Advertisement

Genetic Liability for Internalizing Versus Externalizing Behavior Manifests in the Developing and Adult Hippocampus: Insight From a Meta-analysis of Transcriptional Profiling Studies in a Selectively Bred Rat Model

      Abstract

      Background

      For more than 16 years, we have selectively bred rats for either high or low levels of exploratory activity within a novel environment. These bred high-responder (bHR) and bred low-responder (bLR) rats model temperamental extremes, exhibiting large differences in internalizing and externalizing behaviors relevant to mood and substance use disorders.

      Methods

      We characterized persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation, by meta-analyzing 8 transcriptional profiling datasets (microarray and RNA sequencing) spanning 43 generations of selective breeding (postnatal day 7: n = 22; postnatal day 14: n = 49; postnatal day 21: n = 21; adult: n = 46; all male). We cross-referenced expression differences with exome sequencing within our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. The results were compared with hippocampal profiling from other bred rat models.

      Results

      Genetic and transcriptional profiling results converged to implicate multiple candidate genes, including two previously associated with metabolism and mood: Trhr and Ucp2. Results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, centering on Bmp4 and Mki67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including 2 genes within implicated chromosomal regions: C1qa and Mfge8.

      Conclusions

      These candidate genes and functional pathways may direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Krueger R.F.
        • Markon K.E.
        Reinterpreting comorbidity: A model-based approach to understanding and classifying psychopathology.
        Annu Rev Clin Psychol. 2006; 2: 111-133
        • Smoller J.W.
        The genetics of stress-related disorders: PTSD, depression, and anxiety disorders.
        Neuropsychopharmacology. 2016; 41: 297-319
        • Wray N.R.
        • Ripke S.
        • Mattheisen M.
        • Trzaskowski M.
        • Byrne E.M.
        • Abdellaoui A.
        • et al.
        Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
        Nat Genet. 2018; 50: 668-681
        • Aydin C.
        • Frohmader K.
        • Akil H.
        Revealing a latent variable: Individual differences in affective response to repeated injections.
        Behav Neurosci. 2015; 129: 679-682
        • Chaudhury S.
        • Aurbach E.L.
        • Sharma V.
        • Blandino P.
        • Turner C.A.
        • Watson S.J.
        • Akil H.
        FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3.
        Proc Natl Acad Sci U S A. 2014; 111: 11834-11839
        • Clinton S.M.
        • Vazquez D.M.
        • Kabbaj M.
        • Kabbaj M.-H.
        • Watson S.J.
        • Akil H.
        Individual differences in novelty-seeking and emotional reactivity correlate with variation in maternal behavior.
        Horm Behav. 2007; 51: 655-664
        • Flagel S.B.
        • Robinson T.E.
        • Clark J.J.
        • Clinton S.M.
        • Watson S.J.
        • Seeman P.
        • et al.
        An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: Implications for addiction.
        Neuropsychopharmacology. 2010; 35: 388-400
        • Flagel S.B.
        • Waselus M.
        • Clinton S.M.
        • Watson S.J.
        • Akil H.
        Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty.
        Neuropharmacology. 2014; 76: 425-436
        • Perez J.A.
        • Clinton S.M.
        • Turner C.A.
        • Watson S.J.
        • Akil H.
        A new role for FGF2 as an endogenous inhibitor of anxiety.
        J Neurosci. 2009; 29: 6379-6387
        • Prater K.E.
        • Aurbach E.L.
        • Larcinese H.K.
        • Smith T.N.
        • Turner C.A.
        • Blandino P.
        • et al.
        Selectively bred rats provide a unique model of vulnerability to PTSD-like behavior and respond differentially to FGF2 augmentation early in life.
        Neuropsychopharmacology. 2017; 42: 1706-1714
        • Stead J.D.H.
        • Clinton S.
        • Neal C.
        • Schneider J.
        • Jama A.
        • Miller S.
        • et al.
        Selective breeding for divergence in novelty-seeking traits: Heritability and enrichment in spontaneous anxiety-related behaviors.
        Behav Genet. 2006; 36: 697-712
        • Stedenfeld K.A.
        • Clinton S.M.
        • Kerman I.A.
        • Akil H.
        • Watson S.J.
        • Sved A.F.
        Novelty-seeking behavior predicts vulnerability in a rodent model of depression.
        Physiol Behav. 2011; 103: 210-216
        • Turner C.A.
        • Clinton S.M.
