| 1. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 2. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 3. |
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| 4. |
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| 5. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 10. |
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| 11. |
- Edwards, Robert A., et al.
(författare)
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Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
- 2019
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:10, s. 1727-1736
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Tidskriftsartikel (refereegranskat)abstract
- Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.
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| 12. |
- Randler, C., et al.
(författare)
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Animal welfare attitudes : Effects of gender and diet in university samples from 22 countries
- 2021
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Ingår i: Animals. - : MDPI AG. - 2076-2615. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Animal Welfare Attitudes (AWA) are defined as human attitudes towards the welfare of animals in different dimensions and settings. Demographic factors, such as age and gender are associated with AWA. The aim of this study was to assess gender differences among university students in a large convenience sample from twenty-two nations in AWA. A total of 7914 people participated in the study (5155 women, 2711 men, 48 diverse). Participants completed a questionnaire that collected demographic data, typical diet and responses to the Composite Respect for Animals Scale Short version (CRAS-S). In addition, we used a measure of gender empowerment from the Human Development Report. The largest variance in AWA was explained by diet, followed by country and gender. In terms of diet, 6385 participants reported to be omnivores, 296 as pescatarian, 637 ate a vegetarian diet and 434 were vegans (n = 162 without answer). Diet was related with CRAS-S scores; people with a vegan diet scored higher in AWA than omnivores. Women scored significantly higher on AWA than men. Furthermore, gender differences in AWA increased as gender inequality decreased. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 13. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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| 14. |
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| 15. |
- Coumans, J. M. J., et al.
(författare)
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Emotion-driven impulsiveness and snack food consumption of European adolescents: Results from the I.Family study
- 2018
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Ingår i: Appetite. - : Elsevier BV. - 0195-6663 .- 1095-8304. ; 123, s. 152-159
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate the association between emotion-driven impulsiveness and snack food consumption in 1039 European adolescents aged 12–18 years. During the cross-sectional examination in 2013/2014, complete information was collected on: emotion-driven impulsiveness (using the negative urgency subscale from the Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency (UPPS-P) Impulsive Behaviour Scale) and snacking behaviour operationalised as 1) consumption frequency of daily snacks, 2) consumption frequency of energy-dense snacks (both measured using Food Frequency Questionnaire) and 3) usual energy intake of food consumed per snacking occasion in calories. The latter was measured using online self-administered 24-h dietary recalls and was estimated based on the National Cancer Institute (NCI) Method. Anthropometric variables were measured and BMI z-score (zBMI) calculated. Age, sex, highest education level of the family and country of residence were assessed using a questionnaire. Mixed-effect regression analyses were separately conducted for each snacking behaviour outcome with emotion-driven impulsiveness as the exposure. After controlling for zBMI, age, sex, country and socioeconomic status, emotion-driven impulsiveness was positively associated with daily consumption frequency of snacks (β = 0.07, 95% Confidence Interval (CI) [0.02, 0.12]) and consumption frequency of energy-dense snacks (β = 0.25, 95% CI [0.19, 0.31]), but not with usual energy intake of food per snacking (β = 2.52, 95% CI [-0.55, 5.59]). Adolescents with a stronger emotion-driven impulsiveness tendency reported a higher snacking frequency and specifically more energy-dense snacks, whereas the energy intake of snack food seemed less important. These findings have implications for obesity prevention and treatment as they indicate the importance of targeting emotion-driven impulsiveness as a strategy to avoid excessive snacking.
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| 16. |
- Coumans, J. M. J., et al.
(författare)
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Emotion-driven impulsiveness but not decision-making ability and cognitive inflexibility predicts weight status in adults
- 2019
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Ingår i: Appetite. - : Elsevier BV. - 0195-6663. ; 142
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Tidskriftsartikel (refereegranskat)abstract
- In this study we aimed to determine whether decision-making ability, cognitive inflexibility and emotion-driven impulsiveness are associated with weight status as expressed by body mass index (BMI), percentage body fat, waist circumference and skinfold thickness in adults from eight different European countries taking part in the I.Family study. The Bechara Gambling Task was used to assess decision-making ability (n = 1717). The Berg Card Sorting Test was used to measure cognitive inflexibility (n = 1509). Lastly, the negative urgency subscale from the UPPS-P Impulsive Behavior Scale was used to measure emotion-driven impulsiveness (n = 4450). Hierarchical regression analyses showed that more emotion-driven impulsiveness was statistically significantly associated with a higher BMI, a higher percentage body fat, and a larger waist circumference in adults, controlling for age, sex, socioeconomic status, country and binge eating; but not with skinfold thickness. Cognitive inflexibility and decision-making ability were not statistically significantly associated with any of the weight status related variables. These results support that impulsivity in response to negative emotions, but not decision-making ability or cognitive inflexibility, is associated with the susceptibility to excessive weight (as indicated by a higher BMI, a higher percentage body fat, and a larger waist circumference). In people behaving impulsively when emotional, focusing on reducing negative affect or improving coping skills is of interest in interventions targeting obesity. Clinical trial registration: The I.Family study is registered in the ISRCTN registry (ISRCTN62310987) on February 23, 2018. © 2019
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| 17. |
- Coumans, J M J, et al.
