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  • 51.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hallschmid, Manfred
    Lassen, Arne
    Mahnke, Christin
    Schultes, Bernd
    Schiöth, Helgi Birgir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Born, Jan
    Lange, Tanja
    Acute sleep deprivation reduces energy expenditure in healthy men2011Inngår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 93, nr 6, s. 1229-1236Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Epidemiologic evidence indicates that chronic sleep curtailment increases risk of developing obesity, but the mechanisms behind this relation are largely unknown.

    Objective

    We examined the influence of a single night of total sleep deprivation on morning energy expenditures and food intakes in healthy humans.

    Design

    According to a balanced crossover design, we examined 14 normal-weight male subjects on 2 occasions during a regular 24-h sleep-wake cycle (including 8 h of nocturnal sleep) and a 24-h period of continuous wakefulness. On the morning after regular sleep and total sleep deprivation, resting and postprandial energy expenditures were assessed by indirect calorimetry, and the free-choice food intake from an opulent buffet was tested in the late afternoon at the end of the experiment. Circulating concentrations of ghrelin, leptin, norepinephrine, cortisol, thyreotropin, glucose, and insulin were repeatedly measured over the entire 24-h session.

    Results

    In comparison with normal sleep, resting and postprandial energy expenditures assessed on the subsequent morning were significantly reduced after sleep deprivation by approximate to 5% and 20%, respectively (P < 0.05 and P < 0.0001). Nocturnal wakefulness increased morning plasma ghrelin concentrations (P < 0.02) and nocturnal and daytime circulating concentrations of thyreotropin, cortisol, and norepinephrine (P < 0.05) as well as morning postprandial plasma glucose concentrations (P < 0.05). Changes in food intakes were variable, and no differences between wake and sleep conditions were detected.

    Conclusion

    Our findings show that one night of sleep deprivation acutely reduces energy expenditure in healthy men, which suggests that sleep contributes to the acute regulation of daytime energy expenditure in humans.

  • 52.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Rönnemaa, Elina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sällman Almén, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Brooks, Samantha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schultes, Bernd
    Interdisciplinary Obesity Center, Kantonsspital St. Gallen.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men2011Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, nr 6, s. 1159.e1-1159.e5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.

  • 53.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Television Watching and Effects on Food Intake: Distress vs Eustress2015Inngår i: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 175, nr 3, s. 468-468Artikkel i tidsskrift (Fagfellevurdert)
  • 54.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Shostak, Anton
    Lange, Tanja
    Brooks, Samantha J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schultes, Bernd
    Born, Jan
    Oster, Henrik
    Hallschmid, Manfred
    Diurnal Rhythm of Circulating Nicotinamide Phosphoribosyltransferase (Nampt/Visfatin/PBEF): Impact of Sleep Loss and Relation to Glucose Metabolism2012Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 2, s. E218-E222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context

     Animal studies indicate that nicotinamide phosphoribosyltransferase [Nampt/visfatin/pre-B-cell colony-enhancing factor (PBEF)] contributes to the circadian fine-tuning of metabolic turnover. However, it is unknown whether circulating Nampt concentrations, which are elevated in type 2 diabetes and obesity, display a diurnal rhythm in humans.

    Objective

     Our objective was to examine the 24-h profile of serum Nampt in humans under conditions of sleep and sleep deprivation and relate the Nampt pattern to morning postprandial glucose metabolism.

    Intervention

    Fourteen healthy men participated in two 24-h sessions starting at 1800 h, including either regular 8-h-night sleep or continuous wakefulness. Serum Nampt and leptin were measured in 1.5- to 3-h intervals. In the morning, plasma glucose and serum insulin responses to standardized breakfast intake were determined.

    Main Outcome Measures

     Under regular sleep-wake conditions, Nampt levels displayed a pronounced diurnal rhythm, peaking during early afternoon (P < 0.001) that was inverse to leptin profiles peaking in the early night. When subjects stayed awake, the Nampt rhythm was preserved but phase advanced by about 2 h (P < 0.05). Two-hour postprandial plasma glucose concentrations were elevated after sleep loss (P < 0.05), whereas serum insulin was not affected. The relative glucose increase due to sleep loss displayed a positive association with the magnitude of the Nampt phase shift (r = 0.54; P < 0.05).

    Conclusions

    Serum Nampt concentrations follow a diurnal rhythm, peaking in the afternoon. Sleep loss induces a Nampt rhythm phase shift that is positively related to the impairment of postprandial glucose metabolism due to sleep deprivation, suggesting a regulatory impact of Nampt rhythmicity on glucose homeostasis.

  • 55.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Jonas, Wenke
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Woting, Anni
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Blaut, Michael
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Schuermann, Annette
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals2016Inngår i: Molecular Metabolism, ISSN 2212-8778, Vol. 5, nr 12, s. 1175-1186Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Changes to the microbial community in the human gut have been proposed to promote metabolic disturbances that also occur after short periods of sleep loss (including insulin resistance). However, whether sleep loss affects the gut microbiota remains unknown. Methods: In a randomized within-subject crossover study utilizing a standardized in-lab protocol (with fixed meal times and exercise schedules), we studied nine normal-weight men at two occasions: after two nights of partial sleep deprivation (PSD; sleep opportunity 02: 45-07: 00 h), and after two nights of normal sleep (NS; sleep opportunity 22: 30-07: 00 h). Fecal samples were collected within 24 h before, and after two in-lab nights, of either NS or PSD. In addition, participants underwent an oral glucose tolerance test following each sleep intervention. Results: Microbiota composition analysis (V4 16S rRNA gene sequencing) revealed that after two days of PSD vs. after two days of NS, individuals exhibited an increased Firmicutes: Bacteroidetes ratio, higher abundances of the families Coriobacteriaceae and Erysipelotrichaceae, and lower abundance of Tenericutes (all P < 0.05) - previously all associated with metabolic perturbations in animal or human models. However, no PSD vs. NS effect on beta diversity or on fecal short-chain fatty acid concentrations was found. Fasting and postprandial insulin sensitivity decreased after PSD vs. NS (all P < 0.05). Discussion: Our findings demonstrate that short-term sleep loss induces subtle effects on human microbiota. To what extent the observed changes to the microbial community contribute to metabolic consequences of sleep loss warrants further investigations in larger and more prolonged sleep studies, to also assess how sleep loss impacts the microbiota in individuals who already are metabolically compromised. (C) 2016 The Author(s). Published by Elsevier GmbH.

  • 56. Bianconi, Santiago
    et al.
    Santillán, María E
    Solís, María Del Rosario
    Martini, Ana C
    Ponzio, Marina F
    Vincenti, Laura M
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Carlini, Valeria P
    Stutz, Graciela
    Effects of dietary omega-3 PUFAs on growth and development: Somatic, neurobiological and reproductive functions in a murine model.2018Inngår i: Journal of Nutritional Biochemistry, ISSN 0955-2863, E-ISSN 1873-4847, Vol. 61, s. 82-90, artikkel-id S0955-2863(17)31051-3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are relevant to fetal and infant growth and development. Objective: to assess whether long-term exposure to dietary ω-3 PUFA imbalance alters pre- and/or postnatal pups' development and reproductive function later in life. Mice dams were fed with ω-3 PUFA Control (soybean oil, 7%), Deficient (sunflower oil, 7%) or Excess (blend oil; 4.2% cod-liver+2.8% soybean) diet before conception and throughout gestation-lactation and later on, their pups received the same diet from weaning to adulthood. Offspring somatic, neurobiological and reproductive parameters were evaluated. Excess pups were lighter during the preweaning period and shorter in length from postnatal day (PND) 7 to 49, compared to Control pups (P<.05). On PND14, the percentage of pups with eye opening in Excess group was lower than those from Control and Deficient groups (P<.05). In Excess female offspring, puberty onset (vaginal opening and first estrus) occurred significantly later and the percentage of parthenogenetic oocytes on PND63 was higher than Control and Deficient ones (P<.05). Deficient pups were shorter in length (males: on PND14, 21, 35 and 49; females: on PND14, 21 and 42) compared with Control pups (P<.05). Deficient offspring exhibited higher percentage of bending spermatozoa compared to Control and Excess offspring (P<.05). These results show that either an excessively high or insufficient ω-3 PUFA consumption prior to conception until adulthood seems inadvisable because of the potential risks of short-term adverse effects on growth and development of the progeny or long-lasting effects on their reproductive maturation and function.

