| 1. |
- Barbier, Estelle, et al.
(författare)
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A molecular mechanism for choosing alcohol over an alternative reward
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 360:6395
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which similar to 15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the g-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.
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| 2. |
- Barbier, Estelle, et al.
(författare)
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Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2
- 2017
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Ingår i: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 22:12, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.
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| 3. |
- Carleial, Samuel, et al.
(författare)
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DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers
- 2021
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Ingår i: Scientific Reports. - : Nature Portfolio. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.
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| 4. |
- Desai Boström, Adrian, 1990-
(författare)
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Epigenetic dysregulation in relation to psychiatric traits in adolescence and adulthood
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epigenetics has evolved into a key research focus in the field of psychiatry. DNA methylation is the most researched epigenetic mechanism. In paper I-III, 130 and 93 adolescents were randomly recruited at two separate intervals. Subjects were evaluated by web-based diagnostic interviews using the Development and Well-Being Assessment (DAWBA), providing computer generated diagnostic predictions of probability of diagnosis, covering several psychiatric disorders. For Paper I-II, the genome-wide DNA methylation pattern was measured from whole blood using the Illumina 450K array, and for paper IV by the Illumina EPIC BeadChip. In paper I, a methylome-wide association study (MWAS) was conducted (n=93) followed by a validation analysis (n=78), contrasting methylation levels in groups stratified by DAWBA depression risk scores. A microRNA4646 (MIR4646) associated methylation locus was differentially methylated in the MWAS (pbonf<0.05) and results were replicated in the validation cohort (p<0.05). Methylation levels at the identified locus correlated inversely with gene expression levels of MIR4456 (p<0.05). In silico analysis suggests MIR4646 may influence synthesis of omega-3 fatty acids, previously implicated in major depressive disorder. In paper II, 37 single nucleotide polymorphisms (SNP:s) previously associated with psychiatric disease were evaluated in relation to genome-wide DNA methylation levels in 130 adolescents in a methylome-wide (mQTL) analysis. Five SNP-CpG pairs were identified (pbonf<0.05) and replicated (p<0.05). Methylation of three of these were shown to be significantly correlated with gene expression levels of the associated genes (p<0.05). One identified GAD1-coupled methylation site was differentially methylated to a general psychiatric risk score in adolescents (p<0.05). In Paper III, hypothalamic-pituitary-adrenal (HPA)-axis coupled DNA methylation loci were investigated in 88 suicide attempters to identify associations to severity of suicide attempt. One corticotropin releasing hormone (CRH)-associated CpG-site was significantly hypomethylated in the high-risk group of suicide-attempters (n=31)(cg19035496, p<0.001) and exhibited hypermethylation in an external study group of adolescents in dependency of a general psychiatric risk score (p<0.05). In paper IV, 8,852 microRNA (miRNA) associated CpG-sites were investigated for an association with hypersexual disorder (HD). A microRNA-4456 (MIR4456) associated CpG-site (cg01299774) was borderline significant in HD (pFDR=5.81E-02) and differentially methylated in alcohol dependence (p<0.05) in an independent study group. Methylation levels at cg01299774 correlated inversely with expression levels of MIR4456 (p<0.01) and MIR4456 was lower expressed in HD (p<0.05). In-silico analyses suggests MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signaling pathway.
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| 5. |
- Elfwing, Magnus, et al.
(författare)
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Early stress causes sex-specific, life-long changes in behaviour, levels of gonadal hormones, and gene expression in chickens
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Early stress can have long-lasting phenotypic effects. Previous research shows that male and female chickens differ in many behavioural aspects, and respond differently to chronic stress. The present experiment aimed to broadly characterize long-term sex differences in responses to brief events of stress experienced during the first weeks of life. Chicks from a commercial egg-laying hybrid were exposed to stress by inducing periods of social isolation during their first three weeks of life, followed by a broad behavioural, physiological and genomic characterization throughout life. Early stressed males, but not females, where more anxious in an open field-test, stayed shorter in tonic immobility and tended to have delayed sexual maturity, as shown by a tendency for lower levels of testosterone compared to controls. While early stressed females did not differ from non-stressed in fear and sexual maturation, they were more socially dominant than controls. The differential gene expression profile in hypothalamus was significantly correlated from 28 to 213 days of age in males, but not in females. In conclusion, early stress had a more pronounced long-term effect on male than on female chickens, as evidenced by behavioral, endocrine and genomic responses. This may either be attributed to inherent sex differences due to evolutionary causes, or possibly to different stress related selection pressures on the two sexes during commercial chicken breeding.
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| 6. |
- Goerlich, Vivian C., et al.
