Browsing by Subject "serotonin"

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  • Abdurakhmanova, Shamsiiat; Semenova, Svetlana; Piepponen, T. Petteri; Panula, Pertti (2019)
    Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc). The mutant mice showed a distinct behavioral pattern during exploration of novel environment, specifically, increased frequency of rearing seated against the wall, jumping and head/body shakes. This behavioral phenotype was associated with decreased levels of striatal dopamine and serotonin and increased level of dopamine metabolite DOPAC. Gene expression levels of dynorphin and enkephalin, opioids released by medium spiny neurons of striatal direct and indirect pathways respectively, were lower in Hdc mutant mice than in control animals. A low dose of amphetamine led to similar behavioral and biochemical outcomes in both genotypes. Increased striatal dopamine turnover was observed in Hdc KO mice after treatment with dopamine precursor l-Dopa. Overall, our study suggests a role for striatal dopamine and opioid peptides in formation of distinct behavioral phenotype of Hdc KO mice.
  • Chalazonitis, Alcmène; Li, ZhiShan; Pham, Tuan D.; Chen, Jason; Rao, Meenakshi; Lindholm, Päivi; Saarma, Mart; Lindahl, Maria; Gershon, Michael D. (2020)
    Abstract Cerebral dopamine neurotrophic factor (CDNF) is expressed in the brain and is neuroprotective. We have previously shown that CDNF is also expressed in the bowel and that its absence leads to degeneration and autophagy in the enteric nervous system (ENS), particularly in the submucosal plexus. We now demonstrate that enteric CDNF immunoreactivity is restricted to neurons (submucosal > myenteric) and is not seen in glia, interstitial cells of Cajal, or smooth muscle. Expression of CDNF, moreover, is essential for the normal development and survival of enteric dopaminergic neurons; thus, expression of the dopaminergic neuronal markers, dopamine, tyrosine hydroxylase, and dopamine transporter are deficient in the ileum of Cdnf -/- mice. The normal age-related decline in proportions of submucosal dopaminergic neurons is exacerbated in Cdnf -/- animals. The defect in Cdnf -/- animals is not dopamine-restricted; proportions of other submucosal neurons (NOS-, GABA-, and CGRP-expressing), are also deficient. The deficits in submucosal neurons are reflected functionally in delayed gastric emptying, slowed colonic motility, and prolonged total gastrointestinal transit. CDNF is expressed selectively in isolated enteric neural crest-derived cells (ENCDC), which also express the dopamine-related transcription factor Foxa2. Addition of CDNF to ENCDC promotes development of dopaminergic neurons; moreover, survival or these neurons becomes CDNF-dependent after exposure to bone morphogenetic protein 4. The effects of neither glial cell-derived neurotrophic factor (GDNF) nor serotonin are additive with CDNF. We suggest that CDNF plays a critical role in development and long-term maintenance of dopaminergic and other sets of submucosal neurons. This article is protected by copyright. All rights reserved.
  • Sahu, Madhusmita P.; Pazos-Boubeta, Yago; Steinzeig, Anna; Kaurinkoski, Katja; Palmisano, Michela; Borowecki, Olgierd; Piepponen, Timo Petteri; Castren, Eero (2021)
    Neurotrophin brain-derived neurotrophic factor (BDNF) and neurotransmitter serotonin (5-HT) regulate each other and have been implicated in several neuronal mechanisms, including neuroplasticity. We have investigated the effects of BDNF on serotonergic neurons by deleting BDNF receptor TrkB from serotonergic neurons in the adult brain. The transgenic mice show increased 5-HT and Tph2 levels with abnormal behavioral phenotype. In spite of increased food intake, the transgenic mice are significantly leaner than their wildtype littermates, which may be due to increased metabolic activity. Consistent with increased 5-HT, the proliferation of hippocampal progenitors is significantly increased, however, long-term survival of newborn cells is unchanged. Our data indicates that BDNF-TrkB signaling regulates the functional phenotype of 5-HT neurons with long-term behavioral consequences.