  • 57.
    Birgner, Carolina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kindlundh-Högberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Alsiö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bergström, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The anabolic androgenic steroid nandrolone decanoate affects mRNA expression of dopaminergic but not serotonergic receptors2008Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1240, s. 221-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The abuse of anabolic androgenic steroids (AASs) at supratherapeutic doses is a problem not only in the world of sports, but also among non-athletes using AASs to improve physical appearance and to become more bold and courageous. Investigations of the possible neurochemical effects of AAS have focused partially on the monoaminergic systems, which are involved in aggressive behaviours and the development of drug dependence. In the present study, we administered nandrolone decanoate (3 or 15 mg/kg/day for 14 days) and measured mRNA expression of dopaminergic and serotonergic receptors, transporters and enzymes in the male rat brain using quantitative real-time polymerase chain reaction. Expression of the dopamine D1-receptor transcript was elevated in the amygdala and decreased in the hippocampus while the transcript level of the dopamine D4-receptor was increased in the nucleus accumbens. No changes in transcriptional levels were detected among the serotonin-related genes examined in this study. The altered mRNA expression of the dopamine receptors may contribute to some of the behavioural changes often reported in AAS abusers of increased impulsivity, aggression and drug-seeking.

  • 58.
    Birgner, Carolina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Kindlundh-Högberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Alsiö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bergström, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration2008Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1219, s. 103-110Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens shell using microdialysis. The aim of the present study was to investigate whether the same dose regimen of nandrolone decanoate may affect the activities of the dopamine-metabolizing enzymes monoamine oxidases A and B (MAO-A and MAO-B). A radiometric assay was used to determine the activities of MAO-A and MAO-B in rat brain tissues after 14 days of daily i.m. nandrolone decanoate injections at the doses 3 and 15 mg/kg. Gene transcript contents of MAO-A, MAO-B and cathecol-O-methyltransferase (COMT) were measured with quantitative real-time reverse transcription PCR. 3 mg/kg of nandrolone decanoate significantly reduced the activity of both MAO-A and -B in the caudate putamen. 15 mg/kg of nandrolone decanoate significantly reduced the activity of MAO-A in the amygdala and increased the gene transcript level of MAO-B in the substantia nigra. In conclusion, imbalanced MAO activities may contribute to explain the impulsive and aggressive behaviour often described in AAS abusers. The reduced MAO activities observed are in line with our previously presented findings of decreased extracellular levels of DOPAC and HVA in the rat brain, indicating decreased monoaminergic activity following repeated AAS administration.

  • 59.
    Blunder, Martina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Graz Univ, Dept Pharmacognosy, Inst Pharmaceut Sci, Univ Pl 4, A-8010 Graz, Austria.
    Orthaber, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik. Graz Univ, Dept Pharmaceut Chem, Inst Pharmaceut Sci, Univ Pl 1, A-8010 Graz, Austria.
    Bauer, Rudolf
    Graz Univ, Dept Pharmacognosy, Inst Pharmaceut Sci, Univ Pl 4, A-8010 Graz, Austria.
    Bucar, Franz
    Graz Univ, Dept Pharmacognosy, Inst Pharmaceut Sci, Univ Pl 4, A-8010 Graz, Austria.
    Kunert, Olaf
    Graz Univ, Dept Pharmaceut Chem, Inst Pharmaceut Sci, Univ Pl 1, A-8010 Graz, Austria.
    Efficient identification of flavones, flavanones and their glycosides in routine analysis via off-line combination of sensitive NMR and HPLC experiments2017Inngår i: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 218, s. 600-609Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a standardized, straightforward and efficient approach applicable in routine analysis of flavonoids combining sensitive NMR and HPLC experiments. The determination of the relative configuration of sugar moieties usually requires the acquisition of 13C NMR shift values. We use a combination of HPLC and sensitive NMR experiments (1D-proton, 2D-HSQC) for the unique identification of known flavones, flavanones, flavonols and their glycosides. Owing to their broad range of polarity, we developed HPLC and UHPLC methods (H2O/MeOH/MeCN/HCOOH) which we applied and validated by analyzing 46 common flavones and flavanones and exemplified for four plant extracts. A searchable data base is provided with full data comprising complete proton and carbon resonance assignments, expansions of HSQC-spectra, HPLC parameters (retention time, relative retention factor), UV/Vis and mass spectral data of all compounds, which enables a rapid identification and routine analysis of flavones and flavanones from plant extracts and other products in nutrition and food chemistry.

  • 60.
    Boström, Adrian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ciuculete, Diana-Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Attwood, Misty M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Krattinger, Regina
    Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Nikontovic, Lamia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Titova, Olga E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kullak-Ublick, Gerd A.
    Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
    Mwinyi, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    A MIR4646 associated methylation locus is hypomethylated in adolescent depression2017Inngår i: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 220, s. 117-128Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. Methods: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n = 93) and validation data set 1 (n = 78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n = 58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. Results: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p < 10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p < 0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p < 0.05). Limitations: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. Conclusion: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.

  • 61.
    Boström, Adrian E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Mwinyi, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Voisin, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Wu, Wenting
    Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA..
    Schultes, Bernd
    eSwiss Med & Surg Ctr, St Gallen, Switzerland..
    Zhang, Kang
    Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA..
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension2016Inngår i: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, artikkel-id 20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p < 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p < 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension.

  • 62.
    Bringeland, Nathalie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    DNA methylation correlation networks in overweight and normal-weight adolescents reveal differential coordination2013Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Multiple health issues are associated with obesity and numerous factors are causative of the disease. The role of genetic factors is well established, as is the knowledge that dietary and sedentary behavior promotes weight gain. Although there is strong suspicion towards the role of epigenetics as a driving force toward disease, this field remains l in the context of obesity. DNA methylation correlation networks were profiled from blood samples of 69 adolescents of two distinct weight-classes; obese (n=35) and normal-weight (n=34). The network analysis revealed major differences in the organization of the networks where the network of the obese had less modularity compared to normal-weight. This is manifested by more and smaller clusters in the obese, pertaining to genes of related functions and pathways, than the network of the normal-weight. Consequently, this suggests that biological pathways have a lower order of coordination between each other in means of DNA methylation in obese than normal-weight. Analysis of highly connected genes, hubs, in the two networks suggests that the difference in coordination between biological pathways may be derived by changes of the methylation pattern of these hubs; highly connected genes in one network had an intriguingly low connectivity in the other. In conclusion, the results suggest differential regulation of transcription through changes in the coordination of DNA methylation in overweight and normal weighted individuals. The findings of this study are a major step towards understanding the role of DNA methylation in obesity and provide potential biomarkers for diagnosing and predicting obesity.

  • 63.
    Brooks, S. J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Cape Town, South Africa.;Univ Cape Town, MRC Unit Anxiety & Stress Disorders, ZA-7700 Rondebosch, South Africa..
    Burch, K. H.
    Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Cape Town, South Africa.;Univ Cape Town, MRC Unit Anxiety & Stress Disorders, ZA-7700 Rondebosch, South Africa.;Univ Nottingham, Dept Neurosci, Nottingham NG7 2RD, England..
    Maiorana, S. A.
    Univ Cape Town, Dept Psychol, ZA-7700 Rondebosch, South Africa..
    Cocolas, E.
    Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Cape Town, South Africa.;Univ Cape Town, MRC Unit Anxiety & Stress Disorders, ZA-7700 Rondebosch, South Africa..
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nilsson, Emil K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kamaloodien, K.
    Univ Western Cape, Dept Psychol, Cape Town, South Africa..
    Stein, D. J.
    Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Cape Town, South Africa.;Univ Cape Town, MRC Unit Anxiety & Stress Disorders, ZA-7700 Rondebosch, South Africa..
    Psychological intervention with working memory training increases basal ganglia volume: A VBM study of inpatient treatment for methamphetamine use2016Inngår i: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 12, s. 478-491Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Protracted methamphetamine (MA) use is associated with decreased control over drug craving and altered brain volume in the frontostriatal network. However, the nature of volumetric changes following a course of psychological intervention for MA use is not yet known. Methods: 66 males (41 MA patients, 25 healthy controls, HC) between the ages of 18-50 were recruited, the MA patients from new admissions to an in-patient drug rehabilitation centre and the HC via public advertisement, both in Cape Town, South Africa. 17 MA patients received 4 weeks of treatment as usual (TAU), and 24 MA patients completed TAU plus daily 30-minute cognitive training (CT) using an N-back working memory task. Magnetic resonance imaging (MRI) at baseline and 4-week follow-up was acquired and voxel-based morphometry (VBM) was used for analysis. Results: TAU was associated with larger bilateral striatum (caudate/putamen) volume, whereas CT was associated with more widespread increases of the bilateral basal ganglia (incorporating the amygdala and hippocampus) and reduced bilateral cerebellum volume coinciding with improvements in impulsivity scores. Conclusions: While psychological intervention is associated with larger volume in mesolimbic reward regions, the utilisation of additional working memory training as an adjunct to treatment may further normalize frontostriatal structure and function.

