condensation of chromatin. These processes are therefore potential regulators of the molecular changes underlying permanent pain states. A handful of studies have emerged in the field of pain epigenetics; however, the field is still very much in its infancy. This chapter draws upon other specialities which have extensively investigated epigenetic mechanisms, such as learning and memory and oncology. After defining epigenetics as well as the recent field of "neuroepigenetics" and the main molecular mechanisms involved, this chapter describes the role of these mechanisms in the synaptic plasticity seen in learning and memory, and address those epigenetic mechanisms that have been linked with the development of acute and prolonged pain states. Finally, the idea that long-lasting epigenetic modifications could contribute to the transition from acute to chronic pain states by supporting maladaptive molecular changes is discussed. © 2015 Elsevier Inc. All rights reserved.

DMPD: Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 15331118 Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Wu...e-associated up-regulation in macrophage PGE2 synthesis. PubmedID 15331118 Title Mechanism of age-associated... up-regulation in macrophage PGE2 synthesis. Authors Wu D, Meydani SN. Publicatio

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

Directory of Open Access Journals (Sweden)

Junlin eZhang

2013-05-01

Full Text Available Manipulation of serotonin (5HT during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM. Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days, OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs, these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

Colon preneoplasia after carcinogen exposure is enhanced and colonic serotonergic system is suppressed by food deprivation.

Science.gov (United States)

Kannen, Vinicius; Fernandes, Cleverson R; Stopper, Helga; Zanette, Dalila L; Ferreira, Frederico R; Frajacomo, Fernando T; Carvalho, Milene C; Brandão, Marcus L; Elias Junior, Jorge; Jordão Junior, Alceu Afonso; Uyemura, Sérgio Akira; Waaga-Gasser, Ana Maria; Garcia, Sérgio B

2013-10-04

Calorie restriction regimens usually promote health and extend life-span in mammals. This is partially related to their preventive effects against malignancies. However, certain types of nutritional restriction failed to induce beneficial effects. The American Institute of Nutrition defines calorie restriction as diets which have only 40% fewer calories, but provide normal amounts of necessary food components such as protein, vitamins and minerals; whereas, food restriction means 40% less of all dietary ingredients plus 40% less calories. Our study aimed to test the hypothesis that the latter type of food deprivation (40% less food than consumed by standard fed rats) might increase cancer risk instead of reducing it, as is generally assumed for all dietary restrictive regimens. Since the endogenous modulation of the colon serotonergic system has been observed to play a role during the early steps of carcinogenesis we also investigated whether the serotoninergic system could be involved in the food intake modulation of cancer risk. For this, rats were exposed to a carcinogen and subjected to food deprivation for 56 days. Triglyceride levels and visceral adipose tissue were reduced while hepatic and colonic lipid peroxidation was increased. This dietary restriction also decreased serotonin levels in colon, and gene expression of its intestinal transporter and receptors. Finally, the numbers of preneoplastic lesions in the colon tissue of carcinogen-exposed rats were increased. Our data suggest that food deprivation enhances formation of early tumorigenic lesions by suppressing serotonergic activity in colon tissue. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

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Dina Popova

Full Text Available 3,4-methylenedioxymethamphetamine (MDMA; ecstasy is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT, that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A. The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

Science.gov (United States)

Popova, Dina; Forsblad, Andréas; Hashemian, Sanaz; Jacobsson, Stig O P

2016-01-01

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition

NARCIS (Netherlands)

Madoori, Pramod Kumar; Agustiandari, Herfita; Driessen, Arnold J. M.; Thunnissen, Andy-Mark W. H.

2009-01-01

LmrR is a PadR-related transcriptional repressor that regulates the production of LmrCD, a major multidrug ABC transporter in Lactococcus lactis. Transcriptional regulation is presumed to follow a drug-sensitive induction mechanism involving the direct binding of transporter ligands to LmrR. Here,

Signal transduction mechanisms of K+-Cl- cotransport regulation and relationship to disease.

Science.gov (United States)

Adragna, N C; Ferrell, C M; Zhang, J; Di Fulvio, M; Temprana, C F; Sharma, A; Fyffe, R E W; Cool, D R; Lauf, P K

2006-01-01

The K+-Cl- cotransport (COT) regulatory pathways recently uncovered in our laboratory and their implication in disease state are reviewed. Three mechanisms of K+-Cl- COT regulation can be identified in vascular cells: (1) the Li+-sensitive pathway, (2) the platelet-derived growth factor (PDGF)-sensitive pathway and (3) the nitric oxide (NO)-dependent pathway. Ion fluxes, Western blotting, semi-quantitative RT-PCR, immunofluorescence and confocal microscopy were used. Li+, used in the treatment of manic depression, stimulates volume-sensitive K+-Cl- COT of low K+ sheep red blood cells at cellular concentrations 3 mM, causes cell swelling, and appears to regulate K+-Cl- COT through a protein kinase C-dependent pathway. PDGF, a potent serum mitogen for vascular smooth muscle cells (VSMCs), regulates membrane transport and is involved in atherosclerosis. PDGF stimulates VSM K+-Cl- COT in a time- and concentration-dependent manner, both acutely and chronically, through the PDGF receptor. The acute effect occurs at the post-translational level whereas the chronic effect may involve regulation through gene expression. Regulation by PDGF involves the signalling molecules phosphoinositides 3-kinase and protein phosphatase-1. Finally, the NO/cGMP/protein kinase G pathway, involved in vasodilation and hence cardiovascular disease, regulates K+-Cl- COT in VSMCs at the mRNA expression and transport levels. A complex and diverse array of mechanisms and effectors regulate K+-Cl- COT and thus cell volume homeostasis, setting the stage for abnormalities at the genetic and/or regulatory level thus effecting or being affected by various pathological conditions.

The effect of tryptophan supplemented diets on brain serotonergic activity and plasma cortisol under undisturbed and stressed conditions in grouped-housed Nile tilapia Oreochromis niloticus

DEFF Research Database (Denmark)

Martins, C.I.M.; Silva, P.I.M.; Costas, B.

2013-01-01

-term supplementation with TRP supplemented diets changes brain serotonergic activity and the stress response associated with slaughter handling in grouped-housed Nile tilapia Oreochromis niloticus. Adult fish (n. =. 108, 490.6. ±. 4.0. g, 12 individuals per tank) were exposed to one of the three treatments...

A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains.

Directory of Open Access Journals (Sweden)

Alexandr P Kornev

2008-04-01

Full Text Available Cyclic nucleotides (cAMP and cGMP regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1 the phosphate binding cassette (PBC, which binds the cAMP ribose-phosphate, 2 the "hinge," a flexible helix, which contacts the PBC, 3 the beta(2,3 loop, which provides precise positioning of an invariant arginine from the PBC, and 4 a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif. The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the beta(2,3 loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains.

The effect of natural whey proteins on mechanisms of blood pressure regulation

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Halina Car

2014-02-01

Full Text Available Whey is a rich natural source of peptides and amino acids. It has been reported in numerous studies that biological active peptides isolated from cow’s milk whey may affect blood pressure regulation. Studies on animals and humans have shown that α-lactalbumin and β-lactoglobulin obtained from enzymatically hydrolysed whey inhibit angiotensin converting enzyme (ACE, while lactorphins lower blood pressure by normalizing endothelial function or by opioid receptors dependent mechanism. Whey proteins or their bioactive fragments decrease total cholesterol, LDL fraction and triglycerides, thus reducing the risk factors of cardiovascular diseases. The aim of this review is to discuss the effects of whey proteins on the mechanisms of blood pressure regulation.

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

OpenAIRE

David M. Virshup; Rajesh Narasimamurthy

2017-01-01

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entr...

Mechanisms regulating brain docosahexaenoic acid uptake: what is the recent evidence?

Science.gov (United States)

Chouinard-Watkins, Raphaël; Lacombe, R J Scott; Bazinet, Richard P

2018-03-01

To summarize recent advances pertaining to the mechanisms regulating brain docosahexaenoic acid (DHA) uptake. DHA is an omega-3 polyunsaturated fatty acid highly enriched in neuronal membranes and it is implicated in several important neurological processes. However, DHA synthesis is extremely limited within the brain. There are two main plasma pools that supply the brain with DHA: the nonesterified pool and the lysophosphatidylcholine (lysoPtdCho) pool. Quantitatively, plasma nonesterified-DHA (NE-DHA) is the main contributor to brain DHA. Fatty acid transport protein 1 (FATP1) in addition to fatty acid-binding protein 5 (FABP5) are key players that regulate brain uptake of NE-DHA. However, the plasma half-life of lysoPtdCho-DHA and its brain partition coefficient are higher than those of NE-DHA after intravenous administration. The mechanisms regulating brain DHA uptake are more complicated than once believed, but recent advances provide some clarity notably by suggesting that FATP1 and FABP5 are key contributors to cellular uptake of DHA at the blood-brain barrier. Elucidating how DHA enters the brain is important as we might be able to identify methods to better deliver DHA to the brain as a potential therapeutic.

Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

International Nuclear Information System (INIS)

Brady, Robert T.; O'Brien, Fergal J.; Hoey, David A.

2015-01-01

Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

Energy Technology Data Exchange (ETDEWEB)

Brady, Robert T. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); O' Brien, Fergal J. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Hoey, David A., E-mail: david.hoey@ul.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); The Centre for Applied Biomedical Engineering Research, University of Limerick (Ireland); Materials & Surface Science Institute, University of Limerick (Ireland)

2015-03-27

Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

The Association between Use of Serotonergic Antidepressants and Perioperative Bleeding during Total Hip Arthroplasty - A Cohort Study

DEFF Research Database (Denmark)

Dall, M.; Primdahl, A.; Damborg, F.

2014-01-01

on the observed blood loss and the need for blood transfusions among this group. We compared the blood loss between users of SA, users of non-serotonergic antidepressants (NSA) and non-users, while adjusting for potential confounders using multivariate linear regression. We indentified 1318 patients...... that underwent a THA in the study period. The average volume of surgical bleeding was 350 ml. The adjusted incremental blood loss associated with use of SA and NSA was 93, 95% confidence interval (38-147) ml and -50 (-125 to 25) ml compared with non-use. Only 48 subjects (3.6%) had transfusions. Use of SA...

Different types of centrally acting antihypertensives and their targets in the central nervous system

NARCIS (Netherlands)

van Zwieten, P. A.; Chalmers, J. P.

1994-01-01

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for

Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry

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Ross A. McDevitt

2014-09-01

Full Text Available The dorsal raphe nucleus (DRN contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA. Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.

A contextual model of self-regulation change mechanisms among individuals with addictive disorders.

Science.gov (United States)

Roos, Corey R; Witkiewitz, Katie

2017-11-01

Numerous behavioral treatments for addictive disorders include components explicitly aimed at targeting self-regulation (e.g., coping and emotion regulation). We first provide a summary of key findings to date among studies that have examined self-regulation as a mechanism of behavior change (MOBC) in behavioral treatments for addictive disorders. Based on our review, we conclude that the role of self-regulation as a MOBC across behavioral treatments for addictive disorders is not well-characterized and findings are inconsistent across studies. For example, our review indicates that there is still inconsistent evidence that coping is a unique MOBC in cognitive-behavioral approaches for addictive behaviors. We propose that there has been slow progress in understanding self-regulation as a MOBC in addiction treatment because of a lack of attention to contextual factors. Accordingly, in the second half of this paper, we propose a contextual model of self-regulation change mechanisms, which emphasizes that the role of various facets of self-regulation as MOBC may depend on contextual factors in the immediate situational context (e.g., fluctuating internal and external cues) and in the broader context in which an individual is embedded (e.g., major life stressors, environmental conditions, dispositions). Additionally, we provide specific recommendations to guide future research for understanding both between-person and within-person self-regulation MOBC in addiction treatment. In particular, we provide key recommendations for how to capitalize on intensive longitudinal measurement methods (e.g., ecological momentary assessment) when bringing a contextual perspective to the study of self-regulation as MOBC in various addiction treatments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of the Serotonergic Genes htr1A, htr1B, htr2A, and slc6A4 in Aggressive Behavior of Golden Retriever Dogs

NARCIS (Netherlands)

Berg, L. van den; Vos-Loohuis, M.; Schilder, M.B.H.; Oost, B.A. van; Hazewinkel, H.A.W.; Wade, C.M.; Karlsson, E.K.; Lindblad-Toh, K.; Liinamo, A.E.; Leegwater, P.A.J.

2008-01-01

Aggressive behavior displays a high heritability in our study group ofGolden Retriever dogs.Alterations in brain serotonin metabolism have been described in aggressive dogs before. Here, we evaluate whether four genes of the canine serotonergic system, coding for the serotonin receptors 1A, 1B,

Exposure to an open-field arena increases c-Fos expression in a subpopulation of neurons in the dorsal raphe nucleus, including neurons projecting to the basolateral amygdaloid complex

DEFF Research Database (Denmark)

Hale, M.W.; Hay-Schmidt, A.; Mikkelsen, J.D.

2008-01-01

Serotonergic systems in the dorsal raphe nucleus are thought to play an important role in the regulation of anxiety states. To investigate responses of neurons in the dorsal raphe nucleus to a mild anxiety-related stimulus, we exposed rats to an open-field, under low-light or high-light conditions....... Treatment effects on c-Fos expression in serotonergic and non-serotonergic cells in the midbrain raphe nuclei were determined 2 h following open-field exposure or home cage control (CO) conditions. Rats tested under both light conditions responded with increases in c-Fos expression in serotonergic neurons...... within subdivisions of the midbrain raphe nuclei compared with CO rats. However, the total numbers of serotonergic neurons involved were small suggesting that exposure to the open-field may affect a subpopulation of serotonergic neurons. To determine if exposure to the open-field activates a subset...

Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling

Science.gov (United States)

2016-10-01

hypothesis using mouse models and human PTOA tissue. We aim to determine: 1) the extent to which mechanical loading regulates PLR in a TGFβ- dependent manner ...the major goals of the project? Major Goals Aim 1: Determine the extent to which mechanical loading regulates PLR in a TGFβ- dependent manner . Aim...dependent manner . Overview: We conducted all of the analyses proposed in Aim 1. As described below, these studies convincingly demonstrate that PLR

Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

Directory of Open Access Journals (Sweden)

Elizabeth Thomas Cox

2011-06-01

Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome.

Science.gov (United States)

de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Ferreira, Célio Marcos Dos Reis; Coimbra, Norberto Cysne

2006-09-01

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.

The Role of Adaptation in Body Load-Regulating Mechanisms During Locomotion

Science.gov (United States)

Ruttley, Tara; Holt, Christopher; Mulavara, Ajitkumar; Bloomberg, Jacob

2010-01-01

Body loading is a fundamental parameter that modulates motor output during locomotion, and is especially important for controlling the generation of stepping patterns, dynamic balance, and termination of locomotion. Load receptors that regulate and control posture and stance in locomotion include the Golgi tendon organs and muscle spindles at the hip, knee, and ankle joints, and the Ruffini endings and the Pacinian corpuscles in the soles of the feet. Increased body weight support (BWS) during locomotion results in an immediate reorganization of locomotor control, such as a reduction in stance and double support duration and decreased hip, ankle, and knee angles during the gait cycle. Previous studies on the effect during exposure to increased BWS while walking showed a reduction in lower limb joint angles and gait cycle timing that represents a reorganization of locomotor control. Until now, no studies have investigated how locomotor control responds after a period of exposure to adaptive modification in the body load sensing system. The goal of this research was to determine the adaptive properties of body load-regulating mechanisms in locomotor control during locomotion. We hypothesized that body load-regulating mechanisms contribute to locomotor control, and adaptive changes in these load-regulating mechanisms require reorganization to maintain forward locomotion. Head-torso coordination, lower limb movement patterns, and gait cycle timing were evaluated before and after a 30-minute adaptation session during which subjects walked on a treadmill at 5.4 km/hr with 40% body weight support (BWS). Before and after the adaptation period, head-torso and lower limb 3D kinematic data were obtained while performing a goal directed task during locomotion with 0% BWS using a video-based motion analysis system, and gait cycle timing parameters were collected by foot switches positioned under the heel and toe of the subjects shoes. Subjects showed adaptive modification in

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

Science.gov (United States)

Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

2018-06-01

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1

MECHANISMS OF STATE REGULATION OF SMALL AND MEDIUM BUSINESSES

Directory of Open Access Journals (Sweden)

Valerii Marenichenko

2016-11-01

Full Text Available Subject of research is the mechanisms of state regulation of small and medium businesses in Ukraine. The purpose of the research is effective mechanisms development of state regulation of small and medium enterprises (SMEs. Methodology. The article uses general and special methods of investigation: empirical research methods (observation, comparison; methods used empirically and theoretically study (abstraction, analysis and synthesis; methods of theoretical research (ascent from the abstract to the concrete, systemic and structural approach. The article highlighted the priority areas of activity in Ukraine, such as agriculture, IT-sector and tourism. In particular, we have analyzed data of the State Statistics Service of Ukraine and international surveys such as Enabling the Business of Agriculture, DOU, Deloitte (Global Survey of R&D Incentives 2015, International SOS and Control Risks, WTTC, UPS, Consulting integrated, Organic Monitor and other. We determined that agriculture must use consistent increasing areas under food crops; introduction of modern technology and innovation; gradual increase in the level of mechanization of agricultural production. Scientific research preparation and training of local staff employed in the agriculture and food industry must become the main aspects of quality development. The article defines that IT market requires quality of the state regulation in readiness for a permanent dialogue with government and comprehensive support for sector as a strategic development of the country; development strategy and projects for development of the sector; effective fight against corruption at all levels. The relevance of government regulation in the development of green international tourism is determined. Modern historical and cultural features of Ukraine can allow providing a range of services for international tourism community. There is analyzed an impact of export orientation for small and medium business in the

Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without Acetylsalicylic Acid in Major Depressive Disorder.

Science.gov (United States)

Zdanowicz, Nicolas; Reynaert, Christine; Jacques, Denis; Lepiece, Brice; Dubois, Thomas

2017-09-01

Antidepressant medication efficacy remains a major research challenge. Here, we explored four questions: whether noradrenergic antidepressants are more effective than serotonergic antidepressants; whether the addition of 100 mg acetylsalicylic acid (ASA) changes antidepressant efficacy; whether the long-term efficacy differs depending on the antidepressant and the addition of ASA; and whether serum levels of brain-derived neurotrophic factor (BDNF) are clinically informative. In a two-year study, forty people with major depressive disorder were randomly assigned to groups that received an SSRI (escitalopram) or an SNRI (duloxetine), each group received concomitant ASA (100 mg) or a placebo. Sociodemographic data were recorded and patients under went regular assessments with the Hamilton depression scale (HDS) and clinical global impression (CGI) scale. Serum levels of BDNF were measured four times per year. There was no significant difference in efficacy between the two antidepressants or between antidepressant treatment with and without ASA. However, subgroup comparisons revealed that the duloxetine + ASA (DASA) subgroup showed a more rapid improvement in HDS score as early as 2 months (t=-3.114, p=0.01), in CGI score at 5 months (t=-2.119, p=0.05), and a better remission rate (χ 2 =6.296, p 0.012) than the escitalopram + placebo (EP) subgroup. Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup (t=3.713; p=0.002). This suggest two hypotheses: either a noradrenergic agent combined with ASA is more effective in treating depression than a serotonergic agent alone, or the level of serum BDNF before treatment is a precursor marker of the response to antidepressants. Further research is needed to test these hypotheses.

A framework for modelling gene regulation which accommodates non-equilibrium mechanisms.

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Ahsendorf, Tobias; Wong, Felix; Eils, Roland; Gunawardena, Jeremy

2014-12-05

Gene regulation has, for the most part, been quantitatively analysed by assuming that regulatory mechanisms operate at thermodynamic equilibrium. This formalism was originally developed to analyse the binding and unbinding of transcription factors from naked DNA in eubacteria. Although widely used, it has made it difficult to understand the role of energy-dissipating, epigenetic mechanisms, such as DNA methylation, nucleosome remodelling and post-translational modification of histones and co-regulators, which act together with transcription factors to regulate gene expression in eukaryotes. Here, we introduce a graph-based framework that can accommodate non-equilibrium mechanisms. A gene-regulatory system is described as a graph, which specifies the DNA microstates (vertices), the transitions between microstates (edges) and the transition rates (edge labels). The graph yields a stochastic master equation for how microstate probabilities change over time. We show that this framework has broad scope by providing new insights into three very different ad hoc models, of steroid-hormone responsive genes, of inherently bounded chromatin domains and of the yeast PHO5 gene. We find, moreover, surprising complexity in the regulation of PHO5, which has not yet been experimentally explored, and we show that this complexity is an inherent feature of being away from equilibrium. At equilibrium, microstate probabilities do not depend on how a microstate is reached but, away from equilibrium, each path to a microstate can contribute to its steady-state probability. Systems that are far from equilibrium thereby become dependent on history and the resulting complexity is a fundamental challenge. To begin addressing this, we introduce a graph-based concept of independence, which can be applied to sub-systems that are far from equilibrium, and prove that history-dependent complexity can be circumvented when sub-systems operate independently. As epigenomic data become increasingly

Characterization and regulation of [3H]-serotonin uptake and release in rodent spinal

International Nuclear Information System (INIS)

Stauderman, K.A.

1986-01-01

The uptake and release of [ 3 H]-serotonin were investigated in rat spinal cord synaptosomes. In the uptake experiments, sodium-dependent and sodium-independent [ 3 H]-serotonin accumulation processes were found. Sodium-dependent [ 3 H]-serotonin accumulation was: linear with sodium concentrations up to 180 mM; decreased by disruption of membrane integrity or ionic gradients; associated with purified synaptosomal fractions; and reduced after description of descending serotonergic neurons in the spinal cord. Of the uptake inhibitors tested, the most potent was fluoxetine (IC 50 75 nM), followed by desipramine (IC 50 430 nM) and nomifensine (IC 50 950 nM). The sodium-independent [ 3 H]-serotonin accumulation process was insensitive to most treatments and probably represents nonspecific membrane binding. Thus, only sodium-dependent [ 3 H]-serotonin uptake represents the uptake process of serotonergic nerve terminals in rat spinal cord homogenates. In the release experiments, K + -induced release of previously accumulated [ 3 H]-serotonin was Ca 2+ -dependent, and originated from serotonergic synaptosomes. Exogenous serotonin and 5-methyoxy-N,N-dimethyltryptamine inhibited [ 3 H]-serotonin release in a concentration-dependent way. Of the antagonists tested, only methiothepin effectively blocked the effect of serotonin. These data support the existence of presynaptic serotonin autoreceptors on serotonergic nerve terminals in the rat spinal cord that act to inhibit a voltage and Ca 2+ -sensitive process linked to serotonin release. Alteration of spinai cord serotonergic function may therefore be possible by drugs acting on presynaptic serotonin autoreceptors in the spinal cord

Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.

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Kubow, Kristopher E; Vukmirovic, Radmila; Zhe, Lin; Klotzsch, Enrico; Smith, Michael L; Gourdon, Delphine; Luna, Sheila; Vogel, Viola

2015-08-14

Despite the crucial role of extracellular matrix (ECM) in directing cell fate in healthy and diseased tissues--particularly in development, wound healing, tissue regeneration and cancer--the mechanisms that direct the assembly and regulate hierarchical architectures of ECM are poorly understood. Collagen I matrix assembly in vivo requires active fibronectin (Fn) fibrillogenesis by cells. Here we exploit Fn-FRET probes as mechanical strain sensors and demonstrate that collagen I fibres preferentially co-localize with more-relaxed Fn fibrils in the ECM of fibroblasts in cell culture. Fibre stretch-assay studies reveal that collagen I's Fn-binding domain is responsible for the mechano-regulated interaction. Furthermore, we show that Fn-collagen interactions are reciprocal: relaxed Fn fibrils act as multivalent templates for collagen assembly, but once assembled, collagen fibres shield Fn fibres from being stretched by cellular traction forces. Thus, in addition to the well-recognized, force-regulated, cell-matrix interactions, forces also tune the interactions between different structural ECM components.

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

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Albert Paul R

2011-05-01

Full Text Available Abstract The serotonin-1A (5-HT1A receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019G (rs6295 polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

Toll-like Receptor 4: Innate Immune Regulator of Neuroimmune and Neuroendocrine interactions in Stress and Major Depressive Disorder

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Jiajun eLiu

2014-09-01

Full Text Available Major depressive disorder (MDD poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behaviour similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signalling, the main question becomes: What is the role of the innate immune system in MDD?The current review presents evidence that toll-like receptor 4 (TLR4, via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4 – related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD. Therefore, apart from exogenous pathogenic mechanisms, TLR4 is involved in immune changes as a result of endogenous stress signals, playing an integral part in the pathophysiology, and could be a potential target for pharmacological treatments to improve current interventions for MDD.

Co-Transcriptional Folding and Regulation Mechanisms of Riboswitches

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Sha Gong

2017-07-01

Full Text Available Riboswitches are genetic control elements within non-coding regions of mRNA. These self-regulatory elements have been found to sense a range of small metabolites, ions, and other physical signals to exert regulatory control of transcription, translation, and splicing. To date, more than a dozen riboswitch classes have been characterized that vary widely in size and secondary structure. Extensive experiments and theoretical studies have made great strides in understanding the general structures, genetic mechanisms, and regulatory activities of individual riboswitches. As the ligand-dependent co-transcriptional folding and unfolding dynamics of riboswitches are the key determinant of gene expression, it is important to investigate the thermodynamics and kinetics of riboswitches both in the presence and absence of metabolites under the transcription. This review will provide a brief summary of the studies about the regulation mechanisms of the pbuE, SMK, yitJ, and metF riboswitches based on the ligand-dependent co-transcriptional folding of the riboswitches.

A palmitoylation switch mechanism regulates Rac1 function and membrane organization

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Navarro-Lérida, Inmaculada; Sánchez-Perales, Sara; Calvo, María; Rentero, Carles; Zheng, Yi; Enrich, Carlos; Del Pozo, Miguel A

2012-01-01

The small GTPase Rac1 plays important roles in many processes, including cytoskeletal reorganization, cell migration, cell-cycle progression and gene expression. The initiation of Rac1 signalling requires at least two mechanisms: GTP loading via the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle, and targeting to cholesterol-rich liquid-ordered plasma membrane microdomains. Little is known about the molecular mechanisms governing this specific compartmentalization. We show that Rac1 can incorporate palmitate at cysteine 178 and that this post-translational modification targets Rac1 for stabilization at actin cytoskeleton-linked ordered membrane regions. Palmitoylation of Rac1 requires its prior prenylation and the intact C-terminal polybasic region and is regulated by the triproline-rich motif. Non-palmitoylated Rac1 shows decreased GTP loading and lower association with detergent-resistant (liquid-ordered) membranes (DRMs). Cells expressing no Rac1 or a palmitoylation-deficient mutant have an increased content of disordered membrane domains, and markers of ordered membranes isolated from Rac1-deficient cells do not correctly partition in DRMs. Importantly, cells lacking Rac1 palmitoylation show spreading and migration defects. These data identify palmitoylation as a mechanism for Rac1 function in actin cytoskeleton remodelling by controlling its membrane partitioning, which in turn regulates membrane organization. PMID:22157745

Proteomic Analysis Reveals the Leaf Color Regulation Mechanism in Chimera Hosta "Gold Standard" Leaves.

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Yu, Juanjuan; Zhang, Jinzheng; Zhao, Qi; Liu, Yuelu; Chen, Sixue; Guo, Hongliang; Shi, Lei; Dai, Shaojun

2016-03-08

Leaf color change of variegated leaves from chimera species is regulated by fine-tuned molecular mechanisms. Hosta "Gold Standard" is a typical chimera Hosta species with golden-green variegated leaves, which is an ideal material to investigate the molecular mechanisms of leaf variegation. In this study, the margin and center regions of young and mature leaves from Hosta "Gold Standard", as well as the leaves from plants after excess nitrogen fertilization were studied using physiological and comparative proteomic approaches. We identified 31 differentially expressed proteins in various regions and development stages of variegated leaves. Some of them may be related to the leaf color regulation in Hosta "Gold Standard". For example, cytosolic glutamine synthetase (GS1), heat shock protein 70 (Hsp70), and chloroplastic elongation factor G (cpEF-G) were involved in pigment-related nitrogen synthesis as well as protein synthesis and processing. By integrating the proteomics data with physiological results, we revealed the metabolic patterns of nitrogen metabolism, photosynthesis, energy supply, as well as chloroplast protein synthesis, import and processing in various leaf regions at different development stages. Additionally, chloroplast-localized proteoforms involved in nitrogen metabolism, photosynthesis and protein processing implied that post-translational modifications were crucial for leaf color regulation. These results provide new clues toward understanding the mechanisms of leaf color regulation in variegated leaves.