(författare)
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The association of emotion-driven impulsiveness, cognitive inflexibility and decision-making with weight status in European adolescents.
- 2018
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Ingår i: International journal of obesity (2005). - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 42, s. 655-661
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Tidskriftsartikel (refereegranskat)abstract
- to explore the association between emotion-driven impulsiveness, cognitive inflexibility, decision-making and with weight status as reflected in BMI z-score (zBMI) in European adolescents.In total 3 354 adolescent aged between 12 and 18 years from the I.Family cohort completed the questionnaire based negative urgency subscale from the UPPS-P Impulsive Behavior Scale to measure emotion-driven impulsiveness in 2013/2014. Furthermore, 1 584 adolescents completed the computer-based Bergs Card Sorting Test to measure cognitive inflexibility, and 1 780 adolescents completed the Hungry Donkey Test to assess decision-making ability. Anthropometric variables were measured objectively; confounding variables (age, sex, socioeconomic status and country) were assessed using a questionnaire. Mixed-effect regression analyses were conducted for each outcome of the test or questionnaire as a predictor with standardised body mass index (zBMI) as the dependent variable in order to investigate association between markers of cognitive functioning and zBMI.After controlling for confounders, results showed that emotion-driven impulsiveness (β=0.18, 95% CI: 0.13 to 0.24, P<0.001), and cognitive inflexibility (β=0.01, 95% CI: 0.002 to 0.02, P=0.016) were positively associated with zBMI. However, decision-making ability was not significantly related to zBMI (β=0.00, 95% CI: -0.001 to 0.003, P=0.47).More emotion-driven impulsiveness and reduced cognitive flexibility were associated with a higher zBMI in adolescents across Europe. These results may indicate that being impulsive in negative situations and having difficulties changing mental sets increase the susceptibility for unhealthy weight development. Reducing impulsivity and training cognitive flexibility seem promising targets for the prevention and intervention programs of obesity.International Journal of Obesity accepted article preview online, 01 November 2017. doi:10.1038/ijo.2017.270.
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| 18. |
- de Vrind, V. A. J., et al.
(författare)
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Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.
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| 19. |
- Masip, G., et al.
(författare)
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The temporal relationship between parental concern of overeating and childhood obesity considering genetic susceptibility: longitudinal results from the IDEFICS/I.Family study
- 2021
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Ingår i: International Journal of Behavioral Nutrition and Physical Activity. - : Springer Science and Business Media LLC. - 1479-5868. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. Methods: The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean +/- SD follow-up 5.8 +/- 0.4). Children examined in 2007/2008 (wave 1) (mean +/- SD age: 4.4 +/- 1.1, range: 2-9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. Results: In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (beta = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (beta = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (beta = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (beta = 0.09, 95% CI: 0.07, 0.12). Conclusions: The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain.
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| 20. |
- Omrani, A., et al.
(författare)
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Identification of Novel Neurocircuitry Through Which Leptin Targets Multiple Inputs to the Dopamine System to Reduce Food Reward Seeking
- 2021
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 90:12, s. 843-852
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Leptin reduces the motivation to obtain food by modulating activity of the mesolimbic dopamine (DA) system upon presentation of cues that predict a food reward. Although leptin directly reduces the activity of ventral tegmental area (VTA) DA neurons, the majority of leptin receptor (LepR)-expressing DA neurons do not project to the nucleus accumbens, the projection implicated in driving food reward seeking. Therefore, the precise locus of leptin action to modulate motivation for a food reward is unresolved. METHODS: We used transgenic mice expressing Cre recombinase under the control of the LepR promoter, anatomical tracing, optogenetics-assisted patch-clamp electrophysiology, in vivo optogenetics with fiber photometric calcium measurements, and chemogenetics to unravel how leptin-targeted neurocircuitry inhibits food reward seeking. RESULTS: A large number of DA neurons projecting to the nucleus accumbens are innervated by local VTA LepR-expressing GABA (gamma-aminobutyric acid) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits nucleus accumbens-projecting DA neurons. In addition, we find that lateral hypothalamic LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate DA neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating lateral hypothalamic LepR projections to the VTA potently activates DA neurons in vivo. Moreover, we found that chemogenetic activation of lateral hypothalamic LepR neurons increases the motivation to obtain a food reward only when mice are in a positive energy balance. CONCLUSIONS: We identify neurocircuitry through which leptin targets multiple inputs to the DA system to reduce food reward seeking.
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| 21. |
- Roelofs, T. J. M., et al.
