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- Dubol, Manon, et al.
(författare)
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Acute nicotine exposure blocks aromatase in the limbic brain of healthy women : A [11C]cetrozole PET study
- 2023
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Ingår i: Comprehensive Psychiatry. - : Elsevier. - 0010-440X .- 1532-8384. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- Background: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain.Methods: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI -based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential.Results: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d =-0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend.Conclusions: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.
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| 2. |
- Immenschuh, Jana, et al.
(författare)
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Long-term effects of early life stress on Cyp19a1 mRNA expression and DNA methylation levels in male rats
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Early life stress (ELS) raises the risk of developing mental disorders later in life by inducing lasting epigenetic changes that can impact gene expression. Aromatase, the enzyme responsible for the synthesis of estrogen, is highly expressed in the limbic brain, a key circuit in mental wellbeing. Its neuroprotective role has been investigated in relation to brain trauma but not emotional stress. The present study aimed to investigate the effect of ELS on the expression of the aromatase gene (Cyp19a1), and whether a relation can be observed with the methylation of the gene, in the limbic brain of young adult male rats. ELS was modelled by daily maternal separation for 360 minutes (MS360) in the first three postnatal weeks and compared to a control group (MS15). Cyp19a1 mRNA levels in the cingulate cortex (CCX), medial prefrontal cortex (mPFC), hypothalamus, hippocampus, and amygdala, were quantified by real-time qPCR. Additionally, CpG methylation levels in the Cyp19a1 gene were assessed via targeted next generation bisulfite sequencing. Lower levels of Cyp19a1 were found in the mPFC in MS360 rats compared to MS15, while the opposite trend was observed in the amygdala. Additionally, higher methylation levels were observed in CpGs of intron 2 in the mPFC of MS360 compared with MS15 rats. The methylation levels of intron 2 were negatively correlated with gene expression in the mPFC of MS15 rats, while the correlation was positive for MS360 rats. These findings suggest that ELS might exert a region-specific, long-term effect on both gene expression and methylation of Cyp19a1, especially in the mPFC, a key regions in stress response regulation.
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| 3. |
- Immenschuh, Jana, et al.
(författare)
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Multimodal neuroimaging reveals neural correlates of aromatase availability in the female brain
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Estrogens extend their influence beyond reproduction, having been associated with neural plasticity and therefore the potential to shape the brain. It is unknown if the availability of aromatase, which is responsible for local estrogen synthesis in the brain, is associated with neural morphology. Here the correlation between in vivo brain availability of aromatase, grey and white matter structure, and peripheral levels of estradiol in healthy, young women was investigated.Methods: [11C]cetrozole positron emission tomography was performed together with structural and diffusion magnetic resonance imaging to assess the availability of aromatase, grey and white matter volumes, cortical surface architecture and white matter microstructure, respectively. Bioavailable gonadal hormone levels were measured. Results: Aromatase availability was notably high in the thalamus, hypothalamus, and amygdala, positively correlating with the grey matter volume of these regions. Cortical thickness and gyrification of the prefrontal cortex, as well as white matter properties of the fornix, were associated with aromatase availability. This suggests the impact of estrogens on the grey matter areas to which high aromatase-expressing regions are connected, and projecting white matter tracts, all part of the limbic brain that is often involved in mental disorders. Brain aromatase availability did not correlate with peripheral bioavailable hormone levels, pointing to a unique role of brain-derived estrogens. Conclusions: These findings provide the first evidence of brain morphological characteristics being associated with aromatase availability, shedding light on the impact of estrogens on brain structure.
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| 4. |
- Immenschuh, Jana, et al.
(författare)
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Sex differences in distribution and identity of aromatase gene expressing cells in the young adult rat brain
- 2023
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Ingår i: Biology of Sex Differences. - : BMC. - 2042-6410. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene (Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene.Methods: Cyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied.Results:In the male brain, the highest percentage of Cyp19a1+ cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1+ cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1+ cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3, suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1+ cells.Conclusions: Females show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.
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