Pattern of distribution of serotonergic fibers to the amygdala and extended amygdala in the rat.

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Linley, Stephanie B; Olucha-Bordonau, Francisco; Vertes, Robert P

2017-01-01

As is well recognized, serotonergic (5-HT) fibers distribute widely throughout the forebrain, including the amygdala. Although a few reports have examined the 5-HT innervation of select nuclei of the amygdala in the rat, no previous report has described overall 5-HT projections to the amygdala in the rat. Using immunostaining for the serotonin transporter, SERT, we describe the complete pattern of distribution of 5-HT fibers to the amygdala (proper) and to the extended amygdala in the rat. Based on its ontogenetic origins, the amygdala was subdivided into two major parts, pallial and subpallial components, with the pallial component further divided into superficial and deep nuclei (Olucha-Bordonau et al. 2015). SERT + fibers were shown to distributed moderately to densely to the deep and cortical pallial nuclei, but, by contrast, lightly to the subpallial nuclei. Specifically, 1) of the deep pallial nuclei, the lateral, basolateral, and basomedial nuclei contained a very dense concentration of 5-HT fibers; 2) of the cortical pallial nuclei, the anterior cortical and amygdala-cortical transition zone rostrally and the posteromedial and posterolateral nuclei caudally contained a moderate concentration of 5-HT fibers; and 3) of the subpallial nuclei, the anterior nuclei and the rostral part of the medial (Me) nuclei contained a moderate concentration of 5-HT fibers, whereas caudal regions of Me as well as the central nuclei and the intercalated nuclei contained a sparse/light concentration of 5-HT fibers. With regard to the extended amygdala (primarily the bed nucleus of stria terminalis; BST), on the whole, the BST contained moderate numbers of 5-HT fibers, spread fairly uniformly throughout BST. The findings are discussed with respect to a critical serotonergic influence on the amygdala, particularly on the basal complex, and on the extended amygdala in the control of states of fear and anxiety. J. Comp. Neurol. 525:116-139, 2017. © 2016 Wiley Periodicals, Inc. �

Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D.

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Wei, Ran; Christakos, Sylvia

2015-09-24

Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of key components of the immune system. An understanding of the mechanisms involved will lead to potential therapeutic applications for the treatment of immune mediated diseases.

Effects of hypergravic fields on serotonergic neuromodulation in the rat hippocampus.

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Horrigan, D J; Fuller, C A; Horowitz, J M

1997-10-01

The effects of 7 day exposure to 2G fields on serotonergic modulation at two synapses on a hippocampal pathway were examined by recording dentate gyrus and CA1 pyramidal cell layer electrical activity. Serotonin decreased the amplitude of the population spike (synchronous action potentials in hundreds of neurons) in both the dentate gyrus and CA1 regions of rats exposed to 2G fields for 7 days. The inhibition, averaging 26 +/- 4% (mean +/- SEM) in the dentate gyrus and 80 +/- 5% in the CA1 region, was not significantly different from inhibitory responses observed in 1G controls. The 5-HT1A agonist 8-OH-DPAT mimicked this inhibition in the dentate and CA1 regions of 1G rats. 8-OH-DPAT responses were not affected by exposure to 2G fields. We conclude that the hippocampus contains surplus 5-HT receptors so that decreases in receptor density reported in receptor binding studies do not result in a decrease in modulatory capability. A model to account for the physiological pathway that relates gravitational field strength to 5-HT receptor density without changing the effectiveness of 5-HT neuromodulation is discussed.

Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and related psychostimulants: mechanisms and mediators

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Vanattou-Saïfoudine, N; McNamara, R; Harkin, A

2012-01-01

Concomitant consumption of caffeine with recreational psychostimulant drugs of abuse can provoke severe acute adverse reactions in addition to longer term consequences. The mechanisms by which caffeine increases the toxicity of psychostimulants include changes in body temperature regulation, cardiotoxicity and lowering of the seizure threshold. Caffeine also influences the stimulatory, discriminative and reinforcing effects of psychostimulant drugs. In this review, we consider our current understanding of such caffeine-related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), which has been most recently described and characterized. Co-administration of caffeine profoundly enhances the acute toxicity of MDMA in rats, as manifested by high core body temperature, tachycardia and increased mortality. In addition, co-administration of caffeine enhances the long-term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug-induced toxicity comprising MDMA-related enhancement of dopamine release coupled to a caffeine-mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine-related drug interactions with cocaine, d-amphetamine and ephedrine where similar mechanisms are implicated. Understanding the underlying mechanisms will guide appropriate intervention strategies for the management of severe reactions and potential for increased drug-related toxicity, resulting from concomitant caffeine consumption. PMID:22671762

Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel.

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He, Li; Si, Guangwei; Huang, Jiuhong; Samuel, Aravinthan D T; Perrimon, Norbert

2018-03-01

Somatic stem cells constantly adjust their self-renewal and lineage commitment by integrating various environmental cues to maintain tissue homeostasis. Although numerous chemical and biological signals have been identified that regulate stem-cell behaviour, whether stem cells can directly sense mechanical signals in vivo remains unclear. Here we show that mechanical stress regulates stem-cell differentiation in the adult Drosophila midgut through the stretch-activated ion channel Piezo. We find that Piezo is specifically expressed in previously unidentified enteroendocrine precursor cells, which have reduced proliferation ability and are destined to become enteroendocrine cells. Loss of Piezo activity reduces the generation of enteroendocrine cells in the adult midgut. In addition, ectopic expression of Piezo in all stem cells triggers both cell proliferation and enteroendocrine cell differentiation. Both the Piezo mutant and overexpression phenotypes can be rescued by manipulation of cytosolic Ca 2+ levels, and increases in cytosolic Ca 2+ resemble the Piezo overexpression phenotype, suggesting that Piezo functions through Ca 2+ signalling. Further studies suggest that Ca 2+ signalling promotes stem-cell proliferation and differentiation through separate pathways. Finally, Piezo is required for both mechanical activation of stem cells in a gut expansion assay and the increase of cytosolic Ca 2+ in response to direct mechanical stimulus in a gut compression assay. Thus, our study demonstrates the existence of a specific group of stem cells in the fly midgut that can directly sense mechanical signals through Piezo.

Antidepressant-like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems.

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Can, Özgür Devrim; Turan, Nazlı; Demir Özkay, Ümide; Öztürk, Yusuf

2017-12-01

This study was planned to examine the antidepressant potency of gallic acid (30 and 60mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. Administration of gallic acid at 60mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity. The anti-immobility effect observed in the TST was abolished with pre-treatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100mg/kg i.p. administered for 4-consecutive days), ketanserin (a 5-HT2A/2C antagonist; 1mg/kg i.p.), ondansetron (a 5-HT3 antagonist; 0.3mg/kg i.p.), α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100mg/kg i.p.), phentolamine (non-selective alpha-adrenoceptor antagonist; 5mg/kg i.p.), SCH 23390 (a dopamine D1 antagonist; 0.05mg/kg s.c.), and sulpiride (a dopamine D2/D3 antagonist; 50mg/kg i.p.). However, NAN 190 (a 5-HT1A antagonist; 0.5mg/kg i.p.) and propranolol (a non-selective β-adrenoceptor antagonist; 5mg/kg i.p.) pre-treatments were ineffective at reversing the antidepressant-like effects of gallic acid. The results of the present study indicate that gallic acid seems to have a dual mechanism of action by increasing not only serotonin but also catecholamine levels in synaptic clefts of the central nervous system. Further alpha adrenergic, 5-HT2A/2C and 5-HT3 serotonergic, and D1, D2, and D3 dopaminergic receptors also seem to be involved in this antidepressant-like activity. Copyright © 2017 Elsevier Inc. All rights reserved.

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

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Pesarico, Ana Paula; Sampaio, Tuane Bazanella; Stangherlin, Eluza Curte; Mantovani, Anderson C; Zeni, Gilson; Nogueira, Cristina Wayne

2014-10-03

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems. Copyright © 2014 Elsevier Inc. All rights reserved.

Distinct mechanisms regulate Lck spatial organization in activated T cells

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Natasha eKapoor-Kaushik

2016-03-01

Full Text Available Phosphorylation of the T cell receptor (TCR by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity and protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here we used cross-correlation raster image spectroscopy (ccRICS and photoactivated localization microscopy (PALM to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation, and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.

Cultural differences and similarities in beliefs, practices, and neural mechanisms of emotion regulation.

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Qu, Yang; Telzer, Eva H

2017-01-01

The current research examined whether culture shapes the beliefs, practices, and neural basis of emotion regulation. Twenty-nine American and Chinese participants reported their implicit theory of emotion and frequency of reappraisal use. They also underwent an fMRI scan while completing an emotion regulation task. Chinese (vs. American) participants reported more frequent use of reappraisal, which was mediated by their higher incremental theory of emotion (i.e., believing that emotion is changeable through effort). Although there were some cultural similarities in neural activation during emotion regulation, Chinese participants showed less ventrolateral prefrontal cortex (VLPFC) activation than American participants when regulating negative emotions. Lower VLPFC activation was associated with higher incremental theory of emotion and more frequent use of cognitive reappraisal. Findings suggest that culture may shape how individuals perceive and engage in emotion regulation, and ultimately, the neural mechanisms underlying emotion regulation. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Sleep and dreaming: induction and mediation of REM sleep by cholinergic mechanisms.

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Hobson, J A

1992-12-01

The most important recent work on the neurobiology of sleep has focused on the precise cellular and biochemical mechanisms of rapid eye movement sleep mediation. Direct and indirect evidence implicates acetylcholine-containing neurons in the peribrachial pons as critical in the triggering and maintenance of rapid eye movement sleep. Other new studies provide support for the hypothesis that the cholinergic generator system is gated during waking by serotonergic and noradrenergic influences. A growing consensus regarding the basic neurobiology has stimulated new thinking about the brain basis of consciousness during waking and dreaming.

Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages.

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Fattah Sotoodehnejadnematalahi

Full Text Available Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM, and, intriguingly, show that versican mRNA is up-regulated much more highly (>600 fold by long term hypoxia (5 days than by 1 day of hypoxia (48 fold. We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K, LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression.

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats.

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Ulak, Güner; Mutlu, Oguz; Akar, Füruzan Yildiz; Komsuoğlu, F Ipek; Tanyeri, Pelin; Erden, B Faruk

2008-10-01

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.

Mechanisms and regulation of DNA replication initiation in eukaryotes.

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Parker, Matthew W; Botchan, Michael R; Berger, James M

2017-04-01

Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.

Staying cool when things get hot: Emotion regulation modulates neural mechanisms of memory encoding

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Jasmeet P Hayes

2010-12-01

Full Text Available During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes.

The Mechanisms of Virulence Regulation by Small Noncoding RNAs in Low GC Gram-Positive Pathogens

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Stephanie Pitman

2015-12-01

Full Text Available The discovery of small noncoding regulatory RNAs (sRNAs in bacteria has grown tremendously recently, giving new insights into gene regulation. The implementation of computational analysis and RNA sequencing has provided new tools to discover and analyze potential sRNAs. Small regulatory RNAs that act by base-pairing to target mRNAs have been found to be ubiquitous and are the most abundant class of post-transcriptional regulators in bacteria. The majority of sRNA studies has been limited to E. coli and other gram-negative bacteria. However, examples of sRNAs in gram-positive bacteria are still plentiful although the detailed gene regulation mechanisms behind them are not as well understood. Strict virulence control is critical for a pathogen’s survival and many sRNAs have been found to be involved in that process. This review outlines the targets and currently known mechanisms of trans-acting sRNAs involved in virulence regulation in various gram-positive pathogens. In addition, their shared characteristics such as CU interaction motifs, the role of Hfq, and involvement in two-component regulators, riboswitches, quorum sensing, or toxin/antitoxin systems are described.

Mechanisms of the Regulation of the Intestinal Na+/H+ Exchanger NHE3

Directory of Open Access Journals (Sweden)

Peijian He

2010-01-01

Full Text Available A major of Na+ absorptive process in the proximal part of intestine and kidney is electroneutral exchange of Na+ and H+ by Na+/H+ exchanger type 3 (NHE3. During the past decade, significant advance has been achieved in the mechanisms of NHE3 regulation. A bulk of the current knowledge on Na+/H+ exchanger regulation is based on heterologous expression of mammalian Na+/H+ exchangers in Na+/H+ exchanger deficient fibroblasts, renal epithelial, and intestinal epithelial cells. Based on the reductionist's approach, an understanding of NHE3 regulation has been greatly advanced. More recently, confirmations of in vitro studies have been made using animals deficient in one or more proteins but in some cases unexpected findings have emerged. The purpose of this paper is to provide a brief overview of recent progress in the regulation and functions of NHE3 present in the luminal membrane of the intestinal tract.

The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System.

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Cholewa-Waclaw, Justyna; Bird, Adrian; von Schimmelmann, Melanie; Schaefer, Anne; Yu, Huimei; Song, Hongjun; Madabhushi, Ram; Tsai, Li-Huei

2016-11-09

Neuroepigenetics is a newly emerging field in neurobiology that addresses the epigenetic mechanism of gene expression regulation in various postmitotic neurons, both over time and in response to environmental stimuli. In addition to its fundamental contribution to our understanding of basic neuronal physiology, alterations in these neuroepigenetic mechanisms have been recently linked to numerous neurodevelopmental, psychiatric, and neurodegenerative disorders. This article provides a selective review of the role of DNA and histone modifications in neuronal signal-induced gene expression regulation, plasticity, and survival and how targeting these mechanisms could advance the development of future therapies. In addition, we discuss a recent discovery on how double-strand breaks of genomic DNA mediate the rapid induction of activity-dependent gene expression in neurons. Copyright © 2016 the authors 0270-6474/16/3611427-08$15.00/0.

RecA: Regulation and Mechanism of a Molecular Search Engine.

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Bell, Jason C; Kowalczykowski, Stephen C

2016-06-01

Homologous recombination maintains genomic integrity by repairing broken chromosomes. The broken chromosome is partially resected to produce single-stranded DNA (ssDNA) that is used to search for homologous double-stranded DNA (dsDNA). This homology driven 'search and rescue' is catalyzed by a class of DNA strand exchange proteins that are defined in relation to Escherichia coli RecA, which forms a filament on ssDNA. Here, we review the regulation of RecA filament assembly and the mechanism by which RecA quickly and efficiently searches for and identifies a unique homologous sequence among a vast excess of heterologous DNA. Given that RecA is the prototypic DNA strand exchange protein, its behavior affords insight into the actions of eukaryotic RAD51 orthologs and their regulators, BRCA2 and other tumor suppressors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Critical analysis of mechanisms of incentive regulation operators of electricity and natural gas networks and infrastructures. Final report. Public version, 23 November 2015

International Nuclear Information System (INIS)

2015-01-01

As the first mechanisms of incentive regulation of electricity and gas network operators have been introduced by the French Commission for Energy Regulation (CRE) since 2008 (the report recalls the main objectives of these mechanisms and their consequences), this report proposes a critical analysis of such mechanisms related to investments and to exploitation expenses of operators and which have been implemented in Germany, Spain, Ireland and in the United Kingdom. For each country, the report proposes a detailed description of these mechanisms for the electric power sector and the gas sector (general overview of the regulation framework, objectives, determination of the authorised income, shift processing, specific incentive mechanisms, modalities of management by the regulator), and a feedback of the different concerned actors (operators and regulators). The last part proposes a description of the status of the French regulation, and an analysis of transposition of the four foreign regulations, and states some propositions for evolutions (objectives, overview of recommended evolutions, focus on three types of regulation evolution: processing of arbitral charges, processing of other incited capital charges, processing of arbitral charges)

Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance.

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Bali, Alka; Singh, Shalu

2015-01-01

The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications.

The Prospects of Modernization of the Mechanism for Budgetary Regulation of the Socio-Economic Development of Lviv City

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Pidkhomnyi Oleg M.

2017-11-01

Full Text Available The socio-economic development of country and its individual territories depends on the efficiency of both accumulation and allocation of financial resources, which is determined by the effectiveness of budget process. Therefore the purpose of the article is theoretical and practical substantiation of prospects for modernization of the mechanism for budgetary regulation of the socio-economic development on the example of Lviv. Features and the main instruments of budgetary regulation of the socio-economic development of the city were researched. The efficiency of allocation and accumulation of budgetary funds, including through tax policy and the inter-budget transfers, was analyzed. Tendencies of changes of indicators of the socio-economic condition of Lviv and influence on them of three main elements of the budget regulation mechanism have been determined. Shortcomings of the existing mechanism for budgetary regulation of socio-economic development of the city have been defined, prospective directions of its modernization have been suggested.

Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn

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Leszczyńska, Anna N.; Majczyński, Henryk; Wilczyński, Grzegorz M.; Sławińska, Urszula; Cabaj, Anna M.

2015-01-01

Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3–4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers. PMID

Disrupted integration of sensory stimuli with information about the movement of the body as a mechanism explaining LSD-induced experience.

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Juszczak, Grzegorz R

2017-03-01

LSD (lysergic acid diethylamide) is a model psychedelic drug used to study mechanism underlying the effects induced by hallucinogens. However, despite advanced knowledge about molecular mechanism responsible for the effects induced by LSD and other related substances acting at serotonergic 5-HT 2a receptors, we still do not understand how these drugs trigger specific sensory experiences. LSD-induced experience is characterised by perception of movement in the environment and by presence of various bodily sensations such as floating in space, merging into surroundings and movement out of the physical body (the out-of-body experience). It means that a large part of the experience induced by the LSD can be simplified to the illusory movement that can be attributed to the self or to external objects. The phenomenology of the LSD-induced experience has been combined with the fact that serotonergic neurons provide all major parts of the brain with information about the level of tonic motor activity, occurrence of external stimuli and the execution of orienting responses. Therefore, it has been proposed that LSD-induced stimulation of 5-HT 2a receptors disrupts the integration of the sensory stimuli with information about the movement of the body leading to perception of illusory movement. Copyright © 2017 Elsevier Ltd. All rights reserved.

Circuits regulating pleasure and happiness:the evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates

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Anton J.M. Loonen

2015-10-01

Full Text Available The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system, which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this extrapyramidal system, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first

Circuits regulating pleasure and happiness: the evolution of reward-seeking and misery-fleeing behavioral mechanisms in vertebrates.

Science.gov (United States)

Loonen, Anton J M; Ivanova, Svetlana A

2015-01-01

The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory, and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system (EPS), which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this EPS, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first system is associated with

Serotonin affects association of aversive outcomes to past actions.

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Tanaka, Saori C; Shishida, Kazuhiro; Schweighofer, Nicolas; Okamoto, Yasumasa; Yamawaki, Shigeto; Doya, Kenji

2009-12-16

Impairment in the serotonergic system has been linked to action choices that are less advantageous in a long run. Such impulsive choices can be caused by a deficit in linking a given reward or punishment with past actions. Here, we tested the effect of manipulation of the serotonergic system by tryptophan depletion and loading on learning the association of current rewards and punishments with past actions. We observed slower associative learning when actions were followed by a delayed punishment in the low serotonergic condition. Furthermore, a model-based analysis revealed a positive correlation between the length of the memory trace for aversive choices and subjects' blood tryptophan concentration. Our results suggest that the serotonergic system regulates the time scale of retrospective association of punishments to past actions.

Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3.

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Grieco, Steven F; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore

2017-09-01

We examined mechanisms that contribute to the rapid antidepressant effect of ketamine in mice that is dependent on glycogen synthase kinase-3 (GSK3) inhibition. We measured serotonergic (5HT)-2C-receptor (5HTR2C) cluster microRNA (miRNA) levels in mouse hippocampus after administering an antidepressant dose of ketamine (10 mg/kg) in wild-type and GSK3 knockin mice, after GSK3 inhibition with L803-mts, and in learned helpless mice. Ketamine up-regulated cluster miRNAs 448-3p, 764-5p, 1264-3p, 1298-5p and 1912-3p (2- to 11-fold). This up-regulation was abolished in GSK3 knockin mice that express mutant constitutively active GSK3. The GSK3 specific inhibitor L803-mts was antidepressant in the learned helplessness and novelty suppressed feeding depression-like behaviours and up-regulated the 5HTR2C miRNA cluster in mouse hippocampus. After administration of the learned helplessness paradigm mice were divided into cohorts that were resilient (non-depressed) or were susceptible (depressed) to learned helplessness. The resilient, but not depressed, mice displayed increased hippocampal levels of miRNAs 448-3p and 1264-3p. Administration of an antagonist to miRNA 448-3p diminished the antidepressant effect of ketamine in the learned helplessness paradigm, indicating that up-regulation of miRNA 448-3p provides an antidepressant action. These findings identify a new outcome of GSK3 inhibition by ketamine that may contribute to antidepressant effects.

Agonist-induced down-regulation of endogenous protein kinase c α through an endolysosomal mechanism.

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Lum, Michelle A; Pundt, Krista E; Paluch, Benjamin E; Black, Adrian R; Black, Jennifer D

2013-05-03

Protein kinase C (PKC) isozymes undergo down-regulation upon sustained stimulation. Previous studies have pointed to the existence of both proteasome-dependent and -independent pathways of PKCα processing. Here we demonstrate that these down-regulation pathways are engaged in different subcellular compartments; proteasomal degradation occurs mainly at the plasma membrane, whereas non-proteasomal processing occurs in the perinuclear region. Using cholesterol depletion, pharmacological inhibitors, RNA interference, and dominant-negative mutants, we define the mechanisms involved in perinuclear accumulation of PKCα and identify the non-proteasomal mechanism mediating its degradation. We show that intracellular accumulation of PKCα involves at least two clathrin-independent, cholesterol/lipid raft-mediated pathways that do not require ubiquitination of the protein; one is dynamin-dependent and likely involves caveolae, whereas the other is dynamin- and small GTPase-independent. Internalized PKCα traffics through endosomes and is delivered to the lysosome for degradation. Supportive evidence includes (a) detection of the enzyme in EEA1-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes and (b) inhibition of its down-regulation by lysosome-disrupting agents and leupeptin. Only limited dephosphorylation of PKCα occurs during trafficking, with fully mature enzyme being the main target for lysosomal degradation. These studies define a novel and widespread mechanism of desensitization of PKCα signaling that involves endocytic trafficking and lysosome-mediated degradation of the mature, fully phosphorylated protein.

[Immune regulation activity and mechanism of Tibetan Kefir exopolysaccharide fractions].

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Meng, Li; Zhang, Lanwei

2009-12-01

To investigate the effects and mechanism on immune regulation activity in mice of two Tibetan Kefir exoploysaccharides (EPS) with different molecular weight of 0.1 x 10(5) - 3 x 10(5) (fraction 1) and 1.8 x 10(3) (fraction 2). The immune regulation activity experiment was carried out in vitro based on the Functional Assessment Procedure and Test Methods of Health Food, which was issued by Ministry of Health of China. First, we treated mice subjects with EPS at doses of 40 mg/kg, 80 mg/kg, 120 mg/kg through ig. Then we detected the index of immune organs, the ability of antibody production (tested by HC50), activity of NK cell, delayed type hypersensitivity (DTH) and phagocytosis of macrophage in mice. Finally, we examined the expression of Erk protein in Macrophages by Western Blot assay. Fraction 1 could promote HC50, activity of NK cell and DTH in mice which low dose showed better. Fraction 2 could promote DTH, phagocytosis of macrophage which high dose showed better. The expression of Erk and COX-2 had the same trend with Phagocytic index. We verified the two fractions of Tibetan Kefir EPS could enhance immune functions in mice. Fraction 1 regulated immune function through NK cell and B cell while fraction 2 through macrophage cell and T cell. The effects to macrophage of Tibetan Kefir EPS in mice may realize through extra cellular signal-regulated kinase Erk pathway.

LORETA Neurofeedback in the Precuneus: Operant Conditioning in Basic Mechanisms of Self-Regulation.

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Cannon, Rex L; Baldwin, Debora R; Diloreto, Dominic J; Phillips, Sherman T; Shaw, Tiffany L; Levy, Jacob J

2014-10-01

Low-resolution brain electomagnetic tomography (LORETA) neurofeedback provides a mechanism to influence the electrical activity of the brain in intracranial space. The aim of this study was to determine the effects of LORETA neurofeedback (LNFB) in the precuneus as a mechanism for improving self-regulation in controls and a heterogeneous diagnostic group (DX). Thirteen participants completed between 10 and 20 sessions of LNFB training in a 3-voxel cluster in the left precuneus. The participants included 5 nonclinical university students, and 8 adults with heterogeneous psychiatric diagnoses. We assessed the effects of LNFB with neurophysiological measures as well as pre- and post-Personality Assessment Inventory (PAI) subscales and selected subtests from the Delis-Kaplan Executive Function System (DKEFS). There was a significant total relative power increase at the precuneus for baseline contrasts for the control group. The DX group did not reach significant levels. All participants showed improvements in executive functions and tended to report significantly less psychopathology. The basic neural mechanisms of self-regulation are poorly understood. The data obtained in this study demonstrate that LNFB in a heterogeneous population enhances executive functions while concordantly decreasing endorsement of psychological symptoms. The alpha frequency in the brain may represent integrative functioning relative to operant efficiency and self-regulatory mechanisms. © EEG and Clinical Neuroscience Society (ECNS) 2014.

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types.

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Zhang, Feifan; Bhattacharya, Abhishek; Nelson, Jessica C; Abe, Namiko; Gordon, Patricia; Lloret-Fernandez, Carla; Maicas, Miren; Flames, Nuria; Mann, Richard S; Colón-Ramos, Daniel A; Hobert, Oliver

2014-01-01

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

Development of neural mechanisms of conflict and error processing during childhood: implications for self-regulation.

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Checa, Purificación; Castellanos, M C; Abundis-Gutiérrez, Alicia; Rosario Rueda, M

2014-01-01

Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs), and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4-6, 7-9, and 10-13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation.

Development of neural mechanisms of conflict and error processing during childhood: Implications for self-regulation

Directory of Open Access Journals (Sweden)

Purificación eCheca

2014-04-01

Full Text Available Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs, and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4 to 6, 7 to 9, and 10 to 13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation.

Development of neural mechanisms of conflict and error processing during childhood: implications for self-regulation

Science.gov (United States)

Checa, Purificación; Castellanos, M. C.; Abundis-Gutiérrez, Alicia; Rosario Rueda, M.

2014-01-01

Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs), and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4–6, 7–9, and 10–13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation. PMID:24795676

[New theory of holistic integrative physiology and medicine. I: New insight of mechanism of control and regulation of breathing].

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Sun, Xing-guo

2015-07-01

The modern systemic physiology, based on limit-understand functional classification, has significant limitation and one-sidedness. Human being is organic; we should approach the mechanism of control and regulation of breathing integrating all the systems. We use new theory of holistic integrative physiology and medicine to explain the mechanism of control and regulation of breathing. Except the mean level information, the up-down "W" waveform information of arterial blood gas (ABG) is core signal to control and regulate breathing. In order to do so, we must integrate all systems together. New theory will help to explain some unanswered questions in physiology and medicine, for example: fetal does not breathing; how first breath generate; how respiratory rhythm and frequency generate, etc. Breathing is the sign of life. Mechanism of control and regulation of breathing has to integrate respiration, circulation, nerves, metabolism, exercise, sleep and digestion, absorption and elimination and etc altogether.

Playing it safe but losing anyway--serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion.

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Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2013-08-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has been implicated in processing negative outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to a negative outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopram had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to negative outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to negative outcomes in left amygdala. Critically, these pharmacological effects were restricted to negative outcomes that were caused by low-risk decisions and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of negative outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of negative outcomes in goal-directed behaviors. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Interaction between harmane, a class of β-carboline alkaloids, and the CA1 serotonergic system in modulation of memory acquisition.