(författare)
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Optimization of whole-brain rabies virus tracing technology for small cell populations
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The lateral hypothalamus (LH) is critically involved in the regulation of homeostatic energy balance. Some neurons in the LH express receptors for leptin (LepRb), a hormone known to increase energy expenditure and decrease energy intake. However, the neuroanatomical inputs to LepRb-expressing LH neurons remain unknown. We used rabies virus tracing technology to map these inputs, but encountered non-specific tracing. To optimize this technology for a minor cell population (LepRb is not ubiquitously expressed in LH), we used LepRb-Cre mice and assessed how different titers of the avian tumor virus receptor A (TVA) helper virus affected rabies tracing efficiency and specificity. We found that rabies expression is dependent on TVA receptor expression, and that leakiness of TVA receptors is dependent on the titer of TVA virus used. We concluded that a titer of 1.0-3.0x10(7) genomic copies per mu l of the TVA virus is optimal for rabies tracing. Next, we successfully applied modified rabies virus tracing technology to map inputs to LepRb-expressing LH neurons. We discovered that other neurons in the LH itself, the periventricular hypothalamic nucleus (Pe), the posterior hypothalamic nucleus (PH), the bed nucleus of the stria terminalis (BNST), and the paraventricular hypothalamic nucleus (PVN) are the most prominent input areas to LepRb-expressing LH neurons.
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| 22. |
- Wright, Graham D., et al.
(författare)
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Recognising the importance and impact of Imaging Scientists: Global guidelines for establishing career paths within core facilities
- 2024
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Ingår i: JOURNAL OF MICROSCOPY. - 0022-2720 .- 1365-2818. ; 294:3, s. 397-410
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Tidskriftsartikel (refereegranskat)abstract
- In the dynamic landscape of scientific research, imaging core facilities are vital hubs propelling collaboration and innovation at the technology development and dissemination frontier. Here, we present a collaborative effort led by Global BioImaging (GBI), introducing international recommendations geared towards elevating the careers of Imaging Scientists in core facilities. Despite the critical role of Imaging Scientists in modern research ecosystems, challenges persist in recognising their value, aligning performance metrics and providing avenues for career progression and job security. The challenges encompass a mismatch between classic academic career paths and service-oriented roles, resulting in a lack of understanding regarding the value and impact of Imaging Scientists and core facilities and how to evaluate them properly. They further include challenges around sustainability, dedicated training opportunities and the recruitment and retention of talent. Structured across these interrelated sections, the recommendations within this publication aim to propose globally applicable solutions to navigate these challenges. These recommendations apply equally to colleagues working in other core facilities and research institutions through which access to technologies is facilitated and supported. This publication emphasises the pivotal role of Imaging Scientists in advancing research programs and presents a blueprint for fostering their career progression within institutions all around the world. In the exciting world of scientific research, imaging core facilities are essential hubs where scientists use advanced technologies to conduct experiments and uncover fascinating discoveries. What makes these facilities remarkable is that multiple scientists can access and utilise a variety of instruments for a wide range of multidisciplinary research projects, fostering collaboration and innovation. At the forefront of this scientific adventure are Imaging Scientists, experts who play a crucial role in planning experiments, preparing materials, adapting and acquiring technologies, collecting data, training and supporting researchers, analysing images and forming conclusions. Despite their pivotal contributions, there are challenges in recognising the importance of Imaging Scientists and ensuring they have ample opportunities to advance in their careers. These challenges include a mismatch between the typical academic career path and the unique roles and responsibilities of Imaging Scientists, a lack of widespread understanding of their value plus financial constraints, insufficient training opportunities, and difficulties in attracting and retaining talented individuals. To address these issues, Global BioImaging (GBI; www.globalbioimaging.org) has brought together Imaging Scientists from around the world to develop a generally applicable set of recommendations in three key areas: highlighting the significance and value of Imaging Scientists, making it easier to recruit and retain them, and supporting their ongoing learning and professional growth. A notable concept is to reimagine the traditional separation between academic roles and technical support roles. GBI envisions that these recommendations will not only benefit imaging facilities but also prove valuable for research institutions housing diverse technologies organised into core facilities. Recognising the diverse nature of research performing institutions globally, the GBI community sees this guide as a starting point that will initiate dialogue and instigate change, which should be periodically updated as the needs of Imaging Scientists change. This initial version lays a solid foundation for future enhancements, contributing to the acknowledgement and support of the invaluable work done by Imaging Scientists on a global scale.
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| 23. |
- de Vrind, V. A. J., et al.
(författare)
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Effects of GABA and Leptin Receptor-Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis
- 2019
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 27:7, s. 1123-1132
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma-aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. Methods: LepR-cre and VGAT-cre mice were injected with AAV5-hSyn-DIO-hM3DGq-mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. Results: The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). Conclusions: LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance. © 2019 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS)
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| 24. |
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| 25. |
- Leng, G., et al.
(författare)
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The determinants of food choice
- 2017
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Ingår i: Proceedings of the Nutrition Society. - 0029-6651. ; 76:3, s. 316-327
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Tidskriftsartikel (refereegranskat)abstract
- Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide, and it is natural to look to such approaches to improve health by altering what people choose to eat. However, to produce policy recommendations that are likely to be effective, we need to be able to make valid predictions about the consequences of proposed interventions, and for this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. In addition, our choices are influenced by an array of physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue, which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating. Thus, to develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made. Here we review recent developments in these areas.
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| 26. |
- Pallanti, S., et al.
