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  • 101. Carvajal, Pedro
    et al.
    Carlini, Valeria P.
    Departamento de Farmacología, Facultad de Ciencias Químicas, Haya de la Torre y Medina Allende, Ciudad Universitaria, Universidad Nacional de Córdoba.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Barioglio, Susana R.
    Salvatierra, Nancy A.
    Central ghrelin increases anxiety in the Open Field test and impairs retention memory in a passive avoidance task in neonatal chicks2009In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 91, no 4, p. 402-407Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Grh) is an endogenous ligand for the growth hormone secretagogue receptor. Although Ghr stimulates feeding in rats, it inhibits feeding in neonatal chicks. However, little is known about other central behavioral effects of Ghr. Therefore, we investigated the Ghr effects, injected intracerebroventricularly, on anxiety and memory retention of neonatal chicks in an Open Field test and in a one-trial passive avoidance task, respectively. In the Open Field test, the administration of Ghr in a dose-dependent manner increased the latency to ambulate but decreased ambulation activity, indicating an anxiogenic effect. Furthermore, chicks trained on a passive avoidance task and injected with a dose of 30pmol of Ghr immediately after training showed an impairment of memory retention. However, there were no significant effects on the number of pecks during the pretraining, training, retention and discrimination. In addition, different doses of Ghr produced an inhibition in food intake at different times after injection. Our results indicate that Ghr induces anxiogenesis in chicks. Moreover, we have shown for the first time that Ghr can decrease memory retention in a non-mammalian species, suggesting that Ghr may play an important role in the processes of memory retention in birds.

  • 102.
    Castelnuovo, Gianluca
    et al.
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Giusti, Emanuele Maria
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Manzoni, Gian Mauro
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;eCampus Univ, Fac Psychol, Novedrate, Italy..
    Saviola, Donatella
    Santo Stefano Rehabil Ist, Cardinal Ferrari Rehabil Ctr, Fontanellato, Italy..
    Gabrielli, Samantha
    San Pio X Clin, Pain Med Ctr, Humanitas, Milan, Italy..
    Lacerenza, Marco
    San Pio X Clin, Pain Med Ctr, Humanitas, Milan, Italy..
    Pietrabissa, Giada
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Cattivelli, Roberto
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Spatola, Chiara Anna Maria
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Rossi, Alessandro
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Varallo, Giorgia
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Novelli, Margherita
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Villa, Valentina
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Luzzati, Francesca
    IRCCS Galeazzi Orthoped Inst, Milan, Italy..
    Cottini, Andrea
    IRCCS Galeazzi Orthoped Inst, Milan, Italy..
    Lai, Carlo
    Sapienza Univ Rome, Dept Dynam & Clin Psychol, Rome, Italy..
    Volpato, Eleonora
    Catholic Univ Milan, Dept Psychol, Milan, Italy.;IRCCS Fdn Don Carlo Gnocchi, HD Resp Rehabil Unit, Milan, Italy..
    Cavalera, Cesare
    Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Pagnini, Francesco
    Catholic Univ Milan, Dept Psychol, Milan, Italy.;Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA..
    Tesio, Valentina
    Univ Turin, Dept Psychol, Turin, Italy..
    Castelli, Lorys
    Univ Turin, Dept Psychol, Turin, Italy..
    Tavola, Mario
    ASST Lecco, Anesthesia & Intens Care, Lecce, Italy..
    Torta, Riccardo
    Univ Turin, Dept Neurosci Rita Levi Montalcini, Turin, Italy..
    Arreghini, Marco
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Zanini, Loredana
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Brunani, Amelia
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Seitanidis, Ionathan
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Ventura, Giuseppe
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Capodaglio, Paolo
    San Giuseppe Hosp, Rehabil Unit, Ist Auxol Italiano IRCCS, Verbania, Italy..
    D'Aniello, Guido Edoardo
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Scarpina, Federica
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Brioschi, Andrea
    San Giuseppe Hosp, Dept Neurol & Neurorehabil, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Bigoni, Matteo
    San Giuseppe Hosp, Dept Neurol & Neurorehabil, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Priano, Lorenzo
    Univ Turin, Dept Neurosci Rita Levi Montalcini, Turin, Italy.;San Giuseppe Hosp, Dept Neurol & Neurorehabil, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Mauro, Alessandro
    Univ Turin, Dept Neurosci Rita Levi Montalcini, Turin, Italy.;San Giuseppe Hosp, Dept Neurol & Neurorehabil, Ist Auxol Italiano IRCCS, Verbania, Italy..
    Riva, Giuseppe
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Di Lernia, Daniele
    Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Repetto, Claudia
    Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Regalia, Camillo
    Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Molinari, Enrico
    San Giuseppe Hosp, Psychol Res Lab, Ist Auxol Italiano IRCCS, Verbania, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Notaro, Paolo
    AO Osped Niguarda Ca Granda, Anesthesiol Dept, Pain Med, Milan, Italy..
    Paolucci, Stefano
    Fdn Santa Lucia IRCCS, Rome, Italy..
    Sandrini, Giorgio
    C Mondino Natl Neurol Inst, Pavia, Italy.;Univ Pavia, Dept Brain & Behav Sci, Pavia, Italy..
    Simpson, Susan
    Univ South Australia, Adelaide, SA, Australia.;NHS Lothian, Reg Eating Disorders Unit, Livingston, Scotland..
    Wiederhold, Brenda Kay
    Virtual Real Med Inst, Brussels, Belgium..
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jackson, Jeffrey B.
    Virginia Tech, Falls Church, VA USA..
    Tamburin, Stefano
    Univ Verona, Dept Neurosci Biomed & Movement Sci, Verona, Italy..
    Benedetti, Fabrizio
    Univ Turin, Dept Neurosci Rita Levi Montalcini, Turin, Italy..
    What Is the Role of the Placebo Effect for Pain Relief in Neurorehabilitation?: Clinical Implications From the Italian Consensus Conference on Pain in Neurorehabilitation2018In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 310Article, review/survey (Refereed)
    Abstract [en]

    Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use.

    Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form.

    Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results.

    Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy.

  • 103.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intestinal Gene Expression Profiling and Fatty Acid Responses to a High-fat Diet2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The gastrointestinal tract (GIT) regulates nutrient uptake, secretes hormones and has a crucial gut flora and enteric nervous system. Of relevance for these functions are the G protein-coupled receptors (GPCRs) and the solute carriers (SLCs). The Adhesion GPCR subfamily is known to mediate neural development and immune system functioning, whereas SLCs transport e.g. amino acids, fatty acids (FAs) and drugs over membranes. We aimed to comprehensively characterize Adhesion GPCR and SLC gene expression along the rat GIT. Using qPCR we measured expression of 78 SLCs as well as all 30 Adhesion GPCRs in a twelve-segment GIT model. 21 of the Adhesion GPCRs had a widespread (≥5 segments) or ubiquitous (≥11 segments) expression. Restricted expression patterns were characteristic for most group VII members. Of the SLCs, we found the majority (56 %) of these transcripts to be expressed in all GIT segments. SLCs were predominantly found in the absorption-responsible gut regions. Both Adhesion GPCRs and SLCs were widely expressed in the rat GIT, suggesting important roles. The distribution of Adhesion GPCRs defines them as a potential pharmacological target.