Science.gov (United States)

Nasehi, Mohammad; Ghadimi, Fatemeh; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza

2017-09-01

This study set to assess the involvement of dorsal hippocampus (CA1) serotonergic system on harmane induced memory acquisition deficit. We used one trial step-down inhibitory avoidancetask to evaluate memory retention and then, open field test to evaluate locomotor activity in adult male NMRI mice. The results showed that pre-training intra-peritoneal (i.p.) administration of harmane (12mg/kg) induced impairment of memory acquisition. Pre-training intra-CA1 administration of 5-HT1B/1D receptor agonist (CP94253; 0.5 and 5ng/mouse) and 5-HT2A/2B/2C receptor agonist (α-methyl 5-HT; 50ng/mouse) impaired memory acquisition. Furthermore, intra-CA1 administration of 5-HT1B/1D receptor antagonist (GR127935; 0.5ng/mouse) and 5-HT2 receptor antagonist (cinancerine; 5ng/mouse) improved memory acquisition. In addition, pre-training intra-CA1 injection of sub-threshold dose of CP94253 (0.05ng/mouse) and α-methyl 5-HT (5ng/mouse) potentiated impairment of memory acquisition induced by harmane (12mg/kg, i.p.). On the other hand, pre-training intra-CA1 infusion of sub-threshold dose of GR127935 (0.05ng/mouse) and cinancerine (0.5ng/mouse) with the administration of harmane (12mg/kg, i.p.) weakened impairment of memory acquisition. Moreover, all above doses of drugs did not change locomotor activity. The present findings suggest that there is an interaction between harmane and the CA1 serotonergic system in modulation of memory acquisition. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

Energy Technology Data Exchange (ETDEWEB)

Song, Xiaoling [Iowa State Univ., Ames, IA (United States)

2010-01-01

My research is on the synergistic regulation of PAI-1 by EGF and TGF-β. The mechanism of synergistic regulation of PAI-1 by EGF and TGF-β are addressed. Methods are described for effective identification of RNA accessible sites for antisense oligodexoxynucleotides (ODNs) and siRNA. In this study effective AS-ODN sequences for both Lcn2 and Bcl2 were identified by in vitro tiled microarray studies. Our results suggest that hybridization of ODN arrays to a target mRNA under physiological conditions might be used as a rapid and reliable in vitro method to accurately identify targets on mRNA molecules for effective antisense and potential siRNA activity in vivo.

Mechanism and Regulation of Nucleocytoplasmic Trafficking of Smad

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Chen Xiaochu

2011-12-01

Full Text Available Abstract Smad proteins are the intracellular mediators of transforming growth factor β (TGF-β signaling. Smads function as transcription factors and their activities require carboxyl-terminal phosphorylation by TGF-β receptor kinases which are embedded in the cell membrane. Therefore, the translocation of activated Smads from the cytoplasm into the nucleus is a rate-limiting step in TGF-β signal transduction into the nucleus. On the other hand, the export of Smads out of the nucleus turns off TGF-β effect. Such spatial control of Smad ensures a tight regulation of TGF-β target genes. Several cross-talk pathways have been shown to affect TGF-β signaling by impairing nuclear translocation of Smad, exemplifying the biological importance of the nuclear transport process. Many laboratories have investigated the underlying molecular mechanism of Smad nucleocytoplasmic translocation, combining genetics, biochemistry and sophisticated live cell imaging approaches. The last few years have witnessed the elucidation of several key players in Smad nuclear transport, most importantly the karyopherins that carry Smads across the nuclear envelope and nuclear pore proteins that facilitate the trans-nuclear envelope movement. The foundation is now set to further elucidate how the nuclear transport process is regulated and exploit such knowledge to manipulate TGF-β signaling. In this review we will discuss the current understanding of the molecular machinery responsible for nuclear import and export of Smads.

Pou1f1, the key transcription factor related to somatic growth in tilapia (Orechromis niloticus), is regulated by two independent post-transcriptional regulation mechanisms.

Science.gov (United States)

Wang, Dongfang; Qin, Jingkai; Jia, Jirong; Yan, Peipei; Li, Wensheng

2017-01-29

This study aims to determine the post-transcriptional regulation mechanism of the transcription factor pou1f1 (pou class 1 homeobox 1), which is the key gene for pituitary development, somatic growth in vertebrates, and transcription of several hormone genes in teleost fish. MicroRNA miR-223-3p was identified as a bona fide target of pou1f; overexpression of miR-223-3p in primary pituitary cells led to the down-regulation of pou1f1 and downstream genes, and inhibition of miR-223-3p led to the up-regulation of pou1f1 in Nile tilapia dispersed primary pituitary cells. An adenylate-uridylate-rich element (AU-Rich element) was found in the 3'UTR of pou1f1 mRNA, and deletion of the AU-Rich element led to slower mRNA decay and therefore more protein output. A potential mutual relationship between miR-223-3p and the AU-rich element was also investigated, and the results demonstrated that with or without the AU-Rich element, miR-223-3p induced the up-regulation of a reporter system under serum starvation conditions, indicating that miR-223-3p and the AU-Rich element function independent of each other. This study is the first to investigate the post-transcriptional mechanism of pou1f1, which revealed that miR-223-3p down-regulated pou1f1 and downstream gene expressions, and the AU-Rich element led to rapid decay of pou1f1 mRNA. MicroRNA miR-223-3p and the AU-Rich element co-regulated the post-transcriptional expression of pou1f1 independently in Nile tilapia, demonstrating that pou1f1 is under the control of a dual post-transcription regulation mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

Constant pH Accelerated Molecular Dynamics Investigation of the pH Regulation Mechanism of Dinoflagellate Luciferase.

Science.gov (United States)

Donnan, Patrick H; Ngo, Phong D; Mansoorabadi, Steven O

2018-01-23

The bioluminescence reaction in dinoflagellates involves the oxidation of an open-chain tetrapyrrole by the enzyme dinoflagellate luciferase (LCF). The activity of LCF is tightly regulated by pH, where the enzyme is essentially inactive at pH ∼8 and optimally active at pH ∼6. Little is known about the mechanism of LCF or the structure of the active form of the enzyme, although it has been proposed that several intramolecularly conserved histidine residues in the N-terminal region are important for the pH regulation mechanism. Here, constant pH accelerated molecular dynamics was employed to gain insight into the conformational activation of LCF induced by acidification.

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

DEFF Research Database (Denmark)

Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.

2012-01-01

Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist...... [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L......-DOPA and the 5-HT(1A) agonist, 8-OHDPAT, with microdialysis, and determined [(11) C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [(11) C...

Regulation of Nox enzymes expression in vascular pathophysiology: Focusing on transcription factors and epigenetic mechanisms

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Simona-Adriana Manea

2015-08-01

Full Text Available NADPH oxidases (Nox represent a family of hetero-oligomeric enzymes whose exclusive biological function is the generation of reactive oxygen species (ROS. Nox-derived ROS are essential modulators of signal transduction pathways that control key physiological activities such as cell growth, proliferation, migration, differentiation, and apoptosis, immune responses, and biochemical pathways. Enhanced formation of Nox-derived ROS, which is generally associated with the up-regulation of different Nox subtypes, has been established in various pathologies, namely cardiovascular diseases, diabetes, obesity, cancer, and neurodegeneration. The detrimental effects of Nox-derived ROS are related to alterations in cell signalling and/or direct irreversible oxidative damage of nucleic acids, proteins, carbohydrates, and lipids. Thus, understanding of transcriptional regulation mechanisms of Nox enzymes have been extensively investigated in an attempt to find ways to counteract the excessive formation of Nox-derived ROS in various pathological states. Despite the numerous existing data, the molecular pathways responsible for Nox up-regulation are not completely understood. This review article summarizes some of the recent advances and concepts related to the regulation of Nox expression in the vascular pathophysiology. It highlights the role of transcription factors and epigenetic mechanisms in this process. Identification of the signalling molecules involved in Nox up-regulation, which is associated with the onset and development of cardiovascular dysfunction may contribute to the development of novel strategies for the treatment of cardiovascular diseases.

Mechanisms of Change in the Relationship between Self-Compassion, Emotion Regulation, and Mental Health: A Systematic Review.

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Inwood, Elisa; Ferrari, Madeleine

2018-04-19

Research suggests that self-compassion may improve mental health by promoting emotion regulation (Berking & Whitley, ). This review aimed to identify studies which investigated the relationship between self-compassion, emotion regulation, and mental health in order to examine the role of emotional regulation as a mechanism of change. Searches were conducted in PsycINFO, CINAHL, Medline complete, Web of Science and Scopus databases. Inclusion criteria required publications to be: peer reviewed, published in English, contain validated measures of self-compassion and emotion regulation, and report a direct analysis on the relationship between these constructs. The search yielded five studies which met inclusion criteria. Emotion regulation significantly mediated the relationship between self-compassion and mental health. This pattern was consistent across community and clinical samples, for a range of mental health symptoms including stress, depression, and post-traumatic stress disorder. A critical limitation of the review was that all included studies used cross-sectional data, limiting interpretations regarding causation. Results provide preliminary evidence that emotion regulation may be a mechanism of change in the relationship between self-compassion and mental health. Self-compassion may be a pertinent preliminary treatment target for individuals who avoid experiences of emotions. © 2018 The International Association of Applied Psychology.

Sex differences and serotonergic mechanisms in the behavioural effects of psilocin.

Science.gov (United States)

Tylš, Filip; Páleníček, Tomáš; Kadeřábek, Lukáš; Lipski, Michaela; Kubešová, Anna; Horáček, Jiří

2016-06-01

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology - sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms - the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.

Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation

Science.gov (United States)

Niessen, Carien M.; Leckband, Deborah; Yap, Alpha S.

2013-01-01

This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains; the regulation of cadherin expression at the cell surface; cooperation between cadherins and the actin cytoskeleton; and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields. PMID:21527735

An autocrine ATP release mechanism regulates basal ciliary activity in airway epithelium.

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Droguett, Karla; Rios, Mariana; Carreño, Daniela V; Navarrete, Camilo; Fuentes, Christian; Villalón, Manuel; Barrera, Nelson P

2017-07-15

Extracellular ATP, in association with [Ca 2+ ] i regulation, is required to maintain basal ciliary beat frequency. Increasing extracellular ATP levels increases ciliary beating in airway epithelial cells, maintaining a sustained response by inducing the release of additional ATP. Extracellular ATP levels in the millimolar range, previously associated with pathophysiological conditions of the airway epithelium, produce a transient arrest of ciliary activity. The regulation of ciliary beat frequency is dependent on ATP release by hemichannels (connexin/pannexin) and P2X receptor activation, the blockage of which may even stop ciliary movement. The force exerted by cilia, measured by atomic force microscopy, is reduced following extracellular ATP hydrolysis. This result complements the current understanding of the ciliary beating regulatory mechanism, with special relevance to inflammatory diseases of the airway epithelium that affect mucociliary clearance. Extracellular nucleotides, including ATP, are locally released by the airway epithelium and stimulate ciliary activity in a [Ca 2+ ] i -dependent manner after mechanical stimulation of ciliated cells. However, it is unclear whether the ATP released is involved in regulating basal ciliary activity and mediating changes in ciliary activity in response to chemical stimulation. In the present study, we evaluated ciliary beat frequency (CBF) and ciliary beating forces in primary cultures from mouse tracheal epithelium, using videomicroscopy and atomic force microscopy (AFM), respectively. Extracellular ATP levels and [Ca 2+ ] i were measured by luminometric and fluorimetric assays, respectively. Uptake of ethidium bromide was measured to evaluate hemichannel functionality. We show that hydrolysis of constitutive extracellular ATP levels with apyrase (50 U ml -1 ) reduced basal CBF by 45% and ciliary force by 67%. The apyrase effect on CBF was potentiated by carbenoxolone, a hemichannel inhibitor, and oxidized ATP, an

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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Zhen-Ye Zhang

2017-09-01

Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

Altered serotonin transporter availability in patients with multiple sclerosis

International Nuclear Information System (INIS)

Hesse, Swen; Sabri, Osama; Moeller, Franziska; Thomae, Eva; Then Bergh, Florian; Petroff, David; Lobsien, Donald; Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M.; Regenthal, Ralf

2014-01-01

Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [ 11 C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

Altered serotonin transporter availability in patients with multiple sclerosis

Energy Technology Data Exchange (ETDEWEB)

Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig (Germany); Moeller, Franziska; Thomae, Eva; Then Bergh, Florian [University of Leipzig, Department of Neurology, Leipzig (Germany); Petroff, David [University of Leipzig, Coordinating Centre for Clinical Studies, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Luthardt, Julia; Becker, Georg-Alexander; Patt, Marianne; Seese, Anita; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Regenthal, Ralf [University of Leipzig, Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig (Germany)

2014-05-15

Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [{sup 11}C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS. (orig.)

Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.

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Enculescu, Mihaela; Metzendorf, Christoph; Sparla, Richard; Hahnel, Maximilian; Bode, Johannes; Muckenthaler, Martina U; Legewie, Stefan

2017-01-01

Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional

Design of an Adaptive Power Regulation Mechanism and a Nozzle for a Hydroelectric Power Plant Turbine Test Rig

Science.gov (United States)

Mert, Burak; Aytac, Zeynep; Tascioglu, Yigit; Celebioglu, Kutay; Aradag, Selin; ETU Hydro Research Center Team

2014-11-01

This study deals with the design of a power regulation mechanism for a Hydroelectric Power Plant (HEPP) model turbine test system which is designed to test Francis type hydroturbines up to 2 MW power with varying head and flow(discharge) values. Unlike the tailor made regulation mechanisms of full-sized, functional HEPPs; the design for the test system must be easily adapted to various turbines that are to be tested. In order to achieve this adaptability, a dynamic simulation model is constructed in MATLAB/Simulink SimMechanics. This model acquires geometric data and hydraulic loading data of the regulation system from Autodesk Inventor CAD models and Computational Fluid Dynamics (CFD) analysis respectively. The dynamic model is explained and case studies of two different HEPPs are performed for validation. CFD aided design of the turbine guide vanes, which is used as input for the dynamic model, is also presented. This research is financially supported by Turkish Ministry of Development.

Mechanisms of regulation in the interferon factor 3 (IRF- 3) pathway

OpenAIRE

Limmer, Kirsten

2008-01-01

Interferon regulatory factor 3 (IRF-3) plays a critical role in the host cell response to both bacterial and viral infection. IRF-3 is activated by Toll-like receptors (TLRs) and cytoplasmic nucleic acid sensors, and serves to upregulate interferon beta and interferon stimulated genes (ISGs), thereby providing a quick and effective response to infection. In this work, two novel mechanisms of regulation in the IRF-3 pathway are revealed. The first part of this thesis work shows that upon bindi...

Regulation of mRNA Translation Is a Novel Mechanism for Phthalate Toxicity.

Directory of Open Access Journals (Sweden)

Jun Ling

Full Text Available Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression. Butyl benzyl phthalate (BBP was found to directly inhibit mRNA translation in vitro but showed a complicated pattern of affecting mRNA translation in cells. In human kidney embryonic cell (HEK-293T, BBP increased cap-dependent mRNA translation at lower concentrations but showed inhibitory effect at higher concentrations. Cap-independent translation was not affected. On the other hand, mono (2-ethylhexyl phthalate (MEHP as a major metabolite of another important phthalate di (2-ethylhexyl phthalate (DEHP inhibited both can-dependent and -independent mRNA translation in vivo. In contrast, BBP and MEHP exhibited an overall promoting effect on mRNA translation in cancer cells. Mechanistic studies identified that the level and phosphorylation of eIF4E-BP (eIF4E binding protein and the amount of eIF4GI in eIF4F complex were altered in accordance with the effect of BBP on translation. BBP was also identified to directly bind to eIF4E, providing a further mechanism underlying the regulation of mRNA by phthalate. At the cellular level BBP inhibited normal cell growth but slightly promoted cancer cells (HT29 growth. Overall, this study provides the first evidence that phthalates can directly regulate mRNA translation as a novel mechanism to mediate their biological toxicities.

Serotonergic changes following proestrous treatment with p,p'-DDT

International Nuclear Information System (INIS)

Uphouse, L.; Eckols, K.; Croissant, D.; Stewart, G.

1990-01-01

The effects of 25 and 75 mg/kg p,p'-DDT on the CNS serotonergic system were examined in proestrous female rats. Females were treated with p,p'-DDT on the morning of proestrus and were sacrificed that evening. Levels of serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were examined in cortex, hippocampus, hypothalamus and preoptic areas. The binding of 3'-8-OH-DPAT [2-hydroxy-2-N, N-(di-propylamino)-tetralin], an agonist for 5-HT1A receptors, was examined in hippocampus and frontal cortex. P,p'-DDT decreased the level of 5-HT in frontal cortex and hippocampus. Elevations in 5-HIAA were present in the hypothalamus but only at the higher dose of p,p'-DDT. The dose of 25 mg/kg p,p'-DDT produced an increase in the Bmax for 3H-8-OH-DPAT binding to frontal cortical and hippocampal membranes. Membrane preparations from females given 75 mg/kg p,p'-DDT fell into two categories. Some were similar to the control but with a slightly higher Kd; others could not be analyzed by traditional linear or nonlinear regression procedures because they showed a constant proportion of bound label, independent of the concentration of 3H-ligand in the reaction. In vitro, p,p'-DDT did not compete with 3H-8-OH-DPAT for binding to cortical membranes so it is unlikely that residual pesticide in the membrane preparation accounted for the binding results. These binding results are particularly interesting because, in previous studies, the dose of 25 mg/kg p,p'-DDT was shown to be more potent than 75 mg/kg p,p'-DDT in reducing female rodent lordosis behavior

Association Between Genetic Polymorphisms in the Serotonergic System and Comorbid Personality Disorders Among Patients with First-Episode Depression

DEFF Research Database (Denmark)

Bukh, Jens D; Bock, Camilla; Kessing, Lars V

2014-01-01

Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid...... personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding...... the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C...

Stiff mutant genes of Phycomyces target turgor pressure and wall mechanical properties to regulate elongation growth rate

Directory of Open Access Journals (Sweden)

Joseph K. E. Ortega

2012-05-01

Full Text Available Regulation of cell growth is paramount to all living organisms. In plants, algae and fungi, regulation of expansive growth of cells is required for development and morphogenesis. Also, many sensory responses of stage IVb sporangiophores of Phycomyces blakesleeanus are produced by regulating elongation growth rate (growth responses and differential elongation growth rate (tropic responses. Stiff mutant sporangiophores exhibit diminished tropic responses and are found to be defective in at least four genes; madD, madE, madF and madG. Prior experimental research suggests that the defective genes affect growth regulation, but this was not verified. All the growth of the single-celled stalk of the stage IVb sporangiophore occurs in a short region termed the growth zone. Prior experimental and theoretical research indicates that elongation growth rate of the stage IVb sporangiophore can be regulated by controlling the cell wall mechanical properties within the growth zone and the magnitude of the turgor pressure. A quantitative biophysical model for elongation growth rate is required to elucidate the relationship between wall mechanical properties and turgor pressure during growth regulation. In this study, it is hypothesized that the mechanical properties of the wall within the growth zone of stiff mutant sporangiophores are different compared to wild type. A biophysical equation for elongation growth rate is derived for fungal and plant cells with a growth zone. Two strains of stiff mutants are studied, C149 madD120 (- and C216 geo- (-. Experimental results demonstrate that turgor pressure is larger but irreversible deformation rates of the wall within the growth zone and growth zone length are smaller for stiff mutant sporangiophores compared to wild type. These findings explain the diminished tropic responses of the stiff mutant sporangiophores and suggest that the defective genes affect the amount of wall-building material delivered to the inner

Circuits Regulating Pleasure and Happiness-Mechanisms of Depression.

Science.gov (United States)

Loonen, Anton J M; Ivanova, Svetlana A

2016-01-01

According to our model of the regulation of appetitive-searching vs. distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure). Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above) of the regulation of reward-seeking vs. misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood) may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating depression with

The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin.

Science.gov (United States)

Williamson, Danielle M; Elferich, Johannes; Ramakrishnan, Parvathy; Thomas, Gary; Shinde, Ujwal

2013-06-28

The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide-enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation.

The Mechanism by Which a Propeptide-encoded pH Sensor Regulates Spatiotemporal Activation of Furin*

Science.gov (United States)

Williamson, Danielle M.; Elferich, Johannes; Ramakrishnan, Parvathy; Thomas, Gary; Shinde, Ujwal

2013-01-01

The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide-enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation. PMID:23653353

Regulation Mechanism of the ald Gene Encoding Alanine Dehydrogenase in Mycobacterium smegmatis and Mycobacterium tuberculosis by the Lrp/AsnC Family Regulator AldR.

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Jeong, Ji-A; Hyun, Jaekyung; Oh, Jeong-Il

2015-10-01

In the presence of alanine, AldR, which belongs to the Lrp/AsnC family of transcriptional regulators and regulates ald encoding alanine dehydrogenase in Mycobacterium smegmatis, changes its quaternary structure from a homodimer to an octamer with an open-ring conformation. Four AldR-binding sites (O2, O1, O4, and O3) with a consensus sequence of GA/T-N2-NWW/WWN-N2-A/TC were identified upstream of the M. smegmatis ald gene by means of DNase I footprinting analysis. O2, O1, and O4 are required for the induction of ald expression by alanine, while O3 is directly involved in the repression of ald expression. In addition to O3, both O1 and O4 are also necessary for full repression of ald expression in the absence of alanine, due to cooperative binding of AldR dimers to O1, O4, and O3. Binding of a molecule of the AldR octamer to the ald control region was demonstrated to require two AldR-binding sites separated by three helical turns between their centers and one additional binding site that is in phase with the two AldR-binding sites. The cooperative binding of AldR dimers to DNA requires three AldR-binding sites that are aligned with a periodicity of three helical turns. The aldR gene is negatively autoregulated independently of alanine. Comparative analysis of ald expression of M. smegmatis and Mycobacterium tuberculosis in conjunction with sequence analysis of both ald control regions led us to suggest that the expression of the ald genes in both mycobacterial species is regulated by the same mechanism. In mycobacteria, alanine dehydrogenase (Ald) is the enzyme required both to utilize alanine as a nitrogen source and to grow under hypoxic conditions by maintaining the redox state of the NADH/NAD(+) pool. Expression of the ald gene was reported to be regulated by the AldR regulator that belongs to the Lrp/AsnC (feast/famine) family, but the underlying mechanism was unknown. This study revealed the regulation mechanism of ald in Mycobacterium smegmatis and

An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression.

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Bali, Anjana; Jaggi, Amteshwar Singh

2016-01-01

Ghrelin is orexigenic hormone primarily synthesized by endocrine X/A-like cells of gastric oxyntic mucosa to stimulate appetite and food intake along with regulation of growth hormone and insulin secretion; glucose and lipid metabolism; gastrointestinal motility; blood pressure, heart rate and neurogenesis. Furthermore, peripherally (after crossing the blood brain barrier) as well as centrally synthesized ghrelin (in the hypothalamus) regulates diverse functions of central nervous system including stress-associated behavioral functions. Exposure to stress alters the ghrelin levels and alteration in ghrelin levels significantly affects neuro-endocrinological parameters; metabolism-related physiology, behavior and mood. Studies have shown both anxiolytic and anxiogenic role of ghrelin suggesting its dual role in modulating anxiety-related behavior. However, it is proposed that increase in ghrelin levels during stress condition is an endogenous stress coping behavior and increased ghrelin levels may be required to prevent excessive anxiety. In preclinical and clinical studies, an elevation in ghrelin levels during depression has been correlated with their antidepressant activities. Ghrelin-induced modulation of stress and associated conditions has been linked to alteration in hypothalamic-pituitary-adrenal (HPA) axis; autonomic nervous system (mainly sympathetic nervous system and serotonergic neurotransmission. A reciprocal relationship has been reported between corticotropin-releasing hormone (CRH) and ghrelin as ghrelin increases the release of CRH, ACTH and corticosteroids; while CRH decreases the expression of ghrelin. Similarly, ghrelin increases the serotonin turnover and in turn, serotonin controls ghrelin signaling to modulate anxiety-related behavior. The present review discusses the dual role of ghrelin in stress and related behavioral disorders along with possible mechanisms.

A rho scaffold integrates the secretory system with feedback mechanisms in regulation of auxin distribution.

Directory of Open Access Journals (Sweden)

Ora Hazak

2010-01-01

Full Text Available Development in multicellular organisms depends on the ability of individual cells to coordinate their behavior by means of small signaling molecules to form correctly patterned tissues. In plants, a unique mechanism of directional transport of the signaling molecule auxin between cells connects cell polarity and tissue patterning and thus is required for many aspects of plant development. Direction of auxin flow is determined by polar subcellular localization of PIN auxin efflux transporters. Dynamic PIN polar localization results from the constitutive endocytic cycling to and from the plasma membrane, but it is not well understood how this mechanism connects to regulators of cell polarity. The Rho family small GTPases ROPs/RACs are master regulators of cell polarity, however their role in regulating polar protein trafficking and polar auxin transport has not been established. Here, by analysis of mutants and transgenic plants, we show that the ROP interactor and polarity regulator scaffold protein ICR1 is required for recruitment of PIN proteins to the polar domains at the plasma membrane. icr1 mutant embryos and plants display an a array of severe developmental aberrations that are caused by compromised differential auxin distribution. ICR1 functions at the plasma membrane where it is required for exocytosis but does not recycle together with PINs. ICR1 expression is quickly induced by auxin but is suppressed at the positions of stable auxin maxima in the hypophysis and later in the embryonic and mature root meristems. Our results imply that ICR1 is part of an auxin regulated positive feedback loop realized by a unique integration of auxin-dependent transcriptional regulation into ROP-mediated modulation of cell polarity. Thus, ICR1 forms an auxin-modulated link between cell polarity, exocytosis, and auxin transport-dependent tissue patterning.

Hydroethanolic extract of Carthamus tinctorius induces antidepressant-like effects: modulation by dopaminergic and serotonergic systems in tail suspension test in mice.

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Abbasi-Maleki, Saeid; Mousavi, Zahra

2017-09-01

Studies indicate that major deficiency in the levels of monoaminergic transmitters is a reason for severe depression. On the other hand, it is shown that Carthamus tinctorius L. (CT) may improve neuropsychological injuries by regulation of the monoamine transporter action. Hence, the present study was undertaken to evaluate the involvement of monoaminergic systems in antidepressant-like effect of CT extract in the tail suspension test (TST) in mice. The mice were intraperitoneally (IP) treated with CT extract (100-400 mg/kg) 1 hr before the TST. To investigate the involvement of monoaminergic systems in antidepressant-like effect, the mice were treated with receptor antagonists 15 min before CT extract treatment (400 mg/kg, IP) and 1 hr before the TST. Findings showed that CT extract (100-400 mg/kg, IP), dose-dependently induced antidepressant-like effect ( P open-field test. Pretreatment of mice with SCH23390, sulpiride, haloperidol, WAY100135, cyproheptadine, ketanserin and p-chlorophenylalanine (PCPA) inhibited the antidepressant-like effect of CT extract (400 mg/kg, IP), but not with prazosin and yohimbine. Co-administration of CT extract (100 mg/kg, IP) with sub-effective doses of fluoxetine (5 mg/kg, IP) or imipramine (5 mg/kg, IP) increased their antidepressant-like response. Our findings firstly showed that components (especially N-Hexadecanoic acid) of CT extract induce antidepressant-like effects by interaction with dopaminergic (D1 and D2) and serotonergic (5HT1A, 5-HT2A receptors) systems. These findings validate the folk use of CT extract for the management of depression.

[Functional organization and structure of the serotonergic neuronal network of terrestrial snail].