(författare)
-
Manifesto for an ECNP Neuromodulation Thematic Working Group (TWG): Non-invasive brain stimulation as a new Super-subspecialty
- 2021
-
Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 52, s. 72-83
-
Tidskriftsartikel (refereegranskat)abstract
- Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from “mental” to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new “Super-Specialty” and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP). © 2021
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| 27. |
- Roelofs, T. J. M., et al.
(författare)
-
Good taste or gut feeling? A new method in rats shows oro-sensory stimulation and gastric distention generate distinct and overlapping brain activation patterns
- 2021
-
Ingår i: International Journal of Eating Disorders. - : Wiley. - 0276-3478 .- 1098-108X. ; 54:7, s. 1116-1126
-
Tidskriftsartikel (refereegranskat)abstract
- Satiation is influenced by a variety of signals including gastric distention and oro-sensory stimulation. Here we developed a high-field (9.4 T) functional magnetic resonance imaging (fMRI) protocol to test how oro-sensory stimulation and gastric distention, as induced with a block-design paradigm, affect brain activation under different states of energy balance in rats. Repeated tasting of sucrose induced positive and negative fMRI responses in the ventral tegmental area and septum, respectively, and gradual neural activation in the anterior insula and the brain stem nucleus of the solitary tract (NTS), as revealed using a two-level generalized linear model-based analysis. These unique findings align with comparable human experiments, and are now for the first time identified in rats, thereby allowing for comparison between species. Gastric distention induced more extensive brain activation, involving the insular cortex and NTS. Our findings are largely in line with human studies that have shown that the NTS is involved in processing both visceral information and taste, and anterior insula in processing sweet taste oro-sensory signals. Gastric distention and sucrose tasting induced responses in mesolimbic areas, to our knowledge not previously detected in humans, which may reflect the rewarding effects of a full stomach and sweet taste, thereby giving more insight into the processing of sensory signals leading to satiation. The similarities of these data to human neuroimaging data demonstrate the translational value of the approach and offer a new avenue to deepen our understanding of the process of satiation in healthy people and those with eating disorders.
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| 28. |
- Romero-Picó, Amparo, et al.
(författare)
-
Hypothalamic κ-Opioid Receptor Modulates the Orexigenic Effect of Ghrelin.
- 2013
-
Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 38:7, s. 1296-307
-
Tidskriftsartikel (refereegranskat)abstract
- The opioid system is well recognized as an important regulator of appetite and energy balance. We now hypothesized that the hypothalamic opioid system might modulate the orexigenic effect of ghrelin. Using pharmacological and gene silencing approaches, we demonstrate that ghrelin utilizes a hypothalamic κ-opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin-induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. Our novel data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin.
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| 29. |
- van Meer, Floor, et al.
(författare)
-
Development and body mass inversely affect children's brain activation in dorsolateral prefrontal cortex during food choice
- 2019
-
Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 201, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- Childhood obesity is a rising problem caused in part by unhealthy food choices. Food choices are based on a neural value signal encoded in the ventromedial prefrontal cortex, and self-control involves modulation of this signal by the dorsolateral prefrontal cortex (dlPFC). We determined the effects of development, body mass (BMI Cole score) and body mass history on the neural correlates of healthy food choice in children. 141 children (aged 10-17y) from Germany, Hungary and Sweden were scanned with fMRI while performing a food choice task. Afterwards health and taste ratings of the foods were collected. In the food choice task children were asked to consider the healthiness or tastiness of the food or to choose naturally. Overall, children made healthier choices when asked to consider healthiness. However, children who had a higher weight gain per year chose less healthy foods when considering healthiness but not when choosing naturally. Pubertal development stage correlated positively while current body mass correlated negatively with dlPFC activation when accepting foods. Pubertal development negatively and current body mass positively influenced the effect of considering healthiness on activation of brain areas involved in salience and motivation. In conclusion, children in earlier stages of pubertal development and children with a higher body weight exhibited less activation in the dlPFC, which has been implicated in self-control during food choice. Furthermore, pubertal development and body mass influenced neural responses to a health cue in areas involved in salience and motivation. Thus, these findings suggest that children in earlier stages of pubertal development, children with a higher body mass gain and children with overweight may possibly be less susceptible to healthy eating interventions that rely on self-control or that highlight health aspects of food.
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| 30. |
- Verharen, J. P. H., et al.
(författare)
-
Insensitivity to Losses: A Core Feature in Patients With Anorexia Nervosa?
- 2019
-
Ingår i: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. - : Elsevier BV. - 2451-9022.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with anorexia nervosa (AN) demonstrate aberrations in choice behavior, including impairments in laboratory measures of decision making. Although a wealth of studies suggest that these aberrations arise from alterations in value processing, it remains unclear by which core component of value processing this is mediated. Methods: We fit trial-by-trial data of patients with AN (n = 60 first cohort, n = 216 second cohort) and healthy control participants (n = 55) performing the Iowa Gambling Task to a computational model based on prospect utility theory. We determined, per participant, the best-fit model parameters and compared these between the groups. Results: Analyses revealed a decreased estimate of model parameter λ in patients with AN, indicative of an attenuation of loss-aversive behavior in the Iowa Gambling Task. In comparison, measures of reward sensitivity, value-based learning, and exploration versus exploitation were unaltered in patients with AN. A measurement in a second independent cohort replicated the finding that loss aversion, typically observed in healthy individuals, is reduced in patients with AN. Conclusions: We show that patients with AN, in contrast to healthy control participants, demonstrate reduced loss-aversive behavior. This finding provides important fundamental insights into the decision-making capacity of patients with AN, suggesting alterations in the mechanisms involved in value processing related to negative feedback. © 2019
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| 31. |
- Yeo, G. S. H., et al.