        • Thompson R.C.
        • Watson S.J.
        • Akil H.
        Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals.
        Proc Natl Acad Sci U S A. 2011; 108: 8021-8025
        • Clinton S.M.
        • Stead J.D.H.
        • Miller S.
        • Watson S.J.
        • Akil H.
        Developmental underpinnings of differences in rodent novelty-seeking and emotional reactivity.
        Eur J Neurosci. 2011; 34: 994-1005
        • Turner C.A.
        • Hagenauer M.H.
        • Aurbach E.L.
        • Maras P.M.
        • Fournier C.L.
        • Blandino P.
        • et al.
        Effects of early-life FGF2 on ultrasonic vocalizations (USVs) and the mu-opioid receptor in male Sprague-Dawley rats selectively-bred for differences in their response to novelty.
        Brain Res. 2019; 1715: 106-114
        • Robinson J.L.
        • Kagan J.
        • Reznick J.S.
        • Corley R.
        The heritability of inhibited and uninhibited behavior: A twin study.
        Dev Psychol. 1992; 28: 1030-1037
        • Turner C.A.
        • Flagel S.B.
        • Blandino P.
        • Watson S.J.
        • Akil H.
        Utilizing a unique animal model to better understand human temperament.
        Curr Opin Behav Sci. 2017; 14: 108-114
        • Fanselow M.S.
        • Dong H.-W.
        Are the dorsal and ventral hippocampus functionally distinct structures?.
        Neuron. 2010; 65: 7-19
        • Gray J.A.
        The Neuropsychology of Anxiety: An Enquiry Into the Functions of the Septo-hippocampal System.
        Clarendon/Oxford University Press, New York1982
        • Papez J.W.
        A proposed mechanism of emotion.
        Arch Neurol Psychiatry. 1937; 38: 725-743
        • Campbell S.
        • Macqueen G.
        The role of the hippocampus in the pathophysiology of major depression.
        J Psychiatry Neurosci. 2004; 29: 417-426
        • Gerlach J.L.
        • McEwen B.S.
        Rat brain binds adrenal steroid hormone: Radioautography of hippocampus with corticosterone.
        Science. 1972; 175: 1133-1136
        • Clinton S.
        • Miller S.
        • Watson S.J.
        • Akil H.
        Prenatal stress does not alter innate novelty-seeking behavioral traits, but differentially affects individual differences in neuroendocrine stress responsivity.
        Psychoneuroendocrinology. 2008; 33: 162-177
        • Kabbaj M.
        • Devine D.P.
        • Savage V.R.
        • Akil H.
        Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: Differential expression of stress-related molecules.
        J Neurosci. 2000; 20: 6983-6988
        • Zhou Z.
        • Blandino P.
        • Yuan Q.
        • Shen P.-H.
        • Hodgkinson C.A.
        • Virkkunen M.
        • et al.
        Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.
        Proc Natl Acad Sci U S A. 2019; 116: 13107-13115
        • Aurbach E.L.
        • Inui E.G.
        • Turner C.A.
        • Hagenauer M.H.
        • Prater K.E.
        • Li J.Z.
        • et al.
        Fibroblast growth factor 9 is a novel modulator of negative affect.
        Proc Natl Acad Sci U S A. 2015; 112: 11953-11958
        • Isgor C.
        • Kabbaj M.
        • Akil H.
        • Watson S.J.
        Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats.
        Hippocampus. 2004; 14: 636-648
        • Cohen J.L.
        • Glover M.E.
        • Pugh P.C.
        • Fant A.D.
        • Simmons R.K.
        • Akil H.
        • et al.
        Maternal style selectively shapes amygdalar development and social behavior in rats genetically prone to high anxiety.
        Dev Neurosci. 2015; 37: 203-214
        • Irizarry R.A.
        • Hobbs B.
        • Collin F.
        • Beazer-Barclay Y.D.
        • Antonellis K.J.
        • Scherf U.
        • Speed T.P.
        Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
        Biostatistics. 2003; 4: 249-264
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Softw. 2010; 36https://doi.org/10.18637/jss.v036.i03
        • Pollard K.S.
        • Dudoit S.
        • van der Laan M.J.
        Multiple testing procedures: The multtest package and applications to genomics.
        in: Gentleman R. Carey V. Huber W. Irizarry R. Dudoit S. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Springer, New York2005: 249-271
        • Meckes J.K.
        • Lim P.H.
        • Wert S.L.
        • Luo W.