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Nikitin, E S; Balaban, P M

2011-01-01

The extension of knowledge how the brain works requires permanent improvement of methods of recording of neuronal activity and increase in the number of neurons recorded simultaneously to better understand the collective work of neuronal networks and assemblies. Conventional methods allow simultaneous intracellular recording up to 2-5 neurons and their membrane potentials, currents or monosynaptic connections or observation of spiking of neuronal groups with subsequent discrimination of individual spikes with loss of details of the dynamics of membrane potential. We recorded activity of a compact group of serotonergic neurons (up to 56 simultaneously) in the ganglion of a terrestrial mollusk using the method of optical recording of membrane potential that allowed to record individual action potentials in details with action potential parameters and to reveal morphology of the neurons rcorded. We demonstrated clear clustering in the group in relation with the dynamics of action potentials and phasic or tonic components in the neuronal responses to external electrophysiological and tactile stimuli. Also, we showed that identified neuron Pd2 could induce activation of a significant number of neurons in the group whereas neuron Pd4 did not induce any activation. However, its activation is delayed with regard to activation of the reacting group of neurons. Our data strongly support the concept of possible delegation of the integrative function by the network to a single neuron.

A role for the hippocampal serotonergic system in the pathology of schizophrenia?

International Nuclear Information System (INIS)

Scarr, E.; Pavey, G.M.; Copolov, D.L.; Dean, B.

2002-01-01

Full text: Theories of a role for serotonin in the pathology of schizophrenia predate the dopamine hypothesis of schizophrenia. More recently, interest in the involvement of serotonin in the disorder is primarily due to the fact that the 'atypical' neuroleptic drugs target the serotonergic system, amongst others. We have previously reported decreases in the 5-HT 2A receptors in hippocampi obtained postmortem from subjects with schizophrenia. In the same cohort of subjects we now report decreases (p 3 H]citalopram binding in the CA1 region (17.5 ± 1.4 vs. 21.7 ± 1.3 fmole/mg ETE) and methiothepin-insensitive [3H]sumatriptan binding in the CA1 (2.85 ± 0.25 vs. 3.90 ± 0.33 fmole/mg ETE), the stratum radiatum/lacunosum moleculare (4.11 ± 0.32 vs. 5.35 ± 0.46 fmole/mg ETE) and subiculum (3.87 ± 0.26 vs. 5.08 ± 0.39 fmole/mg ETE) from subjects with schizophrenia. No changes were found in [ 3 H]8-OHDPAT or methiothepin-sensitive [ 3 H]sumatriptan binding. These data indicate that there are regionally specific decreases in the densities of hippocampal serotonin transporter and 5-HT 1F receptors which may be involved in the pathology of schizophrenia. Copyright (2002) Australian Neuroscience Society

Context-dependent fluctuation of serotonin in the auditory midbrain: the influence of sex, reproductive state and experience

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Hanson, Jessica L.; Hurley, Laura M.

2014-01-01

In the face of changing behavioral situations, plasticity of sensory systems can be a valuable mechanism to facilitate appropriate behavioral responses. In the auditory system, the neurotransmitter serotonin is an important messenger for context-dependent regulation because it is sensitive to both external events and internal state, and it modulates neural activity. In male mice, serotonin increases in the auditory midbrain region, the inferior colliculus (IC), in response to changes in behavioral context such as restriction stress and social contact. Female mice have not been measured in similar contexts, although the serotonergic system is sexually dimorphic in many ways. In the present study, we investigated the effects of sex, experience and estrous state on the fluctuation of serotonin in the IC across contexts, as well as potential relationships between behavior and serotonin. Contrary to our expectation, there were no sex differences in increases of serotonin in response to a restriction stimulus. Both sexes had larger increases in second exposures, suggesting experience plays a role in serotonergic release in the IC. In females, serotonin increased during both restriction and interactions with males; however, the increase was more rapid during restriction. There was no effect of female estrous phase on the serotonergic change for either context, but serotonin was related to behavioral activity in females interacting with males. These results show that changes in behavioral context induce increases in serotonin in the IC by a mechanism that appears to be uninfluenced by sex or estrous state, but may depend on experience and behavioral activity. PMID:24198252

Mechanical confinement regulates cartilage matrix formation by chondrocytes

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Lee, Hong-Pyo; Gu, Luo; Mooney, David J.; Levenston, Marc E.; Chaudhuri, Ovijit

2017-12-01

Cartilage tissue equivalents formed from hydrogels containing chondrocytes could provide a solution for replacing damaged cartilage. Previous approaches have often utilized elastic hydrogels. However, elastic stresses may restrict cartilage matrix formation and alter the chondrocyte phenotype. Here we investigated the use of viscoelastic hydrogels, in which stresses are relaxed over time and which exhibit creep, for three-dimensional (3D) culture of chondrocytes. We found that faster relaxation promoted a striking increase in the volume of interconnected cartilage matrix formed by chondrocytes. In slower relaxing gels, restriction of cell volume expansion by elastic stresses led to increased secretion of IL-1β, which in turn drove strong up-regulation of genes associated with cartilage degradation and cell death. As no cell-adhesion ligands are presented by the hydrogels, these results reveal cell sensing of cell volume confinement as an adhesion-independent mechanism of mechanotransduction in 3D culture, and highlight stress relaxation as a key design parameter for cartilage tissue engineering.

Black Cohosh: Insights into its Mechanism(s of Action

Directory of Open Access Journals (Sweden)

Rachel L. Ruhlen

2008-01-01

Full Text Available The Women’s Health Initiative found that combination estrogen and progesterone hormone replacement therapy increases breast cancer and cardiovascular disease risk, which compelled many women to seek herbal alternatives such as black cohosh extract (BCE to relieve their menopausal symptoms. While several clinical trials document the efficacy of BCE in alleviating menopausal symptoms, preclinical studies to determine how BCE works have yielded conflicting results. Part of this is because there is not a universally accepted method to standardize the dose of black cohosh triterpenes, the presumed active ingredients in the extract. Although the mechanism by which BCE relieves symptoms is unknown, several hypotheses have been proposed: it acts 1 as a selective estrogen receptor modulator, 2 through serotonergic pathways, 3 as an antioxidant, or 4 on inflammatory pathways. We found that while the most prominent triterpene in BCE, 23-epi- 26-deoxyactein, suppresses cytokine-induced nitric oxide production in brain microglial cells, the whole BCE extract actually enhanced this pathway. A variety of activities have been reported for black cohosh and its compounds, but the absorption and tissue distribution of these compounds is unknown.

Self-awareness, self-regulation, and self-transcendence (S-ART): a framework for understanding the neurobiological mechanisms of mindfulness.

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Vago, David R; Silbersweig, David A

2012-01-01

Mindfulness-as a state, trait, process, type of meditation, and intervention has proven to be beneficial across a diverse group of psychological disorders as well as for general stress reduction. Yet, there remains a lack of clarity in the operationalization of this construct, and underlying mechanisms. Here, we provide an integrative theoretical framework and systems-based neurobiological model that explains the mechanisms by which mindfulness reduces biases related to self-processing and creates a sustainable healthy mind. Mindfulness is described through systematic mental training that develops meta-awareness (self-awareness), an ability to effectively modulate one's behavior (self-regulation), and a positive relationship between self and other that transcends self-focused needs and increases prosocial characteristics (self-transcendence). This framework of self-awareness, -regulation, and -transcendence (S-ART) illustrates a method for becoming aware of the conditions that cause (and remove) distortions or biases. The development of S-ART through meditation is proposed to modulate self-specifying and narrative self-networks through an integrative fronto-parietal control network. Relevant perceptual, cognitive, emotional, and behavioral neuropsychological processes are highlighted as supporting mechanisms for S-ART, including intention and motivation, attention regulation, emotion regulation, extinction and reconsolidation, prosociality, non-attachment, and decentering. The S-ART framework and neurobiological model is based on our growing understanding of the mechanisms for neurocognition, empirical literature, and through dismantling the specific meditation practices thought to cultivate mindfulness. The proposed framework will inform future research in the contemplative sciences and target specific areas for development in the treatment of psychological disorders.

Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition.

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Madoori, Pramod Kumar; Agustiandari, Herfita; Driessen, Arnold J M; Thunnissen, Andy-Mark W H

2009-01-21

LmrR is a PadR-related transcriptional repressor that regulates the production of LmrCD, a major multidrug ABC transporter in Lactococcus lactis. Transcriptional regulation is presumed to follow a drug-sensitive induction mechanism involving the direct binding of transporter ligands to LmrR. Here, we present crystal structures of LmrR in an apo state and in two drug-bound states complexed with Hoechst 33342 and daunomycin. LmrR shows a common topology containing a typical beta-winged helix-turn-helix domain with an additional C-terminal helix involved in dimerization. Its dimeric organization is highly unusual with a flat-shaped hydrophobic pore at the dimer centre serving as a multidrug-binding site. The drugs bind in a similar manner with their aromatic rings sandwiched in between the indole groups of two dimer-related tryptophan residues. Multidrug recognition is facilitated by conformational plasticity and the absence of drug-specific hydrogen bonds. Combined analyses using site-directed mutagenesis, fluorescence-based drug binding and protein-DNA gel shift assays reveal an allosteric coupling between the multidrug- and DNA-binding sites of LmrR that most likely has a function in the induction mechanism.

Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism.

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Granovsky, Alexey E; Clark, Matthew C; McElheny, Dan; Heil, Gary; Hong, Jia; Liu, Xuedong; Kim, Youngchang; Joachimiak, Grazyna; Joachimiak, Andrzej; Koide, Shohei; Rosner, Marsha Rich

2009-03-01

Raf kinase inhibitory protein (RKIP/PEBP1), a member of the phosphatidylethanolamine binding protein family that possesses a conserved ligand-binding pocket, negatively regulates the mammalian mitogen-activated protein kinase (MAPK) signaling cascade. Mutation of a conserved site (P74L) within the pocket leads to a loss or switch in the function of yeast or plant RKIP homologues. However, the mechanism by which the pocket influences RKIP function is unknown. Here we show that the pocket integrates two regulatory signals, phosphorylation and ligand binding, to control RKIP inhibition of Raf-1. RKIP association with Raf-1 is prevented by RKIP phosphorylation at S153. The P74L mutation increases kinase interaction and RKIP phosphorylation, enhancing Raf-1/MAPK signaling. Conversely, ligand binding to the RKIP pocket inhibits kinase interaction and RKIP phosphorylation by a noncompetitive mechanism. Additionally, ligand binding blocks RKIP association with Raf-1. Nuclear magnetic resonance studies reveal that the pocket is highly dynamic, rationalizing its capacity to interact with distinct partners and be involved in allosteric regulation. Our results show that RKIP uses a flexible pocket to integrate ligand binding- and phosphorylation-dependent interactions and to modulate the MAPK signaling pathway. This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics.

Notch1-Dll4 signaling and mechanical force regulate leader cell formation during collective cell migration

OpenAIRE

Riahi, Reza; Sun, Jian; Wang, Shue; Long, Min; Zhang, Donna D.; Wong, Pak Kin

2015-01-01

At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct “leader” phenotype with characteristic morphology and motility. However, the factors driving leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here, we use single cell gene expression analysis and computational modeling to show that leader cell identity is dynamically regulated by Dll4 sign...

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization.

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Kim, Jung; Bilder, David; Neufeld, Thomas P

2018-01-15

Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. © 2018 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

Analysis of barosensitive mechanisms in yeast for Pressure Regulated Fermentation

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Nomura, Kazuki; Iwahashi, Hitoshi; Iguchi, Akinori; Shigematsu, Toru

2013-06-01

Introduction: We are intending to develop a novel food processing technology, Pressure Regulated Fermentation (PReF), using pressure sensitive (barosensitive) fermentation microorganisms. Objectives of our study are to clarify barosensitive mechanisms for application to PReF technology. We isolated Saccharomyces cerevisiae barosensitive mutant a924E1 that was derived from the parent KA31a. Methods: Gene expression levels were analyzed by DNA microarray. The altered genes of expression levels were classified according to the gene function. Mutated genes were estimated by mating and producing diploid strains and confirmed by PCR of mitochondrial DNA (mtDNA). Results and Discussion: Gene expression profiles showed that genes of `Energy' function and that of encoding protein localized in ``Mitochondria'' were significantly down regulated in the mutant. These results suggest the respiratory deficiency and relationship between barosensitivity and respiratory deficiency. Since the respiratory functions of diploids showed non Mendelian inheritance, the respiratory deficiency was indicated to be due to mtDNA mutation. PCR analysis showed that the region of COX1 locus was deleted. COX1 gene encodes the subunit 1 of cytochrome c oxidase. For this reason, barosensitivity is strongly correlated with mitochondrial functions.

Topical thermal therapy with hot packs suppresses physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF.

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Nakagawa, Tatsuki; Hiraga, Shin-Ichiro; Mizumura, Kazue; Hori, Kiyomi; Ozaki, Noriyuki; Koeda, Tomoko

2017-10-12

We focused on the analgesic effect of hot packs for mechanical hyperalgesia in physically inactive rats. Male Wistar rats were randomly divided into four groups: control, physical inactivity (PI), PI + sham treatment (PI + sham), and PI + hot pack treatment (PI + hot pack) groups. Physical inactivity rats wore casts on both hind limbs in full plantar flexed position for 4 weeks. Hot pack treatment was performed for 20 min a day, 5 days a week. Although mechanical hyperalgesia and the up-regulation of NGF in the plantar skin and gastrocnemius muscle were observed in the PI and the PI + sham groups, these changes were significantly suppressed in the PI + hot pack group. The present results clearly demonstrated that hot pack treatment was effective in reducing physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF in plantar skin and gastrocnemius muscle.

Studies on the mechanism of quinone action on hormonal regulation of metabolism in the rat liver

International Nuclear Information System (INIS)

Cheng, E.Y.

1989-01-01

The mechanism of quinone actions in liver cell metabolism had been investigated using menadione as a model compound. Previous reports suggested that quinones and free radicals could produce perturbations in cellular calcium homeostasis. Since calcium plays an important role in the regulation of cellular metabolic processes, then regulation of cytosolic calcium concentrations, and thus of cellular metabolism, by calcium-mobilizing hormones such as phenylephrine and vasopressin could possibly be modified by quinones such as menadione. Methods used to approach this hypothesis included the assay for activation of glycogen phosphorylase, an indirect index of calcium mobilization; the determination of calcium mobilization with 45 Ca efflux exchange and with fluorescent calcium indicator fura-2; and the measurement of phosphatidylinositides, an important link in the membrane-associated receptor-mediated signal transduction mechanism

Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

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Briz, Victor; Baudry, Michel

2014-01-01

Estrogen rapidly modulates hippocampal synaptic plasticity by activating selective membrane-associated receptors. Reorganization of the actin cytoskeleton and stimulation of mammalian target of rapamycin (mTOR)-mediated protein synthesis are two major events required for the consolidation of hippocampal long-term potentiation and memory. Estradiol regulates synaptic plasticity by interacting with both processes, but the underlying molecular mechanisms are not yet fully understood. Here, we used acute rat hippocampal slices to analyze the mechanisms underlying rapid changes in mTOR activity and actin polymerization elicited by estradiol. Estradiol-induced mTOR phosphorylation was preceded by rapid and transient activation of both extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) and by phosphatase and tensin homolog (PTEN) degradation. These effects were prevented by calpain and ERK inhibitors. Estradiol-induced mTOR stimulation did not require activation of classical estrogen receptors (ER), as specific ERα and ERβ agonists (PPT and DPN, respectively) failed to mimic this effect, and ER antagonists could not block it. Estradiol rapidly activated both RhoA and p21-activated kinase (PAK). Furthermore, a specific inhibitor of RhoA kinase (ROCK), H1152, and a potent and specific PAK inhibitor, PF-3758309, blocked estradiol-induced cofilin phosphorylation and actin polymerization. ER antagonists also blocked these effects of estrogen. Consistently, both PPT and DPN stimulated PAK and cofilin phosphorylation as well as actin polymerization. Finally, the effects of estradiol on actin polymerization were insensitive to protein synthesis inhibitors, but its stimulation of mTOR activity was impaired by latrunculin A, a drug that disrupts actin filaments. Taken together, our results indicate that estradiol regulates local protein synthesis and cytoskeletal reorganization via different molecular mechanisms and signaling pathways. PMID:24611062

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

International Nuclear Information System (INIS)

Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

2012-01-01

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

Ethanol induced antidepressant-like effect in the mouse forced swimming test: modulation by serotonergic system.

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Jain, Nishant S; Kannamwar, Uday; Verma, Lokesh

2017-02-01

The present investigation explored the modulatory role of serotonergic transmission in the acute ethanol-induced effects on immobility time in the mouse forced swim test (FST). Acute i.p. administration of ethanol (20% w/v, 2 or 2.5 g/kg, i.p.) decreased the immobility time in FST of mice, indicating its antidepressant-like effect while lower doses of ethanol (1, 1.5 g/kg, i.p.) were devoid of any effect in the FST. The mice pre-treated with a sub-effective dose of 5-HT 2A agonist, DOI (10 μg/mouse, i.c.v.) or 5-HT 1A receptor antagonist, WAY 100635 (0.1 μg/mouse, i.c.v.) but not with the 5-HT 2A/2C antagonist, ketanserin (1.5 μg/mouse, i.c.v.) exhibited a synergistic reduction in the immobility time induced by sub-effective dose of ethanol (1.5 g/kg, i.p.). On the other hand, ethanol (2.5 g/kg, i.p.) failed to decrease the immobility time in mice, pre-treated with 5-HT 1A agonist, 8-OH-DPAT (0.1 μg/mouse, i.c.v.) or ketanserin (1.5 μg/mouse, i.c.v.). In addition, pre-treatment with a 5-HT neuronal synthesis inhibitor, p-CPA (300 mg/kg, i.p. × 3 days) attenuated the anti-immobility effect ethanol (2.5 g/kg, i.p.) in mouse FST. Thus, the results of the present study points towards the essentiality of the central 5-HT transmission at the synapse for the ethanol-induced antidepressant-like effect in the FST wherein the regulatory role of the 5-HT 1A receptor or contributory role of the 5-HT 2A/2C receptor-mediated mechanism is proposed in the anti-immobility effect of acute ethanol in mouse FST.

Action of naftopidil on spinal serotonergic neurotransmission for inhibition of the micturition reflex in rats.

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Sugaya, Kimio; Nishijima, Saori; Kadekawa, Katsumi; Ashitomi, Katsuhiro; Ueda, Tomoyuki; Yamamoto, Hideyuki; Hattori, Tsuyoshi

2017-03-01

We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil. PCPA decreased and 5-HTP increased urinary 5-HIAA/creatinine. Intraperitoneal injection of PCPA did not influence cystometric parameters. Intraperitoneal injection of 5-HTP significantly shortened the interval between bladder contractions. Intravenous injection of naftopidil transiently abolished bladder contractions. However, the duration of abolishment of bladder contractions after injection of naftopidil in rats given PCPA was significantly shorter than that in rats given vehicle, but significantly longer than that in rats given PCPA and 5-HTP. Intrathecal injection of 5-HT1B, 5-HT3, or 5-HT7 receptor antagonists significantly prolonged the interval between bladder contractions. Intrathecal injection of 5-HT1D or 5-HT2B receptor antagonists significantly shortened the interval between bladder contractions. Combined administration of the maximum non-effective dose of 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, or 5-HT3 receptor antagonists and intravenous injection of naftopidil significantly shortened the duration of abolishment of bladder contraction compared to intravenous injection of naftopidil alone. Naftopidil may inhibit the micturition reflex via 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors in the spinal cord. Neurourol. Urodynam. 36:604-609, 2017. © 2016 Wiley Periodicals, Inc. �

Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses.

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Shin, Hee Soon; Shon, Dong-Hwa

2015-01-01

An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders.

Suanzaoren Formulae for Insomnia: Updated Clinical Evidence and Possible Mechanisms

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Qi-Hui Zhou

2018-02-01

Full Text Available Insomnia disorder is a widespread and refractory disease. Semen Ziziphi Spinosae, Suanzaoren, a well-known Chinese herbal medicine, has been used for treating insomnia for thousands of years. Here, we aimed to assess the available evidence of Chinese herbal formulae that contains Suanzaoren (FSZR for insomnia according to high-quality randomized controlled trials (RCTs and reviewed their possible mechanisms based on animal-based studies. Electronic searches were performed in eight databases from inception to November 2016. The primary outcome measures were polysomnography index and Pittsburgh sleep quality index. The secondary outcome measures were clinical effective rate and adverse events. The methodological quality of RCTs was assessed by Cochrane's collaboration tool, and only RCTs with positive for 4 out of 7 for the Cochrane risk of bias domains were included in analyses. Thirteen eligible studies with 1,454 patients were identified. Meta-analysis of high-quality RCTs showed that FSZR monotherapy was superior to placebo (P < 0.01; FSZR plus Diazepam was superior to Diazepam alone (P < 0.05; there were mixed results comparing FSZR with Diazepam (P > 0.05 or P < 0.05. Furthermore, FSZR caused fewer side effects than that of Diazepam. Suanzaoren contains complex mixtures of phytochemicals including sanjoinine A, Jujuboside A, spinosin and other flavonoids, which has sedative and hypnotic functions primarily mediated by the GABAergic and serotonergic system. In conclusion, the findings of present study supported that FSZR could be an alternative treatment for insomnia in clinic. FSZR exerted sedative and hypnotic actions mainly through the GABAergic and serotonergic system.

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

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Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

2016-10-13

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

Generic concept to program the time domain of self-assemblies with a self-regulation mechanism.

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Heuser, Thomas; Steppert, Ann-Kathrin; Lopez, Catalina Molano; Zhu, Baolei; Walther, Andreas

2015-04-08

Nature regulates complex structures in space and time via feedback loops, kinetically controlled transformations, and under energy dissipation to allow non-equilibrium processes. Although man-made static self-assemblies realize excellent control over hierarchical structures via molecular programming, managing their temporal destiny by self-regulation is a largely unsolved challenge. Herein, we introduce a generic concept to control the time domain by programming the lifetimes of switchable self-assemblies in closed systems. We conceive dormant deactivators that, in combination with fast promoters, enable a unique kinetic balance to establish an autonomously self-regulating, transient pH-state, whose duration can be programmed over orders of magnitude-from minutes to days. Coupling this non-equilibrium state to pH-switchable self-assemblies allows predicting their assembly/disassembly fate in time, similar to a precise self-destruction mechanism. We demonstrate a platform approach by programming self-assembly lifetimes of block copolymers, nanoparticles, and peptides, enabling dynamic materials with a self-regulation functionality.

Theoretical study of Beloussov's hyper-restoration hypothesis for mechanical regulation of morphogenesis.

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Taber, Larry A

2008-12-01

Computational models were used to explore the idea that morphogenesis is regulated, in part, by feedback from mechanical stress according to Beloussov's hyper-restoration (HR) hypothesis. According to this hypothesis, active tissue responses to stress perturbations tend to restore, but overshoot, the original (target) stress. To capture this behavior, the rate of growth or contraction is assumed to depend on the difference between the current and target stresses. Stress overshoot is obtained by letting the target stress change at a rate proportional to the same stress difference. The feasibility of the HR hypothesis is illustrated by models for stretching of epithelia, cylindrical bending of plates, invagination of cylindrical and spherical shells, and early amphibian development. In each case, an initial perturbation leads to an active mechanical response that changes the form of the tissue. The results show that some morphogenetic processes can be entirely self-driven by HR responses once they are initiated (possibly by genetic activity). Other processes, however, may require secondary mechanisms or perturbations to proceed to completion.

Serotonin Drives Predatory Feeding Behavior via Synchronous Feeding Rhythms in the Nematode Pristionchus pacificus

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Misako Okumura

2017-11-01

Full Text Available Feeding behaviors in a wide range of animals are regulated by the neurotransmitter serotonin, although the exact neural circuits and associated mechanism are often unknown. The nematode Pristionchus pacificus can kill other nematodes by opening prey cuticles with movable teeth. Previous studies showed that exogenous serotonin treatment induces a predatory-like tooth movement and slower pharyngeal pumping in the absence of prey; however, physiological functions of serotonin during predation and other behaviors in P. pacificus remained completely unknown. Here, we investigate the roles of serotonin by generating mutations in Ppa-tph-1 and Ppa-bas-1, two key serotonin biosynthesis enzymes, and by genetic ablation of pharynx-associated serotonergic neurons. Mutations in Ppa-tph-1 reduced the pharyngeal pumping rate during bacterial feeding compared with wild-type. Moreover, the loss of serotonin or a subset of serotonergic neurons decreased the success of predation, but did not abolish the predatory feeding behavior completely. Detailed analysis using a high-speed camera revealed that the elimination of serotonin or the serotonergic neurons disrupted the timing and coordination of predatory tooth movement and pharyngeal pumping. This loss of synchrony significantly reduced the efficiency of successful predation events. These results suggest that serotonin has a conserved role in bacterial feeding and in addition drives the feeding rhythm of predatory behavior in Pristionchus.

Serotonin and Blood Pressure Regulation

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Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

2012-01-01

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

A conserved inter-domain communication mechanism regulates the ATPase activity of the AAA-protein Drg1.

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Prattes, Michael; Loibl, Mathias; Zisser, Gertrude; Luschnig, Daniel; Kappel, Lisa; Rössler, Ingrid; Grassegger, Manuela; Hromic, Altijana; Krieger, Elmar; Gruber, Karl; Pertschy, Brigitte; Bergler, Helmut

2017-03-17

AAA-ATPases fulfil essential roles in different cellular pathways and often act in form of hexameric complexes. Interaction with pathway-specific substrate and adaptor proteins recruits them to their targets and modulates their catalytic activity. This substrate dependent regulation of ATP hydrolysis in the AAA-domains is mediated by a non-catalytic N-terminal domain. The exact mechanisms that transmit the signal from the N-domain and coordinate the individual AAA-domains in the hexameric complex are still the topic of intensive research. Here, we present the characterization of a novel mutant variant of the eukaryotic AAA-ATPase Drg1 that shows dysregulation of ATPase activity and altered interaction with Rlp24, its substrate in ribosome biogenesis. This defective regulation is the consequence of amino acid exchanges at the interface between the regulatory N-domain and the adjacent D1 AAA-domain. The effects caused by these mutations strongly resemble those of pathological mutations of the AAA-ATPase p97 which cause the hereditary proteinopathy IBMPFD (inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia). Our results therefore suggest well conserved mechanisms of regulation between structurally, but not functionally related members of the AAA-family.

Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase.

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Kara R Barber

2017-02-01

Full Text Available Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

A review of visual perception mechanisms that regulate rapid adaptive camouflage in cuttlefish.

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Chiao, Chuan-Chin; Chubb, Charles; Hanlon, Roger T

2015-09-01

We review recent research on the visual mechanisms of rapid adaptive camouflage in cuttlefish. These neurophysiologically complex marine invertebrates can camouflage themselves against almost any background, yet their ability to quickly (0.5-2 s) alter their body patterns on different visual backgrounds poses a vexing challenge: how to pick the correct body pattern amongst their repertoire. The ability of cuttlefish to change appropriately requires a visual system that can rapidly assess complex visual scenes and produce the motor responses-the neurally controlled body patterns-that achieve camouflage. Using specifically designed visual backgrounds and assessing the corresponding body patterns quantitatively, we and others have uncovered several aspects of scene variation that are important in regulating cuttlefish patterning responses. These include spatial scale of background pattern, background intensity, background contrast, object edge properties, object contrast polarity, object depth, and the presence of 3D objects. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. By integrating these visual cues, cuttlefish are able to rapidly select appropriate body patterns for concealment throughout diverse natural environments. This sensorimotor approach of studying cuttlefish camouflage thus provides unique insights into the mechanisms of visual perception in an invertebrate image-forming eye.

Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone

DEFF Research Database (Denmark)

D'Amico, Jessica M; Butler, Annie A; Héroux, Martin E

2017-01-01

that activation of 5-HT1Areceptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones. ABSTRACT: Intense serotonergic drive in the turtle spinal cord results in serotonin...... motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise....

Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection

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Lin, Jingwen; Cunningham, Deirdre; Tumwine, Irene; Kushinga, Garikai; McLaughlin, Sarah; Spence, Philip; Böhme, Ulrike; Sanders, Mandy; Conteh, Solomon; Bushell, Ellen; Metcalf, Tom; Billker, Oliver; Duffy, Patrick E.; Newbold, Chris; Berriman, Matthew; Langhorne, Jean

2017-01-01

Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections1–5, creating an infectious reservoir to sustain transmission1,6. It is widely accepted that maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation7. However, genes involved in this process have been identified in only two of five human-infecting species: P. falciparum and P. knowlesi. Furthermore, little is understood about the early events in establishment of chronic infection in these species. Using a rodent model we demonstrate that only a minority of parasites from among the infecting population, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasite and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintainance of chronic P. falciparum infections7–9. Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Since pir genes are common to most, if not all, species of Plasmodium10, this process may be a common way of regulating the establishment of chronic infections. PMID:28165471

Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage.