(författare)
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The melanocortin pathway and energy homeostasis: From discovery to obesity therapy
- 2021
-
Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 48
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. Scope of review: Herein, we chart the melanocortin pathway & rsquo;s history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. Major conclusions: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.
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| 32. |
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| 33. |
- Adan, Roger A. H., et al.
(författare)
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Translational genetics; expectations for eating disorders and other psychiatric disorders : Translationele genetica: verwachtingen voor eetstoornissen en andere psychiatrische stoornissen
- 2022
-
Ingår i: Tijdschrift voor Psychiatrie. - 0303-7339. ; 64:2022-5, s. 304-308
-
Tidskriftsartikel (refereegranskat)abstract
- Background Translational (genetic) research focuses on the translation of preclinical research into practice. While many genetic studies have been conducted in recent years, the results do not simply translate to the clinic. Aim To visualize the steps through which translational genetic research contributes to the unraveling of the biological backgrounds of psychiatric disorders, in particular of eating disorders. Method Literature review. Results Genetic studies have unraveled a mechanism underlying the hunger and satiety system. There is hope that genome-wide studies of eating disorders will lead to identification of neural circuits in which associated genes cluster. New techniques, such as opto- and chemogenetics, provide the opportunity to define the precise role of these circuits in eating disorders. Conclusion New techniques in molecular neuroscience allow the unravelling of the complexity of how the brain works and some of those techniques (such as chemogenetics) are being further developed for application in humans. However, it will be years before we can definitively translate this into the treatment of psychiatric disorders.
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| 34. |
- de Git, K. C. G., et al.
(författare)
-
Rats that are predisposed to excessive obesity show reduced (leptin-induced) thermoregulation even in the preobese state
- 2019
-
Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 7:14
-
Tidskriftsartikel (refereegranskat)abstract
- Both feeding behavior and thermogenesis are regulated by leptin. The sensitivity to leptin's anorexigenic effects on chow diet was previously shown to predict the development of diet-induced obesity. In this study, we determined whether the sensitivity to leptin's anorexigenic effects correlates with leptin's thermogenic response, and if this response is exerted at the level of the dorsomedial hypothalamus (DMH), a brain area that plays an important role in thermoregulation. Based on the feeding response to injected leptin on a chow diet, rats were divided into leptin-sensitive (LS) and leptin-resistant (LR) groups. The effects of leptin on core body, brown adipose tissue (BAT) and tail temperature were compared after intravenous versus intra-DMH leptin administration. After intravenous leptin injection, LS rats increased their BAT thermogenesis and reduced heat loss via the tail, resulting in a modest increase in core body temperature. The induction of these thermoregulatory mechanisms with intra-DMH leptin was smaller, but in the same direction as with intravenous leptin administration. In contrast, LR rats did not show any thermogenic response to either intravenous or intra-DMH leptin. These differences in the thermogenic response to leptin were associated with a 1°C lower BAT temperature and reduced UCP1 expression in LR rats under adlibitum feeding. The preexisting sensitivity to the anorexigenic effects of leptin, a predictor for obesity, correlates with the sensitivity to the thermoregulatory effects of leptin, which appears to be exerted, at least in part, at the level of the DMH. © 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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| 35. |
- Kallo, I., et al.
(författare)
-
Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens
- 2022
-
Ingår i: Brain Structure & Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 227:3, s. 1083-1098
-
Tidskriftsartikel (refereegranskat)abstract
- Orexin neurons are involved in homeostatic regulatory processes, including arousal and feeding, and provide a major input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. VTA neurons are a central hub processing reward and motivation and target the medial prefrontal cortex (mPFC) and the shell part of nucleus accumbens (NAcs). We investigated whether subpopulations of dopamine (DA) neurons in the VTA projecting either to the mPFC or the medial division of shell part of nucleus accumbens (mNAcs) receive differential input from orexin neurons and whether orexin exerts differential electrophysiological effects upon these cells. VTA neurons projecting to the mPFC or the mNAcs were traced retrogradely by Cav2-Cre virus and identified by expression of yellow fluorescent protein (YFP). Immunocytochemical analysis showed that a higher proportion of all orexin-innervated DA neurons projected to the mNAcs (34.5%) than to the mPFC (5.2%). Of all sampled VTA neurons projecting either to the mPFC or mNAcs, the dopaminergic (68.3 vs. 79.6%) and orexin-innervated DA neurons (68.9 vs. 64.4%) represented the major phenotype. Whole-cell current clamp recordings were obtained from fluorescently labeled neurons in slices during baseline periods and bath application of orexin A. Orexin similarly increased the firing rate of VTA dopamine neurons projecting to mNAcs (1.99 +/- 0.61 Hz to 2.53 +/- 0.72 Hz) and mPFC (0.40 +/- 0.22 Hz to 1.45 +/- 0.56 Hz). Thus, the hypothalamic orexin system targets mNAcs and to a lesser extent mPFC-projecting dopaminergic neurons of the VTA and exerts facilitatory effects on both clusters of dopamine neurons.