  • 64.
    Brooks, Samantha J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    A debate on working memory and cognitive control: can we learn about the treatment of substance use disorders from the neural correlates of anorexia nervosa?2016Inngår i: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 16, artikkel-id 10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Anorexia Nervosa (AN) is a debilitating, sometimes fatal eating disorder (ED) whereby restraint of appetite and emotion is concomitant with an inflexible, attention-to-detail perfectionist cognitive style and obsessive-compulsive behaviour. Intriguingly, people with AN are less likely to engage in substance use, whereas those who suffer from an ED with a bingeing component are more vulnerable to substance use disorder (SUD).

    DISCUSSION: This insight into a beneficial consequence of appetite control in those with AN, which is shrouded by the many other unhealthy, excessive and deficit symptoms, may provide some clues as to how the brain could be trained to exert better, sustained control over appetitive and impulsive processes. Structural and functional brain imaging studies implicate the executive control network (ECN) and the salience network (SN) in the neuropathology of AN and SUD. Additionally, excessive employment of working memory (WM), alongside more prominent cognitive deficits may be utilised to cope with the experience of negative emotions and may account for aberrant brain function. WM enables mental rehearsal of cognitive strategies while regulating, restricting or avoiding neural responses associated with the SN. Therefore, high versus low WM capacity may be one of the factors that unites common cognitive and behavioural symptoms in those suffering from AN and SUD respectively. Furthermore, emerging evidence suggests that by evoking neural plasticity in the ECN and SN with WM training, improvements in neurocognitive function and cognitive control can be achieved. Thus, considering the neurocognitive processes of excessive appetite control and how it links to WM in AN may aid the application of adjunctive treatment for SUD.

  • 65.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Barker, Gareth J
    O'Daly, Owen G
    Brammer, Michael
    Williams, Steven Cr
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C
    Restraint of appetite and reduced regional brain volumes in anorexia nervosa: a voxel-based morphometric study2011Inngår i: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 11, s. 179-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Previous Magnetic Resonance Imaging (MRI) studies of people with anorexia nervosa (AN) have shown differences in brain structure. This study aimed to provide preliminary extensions of this data by examining how different levels of appetitive restraint impact on brain volume.

    METHODS:

    Voxel based morphometry (VBM), corrected for total intracranial volume, age, BMI, years of education in 14 women with AN (8 RAN and 6 BPAN) and 21 women (HC) was performed. Correlations between brain volume and dietary restraint were done using Statistical Package for the Social Sciences (SPSS).

    RESULTS:

    Increased right dorsolateral prefrontal cortex (DLPFC) and reduced right anterior insular cortex, bilateral parahippocampal gyrus, left fusiform gyrus, left cerebellum and right posterior cingulate volumes in AN compared to HC. RAN compared to BPAN had reduced left orbitofrontal cortex, right anterior insular cortex, bilateral parahippocampal gyrus and left cerebellum. Age negatively correlated with right DLPFC volume in HC but not in AN; dietary restraint and BMI predicted 57% of variance in right DLPFC volume in AN.

    CONCLUSIONS:

    In AN, brain volume differences were found in appetitive, somatosensory and top-down control brain regions. Differences in regional GMV may be linked to levels of appetitive restraint, but whether they are state or trait is unclear. Nevertheless, these discrete brain volume differences provide candidate brain regions for further structural and functional study in people with eating disorders.

  • 66.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Burgos, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kempton, M J
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nordenskjöld, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nylander, Ruta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study2013Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, nr 2, s. 230-236Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: 

    Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes.

    DESIGN: 

    Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task.

    SUBJECTS: 

    A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m−2) or obese (30 kg m−2).

    RESULTS: 

    People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight.

    CONCLUSION: 

    These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.

  • 67.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Increased prefrontal and parahippocampal activation with reduced dorsolateral prefrontal and insular cortex activation to food images in obesity: a meta-analysis of fMRI studies.2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4, s. e60393-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Obesity is emerging as the most significant health concern of the twenty-first century. A wealth of neuroimaging data suggest that weight gain might be related to aberrant brain function, particularly in prefrontal cortical regions modulating mesolimbic addictive responses to food. Nevertheless, food addiction is currently a model hotly debated. Here, we conduct a meta-analysis of neuroimaging data, examining the most common functional differences between normal-weight and obese participants in response to food stimuli.

    DATA SOURCE: We conducted a search using several journal databases and adhered to the 'Preferred Reporting Items for Systematic Reviews and Meta-analyses' (PRISMA) method. To this aim, 10 studies were found with a total of 126 obese participants, 129 healthy controls, equaling 184 foci (146 increased, 38 decreased activation) using the Activation Likelihood Estimation (ALE) technique. Out of the 10 studies, 7 investigated neural responses to food versus non-food images.

    RESULTS: In response to food images, obese in comparison to healthy weight subjects had increased activation in the left dorsomedial prefrontal cortex, right parahippocampal gyrus, right precentral gyrus and right anterior cingulate cortex, and reduced activation in the left dorsolateral prefrontal cortex and left insular cortex.

    CONCLUSIONS: Prefrontal cortex areas linked to cognitive evaluation processes, such as evaluation of rewarding stimuli, as well as explicit memory regions, appear most consistently activated in response to images of food in those who are obese. Conversely, a reduced activation in brain regions associated with cognitive control and interoceptive awareness of sensations in the body might indicate a weakened control system, combined with hypo-sensitivity to satiety and discomfort signals after eating in those who are prone to overeat.

  • 68.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Funk, Sabina G
    Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
    Young, Susanne Y
    Department of Psychiatry, Stellenbosch University, Bellville, South Africa.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    The Role of Working Memory for Cognitive Control in Anorexia Nervosa versus Substance Use Disorder2017Inngår i: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 8, artikkel-id 1651Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Prefrontal cortex executive functions, such as working memory (WM) interact with limbic processes to foster impulse control. Such an interaction is referred to in a growing body of publications by terms such as cognitive control, cognitive inhibition, affect regulation, self-regulation, top-down control, and cognitive–emotion interaction. The rising trend of research into cognitive control of impulsivity, using various related terms reflects the importance of research into impulse control, as failure to employ cognitions optimally may eventually result in mental disorder. Against this background, we take a novel approach using an impulse control spectrum model – where anorexia nervosa (AN) and substance use disorder (SUD) are at opposite extremes – to examine the role of WM for cognitive control. With this aim, we first summarize WM processes in the healthy brain in order to frame a systematic review of the neuropsychological, neural and genetic findings of AN and SUD. In our systematic review of WM/cognitive control, we found n = 15 studies of AN with a total of n = 582 AN and n = 365 HC participants; and n = 93 studies of SUD with n = 9106 SUD and n = 3028 HC participants. In particular, we consider how WM load/capacity may support the neural process of excessive epistemic foraging (cognitive sampling of the environment to test predictions about the world) in AN that reduces distraction from salient stimuli. We also consider the link between WM and cognitive control in people with SUD who are prone to ‘jumping to conclusions’ and reduced epistemic foraging. Finally, in light of our review, we consider WM training as a novel research tool and an adjunct to enhance treatment that improves cognitive control of impulsivity.

