Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4
Humans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the...
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Frontiers Media S.A.
2018-12-01
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2018.00513/full |
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| author | John Paul Spence Jill L. Reiter Bin Qiu Hao Gu Dawn K. Garcia Lingling Zhang Tamara Graves Kent E. Williams Paula J. Bice Yi Zou Zhao Lai Weidong Yong Tiebing Liang |
| author_facet | John Paul Spence Jill L. Reiter Bin Qiu Hao Gu Dawn K. Garcia Lingling Zhang Tamara Graves Kent E. Williams Paula J. Bice Yi Zou Zhao Lai Weidong Yong Tiebing Liang |
| author_sort | John Paul Spence |
| collection | DOAJ |
| description | Humans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the selectively bred alcohol-preferring (P) and non-preferring (NP) rat lines revealed a highly significant quantitative trait locus (QTL) on rat chromosome 4, with a logarithm of the odds score of 9.2 for alcohol consumption. Recently, interval-specific congenic strains (ISCS) were developed by backcrossing the congenic P.NP line to inbred P (iP) rats to further refine the chromosome 4 QTL region. Two ISCS sub-strains, ISCS-A and ISCS-B, were obtained with a narrowed QTL, where the smallest region of overlap consisted of 8.9 Mb in ISCS-B. Interestingly, we found that females from both ISCS lines consumed significantly less alcohol than female iP controls (p < 0.05), while no differences in alcohol consumption were observed between male ISCS and iP controls. RNA-sequencing was performed on the nucleus accumbens of alcohol-naïve female ISCS-B and iP rats, which revealed differentially expressed genes (DEG) with greater than 2-fold change and that were functionally relevant to behavior. These DEGs included down-regulation of Oxt, Asb4, Gabre, Gabrq, Chat, Slc5a7, Slc18a8, Slc10a4, and Ngfr, and up-regulation of Ttr, Msln, Mpzl2, Wnt6, Slc17a7, Aldh1a2, and Gstm2. Pathway analysis identified significant alterations in gene networks controlling nervous system development and function, as well as cell signaling, GABA and serotonin receptor signaling and G-protein coupled receptor signaling. In addition, β-estradiol was identified as the most significant upstream regulator. The expression levels of estrogen-responsive genes that mapped to the QTL interval and have been previously associated with alcohol consumption were measured using RT-qPCR. We found that expression of the Adcyap1r1 gene, encoding the pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptor, was upregulated in female ISCS-B compared to female iP controls, while no differences were exhibited in males. In addition, sequence variants in the Adcyap1r1 promoter region showed a differential response to estrogen stimulation in vitro. These findings demonstrate that rat chromosome 4 QTL contains genetic variants that respond to estrogen and are associated with female alcohol consumption. |
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| spelling | doaj.art-a7c38cbd3c80470aab9fb44238b5dff92022-12-21T20:44:23ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-12-01910.3389/fgene.2018.00513371655Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4John Paul Spence0Jill L. Reiter1Bin Qiu2Hao Gu3Dawn K. Garcia4Lingling Zhang5Tamara Graves6Kent E. Williams7Paula J. Bice8Yi Zou9Zhao Lai10Weidong Yong11Tiebing Liang12Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesComparative Medical Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaComparative Medical Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaGreehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX, United StatesComparative Medical Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Psychology, Southeast Missouri State University, Cape Girardeau, MO, United StatesGreehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX, United StatesDepartment of Psychology, Southeast Missouri State University, Cape Girardeau, MO, United StatesComparative Medical Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN, United StatesHumans show sex differences related to alcohol use disorders (AUD). Animal model research has the potential to provide important insight into how sex differences affect alcohol consumption, particularly because female animals frequently drink more than males. In previous work, inbred strains of the selectively bred alcohol-preferring (P) and non-preferring (NP) rat lines revealed a highly significant quantitative trait locus (QTL) on rat chromosome 4, with a logarithm of the odds score of 9.2 for alcohol consumption. Recently, interval-specific congenic strains (ISCS) were developed by backcrossing the congenic P.NP line to inbred P (iP) rats to further refine the chromosome 4 QTL region. Two ISCS sub-strains, ISCS-A and ISCS-B, were obtained with a narrowed QTL, where the smallest region of overlap consisted of 8.9 Mb in ISCS-B. Interestingly, we found that females from both ISCS lines consumed significantly less alcohol than female iP controls (p < 0.05), while no differences in alcohol consumption were observed between male ISCS and iP controls. RNA-sequencing was performed on the nucleus accumbens of alcohol-naïve female ISCS-B and iP rats, which revealed differentially expressed genes (DEG) with greater than 2-fold change and that were functionally relevant to behavior. These DEGs included down-regulation of Oxt, Asb4, Gabre, Gabrq, Chat, Slc5a7, Slc18a8, Slc10a4, and Ngfr, and up-regulation of Ttr, Msln, Mpzl2, Wnt6, Slc17a7, Aldh1a2, and Gstm2. Pathway analysis identified significant alterations in gene networks controlling nervous system development and function, as well as cell signaling, GABA and serotonin receptor signaling and G-protein coupled receptor signaling. In addition, β-estradiol was identified as the most significant upstream regulator. The expression levels of estrogen-responsive genes that mapped to the QTL interval and have been previously associated with alcohol consumption were measured using RT-qPCR. We found that expression of the Adcyap1r1 gene, encoding the pituitary adenylate cyclase-activating polypeptide type 1 (PAC1) receptor, was upregulated in female ISCS-B compared to female iP controls, while no differences were exhibited in males. In addition, sequence variants in the Adcyap1r1 promoter region showed a differential response to estrogen stimulation in vitro. These findings demonstrate that rat chromosome 4 QTL contains genetic variants that respond to estrogen and are associated with female alcohol consumption.https://www.frontiersin.org/article/10.3389/fgene.2018.00513/fullalcohol use disordersex-differencecongenic rat modelnucleus accumbensRNA-seqAdcyap1r1 |
| spellingShingle | John Paul Spence Jill L. Reiter Bin Qiu Hao Gu Dawn K. Garcia Lingling Zhang Tamara Graves Kent E. Williams Paula J. Bice Yi Zou Zhao Lai Weidong Yong Tiebing Liang Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 Frontiers in Genetics alcohol use disorder sex-difference congenic rat model nucleus accumbens RNA-seq Adcyap1r1 |
| title | Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 |
| title_full | Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 |
| title_fullStr | Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 |
| title_full_unstemmed | Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 |
| title_short | Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4 |
| title_sort | estrogen dependent upregulation of adcyap1r1 expression in nucleus accumbens is associated with genetic predisposition of sex specific qtl for alcohol consumption on rat chromosome 4 |
| topic | alcohol use disorder sex-difference congenic rat model nucleus accumbens RNA-seq Adcyap1r1 |
| url | https://www.frontiersin.org/article/10.3389/fgene.2018.00513/full |
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