        • Gacek S.A.
        • Platt D.
        • et al.
        Brain region-specific expression of genes mapped within quantitative trait loci for behavioral responsiveness to acute stress in Fisher 344 and Wistar Kyoto male rats.
        PLoS One. 2018; 13e194293
        • Andrus B.M.
        • Blizinsky K.
        • Vedell P.T.
        • Dennis K.
        • Shukla P.K.
        • Schaffer D.J.
        • et al.
        Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models.
        Mol Psychiatry. 2012; 17: 49-61
        • Sabariego M.
        • Morón I.
        • Gómez M.J.
        • Donaire R.
        • Tobeña A.
        • Fernández-Teruel A.
        • et al.
        Incentive loss and hippocampal gene expression in inbred Roman high- (RHA-I) and Roman low- (RLA-I) avoidance rats.
        Behav Brain Res. 2013; 257: 62-70
        • Díaz-Morán S.
        • Palència M.
        • Mont-Cardona C.
        • Cañete T.
        • Blázquez G.
        • Martínez-Membrives E.
        • et al.
        Gene expression in hippocampus as a function of differential trait anxiety levels in genetically heterogeneous NIH-HS rats.
        Behav Brain Res. 2013; 257: 129-139
        • Raghavan N.S.
        • Chen H.
        • Schipma M.
        • Luo W.
        • Chung S.
        • Wang L.
        • Redei E.E.
        Prepubertal ovariectomy exaggerates adult affective behaviors and alters the hippocampal transcriptome in a genetic rat model of depression.
        Front Endocrinol (Lausanne). 2017; 8: 373
        • Garafola C.S.
        • Henn F.A.
        A change in hippocampal protocadherin gamma expression in a learned helpless rat.
        Brain Res. 2014; 1593: 55-64
        • Zhang S.
        • Amstein T.
        • Shen J.
        • Brush F.R.
        • Gershenfeld H.K.
        Molecular correlates of emotional learning using genetically selected rat lines.
        Genes Brain Behav. 2005; 4: 99-109
        • Wilhelm C.J.
        • Choi D.
        • Huckans M.
        • Manthe L.
        • Loftis J.M.
        Adipocytokine signaling is altered in Flinders sensitive line rats, and adiponectin correlates in humans with some symptoms of depression.
        Pharmacol Biochem Behav. 2013; 103: 643-651
        • Blaveri E.
        • Kelly F.
        • Mallei A.
        • Harris K.
        • Taylor A.
        • Reid J.
        • et al.
        Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours.
        PLoS One. 2010; 5e12596
        • Shimoyama M.
        • De Pons J.
        • Hayman G.T.
        • Laulederkind S.J.F.
        • Liu W.
        • Nigam R.
        • et al.
        The Rat Genome Database 2015: Genomic, phenotypic and environmental variations and disease.
        Nucleic Acids Res. 2015; 43: D743-D750
        • De Preter K.
        • Barriot R.
        • Speleman F.
        • Vandesompele J.
        • Moreau Y.
        Positional gene enrichment analysis of gene sets for high-resolution identification of overrepresented chromosomal regions.
        Nucleic Acids Res. 2008; 36: e43
        • Mootha V.K.
        • Lindgren C.M.
        • Eriksson K.-F.
        • Subramanian A.
        • Sihag S.
        • Lehar J.
        • et al.
        PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
        Nat Genet. 2003; 34: 267-273
        • Subramanian A.
        • Tamayo P.
        • Mootha V.K.
        • Mukherjee S.
        • Ebert B.L.
        • Gillette M.A.
        • et al.
        Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles.
        Proc Natl Acad Sci U S A. 2005; 102: 15545-15550
        • Sergushichev A.
        An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation.
        bioRxiv. 2016; https://doi.org/10.1101/060012
        • Powell J.A.C.
        GO2MSIG, an automated GO based multi-species gene set generator for gene set enrichment analysis.
        BMC Bioinformatics. 2014; 15: 146
        • Johnson M.R.
        • Shkura K.
        • Langley S.R.
        • Delahaye-Duriez A.
        • Srivastava P.
        • Hill W.D.
        • et al.
        Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.
        Nat Neurosci. 2016; 19: 223-232
        • Park C.C.
        • Gale G.D.
        • de Jong S.
        • Ghazalpour A.
        • Bennett B.J.
        • Farber C.R.
        • et al.
        Gene networks associated with conditional fear in mice identified using a systems genetics approach.