  • 69.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Naidoo, Vanesh
    Roos, Annerine
    Fouché, Jean-Paul
    Lochner, Christine
    Stein, Dan J
    Early-life adversity and orbitofrontal and cerebellar volumes in adults with obsessive-compulsive disorder: voxel-based morphometry study.2016Inngår i: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 208, nr 1, s. 34-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Early-life adversity is a risk for obsessive-compulsive disorder (OCD), but the impact at the neural level is less clear.

    AIMS: To investigate the association between brain volumes and early-life adversity in individuals with a diagnosis of OCD only.

    METHOD: The Childhood Trauma Questionnaire (CTQ-28) was used to assess early-life adversity in 21 participants with OCD and 25 matched healthy controls. The relationship between global and regional brain volume and early-life adversity was measured using voxel-based morphometry (VBM). All data were corrected for multiple comparisons using family-wise error (FWE) at P<0.05.

    RESULTS: In the OCD group, correlations with total CTQ scores were positively associated with a larger right orbitofrontal cortex volume. Physical neglect was higher in the OCD group than in controls and was positively associated with larger right cerebellum volume in the OCD group only.

    CONCLUSIONS: Larger brain volumes may reflect underlying developmental neuropathology in adults with OCD who also have experience of childhood trauma.

  • 70.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nilsson, Emil K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Stein, Dan J
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 1, s. e82707-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking.

    METHODS: 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF.

    RESULTS: The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes.

    CONCLUSIONS: The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.

  • 71.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen G.
    Uher, Rudolf
    Friederich, Hans-Christoph
    Giampietro, Vincent
    Brammer, Michael
    Williams, Steven C. R.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C.
    Differential Neural Responses to Food Images in Women with Bulimia versus Anorexia Nervosa2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, s. e22259-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Previous fMRI studies show that women with eating disorders (ED) have differential neural activation to viewing food images. However, despite clinical differences in their responses to food, differential neural activation to thinking about eating food, between women with anorexia nervosa (AN) and bulimia nervosa (BN) is not known. Methods: We compare 50 women (8 with BN, 18 with AN and 24 age-matched healthy controls [HC]) while they view food images during functional Magnetic Resonance Imaging (fMRI). Results: In response to food (vs non-food) images, women with BN showed greater neural activation in the visual cortex, right dorsolateral prefrontal cortex, right insular cortex and precentral gyrus, women with AN showed greater activation in the right dorsolateral prefrontal cortex, cerebellum and right precuneus. HC women activated the cerebellum, right insular cortex, right medial temporal lobe and left caudate. Direct comparisons revealed that compared to HC, the BN group showed relative deactivation in the bilateral superior temporal gyrus/insula, and visual cortex, and compared to AN had relative deactivation in the parietal lobe and dorsal posterior cingulate cortex, but greater activation in the caudate, superior temporal gyrus, right insula and supplementary motor area. Conclusions: Women with AN and BN activate top-down cognitive control in response to food images, yet women with BN have increased activation in reward and somatosensory regions, which might impinge on cognitive control over food consumption and binge eating.

  • 72.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen G.
    Uher, Rudolf
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C.
    Subliminal food images compromise superior working memory performance in women with restricting anorexia nervosa2012Inngår i: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 21, nr 2, s. 751-763Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prefrontal cortex (PFC) is dysregulated in women with restricting anorexia nervosa (RAN). It is not known whether appetitive non-conscious stimuli bias cognitive responses in those with RAN. Thirteen women with RAN and 20 healthy controls (HC) completed a dorsolateral PFC (DLPFC) working memory task and an anterior cingulate cortex (ACC) conflict task, while masked subliminal food, aversive and neutral images were presented. During the DLPFC task, accuracy was higher in the RAN compared to the HC group, but superior performance was compromised when subliminal food stimuli were presented: errors positively correlated with self-reported trait anxiety in the RAN group. These effects were not observed in the ACC task. Appetitive activation is intact and anxiogenic in women with RAN, and non-consciously interacts with working memory processes associated with the DLPFC. This interaction mechanism may underlie cognitive inhibition of appetitive processes that are anxiety inducing, in people with AN.

  • 73.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen
    Uher, Rudolf
    Friederich, Hans-Christoph
    Giampietro, Vincent
    Brammer, Michael
    Williams, Steven C. R.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C.
    Thinking about Eating Food Activates Visual Cortex with Reduced Bilateral Cerebellar Activation in Females with Anorexia Nervosa: An fMRI Study2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. e34000-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Women with anorexia nervosa (AN) have aberrant cognitions about food and altered activity in prefrontal cortical and somatosensory regions to food images. However, differential effects on the brain when thinking about eating food between healthy women and those with AN is unknown.

    Methods: Functional magnetic resonance imaging (fMRI) examined neural activation when 42 women thought about eating the food shown in images: 18 with AN (11 RAN, 7 BPAN) and 24 age-matched controls (HC).

    Results: Group contrasts between HC and AN revealed reduced activation in AN in the bilateral cerebellar vermis, and increased activation in the right visual cortex. Preliminary comparisons between AN subtypes and healthy controls suggest differences in cortical and limbic regions.

    Conclusions: These preliminary data suggest that thinking about eating food shown in images increases visual and prefrontal cortical neural responses in females with AN, which may underlie cognitive biases towards food stimuli and ruminations about controlling food intake. Future studies are needed to explicitly test how thinking about eating activates restraint cognitions, specifically in those with restricting vs. binge-purging AN subtypes.

  • 74.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Savov, Vasil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Allzen, E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex: A systematic meta-analysis of fMRI studies2012Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 59, nr 3, s. 2962-2973Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.

  • 75.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Solstrand Dahlberg, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Swenne, Ingemar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Aronsson, Marianne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Zarei, Sanaz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lundberg, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Salonen-Ros, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Rosling, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Obsessive-compulsivity and working memory are associated with differential prefrontal cortex and insula activation in adolescents with a recent diagnosis of an eating disorder2014Inngår i: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 224, nr 3, s. 246-253Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of rumination at the beginning of eating disorder (ED) is not well understood. We hypothesised that impulsivity, rumination and restriction could be associated with neural activity in response to food stimuli in young individuals with eating disorders (ED). We measured neural responses with functional magnetic resonance imaging (fMRI), tested working memory (WM) and administered the eating disorders examination questionnaire (EDE-Q), Barratt impulsivity scale (BIS-11) and obsessive-compulsive inventory (OCI-R) in 15 adolescent females with eating disorder not otherwise specified (EDNOS) (mean age 15 years) and 20 age-matched healthy control females. We found that EDNOS subjects had significantly higher scores on the BIS 11, EDE-Q and OCI-R scales. Significantly increased neural responses to food images in the EDNOS group were observed in the prefrontal circuitry. OCI-R scores in the EDNOS group also significantly correlated with activity in the prefrontal circuitry and the cerebellum. Significantly slower WM responses negatively correlated with bilateral superior frontal gyrus activity in the EDNOS group. We conclude that ruminations, linked to WM, are present in adolescent females newly diagnosed with EDNOS. These may be risk factors for the development of an eating disorder and may be detectable before disease onset.

  • 76.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. UCT Department of Psychiatry and Mental Health Groote Schuur Hospital Cape Town South Africa.
    Wiemerslage, L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Burch, K H
    Maiorana, S A
    Cocolas, E
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kamaloodien, K
    Stein, D J
    The impact of cognitive training in substance use disorder: the effect of working memory training on impulse control in methamphetamine users2017Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, nr 12, s. 1911-1921Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Impulsivity is a vulnerability trait for poor self-regulation in substance use disorder (SUD). Working memory (WM) training improves impulsivity and self-regulation in psychiatric disorders. Here we test WM training in methamphetamine use disorder (MUD).

    METHODS: There are 15 MUD patients receiving inpatient treatment as usual (TAU) and 20 who additionally completed WM cognitive training (CT) and 25 healthy controls (HC). MANCOVA repeated measures analyses examined changes in impulsivity and self-regulation at baseline and after 4 weeks.