  • Leopold, Anna V.; Shcherbakova, Daria; Verkhusha, Vladislav V. (2019)
    Understanding how neuronal activity patterns in the brain correlate with complex behavior is one of the primary goals of modern neuroscience. Chemical transmission is the major way of communication between neurons, however, traditional methods of detection of neurotransmitter and neuromodulator transients in mammalian brain lack spatiotemporal precision. Modern fluorescent biosensors for neurotransmitters and neuromodulators allow monitoring chemical transmission in vivo with millisecond precision and single cell resolution. Changes in the fluorescent biosensor brightness occur upon neurotransmitter binding and can be detected using fiber photometry, stationary microscopy and miniaturized head-mounted microscopes. Biosensors can be expressed in the animal brain using adeno-associated viral vectors, and their cell-specific expression can be achieved with Cre-recombinase expressing animals. Although initially fluorescent biosensors for chemical transmission were represented by glutamate biosensors, nowadays biosensors for GABA, acetylcholine, glycine, norepinephrine, and dopamine are available as well. In this review, we overview functioning principles of existing intensiometric and ratiometric biosensors and provide brief insight into the variety of neurotransmitter-binding proteins from bacteria, plants, and eukaryotes including G-protein coupled receptors, which may serve as neurotransmitter-binding scaffolds. We next describe a workflow for development of neurotransmitter and neuromodulator biosensors. We then discuss advanced setups for functional imaging of neurotransmitter transients in the brain of awake freely moving animals. We conclude by providing application examples of biosensors for the studies of complex behavior with the single-neuron precision.
  • Korchynska, Solomiia; Krassnitzer, Maria; Malenczyk, Katarzyna; Prasad, Rashmi B.; Tretiakov, Evgenii O.; Rehman, Sabah; Cinquina, Valentina; Gernedl, Victoria; Farlik, Matthias; Petersen, Julian; Hannes, Sophia; Schachenhofer, Julia; Reisinger, Sonali N.; Zambon, Alice; Asplund, Olof; Artner, Isabella; Keimpema, Erik; Lubec, Gert; Mulder, Jan; Bock, Christoph; Pollak, Daniela D.; Romanov, Roman A.; Pifl, Christian; Groop, Leif; Hokfelt, Tomas G. M.; Harkany, Tibor (2020)
    Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic beta cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.
  • Tuominen, Lauri; Miettunen, Jouko; Cannon, Dara M.; Drevets, Wayne C.; Frokjaer, Vibe G.; Hirvonen, Jussi; Ichise, Masanori; Jensen, Peter S.; Keltikangas-Järvinen, Liisa; Klaver, Jacqueline M.; Knudsen, Gitte M.; Takano, Akihiro; Suhara, Tetsuya; Hietala, Jarmo (2017)
    Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P = .008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P = .014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.
  • Radoi, Vlad; Jakobsson, Gerd; Palada, Vinko; Nikosjkov, Andrej; Druid, Henrik; Terenius, Lars; Kosek, Eva; Vukojevic, Vladana (2022)
    The importance of the dynamic interplay between the opioid and the serotonin neuromodulatory systems in chronic pain is well recognized. In this study, we investigated whether these two signalling pathways can be integrated at the single-cell level via direct interactions between the mu-opioid (MOP) and the serotonin 1A (5-HT1A) receptors. Using fluorescence cross-correlation spectroscopy (FCCS), a quantitative method with single-molecule sensitivity, we characterized in live cells MOP and 5-HT1A interactions and the effects of prolonged (18 h) exposure to selected non-peptide opioids: morphine, codeine, oxycodone and fentanyl, on the extent of these interactions. The results indicate that in the plasma membrane, MOP and 5-HT1A receptors form heterodimers that are characterized with an apparent dissociation constant K-d(app) = (440 +/- 70) nM). Prolonged exposure to all non-peptide opioids tested facilitated MOP and 5-HT1A heterodimerization and stabilized the heterodimer complexes, albeit to a different extent: K-d,Fentanyl(app) = (80 +/- 70) nM), K-d,FMorphine(app) = (200 +/- 70) nM, K-d,Codeine(app) = (100 +/- 70) nM and K-d,(app)(Oxycodone) = (200 +/- 70) nM. The non-peptide opioids differed also in the extent to which they affected the mitogen-activated protein kinases (MAPKs) p38 and the extracellular signal-regulated kinase (Erk1/2), with morphine, codeine and fentanyl activating both pathways, whereas oxycodone activated p38 but not ERK1/2. Acute stimulation with different non-peptide opioids differently affected the intracellular Ca2+ levels and signalling dynamics. Hypothetically, targeting MOP-5-HT1A heterodimer formation could become a new strategy to counteract opioid induced hyperalgesia and help to preserve the analgesic effects of opioids in chronic pain.
