| 1. |
- Lill, Christina M., et al.
(författare)
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The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:12, s. 1407-1416
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Tidskriftsartikel (refereegranskat)abstract
- A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2's role in AD may involve tau dysfunction. (C) 2015 The Alzheimer's Association.
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| 2. |
- Ruud, J., et al.
(författare)
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The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons
- 2019
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 27:11
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Tidskriftsartikel (refereegranskat)abstract
- Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.
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| 3. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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Dopamine signaling in the amygdala, increased by food ingestion and GLP-1, regulates feeding behavior.
- 2014
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Ingår i: Physiology & behavior. - : Elsevier BV. - 1873-507X .- 0031-9384. ; 136, s. 135-144
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Tidskriftsartikel (refereegranskat)abstract
- Mesolimbic dopamine plays a critical role in food-related reward processing and learning. The literature focuses primarily on the nucleus accumbens as the key dopaminergic target in which enhanced dopamine signaling is associated with reward. Here, we demonstrate a novel neurobiological mechanism by which dopamine transmission in the amygdala regulates food intake and reward. We show that food intake was associated with increased dopamine turnover in the amygdala. Next, we assess the impact of direct intra-amygdala D1 and D2 receptor activation on food intake and sucrose-driven progressive ratio operant conditioning in rats. Amygdala D2 receptor activation reduced food intake and operant behavior for sucrose, whereas D2 receptor blockade increased food intake but surprisingly reduced operant behavior. In contrast, D1 receptor stimulation or blockade did not alter feeding or operant conditioning for food. The glucagon-like peptide 1 (GLP-1) system, a target for type 2 diabetes treatment, in addition to regulating glucose homeostasis, also reduces food intake. We found that central GLP-1R receptor activation is associated with elevated dopamine turnover in the amygdala, and that part of the anorexic effect of GLP-1 is mediated by D2 receptor signaling in the amygdala. Our findings indicate that amygdala dopamine signaling is activated by both food intake and the anorexic brain-gut peptide GLP-1 and that amygdala D2 receptor activation is necessary and sufficient to change feeding behavior. Collectively these studies indicate a novel mechanism by which the dopamine system affects feeding-oriented behavior at the level of the amygdala.
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| 4. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality.
- 2016
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 65, s. 54-66
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.
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| 5. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 1062-1073
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
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| 6. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior.
- 2016
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 14, s. 1199-1209
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Tidskriftsartikel (refereegranskat)abstract
- Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.Neuropsychopharmacology advance online publication, 21 October 2015; doi:10.1038/npp.2015.297.
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| 7. |
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| 8. |
- Dickson, Suzanne L., 1966, et al.
(författare)
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The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.
- 2012
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:14, s. 4812-20
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Tidskriftsartikel (refereegranskat)abstract
- The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.
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| 22. |
- Shahabi, H Niazi, et al.
(författare)
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Cytochrome P450 2E1 gene polymorphisms/haplotypes and Parkinson's disease in a Swedish population.
- 2009
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 116:5, s. 567-73
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Tidskriftsartikel (refereegranskat)abstract
- Cytochrome P450 2E1 (CYP2E1), which inter alia is located in dopamine containing neurons in the substantia nigra, has been hypothesized to be of importance for the pathophysiology of Parkinson's disease (PD), either by its production of reactive oxygen species (ROS) or by its capability to detoxify putative neurotoxins. Numerous polymorphisms in the coding and non-coding regions of the gene for this enzyme have been reported. Different variants may account for inter-individual differences in the activity of the enzyme or production of ROS. In this study, the CYP2E1 gene was examined in a control population (n = 272) and a population with PD (n = 347), using a tag-single nucleotide polymorphism (tSNP) approach founded on HapMap Data. Six tSNPs were used in the analysis and haplotype block data were obtained. In case of significance, the SNP was further examined regarding early/late age of disease onset and presence of relatives with PD. We found an association between allele and genotype frequencies of the C/G polymorphism at intron 7 (rs2070676) of this gene and PD (P value of 0.026 and 0.027, respectively). Furthermore, analysis of the rs2070676 polymorphism in subgroups of patients with age of disease onset higher than 50 years and those not having a relative with PD also demonstrated a significant difference with controls. This was seen in both genotype (corresponding to P value = 0.039 and 0.032) and allele (P = 0.027 and 0.017 respectively) frequency. As a representative of many polymorphisms or in possible linkage disequilibrium with other functional variants, it is possible that rs2070676 could influence the regulation of the enzyme. In conclusion, our results display an association between the rs2070676 polymorphism and PD. Additional investigations are needed to elucidate the importance of this polymorphism for the activity of CYP2E1 and PD susceptibility.
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| 23. |
- Shahabi, H Niazi, et al.
(författare)
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Cytochrome P450 2E1 in the substantia nigra: relevance for dopaminergic neurotransmission and free radical production.
- 2008
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Ingår i: Synapse (New York, N.Y.). - : Wiley. - 0887-4476 .- 1098-2396. ; 62:5, s. 379-88
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Tidskriftsartikel (refereegranskat)abstract
- Cytochrome P450 2E1 (CYP2E1) has been detected in brain regions which are of relevance for the pathophysiology of Parkinson's disease, such as the substantia nigra (SN). Furthermore, CYP2E1 is known to generate reactive oxygen species (ROS), toxic molecules which have been implicated in the pathogenesis of the disease. We have previously reported that CYP2E1 inhibition increases extracellular dopamine (DA) in the SN. The aims of the present study were by using in vivo microdialysis in rat, to elucidate the mechanisms responsible for the increase in extracellular DA induced by CYP2E1 inhibition and to explore whether ROS is produced in the SN, both with and without the presence of an exogenous CYP2E1 substrate. The effect of inhibition of CYP2E1 by phenylethyl isothiocyanate (100 mg/kg) on extracellular DA in the SN was unaltered following pretreatment with gamma-butyrolactone and GBR-12909, drugs that inhibit firing of DA neurons and DA re-uptake, respectively. Preadministration of tetrodotoxin or reserpine, however, abolished the effect of CYP2E1 inhibition. Administration of isoflurane, an anesthetic which is metabolized by CYP2E1, increased the production of *OH in the SN, as measured by the transformation of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid during local perfusion compared with animals given other anesthetics. The results support the notion that CYP2E1 is located near or in the same compartment in the SN as stored DA, tentatively the endoplasmatic reticulum, and that the enzyme activity might modulate the amount of DA that is available for release. Furthermore, our findings indicate that the production of ROS can be stimulated by CYP2E1 substrates.
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