| 1. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 2. |
- Cedernaes, Jonathan
(författare)
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Intestinal Gene Expression Profiling and Fatty Acid Responses to a High-fat Diet
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Kobayashi, Yuki, et al.
(författare)
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Differential expressions of melanocortin receptor subtypes in melanophores and xanthophores of barfin flounder
- 2010
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Ingår i: General and Comparative Endocrinology. - : Elsevier BV. - 0016-6480 .- 1095-6840. ; 168:1, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- alpha-Melanocyte-stimulating hormone (alpha-MSH) is a member of the melanocortin (MC) family, and the MC receptor (MCR) is a member of the G protein-coupled receptor (GPCR) superfamily. We previously found that in barfin flounder, a flatfish, alpha-MSH with an acetyl group at the N-terminus stimulated pigment dispersion in xanthophores; however, this effect was not observed in melanophores. Therefore, the present study was undertaken to find which MCR subtypes are expressed in these pigment cells in order to elucidate how acetylation regulates activities of alpha-MSH-related peptides. Here, we also report the cloning of Mc1r and Mc5r from barfin flounder. Three types of cells-melanophores, xanthophores, and nonchromatophoric dermal cells-were isolated from the skin samples collected from the dorsal fin. These cells were then tested for the expression of Mc1r and Mc5r as well as Mc2r and Mc4r that we had previously cloned. Mc1r and Mc5r transcripts were detected in melanophores, and a sole Mc5r transcript was detected in xanthophores. We had previously found that the efficiency of alpha-MSH was higher than that of desacetyl-alpha-MSH for pigment dispersion in xanthophores. Acetylated MSH peptide may have increased binding affinity to MC5R, whereas alpha-MSH lacks melanin-dispersing activity. Increasing evidences indicate that many GPCRs form heterodimers, and this may affect the affinity of the ligand for the corresponding GPCR. Taken together, the expression of two different Mcr subtypes in melanophores may suggest that a heterodimer consisting of MC1R and MC5R may have a low binding affinity toward alpha-MSH. The present results clarify the types of MCRs that are expressed in melanophores and xanthophores of barfin flounder; furthermore, the results provide important clues about the functional regulation of alpha-MSH-related peptides.
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| 4. |
- Lekholm, Emilia, 1981-
(författare)
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Solute Carriers in Metabolism : Regulation of known and putative solute carriers in the central nervous system
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Solute carriers (SLCs) are membrane-bound transporter proteins, important for nutrient, ion, drug and metabolite transport across membranes. A quarter of the human genome codes for membrane-bound proteins, and SLCs make up the largest group of transporter proteins. Due to their ability to transport a large repertoire of substances across, not just the plasma membrane, but also the membrane of internal organelles, they hold a key position in maintaining homeostasis affecting metabolic pathways. Unfortunately, some of the more than 400 identified SLCs are still not fully characterized, even though a quarter of these are associated with human disease. In addition, there are about 30 membrane-bound proteins with strong resemblance to SLCs, of which very little is known. The aim of this thesis is to characterize some of these putative SLCs, focusing on their localization and function in the central nervous system. Since many of the known SLCs play a vital part in metabolism and related pathways, the response to different nutritional conditions has been used as a key method. MFSD14A and MFSD14B, characterized in Paper I, are putative SLCs belonging to the Major Facilitator Superfamily (MFS) and found to be neuronal, differentially expressed in the mouse central nervous system and transiently upregulated in mouse embryonic cortex cultures due to amino acid deprivation. They were also altered in areas of the mouse brain after starvation as well as after high fat diet. In Paper II, the effect on gene regulation due to complete amino acid starvation was monitored in a mouse hypothalamic cell line and 47 different genes belonging to SLCs, or putative SLCs, were found to be affected. Of these, 15 genes belonged to already known amino acid transporters, whereas 32 were putative SLCs with no known function or SLCs not known to react to amino acids. The three SV2 proteins, SV2A, SV2B and SV2C, were studied in Paper III using human neuroblastoma cell lines. The high metabolic state of cancers often result in an upregulation and alteration of transporter proteins, and alterations of the SV2 proteins were found following different treatments performed in this study. Paper IV focused on putative SLCs of MFS type and their role in glucose metabolism. Mouse embryonic cortex cultures were subjected to glucose starvation and the gene expression of 19 putative transporters were analyzed. All but four of the putative transporters were affected either at 3h or 12h of glucose deprivation. In conclusion, several SLCs and putative SLCs studied in this thesis are strongly affected by alteration in metabolism, either due to amino acids or glucose or both. This makes the putative SLCs dynamic membrane-bound proteins, possibly transporters, highly affected by nutritional status and most likely regulated to maintain homeostasis.
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| 5. |
- Cao, Hao
(författare)
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Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
- 2016
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843.
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Tidskriftsartikel (refereegranskat)abstract
- Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed toDEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects fromDEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP mayhave detrimental effects on metabolic functions.