  • Naskali, Emmi; Dettmer, Katja; Oefner, Peter; Pereira, Pedro A. B.; Krohn, Kai; Auvinen, Petri; Ranki, Annamari; Kluger, Nicolas (2019)
    Objective: Intestinal autoimmunity with gastrointestinal (GI) dysfunction has been shown in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Patients lack entero-endocrine (EE) cells and have circulating autoantibodies (Aabs) against critical enzymes in serotonin (5-HT) biosynthesis. Design: We sought to determine the serum levels of 5-HT, tryptophan (Trp) metabolites and L-DOPA in 37 Finnish APECED patients and to correlate their abundance with the presence of TPH and AADC Aabs, GI dysfunction and depressive symptoms. We also performed an exploratory analysis of the gut microbiome. Methods: Serum 5-HT, L-DOPA and Trp metabolite levels were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). TPH and AADC Aabs were measured by ELISA. Depression was assessed with a structured RBDI questionnaire. The V3-V4 regions of the bacterial 16S rRNA gene were sequenced for gut microbiome exploration. Results: Serum 5-HT levels were significantly decreased (130 +/- 131 nmol/L vs 686 +/- 233 nmol/L, P <0.0001) in APECED patients with TPH-1 (+/- AADC) Aabs compared to controls and patients with only AADC Aabs. Reduced 5-HT levels correlated with constipation. The genus Escherichia/Shigella was overrepresented in the intestinal microbiome. No correlation between serum Trp, 5-HT or L-DOPA levels and the RBDI total score, fatigue or sleep disorders was found. Conclusions: This exploratory study found low serum levels of 5-HT to be associated with constipation and the presence of TPH-1 and AADC Aabs, but not with symptoms of depression. Hence, serum 5-HT, TPH1 and AADC Aabs should be determined in APECED patients presenting with GI symptoms.
  • Naskali, Emmi; Kluger, Nicolas; Ranki, Annamari; Dettmer, Katja; Oefner, Peter; Pereira, Pedro; Krohn, Kai; Auvinen, Petri (Helsingin yliopisto, 2018)
    APECED eli autoimmuunipolyendokrinopatia-kandidiaasi-ektodermidystrofia on suomalaiseen tautiperimään kuuluva harvinainen perinnöllinen sairaus, jonka oireita ovat suun krooninen hiivatulehdus ja useat autoimmuunisairaudet. Lisäksi APECED-potilailla on tutkimuksissa havaittu useita elimistön entsyymejä vastaan toimivia autovasta-aineita verenkierrossaan. Esimerkiksi suolistoon ja mielialaan vaikuttavan serotoniinin aineenvaihdunnan kannalta tärkeitä entsyymejä, aromaatinen L-aminohappodekarboksylaasi (AADC) ja tryptofaanihydroksylaasi (TPH), kohtaan on löydetty vasta-aineita APECED-potilailta. Aiemmissa tutkimuksissa nämä vasta-aineet on liitetty myös suoliston enteroendokriinisolujen puuttumiseen, jotka normaalisti tuottavat suolistossa noin 95% koko elimistön serotoniinista ja yleisen käsityksen vastaisesti vain pieni osa tuotetaan keskushermostossa. Tässä tutkimuksessa keskityimme APECED-potilaiden suolisto- ja mielialaoireisiin. Tutkimuksen tavoitteena oli selvittää potilaiden veren serotoniinin, serotoniiniaineenvaihdunnan entsyymien sekä AADC- ja TPH-autovasta-aineiden pitoisuuksien välistä yhteyttä suolisto- ja mielialaoireisiin. Tutkimukseen osallistui 37 suomalaista APECED-potilasta potilasyhdistyksen kautta. Verinäytteet kerättiin potilailta heidän noudatettuaan vuorokauden ajan vähäserotoniinista ruokavaliota. Samassa yhteydessä