        BMC Syst Biol. 2011; 5: 43
        • Cembrowski M.S.
        • Wang L.
        • Sugino K.
        • Shields B.C.
        • Spruston N.
        Hipposeq: A comprehensive RNA-seq database of gene expression in hippocampal principal neurons.
        eLife. 2016; 5e14997
        • Szklarczyk D.
        • Franceschini A.
        • Wyder S.
        • Forslund K.
        • Heller D.
        • Huerta-Cepas J.
        • et al.
        STRING v10: Protein-protein interaction networks, integrated over the tree of life.
        Nucleic Acids Res. 2015; 43: D447-D452
        • Hagenauer M.H.
        • Schulmann A.
        • Li J.Z.
        • Vawter M.P.
        • Walsh D.M.
        • Thompson R.C.
        • et al.
        Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis.
        PLoS One. 2018; 13e200003
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.
        Methods. 2001; 25: 402-408
        • Yuan J.S.
        • Reed A.
        • Chen F.
        • Stewart C.N.
        Statistical analysis of real-time PCR data.
        BMC Bioinformatics. 2006; 7: 85
        • Calvo N.
        • Cecchi M.
        • Kabbaj M.
        • Watson S.J.
        • Akil H.
        Differential effects of social defeat in rats with high and low locomotor response to novelty.
        Neuroscience. 2011; 183: 81-89
        • Kabbaj M.
        • Evans S.
        • Watson S.J.
        • Akil H.
        The search for the neurobiological basis of vulnerability to drug abuse: Using microarrays to investigate the role of stress and individual differences.
        Neuropharmacology. 2004; 47: 111-122
        • Albert F.W.
        • Carlborg O.
        • Plyusnina I.
        • Besnier F.
        • Hedwig D.
        • Lautenschläger S.
        • et al.
        Genetic architecture of tameness in a rat model of animal domestication.
        Genetics. 2009; 182: 541-554
        • Terenina-Rigaldie E.
        • Moisan M.-P.
        • Colas A.
        • Beaugé F.
        • Shah K.V.
        • Jones B.C.
        • Mormède P.
        Genetics of behaviour: Phenotypic and molecular study of rats derived from high- and low-alcohol consuming lines.
        Pharmacogenetics. 2003; 13: 543-554
        • Conti L.H.
        • Jirout M.
        • Breen L.
        • Vanella J.J.
        • Schork N.J.
        • Printz M.P.
        Identification of quantitative trait loci for anxiety and locomotion phenotypes in rat recombinant inbred strains.
        Behav Genet. 2004; 34: 93-103
        • Baum A.E.
        • Solberg L.C.
        • Churchill G.A.
        • Ahmadiyeh N.
        • Takahashi J.S.
        • Redei E.E.
        Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality.
        Behav Brain Res. 2006; 169: 220-230
        • Johannesson M.
        • Lopez-Aumatell R.
        • Stridh P.
        • Diez M.
        • Tuncel J.
        • Blázquez G.
        • et al.
        A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: The NIH heterogeneous stock.
        Genome Res. 2009; 19: 150-158
        • Fernández-Teruel A.
        • Escorihuela R.M.
        • Gray J.A.
        • Aguilar R.
        • Gil L.
        • Giménez-Llort L.
        • et al.
        A quantitative trait locus influencing anxiety in the laboratory rat.
        Genome Res. 2002; 12: 618-626
        • Solberg L.C.
        • Baum A.E.
        • Ahmadiyeh N.
        • Shimomura K.
        • Li R.
        • Turek F.W.
        • et al.
        Genetic analysis of the stress-responsive adrenocortical axis.
        Physiol Genomics. 2006; 27: 362-369
        • Yamazato M.
        • Ohya Y.
        • Nakamoto M.
        • Sakima A.
        • Tagawa T.
        • Harada Y.
        • et al.
        Sympathetic hyperreactivity to air-jet stress in the chromosome 1 blood pressure quantitative trait locus congenic rats.
        Am J Physiol Regul Integr Comp Physiol. 2006; 290: R709-R714
        • Llamas B.
        • Contesse V.
        • Guyonnet-Duperat V.
        • Vaudry H.
        • Mormède P.
        • Moisan M.-P.
        QTL mapping for traits associated with stress neuroendocrine reactivity in rats.
        Mamm Genome. 2005; 16: 505-515
        • Solberg L.C.
        • Baum A.E.
        • Ahmadiyeh N.
        • Shimomura K.
        • Li R.