    RESULTS:  = 0.3523, p < 0.05). Compared to follow-up TAU, follow-up CT group had higher self-reported mood scores (t = 2.784, p = 0.01) and higher compared to CT baseline (t = 2.386, p = 0.036). Feelings of self-control were higher in CT than TAU at follow-up (t = 2.736, p = 0.012) and also compared to CT baseline (t = 3.390, p = 0.006), lack of planning significantly improved in CT between baseline and follow-up (t = 2.219, p = 0.048), as did total impulsivity scores (t = 2.085, p = 0.048). Measures of self-regulation were improved in the CT group compared to TAU at follow-up, in total score (t = 2.442, p = 0.038), receiving score (t = 2.314, p = 0.029) and searching score (t = 2.362, p = 0.027). Implementing self-regulation was higher in the CT group compared to TAU (t = 2.373, p = 0.026).

    CONCLUSIONS: WM training may improve control of impulsivity and self-regulation in people with MUD.

  • 77.
    Brooks, Samantha Jane
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi Birgir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    A debate on current eating disorder diagnoses in light of neurobiological findings: is it time for a spectrum model?2012Inngår i: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 12, s. 76-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Sixty percent of eating disorders do not meet criteria for anorexia- or bulimia nervosa, as defined by the Diagnostic and Statistical Manual version 4 (DSM-IV). Instead they are diagnosed as 'eating disorders not otherwise specified' (EDNOS). Discrepancies between criteria and clinical reality currently hampering eating disorder diagnoses in the DSM-IV will be addressed by the forthcoming DSM-V. However, future diagnoses for eating disorders will rely on current advances in the fields of neuroimaging and genetics for classification of symptoms that will ultimately improve treatment. Discussion: Here we debate the classification issues, and discuss how brain imaging and genetic discoveries might be interwoven into a model of eating disorders to provide better classification and treatment. The debate concerns: a) current issues in the classification of eating disorders in the DSM-IV, b) changes proposed for DSM-V, c) neuroimaging eating disorder research and d) genetic eating disorder research. Summary: We outline a novel evidence-based 'impulse control' spectrum model of eating disorders. A model of eating disorders is proposed that will aid future diagnosis of symptoms, coinciding with contemporary suggestions by clinicians and the proposed changes due to be published in the DSM-V.

  • 78.
    Brooks, Samantha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Cape Town, Cape Town, South Africa..
    Lochner, Christine
    Univ Stellenbosch, US UCT MRC Unit Anxiety & Stress Disorders, Stellenbosch, South Africa..
    Shoptaw, Steve
    Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA, USA..
    Stein, Dan J.
    Univ Cape Town, US UCT MRC Unit Anxiety & Stress Disorders, Cape Town, South Africa..
    Using the research domain criteria (RDoC) to conceptualize impulsivity and compulsivity in relation to addiction2017Inngår i: Brain Research In Addiction / [ed] Calvey, T Daniels, WMU, ELSEVIER , 2017, s. 177-218Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Nomenclature for mental disorder was updated in 2013 with the publication of the fifth edition of the Diagnostic and Statistical Manual (DSM-5). In DSM-5, substance use disorders are framed as more dimensional. First, the distinction between abuse and dependence is replaced by substance use. Second, the addictions section now covers both substances and behavioral addictions. This contemporary move toward dimensionality and transdiagnosis in the addictions and other disorders embrace accumulating cognitive-affective neurobiological evidence that is reflected in the United States' National Institutes of Health Research Domain Criteria (NIH RDoC). TheRDoCcalls for the further development of transdiagnostic approaches to psychopathy and includes five domains to improve research. Additionally, the RDoC suggests that these domains can be measured in terms of specific units of analysis. In line with these suggestions, recent publications have stimulated updated neurobiological conceptualizations of two transdiagnostic concepts, namely impulsivity and compulsivity and their interactions that are applicable to addictive disorders. However, there has not yet been a review to examine the constructs of impulsivity and compulsivity in relation to addiction in light of the research-oriented RDoC. By doing so it may become clearer as to whether impulsivity and compulsivity function antagonistically, complementarily or in some other way at the behavioral, cognitive, and neural level and how this relationship underpins addiction. Thus, here we consider research into impulsivity and compulsivity in light of the transdiagnostic RDoC to help better understand these concepts and their application to evidence-based clinical intervention for addiction.

  • 79. Bruenner, Y. F.
    et al.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, J.
    Targeting the brain through the nose. Effects of intranasally administered insulin2013Inngår i: Nervenarzt, ISSN 0028-2804, E-ISSN 1433-0407, Vol. 84, nr 8, s. 949-954Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The assumption that the human brain is an insulin-independent organ was disproved with the discovery of insulin receptors in the central nervous system in the year 1978. Evidence has been provided for a high density of insulin receptors in brain regions responsible for cognitive memory processes (hippocampus) and for the regulation of appetite (hypothalamus). Accordingly, in animal studies an increased insulin level in the central nervous system leads to an improvement of hippocampal memory function and a decrease of food intake. Similar results were obtained in humans using the method of intranasal administration of insulin. Intranasal insulin reaches the brain and the cerebrospinal fluid via the olfactory epithelium and olfactory nerve fiber bundles leading through the lamina cribrosa to the olfactory bulb. Thus, this method renders the investigation of specific insulin effects in humans possible. The therapeutic potential of an intranasal insulin administration for the treatment of diseases for which an imbalance of the central nervous insulin metabolism is discussed (e.g. Alzheimer's disease, diabetes mellitus and obesity) can only be estimated with the help of further clinical studies.

  • 80. Bruenner, Yvonne F.
    et al.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, Jessica
    Intranasal Insulin Reduces Olfactory Sensitivity in Normosmic Humans2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 10, s. E1626-E1630Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: High densities of insulin receptors are found throughout the human brain, including the olfactory bulb, an essential brain area for odor processing. This brain region is the phylogenetically oldest part of the olfactory central nervous system. Objective: We hypothesized that enhanced brain insulin signaling would modulate olfactory processing in humans. Design: We applied a double-blind, placebo-controlled, balanced within-subject design. Setting: This study was conducted in the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: A single dose of either insulin (40 IU) or placebo was intranasally administered to 17 normal-weight normosmic participants (7 women). Subjects' olfactory abilities were examined by means of an olfactory threshold test (odorant n-butanol) and an olfactory discrimination test. In addition, circulating concentrations of glucose, insulin, and cortisol levels were measured. Results: After intranasal insulin administration, subjects' sensitivity for the odorant n-butanol was significantly decreased compared with that for the placebo condition (-13%; P = .025), whereas olfactory discrimination ability was not (P = .841). While serum insulin and serum cortisol were not altered after intranasal insulin administration, there was a small but significant drop in plasma glucose levels. Importantly, a correlational analysis demonstrated that this treatment-induced drop in plasma glucose was not related to the effects of intranasal insulin on olfactory sensitivity. Conclusions: These findings suggest that intranasal insulin impairs olfactory sensitivity for a non-food odorant, whereas no such effects were found for olfactory discrimination. Thus, variations in brain insulin signaling most likely have implications for the olfactory threshold of normosmic humans. Bearing in mind the fact that insulin acts as an anorexigenic signal in the human brain, further studies are needed to test whether intranasal insulin also impairs the ability of humans to perceive food-related odors.