potilaita pyydettiin täyttämään oirekysely, jossa kartoitettiin masennusoireita sekä vaikeaa ummetusta ja ripulia. Potilaista 26 suoritti molemmat tutkimuksen osat. Verinäytteiden vasta-ainetasot mitattiin ELISA-menetelmällä omassa laboratoriossamme. Serotoniinin ja kahdentoista muun serotoniiniaineenvaihdunnan metaboliitin tasot tutkittiin massaspektrometrialla yhteistyökumppanimme professori Oefnerin laboratoriossa (Institut für Funktionelle Genomik) Regensburgin yliopistossa Saksassa. Yhteistyössä professori Petri Auvisen tutkimusryhmän kanssa analysoitiin aiemmin potilaista kerättyjen ulostenäytteiden mikrobiomi. Tutkimuksen tuloksena havaitsimme tilastollisesti merkittävän yhteyden APECED-potilaiden matalien serotoniinitasojen ja veren TPH-autovasta-aineiden välillä. Lisäksi veren mataliin serotoniinitasoihin liittyi myös enemmän potilaiden kokemaa ummetusta. Masennusoireilla sekä AADC-autovasta-aineilla emme havainneet selkeää yhteyttä muihin muuttujiin. APECED-potilaiden suolistobakteereissa oli yliedustettuina Shigella- ja Escherichia- ryhmien bakteereita. Tutkimuksen tulokset osoittavat, että APECED-potilailla serotoniinitasot ovat normaalia matalammat johtuen enteroendokriinisolujen puuttumisesta ja tämä on yhteydessä sekä ummetusoireisiin että TPH-autovasta-aineiden esiintymiseen. Tämä on ensimmäinen tutkimus, jossa osoitettiin yhteys matalien serotoniinitasojen ja vaikeiden ummetusoireiden välillä APECED-potilailla. Myös suoliston mikrobiomilla on osoitettu olevan vaikutus serotoniiniaineenvaihduntaan.
  • Wickholm, Grim (Helsingfors universitet, 2016)
    Chronic pain is challenging to treat when the adverse effects of the analgesic agents become significant when used for a long period of time. Acupuncture has been shown to have analgesic effect without adverse effects. The modulatory effect of acupuncture on pain and what substances are involved in the modulation is, however, not completely understood. In this study 19 dogs with chronic pain caused by osteoarthritis in the hip joint was randomly divided into two groups: acupuncture group (AG) and sham group (SG). The AG got three acupuncture treatments with an interval of about one week and the SG got no treatment, they just rested on the floor in the treatment room. The owners and the researchers did not know into which group each dog was divided. Blood samples was taken from each dog in the beginning and at the end of the study to analyse the long-term effect (LT) and before and after one treatment to analyse the short-term effect (ST). From the blood samples the plasma concentration of serotonin (ST), prolactin (LT) and cortisol (ST and LT) were analysed and the concentrations between the groups and between the samples before and after were compared. The result of the study was that there was no statistically significant difference neither between the two groups nor between the before and after samples for neither serotonin, prolactin nor cortisol. There was, however, a strong trend toward significance in the increased concentration of LT cortisol between baseline and end of treatment in the AG (p=0.051), and a decrease of concentration of ST cortisol in both groups (p=0.051 for the AG and p=0.063 for the SG). More research, taking into consideration the limitations of this study, should be done.