    FAs constitute an important energy source and have been implicated in the worldwide obesity increase. FAs and their ratios – indices for activities of e.g. the desaturase enzymes SCD-1 (SCD-16, 16:1n-7/16:0), D6D (18:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) – have been associated with e.g. overall mortality and BMI. We examined whether differences in FAs and their indices in five lipid fractions contributed to obesity susceptibility in rats fed a high fat diet (HFD), and the associations of desaturase indices between lipid fractions in animals on different diets. We found that on a HFD, obesity-prone (OP) rats had a higher SCD-16 index and a lower linoleic acid (LA) proportions in subcutaneous adipose tissue (SAT) than obesity-resistant rats. Desaturase indices were significantly correlated between many of the lipid fractions. The higher SCD-16 may indicate higher SCD-1 activity in SAT in OP rats, and combined with lower LA proportions may provide novel insights into HFD-induced obesity. The associations between desaturase indices show that plasma measurements can serve as proxies for some lipid fractions, but the correlations seem to be affected by diet and weight gain.

  • 104.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Department of Psychology, University of Cambridge, Cambridge.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fatty acid desaturase indices in rats: Associations between plasma, liver and adipose tissue lipid fractions and the effects of a high-fat diet and diet-induced obesityManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Alterations in fatty acid (FA) desaturase indices are linked to obesity-related disorders. As desaturases affect FA composition increased understanding of their regulation across lipid fractions with varying functions is essential. In this study we have examined desaturases and selected FAs to establish their degree of co-regulation in five different lipid fractions and under different dietary conditions, including diet-induced obesity (DIO).

    Methods: Sprague-Dawley rats were randomly grouped into three groups, one fed a chow diet ad libitum (control) and two fed a high-fat diet (HFD): one ad libitum (AL-HFD) and the other one calorically pair fed to the chow-fed group (HFD-paired). FA composition in subcutaneous adipose tissue triacylglycerols (SAT-TG), liver (phospholipids and triacylglycerols) and plasma (phospholipids and cholesterol esters) was assessed. Delta-5 desaturase (D5D), delta-6 desaturase (D6D) and stearoyl-CoA-desaturase 1 (SCD-16) indices were calculated from product-to-precursor FA ratios and proportions of long-chain FAs were measured.

    Results: Positive correlations were found for the desaturase indices between the five lipid fractions, especially for SCD-16 and almost exclusively between liver and plasma fractions. Only SCD-16 in SAT-TG of the AL-HFD group correlated with gain in body weight. Independent of weight gain, the HFD decreased all SCD-16 indices and most FA proportions, but D5D and D6D indices were fraction- and tissue-dependently increased.

    Conclusion: Desaturase indices are especially correlated for SCD-16 and between lipid and plasma lipid fractions, suggesting that SAT-TG desaturation is differentially regulated compared with the other studied lipid fractions. The correlations are however influenced by diet and weight gain, further suggesting such factors should be taken into account when using desaturase indices.

  • 105.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Västermark, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Adipose tissue stearoyl-CoA desaturase 1 index is increased and linoleic acid is decreased in obesity-prone rats fed a high-fat diet2013In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 12, no 2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Fatty acid (FA) composition and desaturase indices are associated with obesity and related metabolic conditions. However, it is unclear to what extent desaturase activity in different lipid fractions contribute to obesity susceptibility. Our aim was to test whether desaturase activity and FA composition are linked to an obese phenotype in rats that are either obesity prone (OP) or resistant (OR) on a high-fat diet (HFD).

    METHODS

    Two groups of Sprague-Dawley rats were given ad libitum (AL-HFD) or calorically restricted (HFD-paired; pair fed to calories consumed by chow-fed rats) access to a HFD. The AL-HFD group was categorized into OP and OR sub-groups based on weight gain over 5 weeks. Five different lipid fractions were examined in OP and OR rats with regard to proportions of essential and very long-chain polyunsaturated FAs: linoleic acid (LA), alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and the stearoyl-CoA desaturase 1 (SCD-1) product 16:1n-7. FA ratios were used to estimate activities of the delta-5-desaturase (20:4n-6/20:3n-6), delta-6-desaturase (18:3n-6/18:2n-6), stearoyl-CoA desaturase 1 (SCD-1; 16:1n-7/16:0, SCD-16 and 18:1n-9/18:0, SCD-18), de novo lipogenesis (16:0/18:2n-6) and FA elongation (18:0/16:0). Fasting insulin, glucose, adiponectin and leptin concentrations were measured in plasma.

    RESULTS

    After AL-HFD access, OP rats had a significantly higher SCD-16 index and 16:1n-7 proportion, but a significantly lower LA proportion, in subcutaneous adipose tissue (SAT) triacylglycerols, as well as significantly higher insulin and leptin concentrations, compared with OR rats. No differences were found between the two phenotypes in liver (phospholipids; triacylglycerols) or plasma (cholesterol esters; phospholipids) lipid fractions or for plasma glucose or adiponectin concentrations. For the desaturase indices of the HFD-paired rats, the only significant differences compared with the OP or OR rats were higher SCD-16 and SCD-18 indices in SAT triacylglycerols in OP compared with HFD-paired rats.

    CONCLUSION

    The higher SCD-16 may reflect higher SCD-1 activity in SAT, which in combination with lower LA proportions may reflect higher insulin resistance and changes in SAT independent of other lipid fractions. Whether a lower SCD-16 index protects against diet-induced obesity is an interesting possibility that warrants further investigation.

  • 106.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bass, Joseph
    Decoding obesity in the brainstem.2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e16393Article in journal (Refereed)
    Abstract [en]

    Neurons in the brainstem are the input for a neural circuit that integrates nutrient signals to control feeding behavior.

  • 107.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Comment on Laker et al. Exercise Prevents Maternal High-Fat Diet-Induced Hypermethylation of the Pgc-1a Gene and Age-Dependent Metabolic Dysfunction in the Offspring. Diabetes 2014; 63:1605-16112014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 5, p. E5-E5Article in journal (Other academic)
  • 108.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Human obesity: FTO, IRX3, or both?2014In: Molecular metabolism, ISSN 2212-8778, Vol. 3, no 5, p. 505-506Article in journal (Other academic)
  • 109.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sleep duration and energy intake: timing matters2014In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 100, no 5, p. 1402-1403Article in journal (Other academic)
  • 110.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brandell, Jon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ros, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Increased Impulsivity in Response to Food Cues after Sleep Loss in Healthy Young Men2014In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 22, no 8, p. 1786-1791Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo investigate whether acute total sleep deprivation (TSD) leads to decreased cognitive control when food cues are presented during a task requiring active attention, by assessing the ability to cognitively inhibit prepotent responses. MethodsFourteen males participated in the study on two separate occasions in a randomized, crossover within-subject design: one night of TSD versus normal sleep (8.5 hours). Following each nighttime intervention, hunger ratings and morning fasting plasma glucose concentrations were assessed before performing a go/no-go task. ResultsFollowing TSD, participants made significantly more commission errors when they were presented no-go food words in the go/no-go task, as compared with their performance following sleep (+56%; P<0.05). In contrast, response time and omission errors to go non-food words did not differ between the conditions. Self-reported hunger after TSD was increased without changes in fasting plasma glucose. The increase in hunger did not correlate with the TSD-induced commission errors. ConclusionsOur results suggest that TSD impairs cognitive control also in response to food stimuli in healthy young men. Whether such loss of inhibition or impulsiveness is food cue-specific as seen in obesitythus providing a mechanism through which sleep disturbances may promote obesity developmentwarrants further investigation.