  • 81. Bruenner, Yvonne F.
    et al.
    Kofoet, Anja
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, Jessica
    Central Insulin Administration Improves Odor-Cued Reactivation of Spatial Memory in Young Men2015Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 1, s. 212-219Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. Objective: The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. Design: We applied a double-blind, placebo-controlled, counterbalanced within-subject design. Setting: The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled similar to 10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Results: Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. Conclusions: These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

  • 82.
    Bruenner, Yvonne F.
    et al.
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Rodriguez-Raecke, Rea
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, Jessica
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Modulation of odor-cued memory processing by intranasal insulin2015Inngår i: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 40, nr 7, s. 603-603Artikkel i tidsskrift (Annet vitenskapelig)
  • 83.
    Bränn, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Papadopoulos, Fotios
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Fransson, Emma
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.; Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden .
    White, Richard
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Edvinsson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Boström, Adrian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Sundström-Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Skalkidou, Alkistis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Inflammatory markers in late pregnancy in association with postpartum depression-A nested case-control study.2017Inngår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 79, s. 146-159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies indicate that the immune system adaptation during pregnancy could play a significant role in the pathophysiology of perinatal depression. The aim of this study was to investigate if inflammation markers in a late pregnancy plasma sample can predict the presence of depressive symptoms at eight weeks postpartum. Blood samples from 291 pregnant women (median and IQR for days to delivery, 13 and 7-23days respectively) comprising 63 individuals with postpartum depressive symptoms, as assessed by the Edinburgh postnatal depression scale (EPDS≥12) and/or the Mini International Neuropsychiatric Interview (M.I.N.I.) and 228 controls were analyzed with an inflammation protein panel using multiplex proximity extension assay technology, comprising of 92 inflammation-associated markers. A summary inflammation variable was also calculated. Logistic regression, LASSO and Elastic net analyses were implemented. Forty markers were lower in late pregnancy among women with depressive symptoms postpartum. The difference remained statistically significant for STAM-BP (or otherwise AMSH), AXIN-1, ADA, ST1A1 and IL-10, after Bonferroni correction. The summary inflammation variable was ranked as the second best variable, following personal history of depression, in predicting depressive symptoms postpartum. The protein-level findings for STAM-BP and ST1A1 were validated in relation to methylation status of loci in the respective genes in a different population, using openly available data. This explorative approach revealed differences in late pregnancy levels of inflammation markers between women presenting with depressive symptoms postpartum and controls, previously not described in the literature. Despite the fact that the results do not support the use of a single inflammation marker in late pregnancy for assessing risk of postpartum depression, the use of STAM-BP or the novel notion of a summary inflammation variable developed in this work might be used in combination with other biological markers in the future.

  • 84.
    Brünner, Yvonne F.
    et al.
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Rodriguez-Raecke, Rea
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Mutic, Smiljana
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, Jessica
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany.;Fraunhofer Inst Proc Engn & Packaging IVV, D-85354 Freising Weihenstephan, Germany..
    Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application2016Inngår i: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 134, nr Part B, s. 256-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40 ID) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance.

  • 85.
    Burger, Antoinette
    et al.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Anzio Rd, ZA-7925 Cape Town, South Africa;Univ Cape Town, Inst Neurosci, Cape Town, South Africa.
    Brooks, Samantha J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Anzio Rd, ZA-7925 Cape Town, South Africa.
    Stein, Dan J.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Anzio Rd, ZA-7925 Cape Town, South Africa;MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa;Univ Cape Town, Inst Neurosci, Cape Town, South Africa.
    Howells, Fleur M.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, Anzio Rd, ZA-7925 Cape Town, South Africa;Univ Cape Town, Inst Neurosci, Cape Town, South Africa.
    The impact of acute and short-term methamphetamine abstinence on brain metabolites: A proton magnetic resonance spectroscopy chemical shift imaging study2018Inngår i: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 185, s. 226-237Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Abuse of methamphetamine (MA) is a global health concern. Previous H-1-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites.

    Methods

    Adults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift H-1-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 +/- 0.6 weeks, n = 31) and short-term MAA (5.1 +/- 0.8 weeks, n = 22). The change in H-1-MRS metabolites over time (n = 19) was also investigated. Standard H-1-MRS metabolites are reported relative to Cr + PCr.

    Results

    Acute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM.

    Conclusion

    In acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first H-1-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA.

  • 86.
    Cai, Gui-Hong
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Theorell-Haglöw, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Elmstahl, S.
    Lund Univ, Div Geriatr Med, Dept Hlth Sci, Lund, Sweden.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Lindberg, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Both weight at age 20 and weight gain have an impact on sleep disturbances later in life – results of the epihealth study2017Inngår i: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 40, nr Supplement 1, s. E195-E195Artikkel i tidsskrift (Annet vitenskapelig)
  • 87.
    Cai, Gui-Hong
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Theorell-Haglöw, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Elmståhl, Sölve
    Lund Univ, Skane Univ Hosp, Sweden CRC, Dept Hlth Sci,Div Geriatr Med, Malmo, Sweden..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindberg, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Both Weight at Age 20 and Weight Gain Have an Impact on Sleep Disturbances Later in Life: Results of the EpiHealth Study2018Inngår i: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 41, nr 1, artikkel-id zsx176Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Study Objectives: Obesity is often associated with impaired sleep, whereas the impact of body mass index (BMI) at younger age and previous weight gain on sleep problems remains unknown.

    Methods: The present study utilized data from the Swedish EpiHealth cohort study. A total of 15 845 participants (45-75 years) filled out an internet-based questionnaire. BMI was calculated from both measured data at study time and self-reported data at age 20 from the questionnaire.

    Results: Sleep-related symptoms were most common among obese individuals (BMI >30 kg/m(2)). An association between weight gain and sleep problems was found and those with a low BMI at age 20 were most vulnerable to weight gain when it came to risk of sleep problems. Among those who were underweight (BMI <18.5 kg/m(2)) at age 20, weight gain (kg/year) was associated with difficulties initiating sleep with an adjusted OR of 2.64 (95% CI: 1.51-4.62) after adjusting for age, sex, smoking, alcohol consumption, physical activity, education, and civil status. The corresponding adjusted OR's among those who had been normal weight (BMI 18.5-24.99) and overweight (BMI 25-29.99 kg/m(2)) at age 20 were 1.89 (1.47-2.45) and 1.02 (0.48-2.13), respectively. Also difficulties maintaining sleep and snoring were most strongly related to weight gain among those who were underweight at age 20 with decreasing odds with increasing BMI at that age.

    Conclusions: Sleep problems are related to weight gain and obesity. The impact of weight is most pronounced among those who had a low BMI when young.

  • 88.
    Cao, Hao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Marttila, Petra S. K. ()
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J. ()
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B. ()
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster2016Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed toDEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects fromDEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP mayhave detrimental effects on metabolic functions.

  • 89.
    Cao, Hao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Most species are constantly exposed to xenobiotic chemicals through multiple routes. Among all categories of xenobiotics, phthalates and bisphenols are two of the most widely used plasticizers and can be found in polyvinyl chloride (PVC) materials, medical devices and even drinking water. In paper I, we found that bis-(2-ethylhexyl) phthalate (DEHP) exposure caused a significant decrease in circulating carbohydrates and insulin-related genes. The Multidrug-Resistance like Protein 1 (MRP1, MRP in Drosophila) belongs to the ATP-binding cassette transporter family, and previous studies revealed the importance of MRP1 for transporting xenobiotics. However, the function of MRP1 in metabolism and other biological processes is still unclear. Therefore, in paper II, we showed that knocking down MRP expression in Malpighian tubules, the physiological equivalence of the vertebrate kidney, led to disrupted lipid homeostasis and oxidative resistance. In paper III and IV, we initially used whole transcriptome sequencing to assess the genetic interferences of exposure to Dibutyl Phthalate (DBP) and Bisphenol A Diglycidyl Ether (BADGE). The reproductive and developmental disruptions of DBP had been reported in many studies. However, the mechanism is still unclear. In paper III, we observed that DBP interfered with neuronal systems associated circadian genes, including in vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Furthermore, we demonstrated that the evolutionarily conserved gene, Hormone receptor-like in 38 (Hr38, human NR4A2) was involved in responding to DBP and regulated Pdf expression as a consequence. In paper IV, BADGE, a BPA-substitute, was tested for its disruptive effects on Drosophila. Based on the transcriptome sequencing, we found that several mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), had detectable overexpression by BADGE exposure. Developmental exposure to BADGE induced a large increase of hemocytes in fly 3rd instar larvae, while it did not damage the morphological structure of lymph gland and blood circulation. To summarize, our studies describe the potential disruptions of the industrial xenobiotics and provide the mechanistic hints for future investigations.