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Uzer, Gunes; Fuchs, Robyn K; Rubin, Janet; Thompson, William R

2016-06-01

Numerous factors including chemical, hormonal, spatial, and physical cues determine stem cell fate. While the regulation of stem cell differentiation by soluble factors is well-characterized, the role of mechanical force in the determination of lineage fate is just beginning to be understood. Investigation of the role of force on cell function has largely focused on "outside-in" signaling, initiated at the plasma membrane. When interfaced with the extracellular matrix, the cell uses integral membrane proteins, such as those found in focal adhesion complexes to translate force into biochemical signals. Akin to these outside-in connections, the internal cytoskeleton is physically linked to the nucleus, via proteins that span the nuclear membrane. Although structurally and biochemically distinct, these two forms of mechanical coupling influence stem cell lineage fate and, when disrupted, often lead to disease. Here we provide an overview of how mechanical coupling occurs at the plasma and nuclear membranes. We also discuss the role of force on stem cell differentiation, with focus on the biochemical signals generated at the cell membrane and the nucleus, and how those signals influence various diseases. While the interaction of stem cells with their physical environment and how they respond to force is complex, an understanding of the mechanical regulation of these cells is critical in the design of novel therapeutics to combat diseases associated with aging, cancer, and osteoporosis. Stem Cells 2016;34:1455-1463. © 2016 AlphaMed Press.

Molecular mechanisms of aging and immune system regulation in Drosophila.

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Eleftherianos, Ioannis; Castillo, Julio Cesar

2012-01-01

Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span.

Anti-Depressant-Like Effect of Kaempferitrin Isolated from Justicia spicigera Schltdl (Acanthaceae in Two Behavior Models in Mice: Evidence for the Involvement of the Serotonergic System

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Julia Cassani

2014-12-01

Full Text Available We evaluated the antidepressant-like effect of kaempferitrin (Km isolated from the plant Justicia spicigera (Asteraceae, which is used in traditional medicine for relieving emotional disorders, such as “la tristeza” (sadness or dysthymia and “el humor” (mood changes. The actions of Km were evaluated in a forced swimming test (FST and a suspension tail test (TST in mice. We explored the involvement of the serotonergic system and the hypothalamic-hypophysis-adrenal axis (HPA in the antidepressant-like effect of Km. To evaluate nonspecific effects of Km on general activity, the open field test (OFT was performed. Km at 5, 10, and 20 mg/kg induced an antidepressant-like effect. Sub-effective dose of Km (1 mg/kg produced a synergistic effect with imipramine (6.25 mg/kg and fluoxetine (10 mg/kg but not with desipramine (3.12 mg/kg. Pretreatment with p-chlorophenylalanine methyl ester (PCPA, a serotonin synthesis inhibitor, N-{2-(4-(2-methoxyphenyl-1-piperazinyl}-N-(2-pyridinylcyclohexecarboxamide (WAY-100635, a selective 5-HT1A receptor antagonist, and 8OH-DPAT, a selective 5-HT1A agonist, but not pindolol (10 mg/kg blocked the anti- immobility effect induced by Km. Taken together, these results indicate that the antidepressant-like effect of Km is related to the serotonergic system, principally 5-HT1A. This effect was not related to changes in locomotor activity.

Research on Double Price Regulations and Peak Shaving Reserve Mechanism in Coal-Electricity Supply Chain

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Hongjun Peng

2013-01-01

Full Text Available The game models were used to study the mechanism of coal-electricity price conflict under conditions of double price regulations of coal and electricity. Based on this, the peak shaving reserve mechanism was designed to probe into the countermeasures against the coal-electricity price conflicts. The study revealed that in the boom seasons of coal demand, the initiatives of the coal enterprises to supply thermal coal and the electricity enterprises to order thermal coal are reduced under conditions of double price regulations. However, under the circumstances of coal price marketization, in the boom seasons of coal demand the thermal coal price may go up obviously, the initiatives of the coal enterprises to supply thermal coal are increased, and meanwhile the initiatives of the power enterprises to order thermal coal are decreased dramatically. The transportation capacity constraint of coal supply leads to the evident decrease of the initiatives of coal enterprises for the thermal coal supply. The mechanism of peak shaving reserve of thermal coal may not only reduce the price of coal market but also increase the enthusiasm of the power enterprises to order more thermal coal and the initiatives of the coal enterprises to supply more thermal coal.

Afferent nerves regulating the cough reflex: Mechanisms and Mediators of Cough in Disease

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Canning, Brendan J.

2010-01-01

Bronchopulmonary C-fibers and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate the cough reflex. These vagal afferent nerves may interact centrally with sensory input arising from afferent nerves innervating the intrapulmonary airways or even extrapulmonary afferents such as those innervating the nasal mucosa and esophagus to produce chronic cough or enhanced cough responsiveness. The mechanisms of cough initiation in health and in disease are briefly described. PMID:20172253

Post-translational regulation enables robust p53 regulation.

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Shin, Yong-Jun; Chen, Kai-Yuan; Sayed, Ali H; Hencey, Brandon; Shen, Xiling

2013-08-30

The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism. We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise. Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.

Status, Antimicrobial Mechanism, and Regulation of Natural Preservatives in Livestock Food Systems.

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Lee, Na-Kyoung; Paik, Hyun-Dong

2016-01-01

This review discusses the status, antimicrobial mechanisms, application, and regulation of natural preservatives in livestock food systems. Conventional preservatives are synthetic chemical substances including nitrates/nitrites, sulfites, sodium benzoate, propyl gallate, and potassium sorbate. The use of artificial preservatives is being reconsidered because of concerns relating to headache, allergies, and cancer. As the demand for biopreservation in food systems has increased, new natural antimicrobial compounds of various origins are being developed, including plant-derived products (polyphenolics, essential oils, plant antimicrobial peptides (pAMPs)), animal-derived products (lysozymes, lactoperoxidase, lactoferrin, ovotransferrin, antimicrobial peptide (AMP), chitosan and others), and microbial metabolites (nisin, natamycin, pullulan, ε-polylysine, organic acid, and others). These natural preservatives act by inhibiting microbial cell walls/membranes, DNA/RNA replication and transcription, protein synthesis, and metabolism. Natural preservatives have been recognized for their safety; however, these substances can influence color, smell, and toxicity in large amounts while being effective as a food preservative. Therefore, to evaluate the safety and toxicity of natural preservatives, various trials including combinations of other substances or different food preservation systems, and capsulation have been performed. Natamycin and nisin are currently the only natural preservatives being regulated, and other natural preservatives will have to be legally regulated before their widespread use.

Circuits regulating pleasure and happiness – mechanisms of depression

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Anton J.M. Loonen

2016-11-01

Full Text Available According to our model of the regulation of appetitive-searching versus distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (prefrontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure. Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness. These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above of the regulation of reward-seeking versus misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating

Regulation mechanisms of the FLT3-ligand after irradiation

International Nuclear Information System (INIS)

Prat-Lepesant, M.

2005-06-01

The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation.

Science.gov (United States)

Wei, Jia; Zhang, Yixiao; Yu, Tai-Yuan; Sadre-Bazzaz, Kianoush; Rudolph, Michael J; Amodeo, Gabriele A; Symington, Lorraine S; Walz, Thomas; Tong, Liang

2016-01-01

Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and attractive targets for drug discovery. Eukaryotic acetyl-CoA carboxylases are 250 kDa single-chain, multi-domain enzymes and function as dimers and higher oligomers. Their catalytic activity is tightly regulated by phosphorylation and other means. Here we show that yeast ACC is directly phosphorylated by the protein kinase SNF1 at residue Ser1157, which potently inhibits the enzyme. Crystal structure of three ACC central domains (AC3-AC5) shows that the phosphorylated Ser1157 is recognized by Arg1173, Arg1260, Tyr1113 and Ser1159. The R1173A/R1260A double mutant is insensitive to SNF1, confirming that this binding site is crucial for regulation. Electron microscopic studies reveal dramatic conformational changes in the holoenzyme upon phosphorylation, likely owing to the dissociation of the biotin carboxylase domain dimer. The observations support a unified molecular mechanism for the regulation of ACC by phosphorylation as well as by the natural product soraphen A, a potent inhibitor of eukaryotic ACC. These molecular insights enhance our understanding of acetyl-CoA carboxylase regulation and provide a basis for drug discovery.

How does early maternal separation and chronic stress in adult rats affect the immunoreactivity of serotonergic neurons within the dorsal raphe nucleus?

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Pollano, Antonella; Trujillo, Verónica; Suárez, Marta M

2018-01-01

Vulnerability to emotional disorders like depression derives from interactions between early and late environments, including stressful conditions. The serotonin (5HT) system is strongly affected by stress and chronic unpredictable stress can alter the 5HT system. We evaluated the distribution of active serotonergic neurons in the dorsal raphe nucleus (DR) through immunohistochemistry in maternally separated and chronically stressed rats treated with an antidepressant, tianeptine, whose mechanism of action is still under review. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h between postnatal days (PND) 1-21, or to animal facility rearing (AFR). Between (PND) days 50-74, rats were exposed to chronic unpredictable stress and were treated daily with tianeptine (10 mg/kg) or vehicle. We found an interaction between the effects of MS and chronic unpredictable stress on Fos-5HT immunoreactive cells at mid-caudal level of the DR. MS-chronically stressed rats showed an increase of Fos-5HT immunoreactive cells compared with AFR-chronically stressed rats. The ventrolateral (DRL/VLPAG) and dorsal (DRD) subdivisions of the DR were significantly more active than the ventral part (DRV). At the rostral level of the DR, tianeptine decreased the number of Fos-5HT cells in DR in the AFR groups, both unstressed and stressed. Overall, our results support the idea of a match in phenotype exhibited when the early and the adult environment correspond.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.

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Sheldon, Claire A; Kwon, Young Joon; Liu, Grant T; McCormack, Shana E

2015-02-01

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran.

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Fisher, Katherine H; Stec, Wojciech; Brown, Stephen; Zeidler, Martin P

2016-02-01

Transmembrane receptors interact with extracellular ligands to transduce intracellular signaling cascades, modulate target gene expression, and regulate processes such as proliferation, apoptosis, differentiation, and homeostasis. As a consequence, aberrant signaling events often underlie human disease. Whereas the vertebrate JAK/STAT signaling cascade is transduced via multiple receptor combinations, the Drosophila pathway has only one full-length signaling receptor, Domeless (Dome), and a single negatively acting receptor, Eye Transformer/Latran (Et/Lat). Here we investigate the molecular mechanisms underlying Et/Lat activity. We demonstrate that Et/Lat negatively regulates the JAK/STAT pathway activity and can bind to Dome, thus reducing Dome:Dome homodimerization by creating signaling-incompetent Dome:Et/Lat heterodimers. Surprisingly, we find that Et/Lat is able to bind to both JAK and STAT92E but, despite the presence of putative cytokine-binding motifs, does not detectably interact with pathway ligands. We find that Et/Lat is trafficked through the endocytic machinery for lysosomal degradation but at a much slower rate than Dome, a difference that may enhance its ability to sequester Dome into signaling-incompetent complexes. Our data offer new insights into the molecular mechanism and regulation of Et/Lat in Drosophila that may inform our understanding of how short receptors function in other organisms. © 2016 Fisher et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Self-Awareness, Self-Regulation, and Self-Transcendence (S-ART: A Framework for Understanding the Neurobiological Mechanisms of Mindfulness

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David R. Vago

2012-10-01

Full Text Available Mindfulness - as a state, trait, process, type of meditation, and intervention has proven to be beneficial across a diverse group of psychological disorders as well as for general stress reduction. Yet, there remains a lack of clarity in the operationalization of this construct, and underlying mechanisms. Here, we provide an integrative theoretical framework and systems-based neurobiological model that explains the mechanisms by which mindfulness reduces biases related to self-processing and creates a sustainable healthy mind. Mindfulness is described through systematic mental training that develops meta-awareness (self-awareness, an ability to effectively modulate one’s behavior (self-regulation, and the development of a positive relationship between self and other that transcends self-focused needs and increases prosocial characteristics (self-transcendence. This framework of self-awareness, regulation, and transcendence (S-ART illustrates a method for becoming aware of the conditions that cause (and remove distortions or biases. The development of S-ART through meditation is proposed to modulate self-specifying and narrative self-networks through an integrative fronto-parietal control network. Relevant perceptual, cognitive, emotional, and behavioral neuropsychological processes are highlighted, including intention and motivation, attention regulation, emotion regulation, extinction and reconsolidation, prosociality, non-attachment and decentering. The S-ART framework and neurobiological model is based on our growing understanding of the mechanisms for neurocognition, empirical literature, and through dismantling the specific meditation practices thought to cultivate mindfulness. The proposed framework will inform future research in the contemplative sciences and target specific areas for development in the treatment of psychological disorders.

Investigation of the mechanisms mediating MDMA "Ecstasy"-induced increases in cerebro-cortical perfusion determined by btASL MRI.

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Rouine, J; Kelly, M E; Jennings-Murphy, C; Duffy, P; Gorman, I; Gormley, S; Kerskens, C M; Harkin, Andrew

2015-05-01

Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI. The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats. Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI. Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion. Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion.

Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes.

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Xiaodong Liu

Full Text Available BACKGROUND: Signal transducer and activator of transcription 3 (Stat3 is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS. METHODS: Stat3 specific siRNA oligo and synthetic selective inhibitor (Stattic were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection. RESULTS: Intrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn. CONCLUSIONS: Stat3 acted as a

Mechanism research of miR-181 regulating human lens epithelial cell apoptosis

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Yu Qin

2015-05-01

Full Text Available AIM: To investigate the expression of miR-181 in the lens tissue of cataract and the regulating mechanism of miR-181 on apoptosis of human lens epithelial cell.METHODS:Real time q-PCR was used to measure the expression of miR-181 in the anterior lens capsules of age-related cataract and human lens epithelial cell apoptosis model. miR-181 mimic and inhibitor were transfected using Lipofectamine 2 000 to regulate the expression of miR-181, and then Real time q-PCR was used to verify transfection efficiency. Flow cytometry was used to detect the change of cell apoptosis rate. RESULTS: Compared with control group, the expression of miR-181 was significantly higher in both the anterior lens capsules of age-related cataract and human lens epithelial cell apoptosis model; the relative expression of miR-181 in lens epithelial cells transfected with miR-181 mimic was increased, whereas decreased in cells transfected with miR-181 inhibitor; the apoptosis rate of cells transfected with miR-181 mimic was increased, while reduced in miR-181 inhibitor group. Each result was statistically significant(PCONCLUSION: High expression of miR-181 is detected in anterior lens capsule of age-related cataract. miR-181 might play a certain role in the pathogenesis of cataract via promoting human lens epithelial cell apoptosis. miR-181 probably becomes a new approach for the nonoperative treatment of cataract, but the concrete mechanism still needs to be further studied.

[The cognitive effects of ecstasy].

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Pázmány, Péter; Petschner, Péter; Ádori, Csaba; Kirilly, Eszter; Andó, Dénes Rómeó; Balogh, Brigitta; Gyöngyösi, Norbert; Bagdy, György

2013-12-01

The recreational drug ecstasy is widely used among dance clubbers for its acute euphoric and entactogenic effects. Ecstasy exerts its acute effects by increasing the extracellular concentration of monoamines in the brain by reversing the functions of reuptake mechanisms. These elevations in extracellular monoamine concentrations result in wake promoting effects, body hyperthermia and reductions in local cerebral blood flow. However, on the long-run, ecstasy reduces serotonin concentration and density of serotonergic markers in several brain areas. Functional deficits, like sleep disturbances, anxiogenic- and aggressive behavioral responses and mood disorders also may occur. However, one of the most prominent adverse effects is related to the cognitive functions. Following ecstasy use attenuated retro- and prospective memory and defective higher order cognitive functions can be observed, especially in heavy users. Several studies indicated the involvement of the endocannabinoid system, the sleep regulating centers and the hypothalamic-pituitary-adrenal axis based on or parallel to serotonergic damage in these processes. Recent evidence, however, also showed that changes in one of the latter systems can influence the functions of each other. In this review we summarize the related literature, and propose a complex mechanism for the long-lasting cognitive deficits following heavy ecstasy use.

Cyclic Mechanical Stretch Up-regulates Hepatoma-Derived Growth Factor Expression in Cultured Rat Aortic Smooth Muscle Cells.

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Kao, Ying-Hsien; Chen, Po-Han; Sun, Cheuk-Kwan; Chang, Yo-Chen; Lin, Yu-Chun; Tsai, Ming-Shian; Lee, Po-Huang; Cheng, Cheng-I

2018-02-21

Hepatoma-derived growth factor (HDGF) is a potent mitogen for vascular smooth muscle cells (SMCs) during embryogenesis and injury repair of vessel walls. Whether mechanical stimuli modulate HDGF expression remains unknown. This study aimed at investigating whether cyclic mechanical stretch plays a regulatory role in HDGF expression and regenerative cytokine production in aortic SMCs. A SMC cell line was grown on a silicone-based elastomer chamber with extracellular matrix coatings (either type I collagen or fibronectin) and received cyclic and uni-axial mechanical stretches with 10% deformation at frequency 1 Hz. Morphological observation showed that fibronectin coating provided better cell adhesion and spreading and that consecutive 6 hours of cyclic mechanical stretch remarkably induced reorientation and realignment of SMCs. Western blotting detection demonstrated that continuous mechanical stimuli elicited up-regulation of HDGF and PCNA, a cell proliferative marker. Signal kinetic profiling study indicated that cyclic mechanical stretch induced signaling activity in RhoA/ROCK and PI3K/Akt cascades. Kinase inhibition study further showed that blockade of PI3K activity suppressed the stretch-induced TNF-a, whereas RhoA/ROCK inhibition significantly blunted the IL-6 production and HDGF over-expression. Moreover, siRNA-mediated HDGF gene silencing significantly suppressed constitutive expression of IL-6, but not TNF-α, in SMCs. These findings support the role of HDGF in maintaining vascular expression of IL-6, which has been regarded a crucial regenerative factor for acute vascular injury. In conclusion, cyclic mechanical stretch may maintain constitutive expression of HDGF in vascular walls and be regarded an important biophysical regulator in vascular regeneration. ©2018 The Author(s).

Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis

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McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E

2015-01-01

Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human...... adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating...

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men

OpenAIRE

Walderhaug, Espen; Herman, Aryeh Isaac; Magnusson, Andres; Morgan, Michael John; Landrø, Nils Inge

2010-01-01

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive ...

Characterization of serotonergic receptors in rabbit, porcine and human conjunctivae.

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Turner, Helen C; Alvarez, Lawrence J; Candia, Oscar A; Bernstein, Audrey M

2003-10-01

To characterize the serotonin (5-HT) receptors linked to the modulation of adenylyl cyclase activity in rabbit, porcine and human conjunctivae. Serotonin receptor-subtype expression was examined using reverse transcription-polymerase chain reaction (RT-PCR) and receptor subtype-specific polyclonal antibodies for the immunofluorescent labeling of conjunctival cryosections. In addition, measurements of the effects of serotonergics on the short-circuit current (I(sc)) across rabbit and porcine conjunctivae were contrasted. RT-PCR assays indicated the expression of 5-HT(1B ) and 5-HT(1D) receptors, subtypes negatively coupled to adenylyl cyclase, in the rabbit conjunctiva. This approach also suggested the co-expression of 5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(4) and 5-HT(7) mRNA's in the porcine conjunctiva, and 5-HT( 1D), 5-HT(1F) and 5-HT(7) in the human conjunctiva. Since the 5-HT(4) and 5-HT(7) receptors are positively linked to adenylyl cyclase, these results implied that the porcine and human tissues exhibited subtypes both positively and negatively linked to the enzyme. However, immunohistochemical observations, using currently available antibodies solely localized the 5-HT(7) moiety in the porcine and human epithelia, suggested that the 1B/1D forms may be minor elements. Consistent with this prospect, 5-HT was a stimulant of the transepithelial I(sc) across the porcine conjunctiva, an opposite response from earlier findings that demonstrated inhibitory effects by 5-HT on the rabbit I(sc), which are now explained by the localization of the 1B/1D receptors in the rabbit stratified epithelium. The 5-HT receptors expressed by mammalian conjunctivae are not identical. In terms of 5-HT receptor expression, the porcine tissue may be a more appropriate model for human, than is the rabbit, in that 5-HT may serve as a secretagogue in the human epithelium.

RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism

International Nuclear Information System (INIS)

Yamaki, Nao; Negishi, Manabu; Katoh, Hironori

2007-01-01

In normal epithelial cells, cell-matrix interaction is required for cell survival and proliferation, whereas disruption of this interaction causes epithelial cells to undergo apoptosis called anoikis. Here we show that the small GTPase RhoG plays an important role in the regulation of anoikis. HeLa cells are capable of anchorage-independent cell growth and acquire resistance to anoikis. We found that RNA interference-mediated knockdown of RhoG promoted anoikis in HeLa cells. Previous studies have shown that RhoG activates Rac1 and induces several cellular functions including promotion of cell migration through its effector ELMO and the ELMO-binding protein Dock180 that function as a Rac-specific guanine nucleotide exchange factor. However, RhoG-induced suppression of anoikis was independent of the ELMO- and Dock180-mediated activation of Rac1. On the other hand, the regulation of anoikis by RhoG required phosphatidylinositol 3-kinase (PI3K) activity, and constitutively active RhoG bound to the PI3K regulatory subunit p85α and induced the PI3K-dependent phosphorylation of Akt. Taken together, these results suggest that RhoG protects cells from apoptosis caused by the loss of anchorage through a PI3K-dependent mechanism, independent of its activation of Rac1

Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs.

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Ufnal, Marcin; Skrzypecki, Janusz

2014-04-01

Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure. Copyright © 2014 Elsevier Ltd. All rights reserved.

Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms.

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Olle Eriksson

Full Text Available To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD and asymptomatic controls.Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women.Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP, radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs: the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain".There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001. Menstrual phase changes in this asymmetry (premenstrual-follicular correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006. The PMD group showed a strong inverse correlation between phase changes (premenstrual-follicular in plasma levels of estradiol and phase changes in the laterality (dx/sin of radiotracer activity in the dorsolateral prefrontal ROI (rs = -0.635; 0.027. The control group showed no such correlation.Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral

Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase.

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Misono, K. S.; Philo, J. S.; Arakawa, T.; Ogata, C. M.; Qiu, Y.; Ogawa, H.; Young, H. S. (Biosciences Division); (Univ. of Nevada); (Alliance Protein Labs.)

2011-06-01

Atrial natriuretic peptide (ANP) and the homologous B-type natriuretic peptide are cardiac hormones that dilate blood vessels and stimulate natriuresis and diuresis, thereby lowering blood pressure and blood volume. ANP and B-type natriuretic peptide counterbalance the actions of the renin-angiotensin-aldosterone and neurohormonal systems, and play a central role in cardiovascular regulation. These activities are mediated by natriuretic peptide receptor-A (NPRA), a single transmembrane segment, guanylyl cyclase (GC)-linked receptor that occurs as a homodimer. Here, we present an overview of the structure, possible chloride-mediated regulation and signaling mechanism of NPRA and other receptor GCs. Earlier, we determined the crystal structures of the NPRA extracellular domain with and without bound ANP. Their structural comparison has revealed a novel ANP-induced rotation mechanism occurring in the juxtamembrane region that apparently triggers transmembrane signal transduction. More recently, the crystal structures of the dimerized catalytic domain of green algae GC Cyg12 and that of cyanobacterium GC Cya2 have been reported. These structures closely resemble that of the adenylyl cyclase catalytic domain, consisting of a C1 and C2 subdomain heterodimer. Adenylyl cyclase is activated by binding of G{sub s}{alpha} to C2 and the ensuing 7{sup o} rotation of C1 around an axis parallel to the central cleft, thereby inducing the heterodimer to adopt a catalytically active conformation. We speculate that, in NPRA, the ANP-induced rotation of the juxtamembrane domains, transmitted across the transmembrane helices, may induce a similar rotation in each of the dimerized GC catalytic domains, leading to the stimulation of the GC catalytic activity.

Hearing loss alters serotonergic modulation of intrinsic excitability in auditory cortex.

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Rao, Deepti; Basura, Gregory J; Roche, Joseph; Daniels, Scott; Mancilla, Jaime G; Manis, Paul B

2010-11-01

Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 μM) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that

Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability

OpenAIRE

Wan, Ruiqian; Weigand, Letitia A.; Bateman, Ryan; Griffioen, Kathleen; Mendelowitz, David; Mattson, Mark P.

2014-01-01

Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haplo...

Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker

DEFF Research Database (Denmark)

Noehr-Jensen, L; Zwisler, S; Larsen, F

2009-01-01

PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels...... of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0......-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype...

Spontaneous regulating mechanisms that may have led to the origin of life

International Nuclear Information System (INIS)

Chela Flores, J.

1992-07-01

According to Salam condensation may be relevant in biochemistry, as a factor contributing to the homochirality of amino acids. We attempt to show that DNA packaging may be modelled, by interpreting chromatin as a form of soft matter, in which a phase transition has induced chromatin into a condensed mode. In the context of the origin of life we show the relevance of simultaneous discussion of DNA packaging, transcription, and DNA replication. Beyond a certain critical length of the protogenome (RNA), physical properties of inert condensed matter may have given rise to a spontaneous regulating mechanism of certain significance for the evolution of life on Earth. (author). 31 refs, 1 tab

The Government Incentive Regulation Model and Pricing Mechanism in Power Transmission and Distribution Market

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Huan Zhang

2016-01-01

Full Text Available The power transmission and distribution (T&D market’s natural monopoly and individual information have been the impediment to improving the energy efficiency in the whole T&D market. In order to improve the whole social welfare, T&D market should be controlled by government. An incentive regulation model with the target of maximizing social welfare has been studied. A list of contracts with transferring payment and quantity of T&D are given to motivate the corporation to reveal the true technical parameter and input the optimal investment. The corporate revenue, optimal investment, and effort are proved to depend on its own technical parameter. The part of incentive regulation model ends with the optimal pricing mechanism of T&D market. At the end of this paper, we give a numerical example to explain our research and confirm its function graphically.

Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

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Tao, Rui; Shokry, Ibrahim M.; Callanan, John J.; Adams, H. Daniel; Ma, Zhiyuan

2014-01-01

Rationale Illicit use of MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors. Objectives Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome. Methods Rats were administered MDMA at doses of 0.3, 1 or 3 mg/kg, and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome. Results Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive NMDA receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam, but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine. Conclusions Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5HT-dependent mechanism), and therefore, is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms). PMID:25300903

Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

Science.gov (United States)

Namkoong, Eun; Shin, Yong-Hwan; Bae, Jun-Seok; Choi, Seulki; Kim, Minkyoung; Kim, Nahyun; Hwang, Sung-Min; Park, Kyungpyo

2015-01-01

Sodium bicarbonate cotransporters (NBCs) are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1) and electrogenic NBC (NBCe1), with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs) and HSG cells. Intracellular pH (pHi) was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands.

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Eun Namkoong

Full Text Available Sodium bicarbonate cotransporters (NBCs are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1 and electrogenic NBC (NBCe1, with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs and HSG cells. Intracellular pH (pHi was measured and the pHi recovery rate from cell acidification induced by an NH4Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pHi recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pHi recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pHi recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH4Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pHi regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.

Circuits Regulating Pleasure and Happiness-Mechanisms of Depression

NARCIS (Netherlands)

Loonen, Anton J.M.; Ivanova, Svetlana A.

2016-01-01

According to our model of the regulation of appetitive-searching vs. distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens,

Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms.