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| 36. |
- Kooij, K. L., et al.
(författare)
-
Intranasal administration of olanzapine has beneficial outcome in a rat activity-based anorexia model
- 2023
-
Ingår i: European Neuropsychopharmacology. - 0924-977X. ; 71, s. 65-74
-
Tidskriftsartikel (refereegranskat)abstract
- The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzap-ine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investi-gated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libi-tum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue.We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further explor-ing intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness.(c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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| 37. |
- Merkestein, Myrte, et al.
(författare)
-
Ghrelin mediates anticipation to a palatable meal in rats.
- 2012
-
Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 20:5, s. 963-71
-
Tidskriftsartikel (refereegranskat)abstract
- Food anticipatory activity (FAA) is displayed in rats when access to food is restricted to a specific time frame of their circadian phase, a behavior thought to reflect both hunger and the motivation to eat. Rats also display FAA in a feeding schedule with ad libitum access to normal chow, but limited availability of a palatable meal, which is thought to involve mainly motivational aspects. The orexigenic hormone ghrelin has been implicated in FAA in rodents with restricted access to chow. Because ghrelin plays an important role not only in the control of food intake, but also in reward, we sought to determine the role of ghrelin in anticipation to a palatable meal. Plasma ghrelin levels of non-restricted rats that anticipated chocolate correlated positively with FAA and were increased compared with chow-fed control rats. Furthermore, centrally injected ghrelin increased, whereas an antagonist of the ghrelin receptor decreased, the anticipation to chocolate. Therefore, we hypothesize that central ghrelin signaling is able to mediate the motivational drive to eat.
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| 38. |
- Morris, Andrew P, et al.
(författare)
-
Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- 2019
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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| 39. |
- Palasz, A.T., et al.
(författare)
-
Effects of hyaluronan, BSA, and serum on bovine embryo in vitro development, ultrastructure, and gene expression patterns
- 2006
-
Ingår i: Molecular Reproduction and Development. - : Wiley-Blackwell. - 1040-452X .- 1098-2795. ; 73:12, s. 1503-1511
-
Tidskriftsartikel (refereegranskat)abstract
- Effects of hyaluronan (HA), BSA, and FCS on in vitro development, ultrastructure, and mRNA transcription of four developmentally important genes: apoptosis (Bax), oxidative stress (SOX), growth factor (IGF-II), and cell-to-cell adhesion (Ecad) were examined. Two biological origin HA, Hylartil and Hyonate and one produced by fermentation (f-HA) MAP-5 were tested. Embryos were cultured in SOF medium with 0.4% BSA or with 0.4% BSA and 10% FCS. HA was added 96 hr post insemination (pi) to half of the embryos from each culture group. Embryo development was not affected by either HA preparation, however, hatching rates were higher in Hyalartil and MAP-5 than in control and Hyonate (P less than 0.05). There was no effect of HA on number of blastocysts developed in SOF + BSA. However, more blastocysts developed in SOF + BSA + f-HA than in SOF + BSA + FCS or with BSA + FCS + f-HA. HA added to SOF + BSA, increased level of expression of epidermal growth factor (EGF)-II and decreased the levels of expression of BAX, SOX, and Ecad (P less than 0.05). Presence of FCS increased the levels of SOX and decreased the level of IGF-II (P less than 0.05) and the addition of f-HA to SOF containing FCS showed no effect on the level of transcription of any analyzed genes. The fine structure of embryos cultured with f-HA irrespective of protein sources used was clearly improved. In summary, f-HA added 96 hr pi to SOF supplemented with BSA but not FCS improved development, molecular composition and fine structure of bovine embryos.
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| 40. |
- van Zessen, R., et al.
(författare)
-
Cue and Reward Evoked Dopamine Activity Is Necessary for Maintaining Learned Pavlovian Associations
- 2021
-
Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 41:23, s. 5004-5014
-
Tidskriftsartikel (refereegranskat)abstract
- Associating natural rewards with predictive environmental cues is crucial for survival. Dopamine (DA) neurons of the ventral tegmental area (VTA) are thought to play a crucial role in this process by encoding reward prediction errors (RPEs) that have been hypothesized to play a role in associative learning. However, it is unclear whether this signal is still necessary after animals have acquired a cue-reward association. In order to investigate this, we trained mice to learn a Pavlovian cue-reward association. After learning, mice show robust anticipatory and consummatory licking behavior. As expected, calcium activity of VTA DA neurons goes up for cue presentation as well as reward delivery. Optogenetic inhibition during the moment of reward delivery disrupts learned behavior, even in the continued presence of reward. This effect is more pronounced over trials and persists on the next training day. Moreover, outside of the task licking behavior and locomotion are unaffected. Similarly to inhibitions during the reward period, we find that inhibiting cue-induced dopamine (DA) signals robustly decreases learned licking behavior, indicating that cue-related DA signals are a potent driver for learned behavior. Overall, we show that inhibition of either of these DA signals directly impairs the expression of learned associative behavior. Thus, continued DA signaling in a learned state is necessary for consolidating Pavlovian associations.