  • 111.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fanelli, Flaminia
    Univ Bologna, S Orsola Malpighi Hosp, Endocrinol Unit, Dept Med & Surg Sci, Bologna, Italy.;Univ Bologna, S Orsola Malpighi Hosp, Ctr Appl Biomed Res, Bologna, Italy..
    Fazzini, Alessia
    Univ Bologna, S Orsola Malpighi Hosp, Endocrinol Unit, Dept Med & Surg Sci, Bologna, Italy.;Univ Bologna, S Orsola Malpighi Hosp, Ctr Appl Biomed Res, Bologna, Italy..
    Pagotto, Uberto
    Univ Bologna, S Orsola Malpighi Hosp, Endocrinol Unit, Dept Med & Surg Sci, Bologna, Italy.;Univ Bologna, S Orsola Malpighi Hosp, Ctr Appl Biomed Res, Bologna, Italy..
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany..
    Dickson, Suzanne L.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol Endocrinol, Gothenburg, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans2016In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 74, p. 258-268Article in journal (Refereed)
    Abstract [en]

    Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7 a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30 p.m.-7 a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5 h after awakening (vs. normal sleep, p< 0.05) when participants were sleep-deprived. This coincided with increased hunger ratings (+25% vs. normal sleep, p < 0.05). Moreover, plasma 2AG was elevated 15 min post-exercise (+44%, p <0.05). Sleep duration did not however modulate this exercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (p < 0.05). Given that activation of the endocannabinoid system has been previously shown to acutely increase appetite and mood, our results could suggest that behavioral effects of acute sleep loss, such as increased hunger and transiently improved psychological state, may partially result from activation of this signaling pathway. In contrast, more pronounced exercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration.

  • 112.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lampola, Lauri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Axelsson, Emil K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Liethof, Lisanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hassanzadeh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Yeganeh, Adine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Faramkologi 3.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, no 1, p. 5-10Article in journal (Refereed)
    Abstract [en]

    The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.

  • 113.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nylander, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 411, no 4, p. 702-707Article in journal (Refereed)
    Abstract [en]

    Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat Cl tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the Cl tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene-derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all Cl tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the Cl tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the Cl tract.

  • 114.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Osler, Megan E.
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden..
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, D-14558 Nuthetal, Germany.;Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Inst Neurosci & Physiol, S-41137 Gothenburg, Sweden..
    Dickson, Suzanne L.
    Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Inst Neurosci & Physiol, S-41137 Gothenburg, Sweden..
    Zierath, Juleen R.
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden..
    Schioth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 9, p. E1255-E1261Article in journal (Refereed)
    Abstract [en]

    Context: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. Objective: This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. Intervention: In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230-0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (8MAL1, CLOCK, CRYT, PERT). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. Main Outcome Measures: In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P =.026) and in two promoter-interacting enhancer regions of PERT (+15%; P =.036; +9%; P =.026). In skeletal muscle, TSD vs sleep decreased gene expression of BMALT (-18%; P =.033) and CRY1 (-22%; P =.047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 932 vs 3178 723 nmol/L; P =.039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 1.63 vs 6.59 1.32 mmol/L; P =.011). Conclusions: Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.

  • 115.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Osorio, Ricardo S
    Center for Brain Health, NYU Langone Medical Center, New York.
    Varga, Andrew W
    NYU Sleep Disorders Center, NYU Langone Medical Center, New York.
    Kam, Korey
    NYU Sleep Disorders Center, NYU Langone Medical Center, New York.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease2017In: Sleep Medicine Reviews, ISSN 1087-0792, E-ISSN 1532-2955, Vol. 31, p. 102-111Article, review/survey (Refereed)
    Abstract [en]

    During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.

  • 116.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rångtell, Frida H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Axelsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Yeganeh, Adine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol & Endocrinol, Gothenburg, Sweden..
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Dickson, Suzanne L.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol & Endocrinol, Gothenburg, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Short Sleep Makes Declarative Memories Vulnerable to Stress in Humans2015In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 38, no 12, p. 1861-1868Article in journal (Refereed)
    Abstract [en]

    Study Objective: This study sought to investigate the role of nocturnal sleep duration for the retrieval of oversleep consolidated memories, both prior to and after being cognitively stressed for similar to 30 minutes the next morning. Design: Participants learned object locations (declarative memory task comprising 15 card pairs) and a finger tapping sequence (procedural memory task comprising 5 digits) in the evening. After learning, participants either had a sleep opportunity of 8 hours (between similar to 23:00 and similar to 07:00, full sleep condition) or they could sleep between similar to 03:00 and similar to 07:00 (short sleep condition). Retrieval of both memory tasks was tested in the morning after each sleep condition, both before (similar to 08:30) and after being stressed (similar to 09:50). Setting: Sleep laboratory. Participants: 15 healthy young men. Results: The analyses demonstrated that oversleep memory changes did not differ between sleep conditions. However, in their short sleep condition, following stress hallmarked by increased subjective stress feelings, the men were unable to maintain their pre-stress performance on the declarative memory task, whereas their performance on the procedural memory task remained unchanged. While men felt comparably subjectively stressed by the stress intervention, overall no differences between pre- and post-stress recalls were observed following a full night of sleep. Conclusions: The findings suggest that 8-h sleep duration, within the range recommended by the US National Sleep Foundation, may not only help consolidate newly learned procedural and declarative memories, but also ensure full access to both during periods of subjective stress.

  • 117.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sand, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Liethof, Lisanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lampola, Lauri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hassanzadeh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Axelsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Yeganeh, Adine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ros, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Learning and sleep-dependent consolidation of spatial and procedural memories are unaltered in young men under a fixed short sleep schedule2016In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 131, p. 87-94Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate if a fixed short sleep schedule impairs one of the main functions of sleep, which is to consolidate newly learned memories. Methods: Sixteen young men participated in two experimental conditions, each of which lasted for 3 consecutive days and nights in our laboratory: a short sleep schedule (4.25-h sleep opportunity per night) versus a normal sleep schedule (8.5 h per night). In the evening after two experimental nights, participants learned locations of 15 card pairs (spatial memory task) and a procedural finger tapping sequence task. Post-sleep retrieval of both memory tasks was tested the next morning. Results: The short sleep schedule, compared with the normal sleep schedule, considerably altered sleep characteristics, e.g. the proportion of time in slow-wave sleep increased across the three experimental nights. In contrast, neither learning in the evening of day 2, nor subsequent overnight memory consolidation (i.e. concerning the change in memory performance between pre-sleep learning on day 2 and post sleep retrieval on day 3) differed between the normal and short sleep schedule conditions. Conclusions: Our findings suggest that learning in the evening and subsequent sleep-dependent consolidation of procedural and spatial memories are unaltered in young men living under a fixed short sleep schedule. Future studies are warranted to validate our findings in other groups (e.g. adolescents and older subjects) and after more prolonged chronic sleep loss paradigms.