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| 6. |
- Cao, Hao
(författare)
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Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most species are constantly exposed to xenobiotic chemicals through multiple routes. Among all categories of xenobiotics, phthalates and bisphenols are two of the most widely used plasticizers and can be found in polyvinyl chloride (PVC) materials, medical devices and even drinking water. In paper I, we found that bis-(2-ethylhexyl) phthalate (DEHP) exposure caused a significant decrease in circulating carbohydrates and insulin-related genes. The Multidrug-Resistance like Protein 1 (MRP1, MRP in Drosophila) belongs to the ATP-binding cassette transporter family, and previous studies revealed the importance of MRP1 for transporting xenobiotics. However, the function of MRP1 in metabolism and other biological processes is still unclear. Therefore, in paper II, we showed that knocking down MRP expression in Malpighian tubules, the physiological equivalence of the vertebrate kidney, led to disrupted lipid homeostasis and oxidative resistance. In paper III and IV, we initially used whole transcriptome sequencing to assess the genetic interferences of exposure to Dibutyl Phthalate (DBP) and Bisphenol A Diglycidyl Ether (BADGE). The reproductive and developmental disruptions of DBP had been reported in many studies. However, the mechanism is still unclear. In paper III, we observed that DBP interfered with neuronal systems associated circadian genes, including in vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Furthermore, we demonstrated that the evolutionarily conserved gene, Hormone receptor-like in 38 (Hr38, human NR4A2) was involved in responding to DBP and regulated Pdf expression as a consequence. In paper IV, BADGE, a BPA-substitute, was tested for its disruptive effects on Drosophila. Based on the transcriptome sequencing, we found that several mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), had detectable overexpression by BADGE exposure. Developmental exposure to BADGE induced a large increase of hemocytes in fly 3rd instar larvae, while it did not damage the morphological structure of lymph gland and blood circulation. To summarize, our studies describe the potential disruptions of the industrial xenobiotics and provide the mechanistic hints for future investigations.
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| 7. |
- Hogenkamp, Pleunie S, et al.
(författare)
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Sweet taste perception not altered after acute sleep deprivation in healthy young men.
- 2013
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Ingår i: Somnologie : Schlafforschung und Schlafmedizin = Somnology : sleep research and sleep medicine. - : Springer Science and Business Media LLC. - 1432-9123 .- 1439-054X. ; 17:2, s. 111-114
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that acutely sleep-deprived participants would rate ascending concentrations of sucrose as more intense and pleasant, than they would do after one night of normal sleep. Such a finding would offer a potential mechanism through which acute sleep loss could promote overeating in humans.
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| 8. |
- Cedernaes, Jonathan, et al.
(författare)
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Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans
- 2018
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 4:8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Olivo, Gaia, MD, 1989-
(författare)
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Brain Structure and Function in Adolescents with Atypical Anorexia Nervosa
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atypical anorexia nervosa (AAN) has a high incidence in adolescents, resulting in significant morbidity and mortality. The weight loss is generally less pronounced than that experienced in full-syndrome anorexia nervosa (AN), but the medical consequences can be as severe. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders, however research on adolescents is limited, and no neuroimaging studies have been conducted in AAN. In paper I, we investigated brain structure through a voxel-based morphometry analysis in 22 drug-naïve adolescent females newly-diagnosed with AAN, and 38 age- and sex-matched healthy controls. In Paper II, we investigated white matter microstructural integrity on 25 drug-naïve adolescent patients with AAN and 25 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. No differences in brain structure could be detected, indicating preserved regional grey matter volumes and white matter diffusivity in patients with AAN compared to controls. These findings suggest that previous observations of brain structure alterations in full syndrome AN may constitute state-related consequences of severe underweight. Alternatively, the preservation of brain structure might indeed differentiate AAN from AN. In paper III, we investigated resting-state functional connectivity in 22 drug-naïve adolescent patients with AAN, and 24 healthy controls. We report reduced connectivity in patients in brain areas involved in face-processing and social cognition, while an increased connectivity, correlating with depressive symptoms, was found in areas involved in the multimodal integration of sensory stimuli, aesthetic judgment, and social rejection anxiety. These findings point toward a core role for an altered development of socio-emotional skills in the pathogenesis of AAN. In Paper IV, we investigated neural connectivity underlying visual processing of foods with different caloric content in a sample of 28 adolescent females diagnosed with AAN, and 33 age- and sex-matched healthy controls. Our results showed higher connectivity in patients in pathways related to the integration of sensory input and memory retrieval, in response to food with high caloric content. This, however, was coupled to lower connectivity in salience and attentional networks, and lower connectivity between areas involved in visual food cues processing and appetite regulatory regions. Thus, despite food with high caloric content is associated to greater processing of somatosensory information in patients, it is attributed less salience and engages patients’ attention less than food with low caloric content.
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| 10. |
- Lagunas-Rangel, Francisco Alejandro, et al.
(författare)
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The potential interaction of environmental pollutants and circadian rhythm regulations that may cause leukemia
- 2022
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Ingår i: Critical reviews in environmental science and technology. - : Informa UK Limited. - 1064-3389 .- 1547-6537. ; 52:22, s. 4094-4112
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Forskningsöversikt (refereegranskat)abstract
- Tumor suppressor genes are highly affected during the development of leukemia, including circadian clock genes. Circadian rhythms constitute an evolutionary molecular machinery involving many genes, such as BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, REV-ERBa, and RORA, for tracking time and optimizing daily life during day-night cycles and seasonal changes. For circulating blood cells many of these genes coordinate their proliferation, output, and function, and therein lies their importance for the development of leukemia. Recent findings suggest that environmental pollutants may affect circadian rhythms and thus affect cancer development and treatment. Such environmental pollutants are often found in mixtures and include benzene, tobacco smoke, pesticides and microplastics. Our understanding of the molecular basis for the interaction mechanisms within complex mixtures is also growing, confirming the plausible occurrence of synergistic (superadditive effect) and antagonistic (cancellation effect) actions of pollutant cocktails. In this work, we discuss the relationship of environmental pollutants and the alteration of circadian rhythms that potentially may cause leukemia. We highlight the need of additional dimensions and perhaps a paradigm shift for future studies in relation to continuously growing magnitude of environmental pollution using multitude of disciplines such as development of high throughput reporter cell lines, other cell screening methods, contaminant measurements in leukemia patients, advanced pharmacology and toxicological measurement of mixtures and highly efficient computer analysis including artificial intelligence, among others.
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