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| 41. |
- Verhagen, Linda A W, et al.
(författare)
-
Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity.
- 2011
-
Ingår i: European neuropsychopharmacology. - : Elsevier BV. - 1873-7862 .- 0924-977X. ; 21:5, s. 384-392
-
Tidskriftsartikel (refereegranskat)abstract
- Using the rodent activity-based anorexia (ABA) model that mimics clinical features of anorexia nervosa that include food restriction-induced hyperlocomotion, we found that plasma ghrelin levels are highly associated with food anticipatory behaviour, measured by running wheel activity in rats. Furthermore, we showed that ghrelin receptor (GHS-R1A) knockout mice do not anticipate food when exposed to the ABA model, unlike their wild type littermate controls. Likewise, food anticipatory activity in the ABA model was suppressed by a GHS-R1A antagonist administered either by acute central (ICV) injection to rats or by chronic peripheral treatment to mice. Interestingly, the GHS-R1A antagonist did not alter food intake in any of these models. Therefore, we hypothesize that suppression of the central ghrelin signaling system via GHS-R1A provides an interesting therapeutic target to treat hyperactivity in patients suffering from anorexia nervosa.
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| 42. |
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| 43. |
- Abreu, P, et al.
(författare)
-
Energy dependence of inclusive spectra in e(+)e(-) annihilation
- 1999
-
Ingår i: PHYSICS LETTERS B. - : ELSEVIER SCIENCE BV. - 0370-2693. ; 459:1-3, s. 397-411
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Inclusive charged hadron distributions as obtained from the DELPHI measurements at 130, 136, 161, 172 and 183 GeV are presented as a function of the variables rapidity, xi(p), p and transversal momenta. Data are compared with event generators and with MLL
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| 44. |
- Adage, Tiziana, et al.
(författare)
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Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats
- 2001
-
Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 21:10, s. 3639-3645
-
Tidskriftsartikel (refereegranskat)abstract
- The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake- independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i. e., corticotropin-releasing hormone (CRH), cocaine- amphetamine- related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle- treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight (similar to 14%) and fat content (similar to 90%), hepatic glycogen content (similar to 40%), and plasma levels of cholesterol (similar to 48%), insulin (similar to 259%), glucagon (similar to 80%), and leptin (similar to 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair- feeding of i3vt SHU9119- treated animals to i3vt vehicle- treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (similar to 31%) and leptin (similar to 104%) and body fat content (similar to 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i. e., CART, POMC, and NPY) and paraventricular (i. e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake- dependent and -independent mechanisms.
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| 45. |
- Adan, Roger A. H., et al.
(författare)
-
Nutritional psychiatry: Towards improving mental health by what you eat
- 2019
-
Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 29:12, s. 1321-1332
-
Tidskriftsartikel (refereegranskat)abstract
- Does it matter what we eat for our mental health? Accumulating data suggests that this may indeed be the case and that diet and nutrition are not only critical for human physiology and body composition, but also have significant effects on mood and mental wellbeing. While the determining factors of mental health are complex, increasing evidence indicates a strong association between a poor diet and the exacerbation of mood disorders, including anxiety and depression, as well as other neuropsychiatric conditions. There are common beliefs about the health effects of certain foods that are not supported by solid evidence and the scientific evidence demonstrating the unequivocal link between nutrition and mental health is only beginning to emerge. Current epidemiological data on nutrition and mental health do not provide information about causality or underlying mechanisms. Future studies should focus on elucidating mechanism. Randomized controlled trials should be of high quality, adequately powered and geared towards the advancement of knowledge from population-based observations towards personalized nutrition. Here, we provide an overview of the emerging field of nutritional psychiatry, exploring the scientific evidence exemplifying the importance of a well-balanced diet for mental health. We conclude that an experimental medicine approach and a mechanistic understanding is required to provide solid evidence on which future policies on diet and nutrition for mental health can be based. (C) 2019 The Author(s). Published by Elsevier B.V.
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| 46. |
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| 47. |
- Cardona Cano, Sebastian, et al.
(författare)
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Role of ghrelin in the pathophysiology of eating disorders: Implications for pharmacotherapy
- 2012
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Ingår i: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 26, s. 281-296
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Forskningsöversikt (refereegranskat)abstract
- Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs. © 2012 Adis Data Information BV. All rights reserved.
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| 48. |
- de Git, K. C. G., et al.
(författare)
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Is leptin resistance the cause or the consequence of diet-induced obesity?