    Delarbeid
    1. Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
    Åpne denne publikasjonen i ny fane eller vindu >>Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
    Vise andre…
    2016 (engelsk)Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, nr 3, s. 309-316Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-303019 (URN)10.1111/bcpt.12587 (DOI)000380889500011 ()27009472 (PubMedID)
    Eksternt samarbeid:
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2016-09-14 Laget: 2016-09-14 Sist oppdatert: 2018-07-31bibliografisk kontrollert
    2. Multidrug-Resistance like Protein 1 activity in Malpighian tubules regulates lipid homeostasis in Drosophila
    Åpne denne publikasjonen i ny fane eller vindu >>Multidrug-Resistance like Protein 1 activity in Malpighian tubules regulates lipid homeostasis in Drosophila
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Multidrug-Resistance like Proteins (MRPs) are ubiquitously expressed essential transporters required for many biological processes. Previous studies revealed that MRPs are pivotal for transporting endo- and xenobiotics, conferring resistance to anti-cancer agents and contributing to clearance of oxidative products. Nonetheless, their functions in other biological processes are still unclear. In our investigation, we suppress the expression of Drosophila Multidrug resistance like Protein 1 (MRP) in Malpighian tubules, the functional equivalent to the human kidney, and find this is sufficient to cause abnormal lipid accumulation, as well as disrupt normal feeding patterns. In addition, we suggest that the elevation of lipid contents may be a result of increasing Hr96 (homolog of human Pregnane X receptor) expression, which is known to play a role in detoxification and lipid metabolism processes. Finally, we validate that Malpighian tubules-specific MRP deficiency increases oxidative resistance in fruit flies. In summary, our results demonstrate that inadequate MRP expression in Malpighian tubules can lead to disrupted lipid homeostasis and feeding behavior. However, it may also elevate the oxidative resistance of the flies.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-356540 (URN)
    Tilgjengelig fra: 2018-07-31 Laget: 2018-07-31 Sist oppdatert: 2018-07-31
    3. Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in Drosophila
    Åpne denne publikasjonen i ny fane eller vindu >>Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in Drosophila
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Due to their common use as industrial plasticizers, agents in cosmetics and inclusion in skin care products, people are constantly exposed to phthalate xenobiotics. Although much research has focused on their ability to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, how phthalates interfere with these biological functions is still unclear. Using whole transcriptome analysis, we demonstrate that exposing the genetically-tractable model system Drosophila melanogaster to the xenobiotic Dibutyl Pthalate (DBP) throughout development interferes with neuronal systems associated with vision and circadian rhythm. Of note, while DBP did not influence with eye development, it inhibited the expression of signaling systems regulating vision, including Rhodopsin 5 (Rh5) and Rhodopsin 6 (Rh6), two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm. Furthermore, DBP influenced the expression of genes central to circadian rhythm regulation, including vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Finally, we demonstrate that DBP disrupts circadian rhythm by interacting with the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which in turn regulates Pdf expression. Our results are the first to provide comprehensive evidence that DBP interferes with the circadian rhythm system.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-356541 (URN)
    Tilgjengelig fra: 2018-07-31 Laget: 2018-07-31 Sist oppdatert: 2018-07-31
    4. Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in Drosophila
    Åpne denne publikasjonen i ny fane eller vindu >>Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in Drosophila
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Since the estrogenic activity of bisphenol A had been reported, the industry started to find a proper replacement. Bisphenol A diglycidyl ether (BADGE) is one of the derivatives of BPA which is used widely in epoxy resin manufactory. Recently, some studies have demonstrated the adverse effects of BADGE on reproduction and development. However, the knowledge of BADGE is still scarce. Because of its hydrolytic property, BADGE is usually detected at a low level in commodities and the influences seem to be underestimated. In our study, we use the whole transcriptome sequencing to assess the effects of developmental BADGE exposure on Drosophila melanogaster. Notably, the genes related to cell proliferation are significantly affected by BADGE exposure. More detailed, a group of mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), are detectable overexpressed. Phenotypically, we observe that BADGE induces severe hemocytes over-proliferation in the 3rd instar larvae, but does not cause morphological damage of the larval lymph gland and blood circulation. In conclusion, we provide evidence to show the carcinogenic potential of BADGE and raise the concern of better understanding of xenobiotics. 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-356544 (URN)
    Tilgjengelig fra: 2018-07-31 Laget: 2018-07-31 Sist oppdatert: 2018-07-31
  • 90.
    Cao, Hao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hosseini, Kimia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Siyahtiri, Mohammad M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Maestri, Giulia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Shirazi, Mehdi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Svedin, Robin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in DrosophilaManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Due to their common use as industrial plasticizers, agents in cosmetics and inclusion in skin care products, people are constantly exposed to phthalate xenobiotics. Although much research has focused on their ability to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, how phthalates interfere with these biological functions is still unclear. Using whole transcriptome analysis, we demonstrate that exposing the genetically-tractable model system Drosophila melanogaster to the xenobiotic Dibutyl Pthalate (DBP) throughout development interferes with neuronal systems associated with vision and circadian rhythm. Of note, while DBP did not influence with eye development, it inhibited the expression of signaling systems regulating vision, including Rhodopsin 5 (Rh5) and Rhodopsin 6 (Rh6), two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm. Furthermore, DBP influenced the expression of genes central to circadian rhythm regulation, including vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Finally, we demonstrate that DBP disrupts circadian rhythm by interacting with the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which in turn regulates Pdf expression. Our results are the first to provide comprehensive evidence that DBP interferes with the circadian rhythm system.

  • 91.
    Cao, Hao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kimari, Moses
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Maronitis, George
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Multidrug-Resistance like Protein 1 activity in Malpighian tubules regulates lipid homeostasis in DrosophilaManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Multidrug-Resistance like Proteins (MRPs) are ubiquitously expressed essential transporters required for many biological processes. Previous studies revealed that MRPs are pivotal for transporting endo- and xenobiotics, conferring resistance to anti-cancer agents and contributing to clearance of oxidative products. Nonetheless, their functions in other biological processes are still unclear. In our investigation, we suppress the expression of Drosophila Multidrug resistance like Protein 1 (MRP) in Malpighian tubules, the functional equivalent to the human kidney, and find this is sufficient to cause abnormal lipid accumulation, as well as disrupt normal feeding patterns. In addition, we suggest that the elevation of lipid contents may be a result of increasing Hr96 (homolog of human Pregnane X receptor) expression, which is known to play a role in detoxification and lipid metabolism processes. Finally, we validate that Malpighian tubules-specific MRP deficiency increases oxidative resistance in fruit flies. In summary, our results demonstrate that inadequate MRP expression in Malpighian tubules can lead to disrupted lipid homeostasis and feeding behavior. However, it may also elevate the oxidative resistance of the flies.

  • 92.
    Cao, Hao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lindkvist, Therese
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Mothes, Tobias J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in DrosophilaManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Since the estrogenic activity of bisphenol A had been reported, the industry started to find a proper replacement. Bisphenol A diglycidyl ether (BADGE) is one of the derivatives of BPA which is used widely in epoxy resin manufactory. Recently, some studies have demonstrated the adverse effects of BADGE on reproduction and development. However, the knowledge of BADGE is still scarce. Because of its hydrolytic property, BADGE is usually detected at a low level in commodities and the influences seem to be underestimated. In our study, we use the whole transcriptome sequencing to assess the effects of developmental BADGE exposure on Drosophila melanogaster. Notably, the genes related to cell proliferation are significantly affected by BADGE exposure. More detailed, a group of mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), are detectable overexpressed. Phenotypically, we observe that BADGE induces severe hemocytes over-proliferation in the 3rd instar larvae, but does not cause morphological damage of the larval lymph gland and blood circulation. In conclusion, we provide evidence to show the carcinogenic potential of BADGE and raise the concern of better understanding of xenobiotics. 

  • 93.
    Cao, Hao
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Wiemerslage, Lyle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Marttila, Petra S. K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster2016Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, nr 3, s. 309-316Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.