  • 118.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Determinants of Shortened, Disrupted, and Mistimed Sleep and Associated Metabolic Health Consequences in Healthy Humans2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1073-1080Article in journal (Refereed)
    Abstract [en]

    Recent increases in the prevalence of obesity and type 2 diabetes mellitus (T2DM) in modern societies have been paralleled by reductions in the time their denizens spend asleep. Epidemiological studies have shown that disturbed sleepcomprising short, low-quality, and mistimed sleepincreases the risk of metabolic diseases, especially obesity and T2DM. Supporting a causal role of disturbed sleep, experimental animal and human studies have found that sleep loss can impair metabolic control and body weight regulation. Possible mechanisms for the observed changes comprise sleep loss-induced changes in appetite-signaling hormones (e.g., higher levels of the hunger-promoting hormone ghrelin) or hedonic brain responses, altered responses of peripheral tissues to metabolic signals, and changes in energy intake and expenditure. Even though the overall consensus is that sleep loss leads to metabolic perturbations promoting the development of obesity and T2DM, experimental evidence supporting the validity of this view has been inconsistent. This Perspective aims at discussing molecular to behavioral factors through which short, low-quality, and mistimed sleep may threaten metabolic public health. In this context, possible factors that may determine the extent to which poor sleep patterns increase the risk of metabolic pathologies within and across generations will be discussed (e.g., timing and genetics).

  • 119.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Efficacy of antibody-based therapies to treat Alzheimer's disease: Just a matter of timing?2014In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 57, p. 104-106Article in journal (Refereed)
    Abstract [en]

    A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (A beta) in the brain, as the formation of A beta plaques is considered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting A beta in the brain, for 78 weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower A beta accumulation in the brain of AD patients who carried APOE epsilon 4. However, this treatment did not improve clinical outcomes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting A beta in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interventions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceutical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting A beta with therapeutic strategies that require patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment.  

  • 120.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schonke, Milena
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Westholm, Jakub Orzechowski
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Med & Pharmarcy Res Ctr, Yantai, Peoples R China.
    Chibalin, Alexander
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Osler, Megan
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Potsdam, Germany.
    Hornaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Dickson, Suzanne L.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol Endocrinol, Gothenburg, Sweden.
    Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Univ Utah, Dept Pathol, Salt Lake City, UT 84132 USA;Binzhou Med Univ, Precis Med, Yantai, Peoples R China.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zierath, Juleen R.
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans2018In: Science Advances, E-ISSN 2375-2548, Vol. 4, no 8, article id eaar8590Article in journal (Refereed)
    Abstract [en]

    Curtailed sleep promotes weight gain and loss of lean mass in humans, although the underlying molecular mechanisms are poorly understood. We investigated the genomic and physiological impact of acute sleep loss in peripheral tissues by obtaining adipose tissue and skeletal muscle after one night of sleep loss and after one full night of sleep. We find that acute sleep loss alters genome-wide DNA methylation in adipose tissue, and unbiased transcriptome-, protein-, and metabolite-level analyses also reveal highly tissue-specific changes that are partially reflected by altered metabolite levels in blood. We observe transcriptomic signatures of inflammation in both tissues following acute sleep loss, but changes involving the circadian clock are evident only in skeletal muscle, and we uncover molecular signatures suggestive of muscle breakdown that contrast with an anabolic adipose tissue signature. Our findings provide insight into how disruption of sleep and circadian rhythms may promote weight gain and sarcopenia.

  • 121.
    Cedernaes, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Westholm, Orzechowski J.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute Sleep Leads To Tissue-Specific Epigenetic And Transcriptional Responses In Healthy Humans2018In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 41, p. A5-A5Article in journal (Other academic)
  • 122. Cerda-Reverter, JM
    et al.
    Haitina, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Schiöth, HB
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Peter, RE
    Gene structure of the goldfish agouti-signaling protein:: a putative role in the dorsla-ventral pigment pattern of fish2005In: Endocrinology, Vol. 146, no 3, p. 1597-610Article in journal (Refereed)
    Abstract [en]

    One of the most successful chromatic adaptations in vertebrates is the dorsal-ventral pigment pattern in which the dorsal skin is darkly colored, whereas the ventrum is light. In fish, the latter pattern is achieved because a melanization inhibition factor inhibits melanoblast differentiation and supports iridophore proliferation in the ventrum. In rodents, the patterned pigmentation results from regional production of the agouti-signaling protein (ASP). This peptide controls the switch between production of eumelanin and pheomelanin by antagonizing alphaMSH effects on melanocortin receptor (MCR) 1 in the melanocytes. In addition, ASP inhibits the differentiation and proliferation of melanoblast. Thus, the mammalian ASP may be homologous to the poikilotherm melanization inhibition factor. By screening of a genomic library, we deduced the amino acid sequence of goldfish ASP. The ASP gene is a four-exon gene spanning 3097 bp that encodes a 125-amino acid precursor. Northern blot analysis identified two different ASP mRNAs in ventral skin of red- and black-pigmented and albino fish, but no expression levels were observed in the dorsal skin of the same fish. The dorsal-ventral expression polarity was also detected in both black dorsally pigmented fish and albino fish. Pharmacological studies demonstrate that goldfish ASP acts as a melanocortin antagonist at Fugu MC1R and goldfish MC4R. In addition, goldfish ASP inhibited Nle4, D-Phe7-MSH-stimulated pigment dispersion in medaka melanophores. Our studies support agouti signaling protein as the melanization inhibition factor, a key factor in the development of the dorsal-ventral pigment pattern in fish.

  • 123.
    Chapman, Colin D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Frey, William H
    Craft, Suzanne
    Danielyan, Lusine
    Hallschmid, Manfred
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intranasal Treatment of Central Nervous System Dysfunction in Humans2013In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 30, no 10, p. 2475-2484Article, review/survey (Refereed)
    Abstract [en]

    One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.

  • 124.
    Chapman, Colin D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Victor C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rångtell, Frida H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    Dickson, Suzanne L.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep deprivation increases food purchasing in men2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 12, p. E555-E560Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate if acute sleep deprivation affects food purchasing choices in a mock supermarket.

    Design and Methods

    On the morning after one night of total sleep deprivation (TSD) or after one night of sleep, 14 normal-weight men were given a fixed budget (300 SEKapproximately 50 USD). They were instructed to purchase as much as they could out of a possible 40 items, including 20 high-caloric foods (>2 kcal/g) and 20 low-caloric foods (<2 kcal/g). The prices of the high-caloric foods were then varied (75%, 100% (reference price), and 125%) to determine if TSD affects the flexibility of food purchasing. Before the task, participants received a standardized breakfast, thereby minimizing the potential confound produced by hunger. In addition, morning plasma concentrations of the orexigenic hormone ghrelin were measured under fasting conditions.