        • Turek F.W.
        • et al.
        Sex- and lineage-specific inheritance of depression-like behavior in the rat.
        Mamm Genome. 2004; 15: 648-662
        • Du R.-H.
        • Wu F.-F.
        • Lu M.
        • Shu X.-D.
        • Ding J.-H.
        • Wu G.
        • Hu G.
        Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression.
        Redox Biol. 2016; 9: 178-187
        • Gimsa U.
        • Kanitz E.
        • Otten W.
        • Aheng C.
        • Tuchscherer M.
        • Ricquier D.
        • et al.
        Alterations in anxiety-like behavior following knockout of the uncoupling protein 2 (ucp2) gene in mice.
        Life Sci. 2011; 89: 677-684
        • Pekary A.E.
        • Sattin A.
        • Lloyd R.L.
        Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral tissues of male rats.
        Peptides. 2015; 69: 66-76
        • Sun X.-L.
        • Liu Y.
        • Dai T.
        • Ding J.-H.
        • Hu G.
        Uncoupling protein 2 knockout exacerbates depression-like behaviors in mice via enhancing inflammatory response.
        Neuroscience. 2011; 192: 507-514
        • Wang D.
        • Zhai X.
        • Chen P.
        • Yang M.
        • Zhao J.
        • Dong J.
        • Liu H.
        Hippocampal UCP2 is essential for cognition and resistance to anxiety but not required for the benefits of exercise.
        Neuroscience. 2014; 277: 36-44
        • Zeng H.
        • Schimpf B.A.
        • Rohde A.D.
        • Pavlova M.N.
        • Gragerov A.
        • Bergmann J.E.
        Thyrotropin-releasing hormone receptor 1-deficient mice display increased depression and anxiety-like behavior.
        Mol Endocrinol. 2007; 21: 2795-2804
        • Hoover A.N.
        • Wynkoop A.
        • Zeng H.
        • Jia J.
        • Niswander L.A.
        • Liu A.
        C2cd3 is required for cilia formation and hedgehog signaling in mouse.
        Development. 2008; 135: 4049-4058
        • Xiao B.
        • Harada Y.
        • Kawakami K.
        • Nabika T.
        A 1.8-Mbp fragment on chromosome 1 affects sympathetic response to stress: Evaluation in reciprocal congenic strains between stroke-prone spontaneously hypertensive rat and Wistar-Kyoto rat.
        J Hypertens. 2011; 29: 257-265
        • Klimes I.
        • Weston K.
        • Gasperíková D.
        • Kovács P.
        • Kvetnanský R.
        • Jezová D.
        • et al.
        Mapping of genetic determinants of the sympathoneural response to stress.
        Physiol Genomics. 2005; 20: 183-187
        • Potenza M.N.
        • Brodkin E.S.
        • Joe B.
        • Luo X.
        • Remmers E.F.
        • Wilder R.L.
        • et al.
        Genomic regions controlling corticosterone levels in rats.
        Biol Psychiatry. 2004; 55: 634-641
        • Belvindrah R.
        • Rougon G.
        • Chazal G.
        Increased neurogenesis in adult mCD24-deficient mice.
        J Neurosci. 2002; 22: 3594-3607
        • Cerezo A.
        • Guadamillas M.C.
        • Goetz J.G.
        • Sánchez-Perales S.
        • Klein E.
        • Assoian R.K.
        • del Pozo M.A.
        The absence of caveolin-1 increases proliferation and anchorage-independent growth by a Rac-dependent, Erk-independent mechanism.
        Mol Cell Biol. 2009; 29: 5046-5059
        • Galach M.
        Molecular mechanisms involved in epithelial differentiation of human induced pluripotent stem cells [dissertation].
        (Available at:) (Accessed May 15, 2018)
        • Head B.P.
        • Peart J.N.
        • Panneerselvam M.
        • Yokoyama T.
        • Pearn M.L.
        • Niesman I.R.
        • et al.
        Loss of caveolin-1 accelerates neurodegeneration and aging.
        PLoS One. 2010; 5e15697
        • Hossain M.B.
        • Shifat R.
        • Li J.
        • Luo X.
        • Hess K.R.
        • Rivera-Molina Y.
        • et al.
        TIE2 associates with caveolae and regulates caveolin-1 to promote their nuclear translocation.
        Mol Cell Biol. 2017; 37 (e142-17)
        • Jo A.
        • Denduluri S.
        • Zhang B.
        • Wang Z.