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Larsen, Brian Roland; MacAulay, Nanna

2017-10-01

During neuronal activity in the mammalian brain, the K + released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na + /K + /2Cl - cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K + ] o and [H + ] o /pH o during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K + and glutamate released into the extracellular space (the K + /Cl - cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na + / HCO3- cotransporter 1 (NBCe1), is activated by the K + -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K + transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K + transients. Isosmotic reduction of extracellular Cl - revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K + clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K + -induced astrocytic depolarization and the activity-dependent metabolism. © 2017 Wiley Periodicals, Inc.

Subordinate Mechanism of Legal Regulation of Relations in the Framework of the Contract Procurement System to Meet the Needs of the Public

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Evgeny V. Solomonov

2016-01-01

Full Text Available The article discusses the theoretical issues of legal regulation mechanism features of separate stages of public procurement. Conclusions about the legal nature of the type of legal regulation, its relationship with the peculiarities of the legal facts and legal relations are given.

Fc-receptor-mediated phagocytosis is regulated by mechanical properties of the target

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Beningo, Karen A.; Wang, Yu-li

2002-01-01

Phagocytosis is an actin-based process used by macrophages to clear particles greater than 0.5 microm in diameter. In addition to its role in immunological responses, phagocytosis is also necessary for tissue remodeling and repair. To prevent catastrophic autoimmune reactions, phagocytosis must be tightly regulated. It is commonly assumed that the recognition/selection of phagocytic targets is based solely upon receptor-ligand binding. Here we report an important new criterion, that mechanical parameters of the target can dramatically affect the efficiency of phagocytosis. When presented with particles of identical chemical properties but different rigidity, macrophages showed a strong preference to engulf rigid objects. Furthermore, phagocytosis of soft particles can be stimulated with the microinjection of constitutively active Rac1 but not RhoA, and with lysophosphatidic acid, an agent known to activate the small GTP-binding proteins of the Rho family. These data suggest a Rac1-dependent mechanosensory mechanism for phagocytosis, which probably plays an important role in a number of physiological and pathological processes from embryonic development to autoimmune diseases.

Computational study on the inhibitor binding mode and allosteric regulation mechanism in hepatitis C virus NS3/4A protein.

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Weiwei Xue

Full Text Available HCV NS3/4A protein is an attractive therapeutic target responsible for harboring serine protease and RNA helicase activities during the viral replication. Small molecules binding at the interface between the protease and helicase domains can stabilize the closed conformation of the protein and thus block the catalytic function of HCV NS3/4A protein via an allosteric regulation mechanism. But the detailed mechanism remains elusive. Here, we aimed to provide some insight into the inhibitor binding mode and allosteric regulation mechanism of HCV NS3/4A protein by using computational methods. Four simulation systems were investigated. They include: apo state of HCV NS3/4A protein, HCV NS3/4A protein in complex with an allosteric inhibitor and the truncated form of the above two systems. The molecular dynamics simulation results indicate HCV NS3/4A protein in complex with the allosteric inhibitor 4VA adopts a closed conformation (inactive state, while the truncated apo protein adopts an open conformation (active state. Further residue interaction network analysis suggests the communication of the domain-domain interface play an important role in the transition from closed to open conformation of HCV NS3/4A protein. However, the inhibitor stabilizes the closed conformation through interaction with several key residues from both the protease and helicase domains, including His57, Asp79, Asp81, Asp168, Met485, Cys525 and Asp527, which blocks the information communication between the functional domains interface. Finally, a dynamic model about the allosteric regulation and conformational changes of HCV NS3/4A protein was proposed and could provide fundamental insights into the allosteric mechanism of HCV NS3/4A protein function regulation and design of new potent inhibitors.

[Molecular mechanisms of autophagy in regulating renal aging and interventional effects of Chinese herbal medicine].

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Tu, Yue; Sun, Wei; Chen, Di-Ping; Wan, Yi-Gang; Wu, Wei; Yao, Jian

2016-11-01

Aging is the gradual functional recession of the living tissues or organs caused by a variety of genetic and environmental factors together. Autophagy is a process of degrading cytoplasmic components mediated by lysosomes in eukaryotic cells. Kidney is a typical target organ of aging. Autophagy regulates renal aging. Decrease in autophagy can accelerate renal aging,whereas,increase in autophagy can delay renal aging. During the process of regulating renal aging,the mammalian target of rapamycin (mTOR) and its related signaling pathways including the adenosine monophosphate activated protein kinase (AMPK)/mTOR,the phosphatidylinositol 3-kinase (PI3K)/ serine-threonine kinase(Akt)/mTOR,the AMPK/silent information regulation 1 (Sirt1) and transforming growth factor β (TGF-β) play the important roles in renal aging. Regulating the key signaling molecules in these pathways in vivo can control renal aging. Some Chinese herbal medicine (CHM) and their extracts with the effects of nourishing kidney or activating stasis, such as Cordyceps sinensis, curcumin and resveratrol have the beneficial effects on renal aging and/or autophagy. Therefore,revealing the pharmacological effects of CHM in anti-renal aging based on the molecular mechanisms of autophagy will become one of the development trends in the future study. Copyright© by the Chinese Pharmaceutical Association.

Constitutive, Institutive and Up-Regulation of Carotenogenesis Regulatory Mechanism via In Vitro Culture Model System and Elicitors

International Nuclear Information System (INIS)

Rashidi Othman; Fatimah Azzahra Mohd Zaifuddin; Norazian Mohd Hassan

2015-01-01

Phyto hormone abscisic acid (ABA) plays a regulatory role in many physiological processes in plants and is regulated and controlled by specific key factors or genes. Different environmental stress conditions such as water, drought, cold, light, and temperature result in increased amounts of ABA. The action of ABA involves modification of gene expression and analysis of in vitro callus model system cultures revealed several potential of constitutive, institutive and up-regulation acting regulatory mechanisms. Therefore, this study was aimed at establishing in vitro cultures as potential research tools to study the regulatory mechanisms of the carotenoid biosynthesis in selected plant species through a controlled environment. The presence and absence of zeaxanthin and neoxanthin in callus cultures and intact plants could be explained by changes in gene expression in response to stress. Abiotic stress can alter gene expression and trigger cellular metabolism in plants. This study suggested that the key factors which involved in regulatory mechanisms of individual carotenoid biosynthesis in a particular biology system of plants can be either be silenced or activated. Therefore, based on the results in this study environmental stress is made possible for enhancement or enrichment of certain carotenoid of interest in food crops without altering the genes. (author)

Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells.

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Viren Kumar Govindaraju

Full Text Available Age related macular degeneration (AMD is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01, which was subsequently mitigated through cysteamine (p < 0.01 or fisetin (p < 0.05 treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05 that were cleared- off with cysteamine (p < 0.05 or fisetin (p < 0.05. Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization and autophagy-flux impairment was significantly (p<0.01 mitigated by cysteamine (p<0.05 or fisetin (p<0.05 treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001 while impacting cell viability (p < 0.001, which was quantified using CMH2DCFDA-dye (ROS and MTS (proliferation or propodium iodide staining (cell viability assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05 and diminished cell viability (p < 0.05. Lastly, CSE was found to induce cellular senescence (p < 0.001, which was significantly ameliorated by cysteamine (p < 0.001 or fisetin (p < 0.001. In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover

Self-Regulation and Mechanisms of Action in Psychotherapy: A Theory-Based Translational Perspective

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Strauman, Timothy J.; Goetz, Elena L.; Detloff, Allison M.; MacDuffie, Katherine E.; Zaunmüller, Luisa; Lutz, Wolfgang

2012-01-01

Psychotherapy is a complex, multi-layered process with the potential to bring about changes at multiple levels of functioning, from the neurobiology of the brain to the individual’s role in the social world. Although studies of the mechanisms by which psychotherapy leads to change continue to appear, there remains much to be learned about how psychological interventions work. To guide explorations of how and for whom particular treatment approaches lead to change, researchers can rely on theory to identify potential loci for change and on translational research methods to integrate basic behavioral science and neuroscience with clinical science. In this article, we describe research linking individual differences in the self-regulation of personal goal pursuit with the etiology and treatment of mood disorders. The research draws upon regulatory focus theory as a model of self-regulation and on microintervention designs – controlled laboratory investigations of a specific therapeutic technique – to generate and test hypotheses about how psychological interventions can help to reverse maladaptive self-regulatory processes. PMID:23072383

Volume regulation in epithelia

DEFF Research Database (Denmark)

Larsen, Erik Hviid; Hoffmann, Else Kay

2016-01-01

to amphibian skin and mammalian cortical collecting tubule of low and intermediate osmotic permeability. Crosstalk between entrance and exit mechanisms interferes with volume regulation both at aniso-osmotic and iso-osmotic volume perturbations. It has been proposed that cell volume regulation is an intrinsic...... regulation are cloned. The volume-regulated anion channel (VRAC) exhibiting specific electrophysiological characteristics seems exclusive to serve cell volume regulation. This is contrary to K+ channels as well as cotransporters and exchange mechanisms that may serve both transepithelial transport and cell...... volume regulation. In the same cell, these functions may be maintained by different ion pathways that are separately regulated. RVD is often preceded by increase in cytosolic free Ca2+, probably via influx through TRP channels, but Ca2+ release from intracellular stores has also been observed. Cell...

Peak regulation right

International Nuclear Information System (INIS)

Gao, Z. |; Ren, Z.; Li, Z.; Zhu, R.

2005-01-01

A peak regulation right concept and corresponding transaction mechanism for an electricity market was presented. The market was based on a power pool and independent system operator (ISO) model. Peak regulation right (PRR) was defined as a downward regulation capacity purchase option which allowed PRR owners to buy certain quantities of peak regulation capacity (PRC) at a specific price during a specified period from suppliers. The PRR owner also had the right to decide whether or not they would buy PRC from suppliers. It was the power pool's responsibility to provide competitive and fair peak regulation trading markets to participants. The introduction of PRR allowed for unit capacity regulation. The PRR and PRC were rated by the supplier, and transactions proceeded through a bidding process. PRR suppliers obtained profits by selling PRR and PRC, and obtained downward regulation fees regardless of whether purchases are made. It was concluded that the peak regulation mechanism reduced the total cost of the generating system and increased the social surplus. 6 refs., 1 tab., 3 figs

Sun-mediated mechanical LINC between nucleus and cytoskeleton regulates βcatenin nuclear access.

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Uzer, Gunes; Bas, Guniz; Sen, Buer; Xie, Zhihui; Birks, Scott; Olcum, Melis; McGrath, Cody; Styner, Maya; Rubin, Janet

2018-06-06

βcatenin acts as a primary intracellular signal transducer for mechanical and Wnt signaling pathways to control cell function and fate. Regulation of βcatenin in the cytoplasm has been well studied but βcatenin nuclear trafficking and function remains unclear. In a previous study we showed that, in mesenchymal stem cells (MSC), mechanical blockade of adipogenesis relied on inhibition of βcatenin destruction complex element GSK3β (glycogen synthase kinase 3β) to increase nuclear βcatenin as well as the function of Linker of Cytoskeleton and Nucleoskeleton (LINC) complexes, suggesting that these two mechanisms may be linked. Here we show that shortly after inactivation of GSK3β due to either low intensity vibration (LIV), substrate strain or pharmacologic inhibition, βcatenin associates with the nucleoskeleton, defined as the insoluble nuclear fraction that provides structure to the integrated nuclear envelope, nuclear lamina and chromatin. Co-depleting LINC elements Sun-1 and Sun-2 interfered with both nucleoskeletal association and nuclear entry of βcatenin, resulting in decreased nuclear βcatenin levels. Our findings reveal that the insoluble structural nucleoskeleton actively participates in βcatenin dynamics. As the cytoskeleton transmits applied mechanical force to the nuclear surface to influence the nucleoskeleton and its LINC mediated interaction, our results suggest a pathway by which LINC mediated connectivity may play a role in signaling pathways that depend on nuclear access of βcatenin. Copyright © 2018 Elsevier Ltd. All rights reserved.

The fidelity of synaptonemal complex assembly is regulated by a signaling mechanism that controls early meiotic progression.

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Silva, Nicola; Ferrandiz, Nuria; Barroso, Consuelo; Tognetti, Silvia; Lightfoot, James; Telecan, Oana; Encheva, Vesela; Faull, Peter; Hanni, Simon; Furger, Andre; Snijders, Ambrosius P; Speck, Christian; Martinez-Perez, Enrique

2014-11-24

Proper chromosome segregation during meiosis requires the assembly of the synaptonemal complex (SC) between homologous chromosomes. However, the SC structure itself is indifferent to homology, and poorly understood mechanisms that depend on conserved HORMA-domain proteins prevent ectopic SC assembly. Although HORMA-domain proteins are thought to regulate SC assembly as intrinsic components of meiotic chromosomes, here we uncover a key role for nuclear soluble HORMA-domain protein HTP-1 in the quality control of SC assembly. We show that a mutant form of HTP-1 impaired in chromosome loading provides functionality of an HTP-1-dependent checkpoint that delays exit from homology search-competent stages until all homolog pairs are linked by the SC. Bypassing of this regulatory mechanism results in premature meiotic progression and licensing of homology-independent SC assembly. These findings identify nuclear soluble HTP-1 as a regulator of early meiotic progression, suggesting parallels with the mode of action of Mad2 in the spindle assembly checkpoint. Copyright © 2014 Elsevier Inc. All rights reserved.

Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells.

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Beatriz Suárez-Alvarez

2010-04-01

Full Text Available Human embryonic stem cells (hESCs are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM components and NKG2D ligands (NKG2D-L in hESCs, induced pluripotent stem cells (iPSCs and NTera2 (NT2 teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1 and tapasin (TPN components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of beta2-microglobulin (beta2m light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and beta2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs. Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.

Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells

Science.gov (United States)

Suárez-Álvarez, Beatriz; Rodriguez, Ramón M.; Calvanese, Vincenzo; Blanco-Gelaz, Miguel A.; Suhr, Steve T.; Ortega, Francisco; Otero, Jesus; Cibelli, Jose B.; Moore, Harry; Fraga, Mario F.; López-Larrea, Carlos

2010-01-01

Background Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored. Methodology/Principal Findings We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation. Conclusions/Significance Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance

Transgenic Analysis of the Leishmania MAP Kinase MPK10 Reveals an Auto-inhibitory Mechanism Crucial for Stage-Regulated Activity and Parasite Viability

DEFF Research Database (Denmark)

Cayla, M.; Rachidi, N.; Leclercq, O.

2014-01-01

Protozoan pathogens of the genus Leishmania have evolved unique signaling mechanisms that can sense changes in the host environment and trigger adaptive stage differentiation essential for host cell infection. The signaling mechanisms underlying parasite development remain largely elusive even...... though Leishmania mitogen-activated protein kinases (MAPKs) have been linked previously to environmentally induced differentiation and virulence. Here, we unravel highly unusual regulatory mechanisms for Leishmania MAP kinase 10 (MPK10). Using a transgenic approach, we demonstrate that MPK10 is stage...... at position 395 that could be implicated in kinase regulation. Finally, we uncovered a feedback loop that limits MPK10 activity through dephosphorylation of the tyrosine residue of the TxY motif. Together our data reveal novel aspects of protein kinase regulation in Leishmania, and propose MPK10...

Assessment of an Impact of Mechanical Regulation on Selected Morphometric and Productive Parameters of Invasive Species Solidago Canadensis Population in Agricultural Land

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Končeková Lýdia

2015-12-01

Full Text Available Repeated mowing is considered as one of the effective control methods against species of the genus Solidago. This paper evaluates the impact of the repeated mowing on selected morphometric and productive characteristics of the invasive neophyte Solidago canadensis in the district of Rimavská Sobota in Central Slovakia. Permanent research plots (PRPs were established within anthropogenic habitat on an abandoned land that was divided into two variants. In the first variant, the mechanical regulation - mowing was applied. The second variant was without the regulation. The mechanical regulation of the populations was carried out in June and August during the growing season 2011. The results showed that the mechanical regulation did not have a clear impact on the population density. The decreasing trend of the number of shoots within the mowed variant was found only in one research plot (PRP3. The other plots showed an increase in the number of individuals by 2.7 and 32.7% between the mowings. Statistically highly significant differences in terms of the mowing impact on the height of the individuals were found in all PRPs. The difference in the weight of dry aboveground biomass between the mowings was 221.87 g, which represents 36.41%. Double the difference (48.8% was recorded in the dry weight of the underground biomass in the regulated stand compared with the unregulated stand (165.1 and 322.5 g/m2, respectively. Although there was a short-term success achieved by the application of the two mowings during the growing period, the pursued objective was not reached.

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses.

Science.gov (United States)

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-03-29

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage.

Methylenedioxymethamphetamine (MDMA, 'Ecstasy': Neurodegeneration versus Neuromodulation

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Elena Puerta

2011-07-01

Full Text Available The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’ is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA along with a lower binding of specific ligands to the 5-HT transporters (SERT. Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.

[New theory of holistic integrative physiology and medicine. III: New insight of neurohumoral mechanism and pattern of control and regulation for core axe of respiration, circulation and metabolism].

Science.gov (United States)

Sun, Xing-guo

2015-07-01

Systemic mechanism of neurohumoral control and regulation for human is limited. We used the new theory of holistic integrative physiology and medicine to approach the mechanism and pattern of neurohumoral control and regulation for life. As the core of human life, there are two core axes of functions. The first one is the common goal of respiration and circulation to transport oxygen and carbon dioxide for cells, and the second one is the goal of gastrointestinal tract and circulation to transport energy material and metabolic product for cells. These two core axes maintain the metabolism. The neurohumoral regulation is holistically integrated and unified for all functions in human body. We simplified explain the mechanism of neurohumoral control and regulation life (respiration and circulation) as the example pattern of sound system. Based upon integrated regulation of life, we described the neurohumoral pattern to control respiration and circulation.

Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes.

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Gao, Song; Carson, James A

2016-01-01

Mechanical stretch can activate muscle and myotube protein synthesis through mammalian target of rapamycin complex 1 (mTORC1) signaling. While it has been established that tumor-derived cachectic factors can induce myotube wasting, the effect of this catabolic environment on myotube mechanical signaling has not been determined. We investigated whether media containing cachectic factors derived from Lewis lung carcinoma (LLC) can regulate the stretch induction of myotube protein synthesis. C2C12 myotubes preincubated in control or LLC-derived media were chronically stretched. Protein synthesis regulation by anabolic and catabolic signaling was then examined. In the control condition, stretch increased mTORC1 activity and protein synthesis. The LLC treatment decreased basal mTORC1 activity and protein synthesis and attenuated the stretch induction of protein synthesis. LLC media increased STAT3 and AMP-activated protein kinase phosphorylation in myotubes, independent of stretch. Both stretch and LLC independently increased ERK1/2, p38, and NF-κB phosphorylation. In LLC-treated myotubes, the inhibition of ERK1/2 and p38 rescued the stretch induction of protein synthesis. Interestingly, either leukemia inhibitory factor or glycoprotein 130 antibody administration caused further inhibition of mTORC1 signaling and protein synthesis in stretched myotubes. AMP-activated protein kinase inhibition increased basal mTORC1 signaling activity and protein synthesis in LLC-treated myotubes, but did not restore the stretch induction of protein synthesis. These results demonstrate that LLC-derived cachectic factors can dissociate stretch-induced signaling from protein synthesis through ERK1/2 and p38 signaling, and that glycoprotein 130 signaling is associated with the basal stretch response in myotubes. Copyright © 2016 the American Physiological Society.

Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms.

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Royston, Kendra J; Paul, Bidisha; Nozell, Susan; Rajbhandari, Rajani; Tollefsbol, Trygve O

2018-07-01

Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.

Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation.

Science.gov (United States)

Gomez-Pinilla, F; Zhuang, Y; Feng, J; Ying, Z; Fan, G

2011-02-01

We have evaluated the possibility that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated :total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova et al. (2006)Nat. Neurosci., 9, 519-525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf. These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Membrane mechanisms and intracellular signalling in cell volume regulation

DEFF Research Database (Denmark)

Hoffmann, Else Kay; Dunham, Philip B.

1995-01-01

Volume regulation, Signal transduction, Calcium-calmodulin, Stretch-activated channels, Eicosanoids, Macromolecular crowding, Cytoskeleton, Protein phosphorylation, dephosphorylation.......Volume regulation, Signal transduction, Calcium-calmodulin, Stretch-activated channels, Eicosanoids, Macromolecular crowding, Cytoskeleton, Protein phosphorylation, dephosphorylation....

Oil pollution control mechanisms - statutes and regulations

International Nuclear Information System (INIS)

1978-04-01

The purpose of this analysis is to provide a detailed picture of federal statutes and regulations, as well as case law, bearing on oil spill prevention and control. Emphasis has been placed on federal action occurring after a spill, although some effort is directed toward review of prevention statutes and regulations. In-depth consideration is given the control of oil pollution under the Federal Water Pollution Control Act but this analysis also touches lightly upon acts that have a lesser effect on oil pollution control. These acts being: The Refuse Act; The Ports and Waterways Safety Act of 1972; The Outer Continental Shelf Lands Act; The Oil Pollution Act of 1961; The Deepwater Port Act of 1974, and The Fish and Wildlife Coordination Act

Monoamine oxidase A gene promoter methylation and transcriptional downregulation in an offender population with antisocial personality disorder.

Science.gov (United States)

Checknita, D; Maussion, G; Labonté, B; Comai, S; Tremblay, R E; Vitaro, F; Turecki, N; Bertazzo, A; Gobbi, G; Côté, G; Turecki, G

2015-03-01

Antisocial personality disorder (ASPD) is characterised by elevated impulsive aggression and increased risk for criminal behaviour and incarceration. Deficient activity of the monoamine oxidase A (MAOA) gene is suggested to contribute to serotonergic system dysregulation strongly associated with impulsive aggression and antisocial criminality. To elucidate the role of epigenetic processes in altered MAOA expression and serotonin regulation in a population of incarcerated offenders with ASPD compared with a healthy non-incarcerated control population. Participants were 86 incarcerated participants with ASPD and 73 healthy controls. MAOA promoter methylation was compared between case and control groups. We explored the functional impact of MAOA promoter methylation on gene expression in vitro and blood 5-HT levels in a subset of the case group. Results suggest that MAOA promoter hypermethylation is associated with ASPD and may contribute to downregulation of MAOA gene expression, as indicated by functional assays in vitro, and regression analysis with whole-blood serotonin levels in offenders with ASPD. These results are consistent with prior literature suggesting MAOA and serotonergic dysregulation in antisocial populations. Our results offer the first evidence suggesting epigenetic mechanisms may contribute to MAOA dysregulation in antisocial offenders. Royal College of Psychiatrists.

Brain serotonin, psychoactive drugs, and effects on reproduction.

Science.gov (United States)

Ayala, María Elena

2009-12-01

Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

Distinct populations of GABAergic neurons in mouse rhombomere 1 express but do not require the homeodomain transcription factor PITX2.

Science.gov (United States)

Waite, Mindy R; Skaggs, Kaia; Kaviany, Parisa; Skidmore, Jennifer M; Causeret, Frédéric; Martin, James F; Martin, Donna M

2012-01-01

Hindbrain rhombomere 1 (r1) is located caudal to the isthmus, a critical organizer region, and rostral to rhombomere 2 in the developing mouse brain. Dorsal r1 gives rise to the cerebellum, locus coeruleus, and several brainstem nuclei, whereas cells from ventral r1 contribute to the trochlear and trigeminal nuclei as well as serotonergic and GABAergic neurons of the dorsal raphe. Recent studies have identified several molecular events controlling dorsal r1 development. In contrast, very little is known about ventral r1 gene expression and the genetic mechanisms regulating its formation. Neurons with distinct neurotransmitter phenotypes have been identified in ventral r1 including GABAergic, serotonergic, and cholinergic neurons. Here we show that PITX2 marks a distinct population of GABAergic neurons in mouse embryonic ventral r1. This population appears to retain its GABAergic identity even in the absence of PITX2. We provide a comprehensive map of markers that places these PITX2-positive GABAergic neurons in a region of r1 that intersects and is potentially in communication with the dorsal raphe. Copyright © 2011 Elsevier Inc. All rights reserved.

mechanisms of drought resistance in grain ii:.stomatal regulation

African Journals Online (AJOL)

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STOMATAL REGULATION AND ROOT GROWTH ... maintenance of high plant water potential in common bean under stress was the function of stomatal regulation and/or root ... disadvantage since it will reduce CO2 fixation and hence may ...

Non-classical mechanisms of transcriptional regulation by the vitamin D receptor: insights into calcium homeostasis, immune system regulation and cancer chemoprevention.

Science.gov (United States)

Dimitrov, Vassil; Salehi-Tabar, Reyhaneh; An, Beum-Soo; White, John H

2014-10-01

Hormonal 1,25-dihydroxyvitamin D [1,25(OH)2D] signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. Gene expression profiling studies have revealed that 1,25(OH)2D signaling through the VDR can lead to activation or repression of target gene transcription in roughly equal proportions. Classically, transcriptional regulation by the VDR, similar to other nuclear receptors, has been characterized by its capacity to recognize high affinity cognate vitamin D response elements (VDREs), located in the regulatory regions of target genes. Several biochemical studies revealed that the VDRE-bound receptor recruits a series of coregulatory proteins, leading to transactivation of adjacent target genes. However, genome-wide and other analyses of VDR binding have revealed that a subset of VDR binding sites does not contain VDREs, and that VDREs are not associated with transcriptionally repressed VDR target genes. Work over the last ∼20 years and in particular recent findings have revealed a diverse array of mechanisms by which VDR can form complexes with several other classes of transcriptional activators, leading to repression of gene transcription. Moreover, these efforts have led to several insights into the molecular basis for the physiological regulation of calcium homeostasis, immune system function and cancer chemoprevention by 1,25(OH)2D/VDR signaling. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Serotonergic Chemosensory Neurons Modify the C. elegans Immune Response by Regulating G-Protein Signaling in Epithelial Cells

Science.gov (United States)

Anderson, Alexandra; Laurenson-Schafer, Henry; Partridge, Frederick A.; Hodgkin, Jonathan; McMullan, Rachel

2013-01-01

The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food. PMID:24348250

Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.

Science.gov (United States)

Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

2017-05-17

Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT 1A receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca 2+ channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.

Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms

DEFF Research Database (Denmark)

Eriksson, Olle; Wall, Anders; Olsson, Ulf

2016-01-01

-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (premenstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity...... here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger...

Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

Directory of Open Access Journals (Sweden)

Simona-Adriana Manea

2018-06-01

Full Text Available Reactive oxygen species (ROS generated by up-regulated NADPH oxidase (Nox contribute to structural-functional alterations of the vascular wall in diabetes. Epigenetic mechanisms, such as histone acetylation, emerged as important regulators of gene expression in cardiovascular disorders. Since their role in diabetes is still elusive we hypothesized that histone deacetylase (HDAC-dependent mechanisms could mediate vascular Nox overexpression in diabetic conditions. Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive vehicle or suberoylanilide hydroxamic acid (SAHA, a pan-HDAC inhibitor. In vitro studies were performed on a human aortic smooth muscle cell (SMC line. Aortic SMCs typically express Nox1, Nox4, and Nox5 subtypes. HDAC1 and HDAC2 proteins along with Nox1, Nox2, and Nox4 levels were found significantly elevated in the aortas of diabetic mice compared to non-diabetic animals. Treatment of diabetic mice with SAHA mitigated the aortic expression of Nox1, Nox2, and Nox4 subtypes and NADPH-stimulated ROS production. High concentrations of glucose increased HDAC1 and HDAC2 protein levels in cultured SMCs. SAHA significantly reduced the high glucose-induced Nox1/4/5 expression, ROS production, and the formation malondialdehyde-protein adducts in SMCs. Overexpression of HDAC2 up-regulated the Nox1/4/5 gene promoter activities in SMCs. Physical interactions of HDAC1/2 and p300 proteins with Nox1/4/5 promoters were detected at the sites of active transcription. High glucose induced histone H3K27 acetylation enrichment at the promoters of Nox1/4/5 genes in SMCs. The novel data of this study indicate that HDACs mediate vascular Nox up-regulation in diabetes. HDAC inhibition reduces vascular ROS production in experimental diabetes, possibly by a mechanism involving negative regulation of Nox expression. Keywords: NADPH oxidase, Epigenetics, HDAC, Histone acetylation, Diabetes

Hard Work in Soft Regulation: A Discussion of the Social Mechanisms in OHS Management Standards and Possible Dilemmas in the Regulation of Psychosocial Work Environment

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Pernille Hohnen

2014-09-01

Full Text Available Certified occupational health and safety (OHS management systems have become a global instrument in regulation of the work environment. However, their actual impact on OHS—in particular on softer psychosocial issues in the work environment—has been questioned. The most important standard of OHS management is OHSAS 18001, which has recently been supplemented with a British publically available guideline (PAS 1010 focusing specifically on psychosocial risk management. On the basis of the international literature on management standards, the present paper analyses OHSAS 18001 and PAS 1010 in order to understand the mechanism by which they work. The paper takes a social constructionist approach conceptualizing standards and their expected mechanisms as socially constructed—based on a particular kind of knowledge and logic—although they are presented as objective. Such a constructionist approach also emphasizes how standards transform specific work environment problems into generic procedures that can be audited. In the case of OHS standards, both the work environment in general and the psychosocial risks in particular are transformed into simple monocausal auditable relations whereby the complexity of psychosocial work environment issues seems to disappear. The new PAS 1010 guideline, which is particularly focusing on regulation of the psychosocial work environment, only partly succeeds in solving these shortcomings of OHSAS 18001.

