Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament
Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2025.1469467/full |
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| author | Elaine K. Hebda-Bauer Megan H. Hagenauer Daniel B. Munro Daniel B. Munro Peter Blandino Fan Meng Keiko Arakawa John D. H. Stead Apurva S. Chitre A. Bilge Ozel Pejman Mohammadi Pejman Mohammadi Stanley J. Watson Shelly B. Flagel Jun Li Abraham A. Palmer Abraham A. Palmer Huda Akil |
| author_facet | Elaine K. Hebda-Bauer Megan H. Hagenauer Daniel B. Munro Daniel B. Munro Peter Blandino Fan Meng Keiko Arakawa John D. H. Stead Apurva S. Chitre A. Bilge Ozel Pejman Mohammadi Pejman Mohammadi Stanley J. Watson Shelly B. Flagel Jun Li Abraham A. Palmer Abraham A. Palmer Huda Akil |
| author_sort | Elaine K. Hebda-Bauer |
| collection | DOAJ |
| description | Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F0-F1-F2) to produce a heterogeneous F2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F0s (n = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F2s (n = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F2 behavior. In F0 and F2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (cis-expression quantitative trait loci or cis-eQTLs). These cis-eQTLs successfully predict bHR/bLR differential gene expression based on F0 genotype. Sixteen of these genes are associated with cis-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders. |
| format | Article |
| id | doaj-art-ff4cd8b92adb4407aab3d8e01e364ff6 |
| institution | DOAJ |
| issn | 1662-5099 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj-art-ff4cd8b92adb4407aab3d8e01e364ff62025-08-20T03:15:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992025-03-011810.3389/fnmol.2025.14694671469467Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperamentElaine K. Hebda-Bauer0Megan H. Hagenauer1Daniel B. Munro2Daniel B. Munro3Peter Blandino4Fan Meng5Keiko Arakawa6John D. H. Stead7Apurva S. Chitre8A. Bilge Ozel9Pejman Mohammadi10Pejman Mohammadi11Stanley J. Watson12Shelly B. Flagel13Jun Li14Abraham A. Palmer15Abraham A. Palmer16Huda Akil17Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesDepartment of Psychiatry, University of California San Diego, La Jolla, CA, United StatesSeattle Children’s Research Institute, University of Washington, Seattle, WA, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesDepartment of Neuroscience, Carleton University, Ottawa, ON, CanadaDepartment of Psychiatry, University of California San Diego, La Jolla, CA, United StatesDepartment of Human Genetics, University of Michigan, Ann Arbor, MI, United StatesSeattle Children’s Research Institute, University of Washington, Seattle, WA, United StatesDepartment of Pediatrics, University of Washington School of Medicine, Seattle, WA, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesDepartment of Human Genetics, University of Michigan, Ann Arbor, MI, United StatesDepartment of Psychiatry, University of California San Diego, La Jolla, CA, United StatesInstitute for Genomic Medicine, University of California San Diego, La Jolla, CA, United StatesMichigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United StatesExternalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F0-F1-F2) to produce a heterogeneous F2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F0s (n = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F2s (n = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F2 behavior. In F0 and F2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (cis-expression quantitative trait loci or cis-eQTLs). These cis-eQTLs successfully predict bHR/bLR differential gene expression based on F0 genotype. Sixteen of these genes are associated with cis-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.https://www.frontiersin.org/articles/10.3389/fnmol.2025.1469467/fulltemperamenthippocampusRNA-Seqlocomotor activityanxietyenergy metabolism |
| spellingShingle | Elaine K. Hebda-Bauer Megan H. Hagenauer Daniel B. Munro Daniel B. Munro Peter Blandino Fan Meng Keiko Arakawa John D. H. Stead Apurva S. Chitre A. Bilge Ozel Pejman Mohammadi Pejman Mohammadi Stanley J. Watson Shelly B. Flagel Jun Li Abraham A. Palmer Abraham A. Palmer Huda Akil Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament Frontiers in Molecular Neuroscience temperament hippocampus RNA-Seq locomotor activity anxiety energy metabolism |
| title | Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament |
| title_full | Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament |
| title_fullStr | Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament |
| title_full_unstemmed | Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament |
| title_short | Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament |
| title_sort | bioenergetic related gene expression in the hippocampus predicts internalizing vs externalizing behavior in an animal model of temperament |
| topic | temperament hippocampus RNA-Seq locomotor activity anxiety energy metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2025.1469467/full |
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