        • Yin L.
        • Yan Z.
        • et al.
        The versatile functions of Sox9 in development, stem cells, and human diseases.
        Genes Dis. 2014; 1: 149-161
        • Li X.-L.
        • Liu L.
        • Li D.-D.
        • He Y.-P.
        • Guo L.-H.
        • Sun L.-P.
        • et al.
        Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma.
        Sci Rep. 2017; 7: 40464
        • Liu C.
        • Goswami M.
        • Talley J.
        • Chesser-Martinez P.L.
        • Lou C.-H.
        • Sater A.K.
        TAK1 promotes BMP4/Smad1 signaling via inhibition of erk MAPK: A new link in the FGF/BMP regulatory network.
        Differentiation. 2012; 83: 210-219
        • Panaliappan T.K.
        • Wittmann W.
        • Jidigam V.K.
        • Mercurio S.
        • Bertolini J.A.
        • Sghari S.
        • et al.
        Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and Hes5 upregulation.
        Development. 2018; 145: dev153791
        • Poché R.A.
        • Furuta Y.
        • Chaboissier M.-C.
        • Schedl A.
        • Behringer R.R.
        Sox9 is expressed in mouse multipotent retinal progenitor cells and functions in Müller glial cell development.
        J Comp Neurol. 2008; 510: 237-250
        • Shakiba N.
        • White C.A.
        • Lipsitz Y.Y.
        • Yachie-Kinoshita A.
        • Tonge P.D.
        • Hussein S.M.I.
        • et al.
        CD24 tracks divergent pluripotent states in mouse and human cells.
        Nat Commun. 2015; 6: 7329
        • Stolt C.C.
        • Lommes P.
        • Sock E.
        • Chaboissier M.-C.
        • Schedl A.
        • Wegner M.
        The Sox9 transcription factor determines glial fate choice in the developing spinal cord.
        Genes Dev. 2003; 17: 1677-1689
        • Suzuki Y.
        • Montagne K.
        • Nishihara A.
        • Watabe T.
        • Miyazono K.
        BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling.
        J Biochem. 2008; 143: 199-206
        • Oldham M.C.
        • Konopka G.
        • Iwamoto K.
        • Langfelder P.
        • Kato T.
        • Horvath S.
        • Geschwind D.H.
        Functional organization of the transcriptome in human brain.
        Nat Neurosci. 2008; 11: 1271-1282
        • Fontanet P.A.
        • Ríos A.S.
        • Alsina F.C.
        • Paratcha G.
        • Ledda F.
        Pea3 transcription factors, Etv4 and Etv5, are required for proper hippocampal dendrite development and plasticity.
        Cereb Cortex. 2018; 28: 236-249
        • Jaworski J.N.
        • Jones D.C.
        The role of CART in the reward/reinforcing properties of psychostimulants.
        Peptides. 2006; 27: 1993-2004
        • Young L.J.
        • Wang Z.
        The neurobiology of pair bonding.
        Nat Neurosci. 2004; 7: 1048-1054
        • Higa K.K.
        • Young J.W.
        • Ji B.
        • Nichols D.E.
        • Geyer M.A.
        • Zhou X.
        Striatal dopamine D1 receptor suppression impairs reward-associative learning.
        Behav Brain Res. 2017; 323: 100-110
        • Milienne-Petiot M.
        • Groenink L.
        • Minassian A.
        • Young J.W.
        Blockade of dopamine D1-family receptors attenuates the mania-like hyperactive, risk-preferring, and high motivation behavioral profile of mice with low dopamine transporter levels.
        J Psychopharmacol (Oxford). 2017; 31: 1334-1346
        • Spittau B.
        • Rilka J.
        • Steinfath E.
        • Zöller T.
        • Krieglstein K.
        TGFβ1 increases microglia-mediated engulfment of apoptotic cells via upregulation of the milk fat globule-EGF factor 8.
        Glia. 2015; 63: 142-153
        • Kettenmann H.
        • Kirchhoff F.
        • Verkhratsky A.
        Microglia: New roles for the synaptic stripper.
        Neuron. 2013; 77: 10-18
        • Zeisel A.
        • Hochgerner H.
        • Lonnerberg P.
        • Johnsson A.
        • Memic F.
        • van der Zwan J.
        • et al.
        Molecular architecture of the mouse nervous system.
        Cell. 2018; 174: 999-1014
        • Fischer S.
        • Ehlert U.