    Results

    Independent of both type of food offered and price condition, sleep-deprived men purchased significantly more calories (+9%) and grams (+18%) of food than they did after one night of sleep (both P<0.05). Morning plasma ghrelin concentrations were also higher after TSD (P<0.05). However, this increase did not correlate with the effects of TSD on food purchasing.

    Conclusions

    This experiment demonstrates that acute sleep loss alters food purchasing behavior in men.

  • 125.
    Chapman, Colin D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Victor C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Thune, Hanna A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Le Greves, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Watching TV and Food Intake: The Role of Content2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e100602-Article in journal (Refereed)
    Abstract [en]

    Obesity is a serious and growing health concern worldwide. Watching television (TV) represents a condition during which many habitually eat, irrespective of hunger level. However, as of yet, little is known about how the content of television programs being watched differentially impacts concurrent eating behavior. In this study, eighteen normal-weight female students participated in three counter-balanced experimental conditions, including a 'Boring' TV condition (art lecture), an 'Engaging' TV condition (Swedish TV comedy series), and a no TV control condition during which participants read (a text on insects living in Sweden). Throughout each condition participants had access to both high-calorie (M&Ms) and low-calorie (grapes) snacks. We found that, relative to the Engaging TV condition, Boring TV encouraged excessive eating (+52% g, P = 0.009). Additionally, the Engaging TV condition actually resulted in significantly less concurrent intake relative to the control 'Text' condition (235% g, P = 0.05). This intake was driven almost entirely by the healthy snack, grapes; however, this interaction did not reach significance (P = 0.07). Finally, there was a significant correlation between how bored participants were across all conditions, and their concurrent food intake (beta = 0.317, P = 0.02). Intake as measured by kcals was similarly patterned but did not reach significance. These results suggest that, for women, different TV programs elicit different levels of concurrent food intake, and that the degree to which a program is engaging (or alternately, boring) is related to that intake. Additionally, they suggest that emotional content (e. g. boring vs. engaging) may be more associated than modality (e. g. TV vs. text) with concurrent intake.

  • 126.
    Chapman, Colin D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Grillo, Claudia A
    Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, School of Medicine, Columbia, SC 29209, USA.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intranasal insulin in Alzheimer's disease: food for thought2018In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 136, p. 196-201Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggests that disrupted brain insulin signaling promotes the development and progression of Alzheimer's disease (AD), driving clinicians to target this circuitry. While both traditional and more modern antidiabetics show promise in combating insulin resistance, intranasal insulin appears to be the most efficient method of boosting brain insulin. Furthermore, intranasal delivery elegantly avoids adverse effects from peripheral insulin administration. However, there remain significant open questions regarding intranasal insulin's efficacy, safety, and potential as an adjunct or mono-therapy. Thus, this review aims to critically evaluate the present evidence and future potential of intranasal insulin as a meaningful treatment for AD.

  • 127.
    Chapman, Colin Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha Jane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lifestyle determinants of the drive to eat: a meta-analysis2012In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 96, no 3, p. 492-497Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is emerging as the most significant health concern of the 21st century. Although this is attributable in part to changes in our environment-including the increased prevalence of energy-dense food-it also appears that several lifestyle factors may increase our vulnerability to this calorie-rich landscape. Epidemiologic studies have begun to show links between adiposity and behaviors such as television watching, alcohol intake, and sleep deprivation. However, these studies leave unclear the direction of this association. In addition, studies that investigated the acute impact of these factors on food intake have reported a wide variety of effect sizes, from highly positive to slightly negative.

    Objective: The purpose of this article was to provide a meta-analysis of the relation between lifestyle choices and increases in acute food intake.

    Design: An initial search was performed on PubMed to collect articles relating television watching, sleep deprivation, and alcohol consumption to food intake. Only articles published before February 2012 were considered. Studies that took place in a controlled, laboratory setting with healthy individuals were included. Studies were analyzed by using 3 meta-analyses with random-effects models. In addition, a 1-factor ANOVA was run to discover any main effect of lifestyle.

    Results: The 3 most prominent lifestyle factors-television watching, alcohol intake, and sleep deprivation-had significant short-term effects on food intake, with alcohol being more significant (Cohen's d = 1.03) than sleep deprivation (Cohen's d = 0.49) and television watching (Cohen's d = 0.2).

    Conclusions: Our results suggest that television watching, alcohol intake, and sleep deprivation are not merely correlated with obesity but likely contribute to it by encouraging excessive eating. Because these behaviors are all known to affect cognitive functions involved in reward saliency and inhibitory control, it may be that they represent common mechanisms through which this eating is facilitated.

  • 128.
    Chapman, Colin Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Experimenter gender and replicability in science2018In: Science Advances, E-ISSN 2375-2548, Vol. 4, no 1, article id e1701427Article, review/survey (Refereed)
    Abstract [en]

    There is a replication crisis spreading through the annals of scientific inquiry. Although some work has been carried out to uncover the roots of this issue, much remains unanswered. With this in mind, this paper investigates how the gender of the experimenter may affect experimental findings. Clinical trials are regularly carried out without any report of the experimenter's gender and with dubious knowledge of its influence. Consequently, significant biases caused by the experimenter's gender may lead researchers to conclude that therapeutics or other interventions are either overtreating or undertreating a variety of conditions. Bearing this in mind, this policy paper emphasizes the importance of reporting and controlling for experimenter gender in future research. As backdrop, it explores what we know about the role of experimenter gender in influencing laboratory results, suggests possible mechanisms, and suggests future areas of inquiry.

  • 129.
    Chapman, Colin Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sex matters: Report experimenter gender2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 356, no 6341, p. 916-917Article in journal (Refereed)
  • 130.
    Chatzittofis, A.
    et al.
    Univ Umea, Dept Clin Sci Psychiat, Umea, Sweden.
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Öberg, K.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Flanagan, J.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Arver, S.
    Karoliska Inst, Dept Med, Stockholm, Sweden.
    Jokinen, J.
    Umea Univ, Dept Clin Sci, Umea, Sweden.
    Testosterone, luteinizing hormone levels and methylation status in men with hypersexual disorders2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S135-S135Article in journal (Other academic)
  • 131.
    Chicca, Andrea
    et al.
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    Nicolussi, Simon
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    Bartholomäus, Ruben
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland..
    Blunder, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil..
    Rey, Alejandro Aparisi
    Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany..
    Petrucci, Vanessa
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    del Carmen Reynoso-Moreno, Ines
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.;Univ Guadalajara, Ctr Univ Ciencias Exactas & Ingn, Guadalajara 44430, Jalisco, Mexico..
    Manuel Viveros-Paredes, Juan
    Univ Guadalajara, Ctr Univ Ciencias Exactas & Ingn, Guadalajara 44430, Jalisco, Mexico..
    Gens, Marianela Dalghi
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    Lutz, Beat
    Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Soeberdt, Michael
    Dr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany..
    Abels, Christoph
    Dr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany..
    Charles, Roch-Philippe
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    Altmann, Karl-Heinz
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland..
    Gertsch, Jürg
    Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
    Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 25, p. E5006-E5015Article in journal (Refereed)
    Abstract [en]