  • 94.
    Carlini, V. P.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ghersi, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Gabach, L.
    Schioth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Perez, M. F.
    Ramirez, O. A.
    Fiol de Cuneo, M.
    de Barioglio, S. R.
    Hippocampal effects of neuronostatin on memory, anxiety-like behavior and food intake in rats2011Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 197, s. 145-152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A 13-amino acid peptide named neuronostatin (NST) encoded in the somatostatin pro-hormone has been recently reported. It is produced throughout the body, particularly in brain areas that have significant actions over the metabolic and autonomic regulation. The present study was performed in order to elucidate the functional role of NST on memory, anxiety-like behavior and food intake and the hippocampal participation in these effects. When the peptide was intra-hippocampally administered at 3.0 nmol/mu l, it impaired memory retention in both, object recognition and step-down test. Also, this dose blocked the hippocampal long-term potentiation (LTP) generation. When NST was intra-hippocampally administered at 0.3 nmol/mu l and 3.0 nmol/mu l, anxiolytic effects were observed. Also, the administration in the third ventricle at the higher dose (3.0 nmol/mu l) induced similar effects, and both doses reduced food intake. The main result of the present study is the relevance of the hippocampal formation in the behavioral effects induced by NST, and these effects could be associated to a reduced hippocampal synaptic plasticity.

  • 95. Carlini, Valeria P
    et al.
    Ghersi, Marisa
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    de Barioglio, Susana R
    Ghrelin and memory: differential effects on acquisition and retrieval2010Inngår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 31, nr 6, s. 1190-1193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a previous paper we have demonstrated that the orexigenic peptide Ghrelin (Ghr), increases memory retention in rats and mice. In the present work we evaluated the Ghr effect when it was administered previous the training session or previous the test session (24h after training) on the memory performance, using step-down test. The results showed that the intra-hippocampal Ghr administration previous the training session improved the long-term memory in this task, but did not modify the short-term memory. Nevertheless, when the Ghr was administrated previous the test session, no changes were observed in the memory performance. Taking into account these results and other previously published by our group, we could hypothesizes that Ghr may modulate specific molecular intermediates involved in memory acquisition/consolidation but not in the retrieval.

  • 96.
    Carlini, Valeria P.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Perez, Mariela F.
    Salde, Estela
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ramirez, Oscar A.
    de Barioglio, Susana R.
    Ghrelin induced memory facilitation implicates nitric oxide synthase activation and decrease in the threshold to promote LTP in hippocampal dentate gyrus2010Inngår i: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 101, nr 1, s. 117-123Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although the hypothalamus has been long considered the main ghrelin (Ghr) target organ mediating orexigenic effects, recently it has been shown that in-vivo Ghr hippocampus administration improves learning and memory in the inhibitory avoidance paradigm. However, the possible mechanisms underlying this memory facilitation effect have not been clarified. Given that the biochemical memory cascade into the hippocampus involves nitric oxide (NO) synthesis via NO synthase (NOS) activation, we investigated 1) if Ghr administration modulated NOS activity in the hippocampus; and 2) if hippocampal NOS inhibition influenced Ghr-induced memory facilitation, using a behavioral paradigm, biochemical determinations and an electrophysiological model. Our results showed that intra-hippocampal Ghr administration increased the NOS activity in a dose dependent manner, and reduced the threshold for LTP generation in dentate gyrus of rat hippocampus. Moreover, pre-administration of NG-nitro-l-arginine (l-NOArg) in the hippocampus partially prevented the Ghr-induced memory improvement, abolished the increase in NOS activity, and prevented the decreased threshold to generate LTP induced by Ghr. These findings suggest that activation of the NOS/NO pathway in hippocampus participates in the effects of Ghr on memory consolidation and is related with plastic properties of the hippocampal three-synaptic loop.

  • 97.
    Caruso, Vanni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hägglund, Maria G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Badiali, Luca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bagchi, Sonchita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Roshanbin, Sahar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ahmad, Tauseef
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    The G protein-coupled receptor GPR162 is widely distributed in the CNS and highly expressed in the hypothalamus and in hedonic feeding areas2014Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 553, nr 1, s. 1-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Rhodopsin family is a class of integral membrane proteins belonging to G protein-coupled receptors (GPCRs). To date, several orphan GPCRs are still uncharacterized and in this study we present an anatomical characterization of the GPR162 protein and an attempt to describe its functional role. Our results show that GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in areas related to energy homeostasis and hedonic feeding such as hypothalamus, amygdala and ventral tegmental area, regions known to be involved in the regulation of palatable food consumption.

  • 98.
    Caruso, Vanni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lagerström, Malin C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Olszewski, Pawel K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Synaptic changes induced by melanocortin signalling2014Inngår i: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 15, nr 2, s. 98-110Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.

  • 99.
    Caruso, Vanni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Le Greves, Madeleine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fard, Shahrzad Shirazi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Haitina, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Olszewski, Pawel K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Alsiö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    The Orphan G Protein-Coupled Receptor Gene GPR178 Is Evolutionary Conserved and Altered in Response to Acute Changes in Food Intake2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikkel-id e0122061Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating physiological functions fundamental for survival, including energy homeostasis. A few years ago, an amino acid sequence of a novel GPCR gene was identified and named GPR178. In this study, we provide new insights regarding the biological significance of Gpr178 protein, investigating its evolutionary history and tissue distribution as well as examining the relationship between its expression level and feeding status. Our phylogenetic analysis indicated that GPR178 is highly conserved among all animal species investigated, and that GPR178 is not a member of a protein family. Real-time PCR and in situ hybridization revealed wide expression of Gpr178 mRNA in both the brain and periphery, with high expression density in the hypothalamus and brainstem, areas involved in the regulation of food intake. Hence, changes in receptor expression were assessed following several feeding paradigms including starvation and overfeeding. Short-term starvation (12-48h) or food restriction resulted in upregulation of Gpr178 mRNA expression in the brainstem, hypothalamus and prefrontal cortex. Conversely, short-term (48h) exposure to sucrose or Intralipid solutions downregulated Gpr178 mRNA in the brainstem; long-term exposure (10 days) to a palatable high-fat and high-sugar diet resulted in a downregulation of Gpr178 in the amygdala but not in the hypothalamus. Our results indicate that hypothalamic Gpr178 gene expression is altered during acute exposure to starvation or acute exposure to palatable food. Changes in gene expression following palatable diet consumption suggest a possible involvement of Gpr178 in the complex mechanisms of feeding reward.

  • 100.
    Caruso, Vanni
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Tasmania UTAS, Fac Pharm, Hobart, Tas 7001, Australia..
    Sreedharan, Smitha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Carlini, Valeria P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Nacl Cordoba, Fac Ciencias Quim Haya Torre & Medina Allende, Dept Farmacol, Ciudad Univ, RA-5016 Cordoba, Argentina..
    Jacobsson, Josefin A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Haitina, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hammer, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Stephansson, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Crona, Filip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Sommer, Wolfgang H.
    Cent Inst Mental Hlth, Dept Psychopharmacol, Mannheim, Germany..
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Marcus, Claude
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Natl Childhood Obes Ctr, Div Pediat, Stockholm, Sweden..
    Heilig, Markus
    NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA..
    de Barioglio, Susana R.
    Univ Nacl Cordoba, Fac Ciencias Quim Haya Torre & Medina Allende, Dept Farmacol, Ciudad Univ, RA-5016 Cordoba, Argentina..
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    mRNA GPR162 changes are associated with decreased food intake in rat, and its human genetic variants with impairments in glucose homeostasis in two Swedish cohorts2016Inngår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 581, nr 2, s. 139-145Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating intercellular interactions of fundamental physiological importance for survival including regulation of food intake, blood pressure, and hormonal sensing signaling, among other roles. Homeostatic alterations in the physiological status of GPCRs are often associated with underlying causes of disease, and to date, several orphan GPCRs are still uncharacterized. Findings from our previous study demonstrate that the Rhodopsin family protein GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in hypothalamus, amygdala, and ventral tegmental area, regions strictly interconnected and involved in the regulation of energy homeostasis and hedonic feeding. In this study, we provide a further anatomical characterization of GPR162 in mouse brain via in situ hybridization as well as detailed mRNA expression in a panel of rat tissues complementing a specie-specific mapping of the receptor. We also provide an attempt to demonstrate a functional implication of GPR162 in food intake-related behavior via antisense knockdown studies. Furthermore, we performed human genetic studies in which for the first time, variants of the GPR162 gene were associated with impairments in glucose homeostasis.

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