An Age-Related Mechanism of Emotion Regulation: Regulating Sadness Promotes Children's Learning by Broadening Information Processing

Science.gov (United States)

Davis, Elizabeth L.

2016-01-01

Emotion regulation predicts positive academic outcomes like learning, but little is known about "why". Effective emotion regulation likely promotes learning by broadening the scope of what may be attended to after an emotional event. One hundred twenty-six 6- to 13-year-olds' (54% boys) regulation of sadness was examined for changes in…

Distributed force feedback in the spinal cord and the regulation of limb mechanics.

Science.gov (United States)

Nichols, T Richard

2018-03-01

This review is an update on the role of force feedback from Golgi tendon organs in the regulation of limb mechanics during voluntary movement. Current ideas about the role of force feedback are based on modular circuits linking idealized systems of agonists, synergists, and antagonistic muscles. In contrast, force feedback is widely distributed across the muscles of a limb and cannot be understood based on these circuit motifs. Similarly, muscle architecture cannot be understood in terms of idealized systems, since muscles cross multiple joints and axes of rotation and further influence remote joints through inertial coupling. It is hypothesized that distributed force feedback better represents the complex mechanical interactions of muscles, including the stresses in the musculoskeletal network born by muscle articulations, myofascial force transmission, and inertial coupling. Together with the strains of muscle fascicles measured by length feedback from muscle spindle receptors, this integrated proprioceptive feedback represents the mechanical state of the musculoskeletal system. Within the spinal cord, force feedback has excitatory and inhibitory components that coexist in various combinations based on motor task and integrated with length feedback at the premotoneuronal and motoneuronal levels. It is concluded that, in agreement with other investigators, autogenic, excitatory force feedback contributes to propulsion and weight support. It is further concluded that coexistent inhibitory force feedback, together with length feedback, functions to manage interjoint coordination and the mechanical properties of the limb in the face of destabilizing inertial forces and positive force feedback, as required by the accelerations and changing directions of both predator and prey.

Ca2+-Dependent Regulations and Signaling in Skeletal Muscle: From Electro-Mechanical Coupling to Adaptation

Science.gov (United States)

Gehlert, Sebastian; Bloch, Wilhelm; Suhr, Frank

2015-01-01

Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca2+ is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca2+ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca2+-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca2+ ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca2+ ions in adult muscle but also highlight recent findings of critical Ca2+-dependent mechanisms essential for skeletal muscle-regulation and maintenance. PMID:25569087

Does drug price-regulation affect healthcare expenditures?

Science.gov (United States)

Ben-Aharon, Omer; Shavit, Oren; Magnezi, Racheli

2017-09-01

Increasing health costs in developed countries are a major concern for decision makers. A variety of cost containment tools are used to control this trend, including maximum price regulation and reimbursement methods for health technologies. Information regarding expenditure-related outcomes of these tools is not available. To evaluate the association between different cost-regulating mechanisms and national health expenditures in selected countries. Price-regulating and reimbursement mechanisms for prescription drugs among OECD countries were reviewed. National health expenditure indices for 2008-2012 were extracted from OECD statistical sources. Possible associations between characteristics of different systems for regulation of drug prices and reimbursement and health expenditures were examined. In most countries, reimbursement mechanisms are part of publicly financed plans. Maximum price regulation is composed of reference-pricing, either of the same drug in other countries, or of therapeutic alternatives within the country, as well as value-based pricing (VBP). No association was found between price regulation or reimbursement mechanisms and healthcare costs. However, VBP may present a more effective mechanism, leading to reduced costs in the long term. Maximum price and reimbursement mechanism regulations were not found to be associated with cost containment of national health expenditures. VBP may have the potential to do so over the long term.

Structural Insight on the Mechanism of Regulation of the MarR Family of Proteins: High-Resolution Crystal Structure of a Transcriptional Repressor from Methanobacterium thermoautotrophicum

Energy Technology Data Exchange (ETDEWEB)

Saridakis, Vivian; Shahinas, Dea; Xu, Xiaohui; Christendat, Dinesh (York); (Toronto); (CG)

2008-03-31

Transcriptional regulators belonging to the MarR family are characterized by a winged-helix DNA binding domain. These transcriptional regulators regulate the efflux and influx of phenolic agents in bacteria and archaea. In Escherichia coli, MarR regulates the multiple antibiotic resistance operon and its inactivation produces a multiple antibiotic resistance phenotype. In some organisms, active efflux of drug compounds will produce a drug resistance phenotype, whereas in other organisms, active influx of chlorinated hydrocarbons results in their rapid degradation. Although proteins in the MarR family are regulators of important biological processes, their mechanism of action is not well understood and structural information about how phenolic agents regulate the activity of these proteins is lacking. This article presents the three-dimensional structure of a protein of the MarR family, MTH313, in its apo form and in complex with salicylate, a known inactivator. A comparison of these two structures indicates that the mechanism of regulation involves a large conformational change in the DNA binding lobe. Electrophoretic mobility shift assay and biophysical analyses further suggest that salicylate inactivates MTH313 and prevents it from binding to its promoter region.

The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism.

Science.gov (United States)

Greco, Maria Cristina; Navarra, Pierluigi; Tringali, Giuseppe

2016-01-15

In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K(+)-stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K(+)-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors. Copyright © 2015 Elsevier Inc. All rights reserved.

Fat metabolism during exercise: mechanisms of regulation

Directory of Open Access Journals (Sweden)

Monique da Silva Gevaerd

2006-12-01

Full Text Available Fats are important energetic fuel to exercise. However, the regulation of fat uptake during exercise is unclear. The main objective of this review was to focus on physiological control mechanisms of mobilization, transport and fat uptake during exercise. The articles of fat metabolism were searched in Pubmed and Lilacs indexes. Classical and current papers were preferred. Evidence suggests that transport of fatty acids (FA from extracellular to intracellular spaces could be the main factor to limit fatty acid uptake. Future studies on fat uptake during exercise can focus on this mechanism. In intense exercise, the lower blood fl ow in the adipose tissue and higher fatty acid reesterifi cation rate impairs fat uptake during exercise. Supplementation of the FA has been used, however, the ideal quantities and forms to prevent gastrointestinal discomfort were not yet determined. In the biological point of view, intramuscular reserve of FA could be more effi cient, because is not necessary to FA to cross the cell membrane. RESUMO Os lipídios são considerados importantes fontes energéticas para a realização de exercícios físicos. Entretanto, os mecanismos de regulação do consumo desse substrato durante o exercício não estão totalmente esclarecidos. O objetivo principal da presente revisão foi abordar mecanismos fisiológicos de controle da mobilização, transporte e utilização de gordura durante o exercício. Os trabalhos indexados no banco de dados Pubmed e Lilacs sobre metabolismo de gordura, foram analisados e os clássicos e recentes foram preferencialmente utilizados. A partir dos dados recentes da literatura, especula-se que o transporte de ácidos graxos do meio extracelular para o meio intracelular pode constituir um dos principais mecanismos limitantes no consumo desse substrato. Estudos sobre o consumo de lipídios durante o exercício devem ser focados sobre esse mecanismo. Em exercício intenso, o menor fl uxo de sangue

Exercise and sleep in aging: emphasis on serotonin.

Science.gov (United States)

Melancon, M O; Lorrain, D; Dionne, I J

2014-10-01

Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Mechanisms regulating amphipod population density within macroalgal communities with low predator impact

Directory of Open Access Journals (Sweden)

Hartvig Christie

2004-04-01

Full Text Available In eight mesocosms (land based basins macroalgae communities with associated fauna were transplanted from the sea and established during two years. Then, different doses of nutrients (N and P were added to the basins throughout the following three years. During the period of nutrient addition, macroinvertebrate grazers showed seasonal fluctuations with densities usually between 500,000 and 1 million individuals per mesocosm during summer and to a level of about 100,000 during winter. The macroinvertebrate grazers mainly consisted of about 10 species of amphipods and isopods, among which the amphipod Gammarus locusta dominated strongly by biomass. Although the number of predators was very low, the grazer populations never reached a density where considerable grazing impact could be found on the macroalgae. No increase in grazer density was found in the basins with improved nutrient conditions. Thus food quality may be insufficient for further population growth, or density dependant regulation mechanisms may have prevented the grazers from flourishing and overgrazing the system. In aquarium experiments we showed that G. locusta could grow and reproduce on Fucus serratus, Ulva lactuca, periphyton and detritus, and that cannibalism by adult G. locusta on juveniles may have great impact on the population growth. The basins were run with a water flow through system. Nets were placed in front of the inflow and outflow tubes to measure immigration and emigration. Only few individuals (and no Gammarus sp. were recorded in the inflowing water, while high numbers of both amphipods and isopods were found in the outflowing water. Emigration reached peak values during night-time, and it was then two to three times as high as during day-time. Emigration of mobile grazers from the basins amounted to 1-2% of the standing stock daily. These mechanisms that regulate grazers do contribute to maintenance of the seaweed dominance and thus the stability of the seaweed

Microorganism-regulated mechanisms of temperature effects on the performance of anaerobic digestion.

Science.gov (United States)

Lin, Qiang; He, Guihua; Rui, Junpeng; Fang, Xiaoyu; Tao, Yong; Li, Jiabao; Li, Xiangzhen

2016-06-03

Temperature is an important factor determining the performance and stability of the anaerobic digestion process. However, the microorganism-regulated mechanisms of temperature effects on the performance of anaerobic digestion systems remain further elusive. To address this issue, we investigated the changes in composition, diversity and activities of microbial communities under temperature gradient from 25 to 55 °C using 16S rRNA gene amplicon sequencing approach based on genomic DNA (refer to as "16S rDNA") and total RNA (refer to as "16S rRNA"). Microbial community structure and activities changed dramatically along the temperature gradient, which corresponded to the variations in digestion performance (e.g., daily CH4 production, total biogas production and volatile fatty acids concentration). The ratios of 16S rRNA to 16S rDNA of microbial taxa, as an indicator of the potentially relative activities in situ, and whole activities of microbial community assessed by the similarity between microbial community based on 16S rDNA and rRNA, varied strongly along the temperature gradient, reflecting different metabolic activities. The daily CH4 production increased with temperature from 25 to 50 °C and declined at 55 °C. Among all the examined microbial properties, the whole activities of microbial community and alpha-diversity indices of both microbial communities and potentially relative activities showed highest correlations to the performance. The whole activities of microbial community and alpha-diversity indices of both microbial communities and potentially relative activities were sensitive indicators for the performance of anaerobic digestion systems under temperature gradient, while beta-diversity could predict functional differences. Microorganism-regulated mechanisms of temperature effects on anaerobic digestion performance were likely realized through increasing alpha-diversity of both microbial communities and potentially relative activities to supply

The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

NARCIS (Netherlands)

Stiedl, O.; Pappa, E.; Konradssson-Geuken, A.; Ogren, S.O.

2015-01-01

Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models.

Sexual conflict explains the extraordinary diversity of mechanisms regulating mitochondrial inheritance.

Science.gov (United States)

Radzvilavicius, Arunas L; Lane, Nick; Pomiankowski, Andrew

2017-10-26

Mitochondria are predominantly inherited from the maternal gamete, even in unicellular organisms. Yet an extraordinary array of mechanisms enforce uniparental inheritance, which implies shifting selection pressures and multiple origins. We consider how this high turnover in mechanisms controlling uniparental inheritance arises using a novel evolutionary model in which control of mitochondrial transmission occurs either during spermatogenesis (by paternal nuclear genes) or at/after fertilization (by maternal nuclear genes). The model treats paternal leakage as an evolvable trait. Our evolutionary analysis shows that maternal control consistently favours strict uniparental inheritance with complete exclusion of sperm mitochondria, whereas some degree of paternal leakage of mitochondria is an expected outcome under paternal control. This difference arises because mito-nuclear linkage builds up with maternal control, allowing the greater variance created by asymmetric inheritance to boost the efficiency of purifying selection and bring benefits in the long term. In contrast, under paternal control, mito-nuclear linkage tends to be much weaker, giving greater advantage to the mixing of cytotypes, which improves mean fitness in the short term, even though it imposes a fitness cost to both mating types in the long term. Sexual conflict is an inevitable outcome when there is competition between maternal and paternal control of mitochondrial inheritance. If evolution has led to complete uniparental inheritance through maternal control, it creates selective pressure on the paternal nucleus in favour of subversion through paternal leakage, and vice versa. This selective divergence provides a reason for the repeated evolution of novel mechanisms that regulate the transmission of paternal mitochondria, both in the fertilized egg and spermatogenesis. Our analysis suggests that the widespread occurrence of paternal leakage and prevalence of heteroplasmy are natural outcomes of

Closed-form solutions for linear regulator design of mechanical systems including optimal weighting matrix selection

Science.gov (United States)

Hanks, Brantley R.; Skelton, Robert E.

1991-01-01

Vibration in modern structural and mechanical systems can be reduced in amplitude by increasing stiffness, redistributing stiffness and mass, and/or adding damping if design techniques are available to do so. Linear Quadratic Regulator (LQR) theory in modern multivariable control design, attacks the general dissipative elastic system design problem in a global formulation. The optimal design, however, allows electronic connections and phase relations which are not physically practical or possible in passive structural-mechanical devices. The restriction of LQR solutions (to the Algebraic Riccati Equation) to design spaces which can be implemented as passive structural members and/or dampers is addressed. A general closed-form solution to the optimal free-decay control problem is presented which is tailored for structural-mechanical system. The solution includes, as subsets, special cases such as the Rayleigh Dissipation Function and total energy. Weighting matrix selection is a constrained choice among several parameters to obtain desired physical relationships. The closed-form solution is also applicable to active control design for systems where perfect, collocated actuator-sensor pairs exist.

Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism

Directory of Open Access Journals (Sweden)

Jae Hoon Jeong

2015-06-01

Conclusion: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMHACh–Rpa5-HT pathway may mediate physiological heat-defense responses to elevated environmental temperature.

Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

Science.gov (United States)

Hasan, Shirin; Mosier, Michael J; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

2017-10-01

Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia. Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages. The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. Copyright © 2017

Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

Energy Technology Data Exchange (ETDEWEB)

Prat-Lepesant, M

2005-06-15

The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

Insight into the mechanisms regulating immune homeostasis in health and disease.

Science.gov (United States)

Sirisinha, Stitaya

2011-03-01

Innate and adaptive immune systems consist of cells and molecules that work together in concert to fight against microbial infection and maintain homeostasis. Hosts encounter microbes / exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) all the time and they must have proper mechanisms to counteract the danger such that appropriate responses (e.g., degree of inflammation and types of mediators induced) can be mounted in different scenarios. Increasing numbers of endogenous danger signals of host origin are being identified including, for example, uric acid and cholesterol crystals, high mobility group box1 (HMGB1) protein, oxidized LDL, vesicans, heat shock proteins (HSPs) and self DNA. Many of these endogenous ligands have been shown to be associated with inflammation-related diseases like atherosclerosis, gout and type 2 diabetes. Several DAMPs appear to have the ability to interact with more than one receptor. We are now beginning to understand how the immune system can distinguish infection from endogenous ligands elaborated following cellular insults and tissue damage. Appropriate responses to maintain the homeostatic state in health and disease depend largely on the recognition and response to these stimuli by germline encoded pattern-recognition receptors (PRRs) present on both immune and non-immune cells. These receptors are, for example, Toll-like receptors (TLRs), C-type lectin receptors (CLRs) and cytosolic receptors (e.g., RLRs, NLRs and some intracellular DNA sensors). Atypical PRR "danger" receptors, like the receptor for advanced glycation end products (RAGE) and their ligands have been identified. A proper response to maintain homeostasis relies on specific negative regulators and regulatory pathways to dampen its response to tissue injury while maintaining the capacity to eliminate infection and induce proper tissue repair. Moreover, some PRRs (e.g., TLR2,TLR4 and NLRP3) and atypical

The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

KAUST Repository

Yunta, Cristina; Martí nez-Ripoll, Martí n; Zhu, Jian-Kang; Albert, Armando

2011-01-01

SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

KAUST Repository

Yunta, Cristina

2011-11-01

SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion

OpenAIRE

Dölker, N.; Górna, M. W.; Sutto, L.; Torralba, A. S.; Superti-Furga, G.; Gervasio, F. L.

2014-01-01

Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys...

Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice

NARCIS (Netherlands)

Marlatt, M.W.; Lucassen, P.J.; van Praag, H.

2010-01-01

Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not

The association between the hypothalamic pituitary adrenal axis and tryptophan metabolism in persons with recurrent major depressive disorder and healthy controls

NARCIS (Netherlands)

Sorgdrager, F. J. H.; Doornbos, B.; Penninx, B. W. J. H.; de Jonge, P.; Kema, I. P.

2017-01-01

Objectives: Persistent changes in serotonergic and hypothalamic pituitary adrenal (HPA) axis functioning are implicated in recurrent types of major depressive disorder (MDD). Systemic tryptophan levels, which influence the rate of serotonin synthesis, are regulated by glucocorticoids produced along

Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain

Science.gov (United States)

Zeidan, F.; Grant, J.A.; Brown, C.A.; McHaffie, J.G.; Coghill, R.C.

2013-01-01

The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain. PMID:22487846

Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis.

Science.gov (United States)

McGlashon, Jacob M; Gorecki, Michelle C; Kozlowski, Amanda E; Thirnbeck, Caitlin K; Markan, Kathleen R; Leslie, Kirstie L; Kotas, Maya E; Potthoff, Matthew J; Richerson, George B; Gillum, Matthew P

2015-05-05

Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparative morphology of serotonergic-like immunoreactive elements in the central nervous system of kinorhynchs (Kinorhyncha, Cyclorhagida).

Science.gov (United States)

Herranz, María; Pardos, Fernando; Boyle, Michael J

2013-03-01

Cycloneuralian taxa exhibit similar organ system architectures, providing informative characters of metazoan evolution, yet very few modern comparative descriptions of cellular and molecular homologies within and among those taxa are available. We immunolabeled and characterized elements of the serotonergic nervous system in the kinorhynchs Echinoderes spinifurca, Antygomonas paulae, and Zelinkaderes brightae using confocal laser scanning microscopy. Fluorescent markers targeting DNA were combined with observations of auto-fluorescent structures to guide interpretations of the internal and external anatomy in each species. Results show a common pattern of the central nervous system with a circumenteric brain divided into ring-shaped anterior and posterior neuronal somata and a central neuropil connected to a multi-stringed, longitudinal ventral nerve cord. Structural similarities and differences in the nervous systems of these species were observed and described, stressing the incomplete ring nature of the anterior region of the kinorhynch brain, the functional relationship between the brain and the movable introvert, and the number and arrangement of nerve strings and somata of the ventral nerve cord. The ventral cord ends in two ventrolateral cell bodies in E. spinifurca, and forms a terminal loop associated with a midterminal spine in A. paulae and Z. brightae. The possible functional and phylogenetic significance of these features and arrangements are discussed. Copyright © 2012 Wiley Periodicals, Inc.

VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?

International Nuclear Information System (INIS)

Yao, Y.-G; Duh, Elia J.

2004-01-01

The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-α, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca 2+ chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells

Burner flow regulators with mechanisms performing two variable function. Meccanismi che generano una funzione di due variabili applicati alla regolazione dei bruciatori

Energy Technology Data Exchange (ETDEWEB)

Borelli, L.; Tagliaferro, B. (R.B.L. Riello Bruciatori, Legnago Spa, Legnago (Italy)); Cossalter, V.; Da Lio, M. (Padua Univ. (Italy). Dip. di Ingegneria Meccanica)

1993-08-01

A new class of fuel oil burners has recently been developed by an Italian firm with the aim of obtaining high performances in terms of both energy efficiency and air pollution abatement. The innovative feature of these burners is that they are equipped with a device which permits the automatic and optimum regulation of the air fuel mixture independent of ambient and operating conditions. To reduce costs, the regulation system is a mechanical one instead of electronic which would require an expensive lambda probe. The mechanical regulating system controls air intake by simply taking into account two main combustion factors - ambient temperature and the nominal fuel flow rate. The special cam mechanism is thus classified as one which performs a single function with two degrees of freedom, i.e., the independent variables of ambient temperature and nominal fuel flow. One of the air intake valve's movements is governed by a temperature transducer, the other (primary), by a screw which allows the registering of the air flow during burner installation or upon completion of periodic maintenance checks. In addition to optimizing combustion control, this control technique affords the possibility to adapt the air flow to the different fuel flows obtained by changing the type of nozzle or supply pressure.

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Energy Technology Data Exchange (ETDEWEB)

Kim, Sangsoo Daniel; Antenos, Monica [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Squires, E. James [Department of Animal and Poultry Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Kirby, Gordon M., E-mail: gkirby@uoguelph.ca [Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada)

2013-07-15

Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine-diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1–6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1–6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1–6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. - Highlights: • The mechanism of Cyp2a5 gene regulation by BR was investigated. • The cytoprotective role of CYP2A5 in BR hepatotoxicity was determined. • BR

Neuroanatomic Relationships between the GABAergic and Serotonergic Systems in the Developing Human Medulla

Science.gov (United States)

Broadbelt, Kevin G.; Paterson, David S.; Rivera, Keith D.; Trachtenberg, Felicia L.; Kinney, Hannah C.

2010-01-01

γ-Amino butyric (GABA) critically influences serotonergic (5-HT) neurons in the raphé and extra-raphé of the medulla oblongata. In this study we hypothesize there are marked changes in the developmental profile of markers of the human medullary GABAergic system relative to the 5-HT system in early life. We used single- and double-label immunocytochemistry and tissue receptor autoradiography in 15 human medullae from fetal and infant cases ranging from 15 gestational weeks to 10 postnatal months, and compared our findings with an extensive 5-HT-related database in our laboratory. In the raphé obscurus, we identified two subsets of GABAergic neurons using glutamic acid decarboxylase (GAD65/67) immunostaining: one comprised of small, round neurons; the other, medium, spindle-shaped neurons. In three term medullae cases, positive immunoflorescent neurons for both tryptophan hydroxylase and GAD65/67 were counted within the raphé obscurus. This revealed approximately 6% of the total neurons counted in this nucleus expressed both GAD65/67 and TPOH suggesting co-production of GABA by a subset of 5-HT neurons. The distribution of GABAA binding was ubiquitous across medullary nuclei, with highest binding in the raphé obscurus. GABAA receptor subtypes α1 and α3 were expressed by 5-HT neurons, indicating the site of interaction of GABA with 5-HT neurons. These receptor subtypes and KCC2, a major chloride transporter, were differentially expressed across early development, from mid-gestation (20wks) and thereafter. The developmental profile of GABAergic markers changed dramatically relative to the 5-HT markers. These data provide baseline information for medullary studies of human pediatric disorders, such as sudden infant death syndrome. PMID:19926534

Genes and Aggressive Behavior: Epigenetic Mechanisms Underlying Individual Susceptibility to Aversive Environments

Directory of Open Access Journals (Sweden)

Sara Palumbo

2018-06-01

Full Text Available Over the last two decades, the study of the relationship between nature and nurture in shaping human behavior has encountered a renewed interest. Behavioral genetics showed that distinct polymorphisms of genes that code for proteins that control neurotransmitter metabolic and synaptic function are associated with individual vulnerability to aversive experiences, such as stressful and traumatic life events, and may result in an increased risk of developing psychopathologies associated with violence. On the other hand, recent studies indicate that experiencing aversive events modulates gene expression by introducing stable changes to DNA without modifying its sequence, a mechanism known as “epigenetics”. For example, experiencing adversities during periods of maximal sensitivity to the environment, such as prenatal life, infancy and early adolescence, may introduce lasting epigenetic marks in genes that affect maturational processes in brain, thus favoring the emergence of dysfunctional behaviors, including exaggerate aggression in adulthood. The present review discusses data from recent research, both in humans and animals, concerning the epigenetic regulation of four genes belonging to the neuroendocrine, serotonergic and oxytocinergic pathways—Nuclear receptor subfamily 3-group C-member 1 (NR3C1, oxytocin receptor (OXTR, solute carrier-family 6 member 4 (SLC6A4 and monoamine oxidase A (MAOA—and their role in modulating vulnerability to proactive and reactive aggressive behavior. Behavioral genetics and epigenetics are shedding a new light on the fine interaction between genes and environment, by providing a novel tool to understand the molecular events that underlie aggression. Overall, the findings from these studies carry important implications not only for neuroscience, but also for social sciences, including ethics, philosophy and law.

An APC:WNT counter-current-like mechanism regulates cell division along the colonic crypt axis: a mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development.

Directory of Open Access Journals (Sweden)

Bruce M Boman

2013-11-01

Full Text Available APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside. WNT signaling, in contrast, is high at the bottom (where SCs reside and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g. survivin are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric. APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly-proliferating cells during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes.

Serotonin synthesis, release and reuptake in terminals: a mathematical model

Directory of Open Access Journals (Sweden)

Best Janet

2010-08-01

Full Text Available Abstract Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to

Serine/threonine/tyrosine phosphorylation regulates DNA binding of bacterial transcriptional regulators

DEFF Research Database (Denmark)

Kalantari, Aida; Derouiche, Abderahmane; Shi, Lei

2015-01-01

Reversible phosphorylation of bacterial transcriptional regulators (TRs) belonging to the family of two-component systems (TCSs) is a well-established mechanism for regulating gene expression. Recent evidence points to the fact that reversible phosphorylation of bacterial TRs on other types...

Goal setting as a self-regulation mechanism

NARCIS (Netherlands)

Suvorov, A.; van de Ven, J.

2009-01-01

We develop a theory of self-regulation based on goal setting for an agent with present-biased preferences. Preferences are assumed to be reference-dependent and exhibit loss aversion, as in prospect theory. The reference point is determined endogenously as an optimal self-sustaining goal. The

Goal setting as a self-regulation mechanism

NARCIS (Netherlands)

Suvorov, A.; van de Ven, J.

2008-01-01

We develop a theory of self-regulation based on goal setting for an agent with present-biased preferences. Preferences are assumed to be reference-dependent and exhibit loss aversion, as in prospect theory. The reference point is determined endogenously as an optimal self-sustaining goal. The

Optimum regulation of grid monopoly in the power trade; Optimal regulering av nettmonopoler i kraftomsetningen

Energy Technology Data Exchange (ETDEWEB)

Hope, E.

1994-06-01

The report discusses the organization and behaviour of grid monopolies in the Norwegian power trade and relations to the socio-economic effectiveness. The main attention is laid on analyzing regulation mechanisms and measures leading to an efficient short-term operation and to the investment of optimum production capacity in a long run. Regarding the management, measures are discussed for increasing the efficiency of total power trade by evaluating the existing marketing function of Statnett. Some basic conditions are accounted concerning the regulation problem of grid monopolies with a particular attention to asymmetric information between the authority and the monopoly. In addition, forms of regulation and regulation mechanisms together with the incentive characteristics of these, are discussed. The existing profit regulation principles in relation to an alternative system design such as maximum price regulation combined with standard regulation, are evaluated. 16 refs., 7 figs.

Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism

OpenAIRE

Cowin, Prue A.; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K.; Foster, Paul M. D.; Scott, Hamish S.; Risbridger, Gail P.

2010-01-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-κB activat...

Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo.

Science.gov (United States)

Kleiman, Robin J; Chapin, Douglas S; Christoffersen, Curt; Freeman, Jody; Fonseca, Kari R; Geoghegan, Kieran F; Grimwood, Sarah; Guanowsky, Victor; Hajós, Mihály; Harms, John F; Helal, Christopher J; Hoffmann, William E; Kocan, Geralyn P; Majchrzak, Mark J; McGinnis, Dina; McLean, Stafford; Menniti, Frank S; Nelson, Fredrick; Roof, Robin; Schmidt, Anne W; Seymour, Patricia A; Stephenson, Diane T; Tingley, Francis David; Vanase-Frawley, Michelle; Verhoest, Patrick R; Schmidt, Christopher J

2012-05-01

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

Sox9 gene regulation and the loss of the XY/XX sex-determining mechanism in the mole vole Ellobius lutescens.

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Bagheri-Fam, Stefan; Sreenivasan, Rajini; Bernard, Pascal; Knower, Kevin C; Sekido, Ryohei; Lovell-Badge, Robin; Just, Walter; Harley, Vincent R

2012-01-01

In most mammals, the Y chromosomal Sry gene initiates testis formation within the bipotential gonad, resulting in male development. SRY is a transcription factor and together with SF1 it directly up-regulates the expression of the pivotal sex-determining gene Sox9 via a 1.3-kb cis-regulatory element (TESCO) which contains an evolutionarily conserved region (ECR) of 180 bp. Remarkably, several rodent species appear to determine sex in the absence of Sry and a Y chromosome, including the mole voles Ellobius lutescens and Ellobius tancrei, whereas Ellobius fuscocapillus of the same genus retained Sry. The sex-determining mechanisms in the Sry-negative species remain elusive. We have cloned and sequenced 1.1 kb of E. lutescens TESCO which shares 75% sequence identity with mouse TESCO indicating that testicular Sox9 expression in E. lutescens might still be regulated via TESCO. We have also cloned and sequenced the ECRs of E. tancrei and E. fuscocapillus. While the three Ellobius ECRs are highly similar (94-97% sequence identity), they all display a 14-bp deletion (Δ14) removing a highly conserved SOX/TCF site. Introducing Δ14 into mouse TESCO increased both basal activity and SF1-mediated activation of TESCO in HEK293T cells. We propose a model whereby Δ14 may have triggered up-regulation of Sox9 in XX gonads leading to destabilization of the XY/XX sex-determining mechanism in Ellobius. E. lutescens/E. tancrei and E. fuscocapillus could have independently stabilized their sex determination mechanisms by Sry-independent and Sry-dependent approaches, respectively.

Effects of serotonergic system on the sleeping time and EEG in rats

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Alaei H

2001-08-01

Full Text Available The phenomenon of sleep is an active nervous and biologic rhythm, which is under influence of neurotransmitters of central nervous system. In this study, the influence of serotonergic system on sleeping time have been assessed by agonist-antagonist drugs using two methods of induction and non-induction behavioral and electrophysiology. The method used for measurement of total sleeing time was Angle method. For assessment of drugs impact on brain waves, after opening two holes in frontal and temporal regions, two non-polarized silvery electrodes were fixed in above regions and was connected to physiograph and computer by linkers for waves analysis. Injection intra-ventriculary is done by stereotax apparatus. Results indicate that diazepam (2.5 mg/kg increases sleeping time in two stages of induction and non-induction (P<0.01. 5-HTP (15, 45 mg/kg increases dose-dependence sleeping time. p-CPA (150, 300 mg/kg shows biphasic influence on sleeping time. The 300 mg/kg dose of p-CPA reduces sleeping time while 150 mg/kg dose inverts sleeping time (P<0.05. Interferential affects of drugs with (5-HTP 45 mg/kg and p-CPA (300 mg/kg doses are similar to control groups. Injection of 5-HTP inverts p-CPA affect. Intra-ventriculary Injection of 5-HTP in 150 µg/kg and 300 µg/kg doses, decreases frequency of delta waves and significantly increases the frequencies of other waves but conversely, 500 µg/kg decreases it. Due to findings of this study, interferential affects of agonist-antagonist of 5-HTP, can not invert p-CPA affect. Supported by GABA affects, diazepam induces its inhibitory affect in per-synaptic and post-synaptic membrane through ascending reticular both systems and blocking stimulation of brain cortical and limbic system. Affects of two other drugs on sleeping time and brain waves are probably caused by increment of released serotonin in pre-synaptic neurons. Although their interferential affects with other neurotransmitter system should be

Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

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Yao, Jiayin; Zhi, Min; Gao, Xiang; Hu, Pinjin; Li, Chujun; Yang, Xiaobo [Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province (China)

2013-03-15

Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg{sup -1}·day{sup -1} silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.

Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

International Nuclear Information System (INIS)

Yao, Jiayin; Zhi, Min; Gao, Xiang; Hu, Pinjin; Li, Chujun; Yang, Xiaobo

2013-01-01

Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg -1 ·day -1 silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms

Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

Directory of Open Access Journals (Sweden)

Jiayin Yao

Full Text Available Our previous study has shown that reduced insulin resistance (IR was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks and an HFD + silibinin group (high-fat diet + 0.5 mg kg-1·day-1 silibinin, starting at the beginning of the protocol. Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR, intraperitoneal glucose tolerance test and insulin tolerance test (ITT were performed. The expression of adipose triglyceride lipase (ATGL and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.

Expression of DACT1 in children with asthma and its regulation mechanism

Science.gov (United States)

Zhang, Cunxue; Yang, Peili; Chen, Yan; Liu, Jing; Yuan, Xiutai

2018-01-01

The aim of the present study was to detect DACT1 expression levels in the lungs of children with asthma, and to investigate its role and molecular mechanisms in regulating the expression of inflammatory factors in RAW264.7 cells. DACT1, DACT2 and DACT3 expression was analyzed in biopsy specimens from 10 cases of newly diagnosed children with asthma and 10 healthy controls by reverse transcription-quantitative polymerase chain reaction, and their expression was confirmed in RAW264.7 cells. DACT1 expression was silenced by small interfering RNA or enhanced by transfection of pcDNA-3.1-DACT1 in RAW264.7 cells, and expression of β-catenin and inflammatory factors, interleukin (IL) 5, IL6 and IL13, was analyzed. Nuclear translocation of β-catenin was detected by western blot analysis, and the effect of DACT1 on β-catenin was investigated with rescue experiments. Regulation of the Wnt signaling pathway by DACT1 and β-catenin was analyzed in RAW264.7 cells after recombinant Wnt5A stimulation. DACT1, DACT2 and DACT3 were significantly upregulated in specimens from children with asthma compared with controls (Pasthma, which could induce higher pro-inflammatory factor expression. DACT1 may act via inhibiting the expression and nuclear translocation of β-catenin, a factor in the Wnt signaling pathway. The present results suggested that DACT1 may be a potential target for the treatment of asthma. PMID:29456669

Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

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Alejandra Gomez-Perez

2016-12-01

Full Text Available Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a 3-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, 3 of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the 3 long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the 3 mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal and osmotic stresses. Our findings empirically validate the hypothesis suggesting that hormetic selective forces can drive the evolution of longevity regulation mechanisms within an ecosystem.

Online Reflective Writing Mechanisms and Its Effects on Self-Regulated Learning: A Case of Web-Based Portfolio Assessment System

Science.gov (United States)

Liang, Chaoyun; Chang, Chi-Cheng; Shu, Kuen-Ming; Tseng, Ju-Shih; Lin, Chun-Yu

2016-01-01

The purpose of the present study was to design reflective writing mechanisms in a web-based portfolio assessment system and evaluate its effects on self-regulated learning. Participants were two classes of juniors majoring in data processing and taking a course called "Website design" at a vocational high school in Taiwan. One class was…

Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT(1A) receptor populations: a study in SERT knockout rats.

NARCIS (Netherlands)

Olivier, J.; Cools, A.R.; Olivier, B.; Homberg, J.R.; Cuppen, E.; Ellenbroek, B.A.

2008-01-01

Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT(-/-)). It is likely that adaptive changes take

Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT(1A) receptor populations : a study in SERT knockout rats

NARCIS (Netherlands)

Olivier, Jocelien D A; Cools, Alexander R; Olivier, Berend; Homberg, Judith R; Cuppen, Edwin; Ellenbroek, Bart A

2008-01-01

Disturbances in the serotonergic system are implicated in many central nervous system disorders. The serotonin transporter (SERT) regulates the serotonin homeostasis in the synapse. We recently developed a rat which lacks the serotonin transporter (SERT(-/-)). It is likely that adaptive changes take

Epigenetic Regulation of Adipokines

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Tho X. Pham

2017-08-01

Full Text Available Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.

An APC:WNT Counter-Current-Like Mechanism Regulates Cell Division Along the Human Colonic Crypt Axis: A Mechanism That Explains How APC Mutations Induce Proliferative Abnormalities That Drive Colon Cancer Development

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Boman, Bruce M.; Fields, Jeremy Z.

2013-01-01

APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT) that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs) at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside). WNT signaling, in contrast, is high at the bottom (where SCs reside) and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g., survivin) are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric). APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly proliferating cells) during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes. PMID:24224156

TRIENNIAL LACTATION SYMPOSIUM/BOLFA: Serotonin and the regulation of calcium transport in dairy cows.

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Hernandez, L L

2017-12-01

The mammary gland regulates maternal metabolism during lactation. Numerous factors within the tissue send signals to shift nutrients to the mammary gland for milk synthesis. Serotonin is a monoamine that has been well documented to regulate several aspects of lactation among species. Maintenance of maternal calcium homeostasis during lactation is a highly evolved process that is elegantly regulated by the interaction of the mammary gland with the bone, gut, and kidney tissues. It is well documented that dietary calcium is insufficient to maintain maternal calcium concentrations during lactation, and mammals must rely on bone resorption to maintain normocalcemia. Our recent work focused on the ability of the mammary gland to function as an accessory parathyroid gland during lactation. It was demonstrated that serotonin acts to stimulate parathyroid hormone-related protein (PTHrP) in the mammary gland during lactation. The main role of mammary-derived PTHrP during mammalian lactation is to stimulate bone resorption to maintain maternal calcium homeostasis during lactation. In addition to regulating PTHrP, it was shown that serotonin appears to directly affect calcium transporters and pumps in the mammary gland. Our current working hypothesis regarding the control of calcium during lactation is as follows: serotonin directly stimulates PTHrP production in the mammary gland through interaction with the sonic hedgehog signaling pathway. Simultaneously, serotonin directly increases calcium movement into the mammary gland and, subsequently, milk. These 2 direct actions of serotonin combine to induce a transient maternal hypocalcemia required to further stimulate PTHrP production and calcium mobilization from bone. Through these 2 routes, serotonin is able to improve maternal calcium concentrations. Furthermore, we have shown that Holstein and Jersey cows appear to regulate calcium in different manners and also respond differently to serotonergic stimulation of the calcium

Mechanisms of acid-base regulation in peritoneal dialysis.

Science.gov (United States)

Sow, Amadou; Morelle, Johann; Hautem, Nicolas; Bettoni, Carla; Wagner, Carsten A; Devuyst, Olivier

2017-11-22

Peritoneal dialysis (PD) contributes to restore acid-base homeostasis in patients with end-stage renal disease. The transport pathways for buffers and carbon dioxide (CO2) across the peritoneal membrane remain poorly understood. Combining well-established PD protocols, whole-body plethysmography and renal function studies in mice, we investigated molecular mechanisms of acid-base regulation in PD, including the potential role of the water channel aquaporin-1 (AQP1). After instillation in peritoneal cavity, the pH of acidic dialysis solutions increased within minutes to rapidly equilibrate with blood pH, whereas the neutral pH of biocompatible solutions remained constant. Predictions from the three-pore model of peritoneal transport suggested that local production of HCO3- accounts at least in part for the changes in intraperitoneal pH observed with acidic solutions. Carbonic anhydrase (CA) isoforms were evidenced in the peritoneal membrane and their inhibition with acetazolamide significantly decreased local production of HCO3- and delayed changes in intraperitoneal pH. On the contrary, genetic deletion of AQP1 had no effect on peritoneal transport of buffers and diffusion of CO2. Besides intraperitoneal modifications, the use of acidic dialysis solutions enhanced acid excretion both at pulmonary and renal levels. These findings suggest that changes in intraperitoneal pH during PD are mediated by bidirectional buffer transport and by CA-mediated production of HCO3- in the membrane. The use of acidic solutions enhances acid excretion through respiratory and renal responses, which should be considered in patients with renal failure. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Viral and cellular SOS-regulated motor proteins: dsDNA translocation mechanisms with divergent functions.

Science.gov (United States)

Wolfe, Annie; Phipps, Kara; Weitao, Tao

2014-01-01

DNA damage attacks on bacterial cells have been known to activate the SOS response, a transcriptional response affecting chromosome replication, DNA recombination and repair, cell division and prophage induction. All these functions require double-stranded (ds) DNA translocation by ASCE hexameric motors. This review seeks to delineate the structural and functional characteristics of the SOS response and the SOS-regulated DNA translocases FtsK and RuvB with the phi29 bacteriophage packaging motor gp16 ATPase as a prototype to study bacterial motors. While gp16 ATPase, cellular FtsK and RuvB are similarly comprised of hexameric rings encircling dsDNA and functioning as ATP-driven DNA translocases, they utilize different mechanisms to accomplish separate functions, suggesting a convergent evolution of these motors. The gp16 ATPase and FtsK use a novel revolution mechanism, generating a power stroke between subunits through an entropy-DNA affinity switch and pushing dsDNA inward without rotation of DNA and the motor, whereas RuvB seems to employ a rotation mechanism that remains to be further characterized. While FtsK and RuvB perform essential tasks during the SOS response, their roles may be far more significant as SOS response is involved in antibiotic-inducible bacterial vesiculation and biofilm formation as well as the perspective of the bacteria-cancer evolutionary interaction.

Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms

DEFF Research Database (Denmark)

Nestoras, Konstantinos; Mohammed, Asma Hadi; Schreurs, Ann-Sofie

2010-01-01

The correct levels of deoxyribonucleotide triphosphates and their relative abundance are important to maintain genomic integrity. Ribonucleotide reductase (RNR) regulation is complex and multifaceted. RNR is regulated allosterically by two nucleotide-binding sites, by transcriptional control, and...

Epigenetic Mechanisms of Genomic Imprinting: Common Themes in the Regulation of Imprinted Regions in Mammals, Plants, and Insects

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William A. MacDonald

2012-01-01

Full Text Available Genomic imprinting is a form of epigenetic inheritance whereby the regulation of a gene or chromosomal region is dependent on the sex of the transmitting parent. During gametogenesis, imprinted regions of DNA are differentially marked in accordance to the sex of the parent, resulting in parent-specific expression. While mice are the primary research model used to study genomic imprinting, imprinted regions have been described in a broad variety of organisms, including other mammals, plants, and insects. Each of these organisms employs multiple, interrelated, epigenetic mechanisms to maintain parent-specific expression. While imprinted genes and imprint control regions are often species and locus-specific, the same suites of epigenetic mechanisms are often used to achieve imprinted expression. This review examines some examples of the epigenetic mechanisms responsible for genomic imprinting in mammals, plants, and insects.

Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice

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Flóra Gölöncsér

2017-10-01

Full Text Available Serotonergic and glutamatergic neurons of median raphe region (MRR play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7 are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate but not GABA in vivo. Similar optical stimulation (OS significantly increased [3H]5-HT and [3H]glutamate release in acute MRR and hippocampal slices. We examined spatial and temporal patterns of [3H]5-HT release and the interaction between the serotonin and glutamate systems. Whilst [3H]5-HT release from MRR neurons was [Ca2+]o-dependent and sensitive to TTX, CNQX and DL-AP-5, release from hippocampal terminals was not affected by the latter drugs. Hippocampal [3H]5-HT released by electrical but not OS was subject to modulation by 5- HT1B/D receptors agonist sumatriptan (1 μM, whereas the selective 5-HT1A agonist buspirone (0.1 μM was without effect. [3H]5-HT released by electrical and optical stimulation was decreased in mice genetically deficient in P2rx7s, and after perfusion with selective P2rx7 antagonists, JNJ-47965567 (0.1 μM, and AZ-10606120 (0.1 μM. Optical and electrical stimulation elevated the extracellular level of ATP. Our results demonstrate for the

MicroRNA regulation of Autophagy

DEFF Research Database (Denmark)

Frankel, Lisa B; Lund, Anders H

2012-01-01

recently contributed to our understanding of the molecular mechanisms of the autophagy machinery, yet several gaps remain in our knowledge of this process. The discovery of microRNAs (miRNAs) established a new paradigm of post-transcriptional gene regulation and during the past decade these small non......RNAs to regulation of the autophagy pathway. This regulation occurs both through specific core pathway components as well as through less well-defined mechanisms. Although this field is still in its infancy, we are beginning to understand the potential implications of these initial findings, both from a pathological...

Phylogeny and ontogeny of the habenular structure

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Hidenori eAizawa

2011-12-01

Full Text Available Habenula is an epithalamic nucleus connecting the forebrain with the ventral midbrain and hindbrain that plays a pivotal role in decision making by regulating dopaminergic and serotonergic activities. Intriguingly, habenula has also attracted interest as a model for brain asymmetry, since many vertebrates show left-right differences in habenula size and neural circuitry. Despite the functional significance of this nucleus, few studies have addressed the molecular mechanisms underlying habenular development. Mammalian habenula consists of the medial and lateral habenulae, which have distinct neural connectivity. The habenula shows phylogenetic conservation from fish to human, and studies using genetically accessible model animals have provided molecular insights into the developmental mechanisms of the habenula. The results suggest that development of the habenular asymmetry is mediated by differential regulation of the neurogenetic period for generating specific neuronal subtypes. Since the orientation and size ratio of the medial and lateral habenulae differ across species, the evolution of those subregions within the habenula may also reflect changes in neurogenesis duration for each habenular subdivision according to the evolutionary process.

Statistical state dynamics-based analysis of the physical mechanisms sustaining and regulating turbulence in Couette flow

Science.gov (United States)

Farrell, Brian F.; Ioannou, Petros J.

2017-08-01

This paper describes a study of the self-sustaining process in wall turbulence. The study is based on a second order statistical state dynamics model of Couette flow in which the state variables are the streamwise mean flow (first cumulant) and perturbation covariance (second cumulant). This statistical state dynamics model is closed by either setting the third cumulant to zero or by replacing it with a stochastic parametrization. Statistical state dynamics models with this form are referred to as S3T models. S3T models have been shown to self-sustain turbulence with a mean flow and second order perturbation structure similar to that obtained by direct numerical simulation of the equations of motion. The use of a statistical state dynamics model to study the physical mechanisms underlying turbulence has important advantages over the traditional approach of studying the dynamics of individual realizations of turbulence. One advantage is that the analytical structure of S3T statistical state dynamics models isolates the interaction between the mean flow and the perturbation components of the turbulence. Isolation of the interaction between these components reveals how this interaction underlies both the maintenance of the turbulence variance by transfer of energy from the externally driven flow to the perturbation components as well as the enforcement of the observed statistical mean turbulent state by feedback regulation between the mean and perturbation fields. Another advantage of studying turbulence using statistical state dynamics models of S3T form is that the analytical structure of S3T turbulence can be completely characterized. For example, the perturbation component of turbulence in the S3T system is demonstrably maintained by a parametric perturbation growth mechanism in which fluctuation of the mean flow maintains the perturbation field which in turn maintains the mean flow fluctuations in a synergistic interaction. Furthermore, the equilibrium

Analysis and synthesis of a system for optimal automatic regulation of the process of mechanical cutting by a combine

Energy Technology Data Exchange (ETDEWEB)

Pop, E.; Coroescu, T.; Poanta, A.; Pop, M.

1978-01-01

Uncontrollable dynamic operating regime of a combine has a negative effect. A consequence of the uncontrolled change in productivity and rate during cutting is total decrease in productivity. The cutters of the cutting mechanism are prematurely worn out. The quality of the coal decreases. Complications with combine control reduce productivity. The motor is exposed to the maximum loads, its service life decreases, and there is an inefficient consumption of electricity. Studies of the optimal automatic regulation of the cutting process were made by the method of modeled analysis on digital and analog machines. The method uses an electronic-automatic device with integrating circuit of domestic production (A-741, A-723). This device controls and regulates the current parameters of the acting motor. The device includes primarily an element of information type of the Hall TH traductor type, the regulating element is an electronic relay, electronic power distributor, etc.

Mechanical loading regulates human MSC differentiation in a multi-layer hydrogel for osteochondral tissue engineering.

Science.gov (United States)

Steinmetz, Neven J; Aisenbrey, Elizabeth A; Westbrook, Kristofer K; Qi, H Jerry; Bryant, Stephanie J

2015-07-01

A bioinspired multi-layer hydrogel was developed for the encapsulation of human mesenchymal stem cells (hMSCs) as a platform for osteochondral tissue engineering. The spatial presentation of biochemical cues, via incorporation of extracellular matrix analogs, and mechanical cues, via both hydrogel crosslink density and externally applied mechanical loads, were characterized in each layer. A simple sequential photopolymerization method was employed to form stable poly(ethylene glycol)-based hydrogels with a soft cartilage-like layer of chondroitin sulfate and low RGD concentrations, a stiff bone-like layer with high RGD concentrations, and an intermediate interfacial layer. Under a compressive load, the variation in hydrogel stiffness within each layer produced high strains in the soft cartilage-like layer, low strains in the stiff bone-like layer, and moderate strains in the interfacial layer. When hMSC-laden hydrogels were cultured statically in osteochondral differentiation media, the local biochemical and matrix stiffness cues were not sufficient to spatially guide hMSC differentiation after 21 days. However dynamic mechanical stimulation led to differentially high expression of collagens with collagen II in the cartilage-like layer, collagen X in the interfacial layer and collagen I in the bone-like layer and mineral deposits localized to the bone layer. Overall, these findings point to external mechanical stimulation as a potent regulator of hMSC differentiation toward osteochondral cellular phenotypes. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Wrecked regulation of intrinsically disordered proteins in diseases: Pathogenicity of deregulated regulators

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Vladimir N. Uversky

2014-07-01

Full Text Available Biologically active proteins without stable tertiary structure are common in all known proteomes. Functions of these intrinsically disordered proteins (IDPs are typically related to regulation, signaling and control. Cellular levels of these important regulators are tightly regulated by a variety mechanisms ranging from firmly controlled expression to precisely targeted degradation. Functions of IDPs are controlled by binding to specific partners, alternative splicing, and posttranslational modifications among other means. In the norm, right amounts of precisely activated IDPs have to be present in right time at right places. Wrecked regulation brings havoc to the ordered world of disordered proteins, leading to protein misfolding, misidentification, and missignaling that give rise to numerous human diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes. Among factors inducing pathogenic transformations of IDPs are various cellular mechanisms, such as chromosomal translocations, damaged splicing, altered expression, frustrated posttranslational modifications, aberrant proteolytic degradation, and defective trafficking. This review presents some of the aspects of deregulated regulation of IDPs leading to human diseases.

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

Science.gov (United States)

Toshchakova, Valentina A.; Bakhtiari, Yalda; Kulikov, Alexander V.; Gusev, Sergey I.; Trofimova, Marina V.; Fedorenko, Olga Yu.; Mikhalitskaya, Ekaterina V.; Popova, Nina K.; Bokhan, Nikolay A.; Hovens, Johannes E.; Loonen, Anton J.M.; Wilffert, Bob; Ivanova, Svetlana A.

2018-01-01

Background Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed. PMID:29621775

Opposing effects of 5,7-DHT lesions to the core and shell of the nucleus accumbens on the processing of irrelevant stimuli.

Science.gov (United States)

Nelson, Andrew J D; Thur, Karen E; Marsden, Charles A; Cassaday, Helen J

2012-05-01

There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7-DHT lesions to the shell produced the opposite effect and potentiated LI.

Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer

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Chen Hairu

2010-10-01

Full Text Available Abstract Background Activated leukocyte cell adhesion molecule (ALCAM is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs. Results A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis-active elements including a functional p65 NF-κB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters. Conclusion Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer.

Probing molecular mechanisms of the Hsp90 chaperone: biophysical modeling identifies key regulators of functional dynamics.

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Anshuman Dixit

Full Text Available Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected

Possible Modulation of the Anexiogenic Effects of Vitex Agnus-castus by the Serotonergic System.

Science.gov (United States)

Yaghmaei, Parichehr; Oryan, Shahrbanoo; Fatehi Gharehlar, Laleh; Salari, Ali-Akbar; Solati, Jalal

2012-03-01

There is well documented evidence for the increase in widespread use of complementary and alternative medicine in the treatment of physical and psychiatric symptoms and disorders within the populations. In the present study, we investigated the influence of V itex agnus-castus (vitex) on anxiety-like behaviors of rats. Elevated plus maze which is one of the methods used for testing anxiety is used in our present study. Rats were orally administrated with vitex for two week. The anxiety test was carried out after two weeks of oral administration of vitex. For evaluating interaction of vitex and serotonergic systems, rats were anaesthetized with ketamine and special cannulas were inserted stereotaxically into the third ventricle (TV) of brain. After 1 week recovery, the effects of serotonegic agents on anxiety were studied. Oral administration of vitex (100, 200, 300 mg/kg) for two weeks induced an anxiogenic-like effect which was shown through specific decreases in the percentages of open arm time (OAT %) and open arm entries (OAE %). Intra - TV infusion of 5HT1A receptor agonist, 8-OH-DPAT (5, 10 and 25 ng/rat) increased OAT% and OAE%, indicating anxiolytic-like behavior. However, injection of 5HT1A receptor antagonist NAN190 (0.25, 0.5 and 1 µg/rat) produced anxiogenic-like behavior. The most effective dose of 8-OH-DPAT (10 ng/rat), when co-administered with vitex (100, 200, 300 mg/kg), attenuated the anxiogenic-like effects of vitex significantly. Injection of the less effective dose of NAN190 (0.5 µg/rat), in combination with vitex (100, 200, 300 mg/kg), potentiate anxiogenic effects of vitex. These results illustrate that 5HT1A receptor is involved in the anxiogenic effects of vitex.

Enhanced down regulation of cortical ±-propranolol sensitive [3H]-DHA binding sites by co-administration of DMI and 5-HT1A partial agonist gepirone

International Nuclear Information System (INIS)

Geissler, M.A.; Yocca, F.D.

1990-01-01

The putative interrelationship between the noradrenergic and serotonergic systems has been supported by numerous studies. Recently, Dudley et al. (1989) demonstrated significant down regulation of cortical β-adrenergic receptors by co-administration of desipramine (DMI), a norepinephrine uptake inhibitor, and the full 5-HT 1A agonist 8-OH-DPAT. To this end, the effects of acute and chronic (4 and 14 day) administration of DMI, gepirone, a selective 5-HT 1A post-synaptic partial agonist, as well as a combination of the two, on cortical (±)-propranolol sensitive [ 3 H]-DHA binding sites were examined in rats. Down regulation was apparent after 4 and 14 day treatment with DMI. However, this was not the case with gepirone. Of particular importance is the demonstration of a greater magnitude of down regulation with co-administration of a greater magnitude of down regulation with co-administration of DMI and gepirone. These results suggests that alteration in rat cortical (±)-propranolol sensitive [ 3 H]-DHA binding sites by noradrenergic uptake inhibitors can be further modulated by selective partial agonist activity at central 5-HT 1A postsynaptic receptors. Further data on the co-administration of DMI and BMY 7378 (7,9-dioxo-8-[2-(4-o-methoxyphenylpiperazinyl)ethyl]-8-azaspiro[4,5]decane dihydrochloride), a weak partial agonist at postsynaptic 5-HT 1A receptors, are also presented

Neural mechanisms of emotion regulation in childhood anxiety

NARCIS (Netherlands)

Hum, K.M.; Manassis, K.; Lewis, M.D.

2013-01-01