    The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl) ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

  • 132.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pettersson, Ulrika S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nilsson, Emil K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Acute sleep deprivation in healthy young men: Impact on population diversity and function of circulating neutrophils2014In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 41, p. 162-172Article in journal (Refereed)
    Abstract [en]

    Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8 h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0 +/- 0.2 x 10(9)/l vs. 2.6 +/- 0.2 x 10(9)/l, sleep vs. TSD, respectively) and the population contained more immature CD16(dim)/CD62L(bright) cells (0.11 +/- 0.040 x 10(9)/l [5.5 +/- 1.1%] vs. 0.26 +/- 0.020 x 10(9)/l [9.9 +/- 1.4%]). As the rise in numbers of circulating mature CD16(bright)/CD62L(bright) neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8 +/- 0.15 x 10(9)/l [88 +/- 1.8%] vs. 2.1 +/- 0.12 x 10(9)/l [82 +/- 2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.  

  • 133. Ciganoka, Darja
    et al.
    Balcere, Inga
    Kapa, Ivo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Peculis, Raitis
    Valtere, Andra
    Nikitina-Zake, Liene
    Lase, Ieva
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pirags, Valdis
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 4, p. 517-525Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics. Design and methods: The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls. Results: In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR) = 3.38; 95% confidence interval (CI), 1.78-6.42; P=0.00016 and OR=2.41; 95% CI, 1.41-4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P=0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient beta=-10.4; P=0.002), increased body mass index (beta=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014). Conclusions: Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.

  • 134. Cinege, Gyöngyi
    et al.
    Zsámboki, János
    Vidal-Quadras, Maite
    Uv, Anne
    Csordás, Gábor
    Honti, Viktor
    Gábor, Erika
    Hegedűs, Zoltán
    Varga, Gergely I B
    Kovács, Attila L
    Juhász, Gábor
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Andó, István
    Kurucz, Éva
    Genes encoding cuticular proteins are components of the Nimrod gene cluster in Drosophila2017In: Insect Biochemistry and Molecular Biology, ISSN 0965-1748, E-ISSN 1879-0240, Vol. 87, p. 45-54Article in journal (Refereed)
    Abstract [en]

    The Nimrod gene cluster, located on the second chromosome of Drosophila melanogaster, is the largest synthenic unit of the Drosophila genome. Nimrod genes show blood cell specific expression and code for phagocytosis receptors that play a major role in fruit fly innate immune functions. We previously identified three homologous genes (vajk-1, vajk-2 and vajk-3) located within the Nimrod cluster, which are unrelated to the Nimrod genes, but are homologous to a fourth gene (vajk-4) located outside the cluster. Here we show that, unlike the Nimrod candidates, the Vajk proteins are expressed in cuticular structures of the late embryo and the late pupa, indicating that they contribute to cuticular barrier functions.

  • 135.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Waeber, G.
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland..
    Vollenweider, P.
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A genetic risk score is significantly associated with statin therapy response in the elderly population2017In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 91, no 3, p. 379-385Article in journal (Refereed)
    Abstract [en]

    The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.

  • 136.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Boström, Adrian E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Tuunainen, Anna-Kaisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sohrabi, Farah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kular, Lara
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Jagodic, Maja
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Victoria Univ, Inst Sport Exercise & Act Living, Melbourne, Victoria, Australia.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents2018In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 102, p. 44-51Article in journal (Refereed)
    Abstract [en]

    Generalized anxiety disorder (GAD) is highly prevalent among adolescents. An early detection of individuals at risk may prevent later psychiatric condition. Genome-wide studies investigating single nucleotide polymorphisms (SNPs) concluded that a focus on epigenetic mechanisms, which mediate the impact of environmental factors, could more efficiently help the understanding of GAD pathogenesis. We investigated the relationship between epigenetic shifts in blood and the risk to develop GAD, evaluated by the Development and Well-Being Assessment (DAWBA) score, in 221 otherwise healthy adolescents. Our analysis focused specifically on methylation sites showing high inter-individual variation but low tissue-specific variation, in order to infer a potential correlation between results obtained in blood and brain. Two statistical methods were applied, 1) a linear model with limma and 2) a likelihood test followed by Bonferroni correction. Methylation findings were validated in a cohort of 160 adults applying logistic models against the outcome variable "anxiety treatment obtained in the past" and studied in a third cohort with regards to associated expression changes measured in monocytes. One CpG site showed 1% increased methylation in adolescents at high risk of GAD (cg16333992, P-adj. = 0.028, estimate = 3.22), as confirmed in the second cohort (p = 0.031, estimate = 1.32). The identified and validated CpG site is located within the STK32B promoter region and its methylation level was positively associated with gene expression. Gene ontology analysis revealed that STK32B is involved in stress response and defense response. Our results provide evidence that shifts in DNA methylation are associated with a modulated risk profile for GAD in adolescence.

  • 137.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Boström, Adrian E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Philipps, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Titova, Olga E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nikontovic, Lamia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score2017In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, article id e1002Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.

  • 138.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Response to Leusink et al.2017In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 92, no 5, p. 566-566Article in journal (Other academic)
  • 139. Civelli, Olivier
    et al.
    Reinscheid, Rainer K
    Zhang, Yan
    Wang, Zhiwei
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    G Protein-Coupled Receptor Deorphanizations2013In: Annual Review of Pharmacology and Toxicology, ISSN 0362-1642, E-ISSN 1545-4304, Vol. 53, p. 127-146Article, review/survey (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands-i.e., "deorphanizing" the GPCRs-gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts.

  • 140.
    Clemensson, Erik Karl Håkan
    et al.
    Univ Tubingen, Inst Med Genet & Appl Genom, Calwerstr 7, D-72076 Tubingen, Germany;Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany;Lund Univ, Dept Expt Med Sci, Basal Ganglia Pathophysiol, Solvegatan 19,BMC F11, S-22184 Lund, Sweden.
    Novati, Arianna
    Univ Tubingen, Inst Med Genet & Appl Genom, Calwerstr 7, D-72076 Tubingen, Germany;Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Tubingen, Inst Med Genet & Appl Genom, Calwerstr 7, D-72076 Tubingen, Germany;Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany.
    Riess, Olaf
    Univ Tubingen, Inst Med Genet & Appl Genom, Calwerstr 7, D-72076 Tubingen, Germany;Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany.
    Nguyen, Huu Phuc
    The BACHD rat model of Huntington disease shows slowed learning in a Go/No-Go-like test of visual discrimination2019In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 359, p. 116-126Article in journal (Refereed)
    Abstract [en]

    Huntington disease is a hereditary neurodegenerative disease, in which patients display a broad range of clinical symptoms. Among these, impaired inhibitory control has been noted. The BACHD rat is a recently developed and established transgenic animal model for Huntington disease, and characterizing the presence of Huntington disease-like behavioural phenotypes in these animals is of importance. Prior studies have indicated that BACHD rats suffer from impaired inhibitory control, although further studies are necessary to fully understand the scope and specific nature of these phenotypes. In the current study, BACHD rats were trained to perform a Go/No-Go-like test of visual discrimination, akin to behavioural tests that have revealed suspected response inhibition impairments in Huntington disease patients. The results indicate that although BACHD rats showed a slow rate of learning to inhibit responses on No-Go trials, once they had learned to handle the basic discrimination, they had an unchanged ability to withhold lever responses during extended periods of time. This suggests that BACHD rats have specific impairments when applying inhibitory control to a new or changed situation. The findings are in line with previous studies of BACHD rats and support the continued use and characterization of this animal model.