(författare)
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Transgenerational effects of early experience on acute stress reactions in behaviour, steroid hormones and gene expression in the precocial chicken
- 2012
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Ingår i: Hormones and Behavior. - : Elsevier BV. - 0018-506X .- 1095-6867. ; 61:5, s. 711-718
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Tidskriftsartikel (refereegranskat)abstract
- Stress during early life can profoundly influence an individual’s phenotype. Effects can manifest in the short-term as well as later in life and even in subsequent generations. Transgenerational effects of stress are potentially mediated via modulation of the hypothalamic-pituitary-adrenal axis (HPA) as well as epigenetic mechanisms causing heritable changes in gene expression. To investigate these pathways we subjected domestic chicks (Gallus gallus) to intermittent social isolation, food restriction, and temperature stress for the first three weeks of life. The early life stress resulted in a dampened corticosterone response to restraint stress in the parents and male offspring. Stress-specific genes, such as early growth response 1 (EGR1) and corticotropin releasing hormone receptor 1 (CRHR1), were upregulated when chicks were tested in the context of restraint stress, but not under baseline conditions. Treatment differences in gene expression were also correlated across generations which indicate transgenerational epigenetic inheritance, possibly mediated by differences in maternal yolk estradiol and testosterone. In an associative learning test early stressed birds made more correct choices suggesting a higher coping ability in stressful situations. This study is the first to show transgenerational effects of early life stress in a precocial species by combining behavioural, endocrinological, and transcriptomic measurements.
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| 7. |
- Jöngren, Markus, 1981-, et al.
(författare)
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Brain gene expression in relation to fearfulness in female red junglefowl (Gallus gallus)
- 2010
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Ingår i: Genes, Brain and Behavior. - : International and Neural genetics Society. - 1601-1848 .- 1601-183X. ; 9:7, s. 751-758
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Tidskriftsartikel (refereegranskat)abstract
- The biology of fear is central to animal welfare and hasbeen a major target for selection during domestication.Fear responses were studied in female red junglefowl(RJF), the ancestor of domesticated chickens. A totalof 31 females were tested in a ground predator test,an aerial predator test and a tonic immobility (TI)test, in order to assess their level of fearfulnessacross different situations. Two to six variables fromeach test were entered into a principal component(PC) analysis, which showed one major fearfulnesscomponent (explaining 27% of the variance). Based onthe PC scores, four high- and four low-fearful birds werethen selected for gene expression analysis. From eachof these birds, the midbrain region (including thalamus,hypothalamus, pituitary, mesencephalon, pons, nucleustractus solitarii and medulla oblongata), was collectedand global gene expression compared between groupsusing a 14k chicken cDNA microarray. There were 13significantly differentially expressed (DE) genes (basedonM > 1 andB > 0; FDR-adjusted P < 0.05) between thefearful and non-fearful females. Among the DE genes,we identified the neuroprotein Axin1, two potentialDNA/RNA regulating proteins and a retrotransposontranscript situated in a well-studied quantitative traitloci (QTL) region on chromosome 1, known to affectseveral domestication-related traits. The differentiallyexpressed genes may be part of a possible molecularmechanism controlling fear responses in fowl.
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| 8. |
- Lindqvist, Christina, et al.
(författare)
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Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
- 2007
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:4, s. e364-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved. Methodology/Principal Findings: Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents. Conclusions/ Significance: Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.
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| 9. |
- Mayo, Leah M., 1987-, et al.
(författare)
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Protective effects of elevated anandamide on stress and fear-related behaviors : translational evidence from humans and mice
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:5, s. 993-1005
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Tidskriftsartikel (refereegranskat)abstract
- Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.
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| 10. |
- Nätt, Daniel
(författare)
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Heritable epigenetic responses to environmental challenges : Effects on behaviour, gene expression and DNA-methylation in the chicken
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phenotypic variation within populations is a crucial factor in evolution and is mainly thought to be driven by heritable changes in the base sequence of DNA. Among our domesticated species we find some of the most variable species on earth today. This variety of breeds has appeared during a relatively short evolutionary time, and so far genetic studies have been unable to explain but a small portion of this variation, which indicates more novel mechanisms of inheritance and phenotypic plasticity. The aim of this study was therefore to investigate some of these alternative routes in the chicken, especially focusing on transgenerational effects of environmental challenges on behaviour and gene expression in relation to domestication. In two experiments a chronically unpredictable environment induced phenotypic changes in the parents that were mirrored in the unexposed offspring raised without parental contact. This transmission was especially clear in domesticated birds. A third experiment showed that repeated stress events very early in life could change the developmental program making the birds more resistant to stress later in life. Here, the phenotypic changes were also mirrored in the unexposed offspring and associated with inheritance of gene expression. Epigenetic factors, such as DNA-methylation, could play an important role in the mechanism of these transgenerational effects. A fourth experiment showed that wild types and domesticated chickens differed substantially in their patterns of DNA-methylation, where the domesticated breed had increased amount of promoter DNA-methylation. In line with the previous experiments, this breed also showed increased transmission of methylation marks to their offspring. Conclusively, parental exposure of environmental challenges that introduce changes in behaviour, physiology and gene expression can under both chronic and temporal conditions be heritably programmed in the parent and transmitted to the unexposed offspring. Since heritable epigenetic variation between wild type and domesticated chickens is stable and numerous, it is possible that selection for favourable epigenomes could add another level to the evolutionary processes and therefore might explain some of the rapid changes in the history of the domesticated chicken.
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