        Hypothalamic-pituitary-thyroid (HPT) axis functioning in anxiety disorders: A systematic review.
        Depress Anxiety. 2018; 35: 98-110
        • Maes M.
        • Vandewoude M.
        • Maes L.
        • Schotte C.
        • Cosyns P.
        A revised interpretation of the TRH test results in female depressed patients: I. TSH responses: Effects of severity of illness, thyroid hormones, monoamines, age, sex hormonal, corticosteroid and nutritional state.
        J Affect Disord. 1989; 16: 203-213
        • Lanni A.
        • Moreno M.
        • Lombardi A.
        • Goglia F.
        Thyroid hormone and uncoupling proteins.
        FEBS Lett. 2003; 543: 5-10
        • Choi J.
        • Kim J.
        • Kim T.-K.
        • Park J.-Y.
        • Lee J.-E.
        • Kim H.
        • et al.
        TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors.
        Neuropharmacology. 2015; 97: 346-356
        • Cichon S.
        • Mühleisen T.W.
        • Degenhardt F.A.
        • Mattheisen M.
        • Miró X.
        • Strohmaier J.
        • et al.
        Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.
        Am J Hum Genet. 2011; 88: 372-381
        • Miró X.
        • Meier S.
        • Dreisow M.L.
        • Frank J.
        • Strohmaier J.
        • Breuer R.
        • et al.
        Studies in humans and mice implicate neurocan in the etiology of mania.
        Am J Psychiatry. 2012; 169: 982-990
        • Rauch U.
        • Feng K.
        • Zhou X.H.
        Neurocan: A brain chondroitin sulfate proteoglycan.
        Cell Mol Life Sci. 2001; 58: 1842-1856
        • Cole A.E.
        • Murray S.S.
        • Xiao J.
        Bone morphogenetic protein 4 signalling in neural stem and progenitor cells during development and after injury.
        Stem Cells Int. 2016; 2016: 9260592
        • Harland R.
        Neural induction.
        Curr Opin Genet Dev. 2000; 10: 357-362
        • Bond A.M.
        • Bhalala O.G.
        • Kessler J.A.
        The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation.
        Dev Neurobiol. 2012; 72: 1068-1084
        • Brooker S.M.
        • Gobeske K.T.
        • Chen J.
        • Peng C.-Y.
        • Kessler J.A.
        Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.
        Mol Psychiatry. 2017; 22: 910-919
        • Gobeske K.T.
        • Das S.
        • Bonaguidi M.A.
        • Weiss C.
        • Radulovic J.
        • Disterhoft J.F.
        • Kessler J.A.
        BMP signaling mediates effects of exercise on hippocampal neurogenesis and cognition in mice.
        PLoS One. 2009; 4: e7506
        • Meyers E.A.
        • Gobeske K.T.
        • Bond A.M.
        • Jarrett J.C.
        • Peng C.-Y.
        • Kessler J.A.
        Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.
        Neurobiol Aging. 2016; 38: 164-175
        • Mira H.
        • Andreu Z.
        • Suh H.
        • Lie D.C.
        • Jessberger S.
        • Consiglio A.
        • et al.
        Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus.
        Cell Stem Cell. 2010; 7: 78-89
        • Gomes W.A.
        • Mehler M.F.
        • Kessler J.A.
        Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment.
        Dev Biol. 2003; 255: 164-177
        • Caronia G.
        • Wilcoxon J.
        • Feldman P.
        • Grove E.A.
        Bone morphogenetic protein signaling in the developing telencephalon controls formation of the hippocampal dentate gyrus and modifies fear-related behavior.
        J Neurosci. 2010; 30: 6291-6301
        • García-Fuster M.J.
        • Perez J.A.
        • Clinton S.M.
        • Watson S.J.
        • Akil H.
        Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse.
        Eur J Neurosci. 2010; 31: 79-89
        • Duman R.S.
        • Monteggia L.M.
        A neurotrophic model for stress-related mood disorders.
        Biol Psychiatry. 2006; 59: 1116-1127
        • Bansod S.
        • Kageyama R.
        • Ohtsuka T.
        Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development.
        Development. 2017; 144: 3156-3167
        • Sakai D.
        • Suzuki T.
        • Osumi N.
        • Wakamatsu Y.
        Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development.
        Development. 2006; 133: 1323-1333
        • Sun W.
        • Cornwell A.
        • Li J.
        • Peng S.
        • Osorio M.J.
        • Aalling N.
        • et al.