  • 141.
    Cocco, Arianna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Williams, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neural expression patterns and protein modeling of the GABAA receptor ζ subunit in the adult zebrafish (Danio rerio Hamilton, 1822)2018In: Zebrafish, ISSN 1545-8547, E-ISSN 1557-8542Article in journal (Refereed)
    Abstract [en]

     

    The zebrafish has a repertoire of twenty-six GABAA receptor subunits, including the paralogues π and ζ, homologous to the mammalian π. The brain mRNA levels of the π subunit are low, but the ζ gene is actively transcribed in D. rerio central nervous system and retinas. With a combined quantitative and qualitative gene expression profiling approach, this research characterized the distribution of the ζ transcript in the brain and eyes of the adult zebrafish. It was demonstrated that there are regional brain differences in the production of this transcript, with the stratum periventriculare of the tecta mesencephali having the highest mRNA levels for ζ. In the adult zebrafish retinas the bipolar cell layer presented staining for the ζ transcript. The three-dimensional structure of the ζ subunit of the GABAA receptor in zebrafish was also calculated in this study, with the human β3 as template. It presented four transmembrane α-helices and an amino-terminal β-loop framed into a disulfide bridge. It was therefore possible to place ζ in the superfamily of Cys-loop membrane proteins, to which GABAA receptor subunits belong. The current study presented a thorough characterization of a unique fish GABAA receptor subunit, which might have specific functions only typical of fish.

  • 142.
    Cocozza, S.
    et al.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Russo, C.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Pisani, A.
    Univ Federico II, Dept Publ Hlth, Nephrol Unit, Naples, Italy..
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Riccio, E.
    Univ Federico II, Dept Publ Hlth, Nephrol Unit, Naples, Italy..
    Cervo, A.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Pontillo, G.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Feriozzi, S.
    Belcolle Hosp, Nephrol & Dialysis Dept, Viterbo, Italy..
    Veroux, M.
    Univ Hosp Catania, Dept Med & Surg Sci & Adv Technol, Catania, Sicily, Italy..
    Battaglia, Y.
    Univ Ferrara, St Anna Hosp, Dept Specialized Med, Div Nephrol & Dialysis, Ferrara, Italy..
    Concolino, D.
    Magna Graecia Univ Catanzaro, Dept Pediat, Catanzaro, Italy..
    Pieruzzi, F.
    Univ Milano Bicocca, Nephrol Unit, Milan, Italy..
    Mignani, R.
    Infermi Hosp, Nephrol & Dialysis Dept, Rimini, Italy..
    Borrelli, P.
    IRCCS SDN, Naples, Italy..
    Imbriaco, M.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Brunetti, A.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Tedeschi, E.
    Univ Federico II, Dept Adv Biomed Sci, Nephrol Unit, Naples, Italy..
    Palma, G.
    CNR, Inst Biostruct & Bioimaging, Naples, Italy..
    Redefining the Pulvinar Sign in Fabry Disease2017In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 38, no 12, p. 2264-2269Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE:

    The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity.

    MATERIALS AND METHODS:

    We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls.

    RESULTS:

    The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables.

    CONCLUSIONS:

    The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.

  • 143.
    Cocozza, Sirio
    et al.
    Univ Federico II, Dept Adv Biomed Sci, Via Pansini 5, I-80131 Naples, Italy..
    Pontillo, Giuseppe
    Univ Federico II, Dept Adv Biomed Sci, Via Pansini 5, I-80131 Naples, Italy..
    Quarantelli, Mario
    CNR, Inst Biostruct & Bioimaging, Naples, Italy..
    Sacca, Francesco
    Univ Federico II, Dept Neurosci & Reprod & Odontostomatol Sci, Naples, Italy..
    Riccio, Eleonora
    Univ Federico II, Dept Publ Hlth, Nephrol Unit, Naples, Italy..
    Costabile, Teresa
    Univ Federico II, Dept Neurosci & Reprod & Odontostomatol Sci, Naples, Italy..
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Morra, Vincenzo Brescia
    Univ Federico II, Dept Neurosci & Reprod & Odontostomatol Sci, Naples, Italy..
    Pisani, Antonio
    Univ Federico II, Dept Publ Hlth, Nephrol Unit, Naples, Italy..
    Brunetti, Arturo
    Univ Federico II, Dept Adv Biomed Sci, Via Pansini 5, I-80131 Naples, Italy..
    Tedeschi, Enrico
    Univ Federico II, Dept Adv Biomed Sci, Via Pansini 5, I-80131 Naples, Italy..
    Default mode network modifications in Fabry disease: A resting-state fMRI study with structural correlations2018In: Human Brain Mapping, ISSN 1065-9471, E-ISSN 1097-0193, Vol. 39, no 4, p. 1755-1764Article in journal (Refereed)
    Abstract [en]

    Aim of the study was to evaluate the presence of Default Mode Network (DMN) modifications in Fabry Disease (FD), and their possible correlations with structural alterations and neuropsychological scores. Thirty-two FD patients with a genetically confirmed diagnosis of classical FD (12 males, mean age 43.3 +/- 12.2) were enrolled, along with 35 healthy controls (HC) of comparable age and sex (14 males, mean age 42.1 +/- 14.5). Resting-State fMRI data were analyzed using a seed-based approach, with six different seeds sampling the main hubs of the DMN. Structural modifications were assessed by means of Voxel-Based Morphometry (VBM) and Tract-Based Spatial Statistics analyses. Between-group differences and correlations with neuropsychological variables were probed voxelwise over the whole brain. Possible correlations between FC modifications and global measures of microstructural alteration were also tested in FD patients with a partial correlation analysis. In the FD group, clusters of increased functional connectivity involving both supratentorial and infratentorial regions emerged, partially correlated to the widespread white matter (WM) damage found in these patients. No gray matter volume differences were found at VBM between the two groups. The connectivity between right inferior frontal gyrus and precuneus was significantly correlated with the Corsi block-tapping test results (p = .0001). Widespread DMN changes are present in FD patients that correlate with WM alterations and cognitive performance. Our results confirm the current view of a cerebral involvement in FD patients not simply associated to major cerebrovascular events, but also related to significant and diffuse microstructural and functional changes.