- 2018
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 42:8, s. 1445-1457
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Tidskriftsartikel (refereegranskat)abstract
- Background/objectives Obesity is strongly associated with leptin resistance. It is unclear whether leptin resistance results from the (over) consumption of energy-dense diets or if reduced leptin sensitivity is also a pre-existing factor in rodent models of diet-induced obesity (DIO). We here tested whether leptin sensitivity on a chow diet predicts subsequent weight gain and leptin sensitivity on a free choice high-fat high-sucrose (fcHFHS) diet. Methods Based upon individual leptin sensitivity on chow diet, rats were grouped in leptin sensitive (LS, n = 22) and leptin resistant (LR, n = 19) rats (P = 0.000), and the development of DIO on a fcHFHS diet was compared. The time-course of leptin sensitivity was measured over weeks in individual rats. Results Both on a chow and a fcHFHS diet, high variability in leptin sensitivity was observed between rats, but not over time per individual rat. Exposure to the fcHFHS diet revealed that LR rats were more prone to develop DIO (P = 0.013), which was independent of caloric intake (p >= 0.320) and the development of diet-induced leptin resistance (P = 0.769). Reduced leptin sensitivity in LR compared with LS rats before fcHFHS diet exposure, was associated with reduced leptin-induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels in the dorsomedial and ventromedial hypothalamus (P <= 0.049), but not the arcuate nucleus (P = 0.558). Conclusions A pre-existing reduction in leptin sensitivity determines the susceptibility to develop excessive DIO after fcHFHS diet exposure. Rats with a pre-existing reduction in leptin sensitivity develop excessive DIO without eating more calories or altering their leptin sensitivity.
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| 49. |
- de Git, K. C. G., et al.
(författare)
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Zona incerta neurons projecting to the ventral tegmental area promote action initiation towards feeding
- 2021
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Ingår i: Journal of Physiology-London. - : Wiley. - 0022-3751 .- 1469-7793. ; 559:2, s. 709-724
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Tidskriftsartikel (refereegranskat)abstract
- Key points The zona incerta (ZI) and ventral tegmental area (VTA) are brain areas that are both implicated in feeding behaviour. The ZI projects to the VTA, although it has not yet been investigated whether this projection regulates feeding. We experimentally (in)activated the ZI to VTA projection by using dual viral vector technology, and studied the effects on feeding microstructure, the willingness to work for food, general activity and body temperature. Activity of the ZI to VTA projection promotes feeding by facilitating action initiation towards food, as reflected in meal frequency and the willingness to work for food reward, without affecting general activity or directly modulating body temperature. We show for the first time that activity of the ZI to VTA projection promotes feeding, which improves the understanding of the neurobiology of feeding behaviour and body weight regulation. Both the zona incerta (ZI) and the ventral tegmental area (VTA) have been implicated in feeding behaviour. The ZI provides prominent input to the VTA, although it has not yet been investigated whether this projection regulates feeding. Therefore, we investigated the role of ZI to VTA projection neurons in the regulation of several aspects of feeding behaviour. We determined the effects of (in)activation of ZI to VTA projection neurons on feeding microstructure, food-motivated behaviour under a progressive ratio schedule of reinforcement, locomotor activity and core body temperature. To activate or inactivate ZI neurons projecting to the VTA, we used a combination of canine adenovirus-2 in the VTA, as well as Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) or tetanus toxin (TetTox) light chain in the ZI. TetTox-mediated inactivation of ZI to VTA projection neurons reduced food-motivated behaviour and feeding by reducing meal frequency. Conversely, DREADD-mediated chemogenetic activation of ZI to VTA projection neurons promoted food-motivated behaviour and feeding. (In)activation of ZI to VTA projection neurons did not affect locomotor activity or directly regulate core body temperature. Taken together, ZI neurons projecting to the VTA exert bidirectional control overfeeding behaviour. More specifically, activity of ZI to VTA projection neurons facilitate action initiation towards feeding, as reflected in both food-motivated behaviour and meal initiation, without affecting general activity.
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| 50. |
- Flores-Dourojeanni, J. P., et al.
(författare)
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Inhibition of ventral tegmental area projections to the nucleus accumbens shell increases premature responding in the five-choice serial reaction time task in rats
- 2023
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Ingår i: Brain Structure & Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661.
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Tidskriftsartikel (refereegranskat)abstract
- Exaggerated impulsivity and attentional impairments are hallmarks of certain disorders of behavioural control such as attention-deficit/hyperactivity disorder (ADHD), schizophrenia and addiction. Pharmacological studies have implicated elevated dopamine (DA) levels in the nucleus accumbens shell (NAcbS) in impulsive actions. The NAcbS receives its DA input from the ventral tegmental area (VTA), and we have previously shown that optogenetic activation of VTA-NAcbS projections impaired impulse control and attention in the five-choice serial reaction time task (5-CSRTT) in rats. To better understand the role of VTA-NAcbS projections in impulsivity and attention, the present study sought to inhibit this projection using optogenetics. We demonstrate that inhibiting VTA-NAcbS efferents during the last seconds of the inter-trial interval (i.e. immediately before presentation of the instructive cue) induces exaggerated impulsive action, in the absence of changes in attentional or motivational parameters in the 5-CSRTT. Together with our earlier observations, this suggests that impulse control in the 5-CSRTT is tightly controlled by VTA-NAcbS activity, with deviations in both directions resulting in increased impulsivity.
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