        SOX9 is an astrocyte-specific nuclear marker in the adult brain outside the neurogenic regions.
        J Neurosci. 2017; 37: 4493-4507
        • Ming G.-L.
        • Song H.
        Adult neurogenesis in the mammalian brain: Significant answers and significant questions.
        Neuron. 2011; 70: 687-702
        • Fuller M.L.
        • DeChant A.K.
        • Rothstein B.
        • Caprariello A.
        • Wang R.
        • Hall A.K.
        • Miller R.H.
        Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions.
        Ann Neurol. 2007; 62: 288-300
        • Yan H.
        • Zhu X.
        • Xie J.
        • Zhao Y.
        • Liu X.
        β-Amyloid increases neurocan expression through regulating Sox9 in astrocytes: A potential relationship between Sox9 and chondroitin sulfate proteoglycans in Alzheimer’s disease.
        Brain Res. 2016; 1646: 377-383
        • Schafer D.P.
        • Stevens B.
        Microglia function in central nervous system development and plasticity.
        Cold Spring Harb Perspect Biol. 2015; 7: a20545
        • Wu Y.
        • Dissing-Olesen L.
        • MacVicar B.A.
        • Stevens B.
        Microglia: Dynamic mediators of synapse development and plasticity.
        Trends Immunol. 2015; 36: 605-613
        • Albus E.
        • Sinningen K.
        • Winzer M.
        • Thiele S.
        • Baschant U.
        • Hannemann A.
        • et al.
        Milk fat globule–epidermal growth factor 8 (MFG-E8) is a novel anti-inflammatory factor in rheumatoid arthritis in mice and humans.
        J Bone Miner Res. 2016; 31: 596-605
        • Fricker M.
        • Neher J.J.
        • Zhao J.-W.
        • Théry C.
        • Tolkovsky A.M.
        • Brown G.C.
        MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation.
        J Neurosci. 2012; 32: 2657-2666
        • Fuller A.D.
        • Van Eldik L.J.
        MFG-E8 regulates microglial phagocytosis of apoptotic neurons.
        J Neuroimmune Pharmacol. 2008; 3: 246-256
        • Vogler S.
        • Pahnke J.
        • Rousset S.
        • Ricquier D.
        • Moch H.
        • Miroux B.
        • Ibrahim S.M.
        Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis.
        Am J Pathol. 2006; 168: 1570-1575
        • Arsenijevic D.
        • Onuma H.
        • Pecqueur C.
        • Raimbault S.
        • Manning B.S.
        • Miroux B.
        • et al.
        Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.
        Nat Genet. 2000; 26: 435-439
        • Jo W.K.
        • Zhang Y.
        • Emrich H.M.
        • Dietrich D.E.
        Glia in the cytokine-mediated onset of depression: Fine tuning the immune response.
        Front Cell Neurosci. 2015; 9: 268
        • Sato K.
        Effects of microglia on neurogenesis.
        Glia. 2015; 63: 1394-1405
        • Mastellos D.C.
        Complement emerges as a masterful regulator of CNS homeostasis, neural synaptic plasticity and cognitive function.
        Exp Neurol. 2014; 261: 469-474
        • Maras P.M.
        • Daugherty J.
        • Hebda-Bauer E.
        • Watson S.J.
        • Akil H.
        Minocycline treatment reduces anxiety- and depressive-like behaviors in a genetic model of internalizing mood disorders.
        (Presented at Neuroscience 2018, November 3–7, San Diego, California) Neuroscience Meeting Planner Program No, 2018 (234.03)
        • Hilde K.L.
        • Hagenauer M.H.
        • Stefanov A.V.
        • Birt I.
        • Hebda-Bauer E.
        • Watson S.J.
        • Akil H.
        Mechanisms of hippocampal development: Molecular and cellular phenotypes in the selectively bred high-responder/low-responder model of affective disorders.
        (Presented at Neuroscience 2018, November 3–7, San Diego, California) Neuroscience Meeting Planner Program No, 2018 (233.04)
        • O’Connor A.M.
        • Pardo T.
        • Birt I.
        • Hagenauer M.H.
        • Maras P.M.
        • Prater K.E.
        • et al.
        The hippocampal glycome contributes to behavioural phenotype in a novel rodent model of mood disorders.
        (Presented at Neuroscience 2018, November 3–7, San Diego, California) Neuroscience Meeting Planner Program No, 2018 (233.01)

      CHORUS Manuscript

      View Open Manuscript