  • 144.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Katarzyna J., Radomska
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Trier Kjær, Marcel
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    Dağlıkoca, E. Duygu
    Bogazici University, Deptartment of Molecular Biology and Genetics, Turkey .
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fex Svenningsen, Åsa
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    The function of GABA and its B-receptor in Schwann cell developmentManuscript (preprint) (Other academic)
  • 145.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Radomska, Katarzyna J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Dağlıkoca, E Duygu
    Godskesen, Randi Elberg
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedikz, Eirikur
    Magnaghi, Valerio
    Fex Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination2015In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 2, p. 285-295Article in journal (Refereed)
    Abstract [en]

    The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.

  • 146.
    Crüsemann, Max
    et al.
    Univ Bonn, Inst Pharmazeut Biol, Bonn, Germany.
    Reher, Raphael
    Schamari, Isabella
    Univ Bonn, Inst Pharmazeut Biol, Bonn, Germany.
    Brachmann, Alexander O
    ] Eidgenoss Tech Hsch ETH Zurich, Inst Mikrobiol, Zurich, Switzerland.
    Ohbayashi, Tsubasa
    Univ Paris Sud, CEA, Gif Sur Yvette, France.
    Kuschak, Markus
    Malfacini, Davide
    Seidinger, Alexander
    Pinto-Carbó, Marta
    Richarz, René
    Reuter, Tatjana
    Kehraus, Stefan
    Hallab, Asis
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mergaert, Peter
    Kikuchi, Yoshitomo
    Bioprod Res Inst AIST Hokkaido, Sapporo, Japan.
    Schäberle, Till F
    Kostenis, Evi
    Wenzel, Daniela
    Müller, Christa E
    Piel, Jörn
    Carlier, Aurélien
    Univ Ghent, Dept Biochem & Microbiol, Ghent, Belgium.
    Eberl, Leo
    König, Gabriele M
    Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR9003592018In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 57, no 3, p. 836-840Article in journal (Refereed)
    Abstract [en]

    The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.

  • 147.
    Dakanalis, Antonios
    et al.
    Univ Pavia, Dept Brain & Behav Sci, Pavia, Italy.;Univ Milano Bicocca, Dept Surg & Interdisciplinary Med, Milan, Italy..
    Clerici, Massimo
    Univ Milano Bicocca, Dept Surg & Interdisciplinary Med, Milan, Italy..
    Caslini, Manuela
    Univ Milano Bicocca, Dept Surg & Interdisciplinary Med, Milan, Italy..
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Campus Biomed, Ctr Integrated Res, Rome, Italy..
    Serino, Silvia
    Catholic Univ, Dept Psychol, Milan, Italy..
    Riva, Giuseppe
    Catholic Univ, Dept Psychol, Milan, Italy.;Ist Auxol Italiano, Appl Technol Neuropsychol Lab, Milan, Italy..
    Carra, Giuseppe
    Univ Milano Bicocca, Dept Surg & Interdisciplinary Med, Milan, Italy.;UCL, Fac Brain Sci, Div Psychiat, London, England..
    Predictors of initiation and persistence of recurrent binge eating and inappropriate weight compensatory behaviors in college men2016In: International Journal of Eating Disorders, ISSN 0276-3478, E-ISSN 1098-108X, Vol. 49, no 6, p. 581-590Article in journal (Refereed)
    Abstract [en]

    ObjectiveThe transition to college is considered as a risk period for the development of behavioral symptoms of eating disorders (BSEDs) and some evidence suggests that, amongst men, these symptoms occurring on a regular basis remain relatively stable over the college period. Nevertheless, little is known about factors associated with persistent engagement in and initiation of recurrent (or regular) binge eating and inappropriate weight compensatory behaviors in this population. The objective of this report was to address these research gaps. MethodData were examined from 2,555 male first-year college students who completed an assessment of potential vulnerability factors and BSEDs at the beginning of the autumn semester (baseline) and nine months later (end of the spring semester; follow-up). ResultsElevated negative affectivity, body dissatisfaction, self-objectification, and lower self-esteem at baseline were predictive of persistent engagement in regular binge eating and four compensatory behaviors (self-induced vomiting, laxative/diuretic abuse, fasting, exercise) at follow-up, as well as initiation of all these behaviors occurring regularly (i.e., at least weekly for 3 months). Self-objectification (thinking and monitoring the body's outward appearance from a third-person perspective) emerged as the largest contributor of both the initiation and persistence of all behavioral symptoms. DiscussionData emphasize that the same psychological factors underlie initiation and persistence of recurrent BSEDs and should shape the focus of future interventions for college men.

  • 148.
    Dakanalis, Antonios
    et al.
    Univ Milano Bicocca, Dept Med & Surg, Via Cadore 48, I-20900 Monza, Italy.;Univ Pavia, Dept Brain & Behav Sci, Pavia, Italy..
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Riva, Giuseppe
    IRCSS Ist Auxol Italiano, Appl Technol Neuropsychol Lab, Milan, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Clerici, Massimo
    Univ Milano Bicocca, Dept Med & Surg, Via Cadore 48, I-20900 Monza, Italy..
    Severity of bulimia nervosa and its impact on treatment outcome2017In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 22, no 4, p. 727-729Article in journal (Other academic)
  • 149.
    Dakanalis, Antonios
    et al.
    Univ Pavia, Dept Brain & Behav Sci, Pza Botta 11, I-27100 Pavia, Italy.;Univ Milano Bicocca, Dept Interdisciplinary Med, Milan, Italy..
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Ctr Integrated Res, Area Diagnost Imaging, Univ Campus Biomed, Rome, Italy..
    Serino, Silvia
    Catholic Univ, Dept Psychol, Milan, Italy..
    Clerici, Massimo
    Univ Milano Bicocca, Dept Interdisciplinary Med, Milan, Italy..
    Carra, Giuseppe
    Univ Milano Bicocca, Dept Interdisciplinary Med, Milan, Italy.;UCL, Fac Brain Sci, Div Psychiat, London, England..
    Riva, Giuseppe
    Catholic Univ, Dept Psychol, Milan, Italy.;IRCCS, Ist Auxol Italiano, Appl Technol Neuropsychol Lab, Milan, Italy..
    Body-image distortion in anorexia nervosa2016In: NATURE REVIEWS DISEASE PRIMERS, ISSN 2056-676X, Vol. 2, article id 16026Article in journal (Refereed)
  • 150.
    Dakanalis, Antonios
    et al.
    Univ Milano Bicocca, Dept Med & Surg, Via Cadore 48, I-20900 Monza, Italy.;Univ Pavia, Dept Brain & Behav Sci, Pavia, Italy..
    Riva, Giuseppe
    IRCSS Ist Auxol Italiano, Appl Technol Neuropsychol Lab, Milan, Italy.;Catholic Univ Milan, Dept Psychol, Milan, Italy..
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Clerici, Massimo
    Univ Milano Bicocca, Dept Med & Surg, Via Cadore 48, I-20900 Monza, Italy..
    Cognitive-behavioral or psychodynamic therapy for people with bulimia nervosa2017In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 22, no 3, p. 555-556Article in journal (Other academic)
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