Association of brain immune genes with social behavior of inbred mouse strains

Journal of Neuroinflammation

Li Tian¹  Heikki Rauvala²  Natalia Kulesskaya²  Sami Piirainen²  Li Ma² 

[1] Psychiatry Research Center, Beijing Huilongguan Hospital, Zhengfu Road, Beijing, 100096, Changping, China;Neuroscience Center, University of Helsinki, Viikinkaari 4, Helsinki, FIN-00014, Finland

关键词: Brain morphology;    Behaviors;    Immune genes;    Inbred mouse strains;    Social deficit;   

Others  :  1226205
DOI  :  10.1186/s12974-015-0297-5

 received in 2015-02-05, accepted in 2015-04-07,  发布年份 2015

【 摘 要 】

Background

Social deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far.

Methods

To decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors.

Results

A group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice.

Conclusions

Our study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.

【 授权许可】

   
2015 Ma et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Schizophrenia Working Group of the Psychiatric Genomics C: Biological insights from 108 schizophrenia-associated genetic loci Nature 2014, 511(7510):421-7.
• [2]Carter CS, Bullmore ET, Harrison P: Is there a flame in the brain in psychosis? Biol Psychiatry 2014, 75(4):258-9.
• [3]Onore C, Careaga M, Ashwood P: The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 2012, 26(3):383-92.
• [4]Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH: Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 2012, 26(4):607-16.
• [5]Rezacova P, Krejcirikova V, Borek D, Moy SF, Joachimiak A, Otwinowski Z: The crystal structure of the effector-binding domain of the trehalose repressor TreR from Bacillus subtilis 168 reveals a unique quarternary assembly. Proteins 2007, 69(3):679-82.
• [6]Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH: Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A 2012, 109(31):12776-81.
• [7]Horvath S, Mirnics K: Immune system disturbances in schizophrenia. Biol Psychiatry 2014, 75(4):316-23.
• [8]Brown AS, Derkits EJ: Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010, 167(3):261-80.
• [9]Network, Pathway Analysis Subgroup of the Psychiatric Genomics C, International Inflammatory Bowel Disease Genetics C, International Inflammatory Bowel Disease Genetics Consortium I: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways Nat Neurosci 2015, 18(2):199-209.
• [10]Raison CL, Miller AH: The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry 2013, 18(1):15-37.
• [11]Haroon E, Raison CL, Miller AH: Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012, 37(1):137-62.
• [12]Powell ND, Sloan EK, Bailey MT, Arevalo JM, Miller GE, Chen E, et al.: Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. Proc Natl Acad Sci U S A 2013, 110(41):16574-9.
• [13]Ehninger D, Sano Y, de Vries PJ, Dies K, Franz D, Geschwind DH, et al.: Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice. Mol Psychiatry 2012, 17(1):62-70.
• [14]Smith SE, Li J, Garbett K, Mirnics K, Patterson PH: Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007, 27(40):10695-702.
• [15]Pineda E, Shin D, You SJ, Auvin S, Sankar R, Mazarati A: Maternal immune activation promotes hippocampal kindling epileptogenesis in mice. Ann Neurol 2013, 74(1):11-9.
• [16]Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, et al.: CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 2007, 446(7131):41-5.
• [17]Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH: Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry 2014, 75(4):332-41.
• [18]Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, et al.: Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 2014, 17(3):400-6.
• [19]Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, et al.: Microglia modulate wiring of the embryonic forebrain. Cell Reports 2014, 8(5):1271-9.
• [20]Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, et al.: Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 2012, 484(7392):105-9.
• [21]Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, et al.: Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 2010, 141(5):775-85.
• [22]Perry VH, O’Connor V: C1q: the perfect complement for a synaptic feast? Nat Rev Neurosci 2008, 9(11):807-11.
• [23]Tian L, Rauvala H, Gahmberg CG: Neuronal regulation of immune responses in the central nervous system. Trends Immunol 2009, 30(2):91-9.
• [24]McAllister AK: Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry 2014, 75(4):262-8.
• [25]Holmes A, Wrenn CC, Harris AP, Thayer KE, Crawley JN: Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice. Genes Brain Behav 2002, 1(1):55-69.
• [26]Olivier B, Leahy C, Mullen T, Paylor R, Groppi VE, Sarnyai Z, et al.: The DBA/2 J strain and prepulse inhibition of startle: a model system to test antipsychotics? Psychopharmacology (Berl) 2001, 156(2–3):284-90.
• [27]Voikar V, Polus A, Vasar E, Rauvala H: Long-term individual housing in C57BL/6 J and DBA/2 mice: assessment of behavioral consequences. Genes Brain Behav 2005, 4(4):240-52.
• [28]Li Z, Ma L, Kulesskaya N, Voikar V, Tian L: Microglia are polarized to M1 type in high-anxiety inbred mice in response to lipopolysaccharide challenge. Brain Behav Immun 2014, 38:237-48.
• [29]Kas MJ, Kahn RS, Collier DA, Waddington JL, Ekelund J, Porteous DJ, et al.: Translational neuroscience of schizophrenia: seeking a meeting of minds between mouse and man. Sci Transl Med 2011, 3(102):102mr-3.
• [30]Wahlsten D: The hunt for gene effects pertinent to behavioral traits and psychiatric disorders: from mouse to human. Dev Psychobiol 2012, 54(5):475-92.
• [31]Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, et al.: Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 2007, 176(1):4-20.
• [32]Kulesskaya N, Karpova NN, Ma L, Tian L, Voikar V: Mixed housing with DBA/2 mice induces stress in C57BL/6 mice: implications for interventions based on social enrichment. Front Behav Neurosci 2014, 8:257.
• [33]Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A, et al.: Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 2004, 3(5):303-14.
• [34]Bhave SV, Hornbaker C, Phang TL, Saba L, Lapadat R, Kechris K, et al.: The PhenoGen informatics website: tools for analyses of complex traits. BMC Genet 2007, 8:59. BioMed Central Full Text
• [35]da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4(1):44-57.
• [36]Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al.: STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013, 41:D808-15.
• [37]Maddatu TP, Grubb SC, Bult CJ, Bogue MA: Mouse Phenome Database (MPD). Nucleic Acids Res 2012, 40(Database issue):D887-94.
• [38]Cook MN, Williams RW, Flaherty L: Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration. Behav Neurosci 2001, 115(2):468-76.
• [39]Wahlsten D, Bachmanov A, Finn DA, Crabbe JC: Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proc Natl Acad Sci U S A 2006, 103(44):16364-9.
• [40]Brown RE, Wong AA: The influence of visual ability on learning and memory performance in 13 strains of mice. Learn Mem 2007, 14(3):134-44.
• [41]Fraser LM, Brown RE, Hussin A, Fontana M, Whittaker A, O’Leary TP, et al.: Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests. Psychopharmacology (Berl) 2010, 211(1):99-112.
• [42]Park CC, Gale GD, de Jong S, Ghazalpour A, Bennett BJ, Farber CR, et al.: Gene networks associated with conditional fear in mice identified using a systems genetics approach. BMC Syst Biol 2011, 5:43. BioMed Central Full Text
• [43]Crowley JJ, Adkins DE, Pratt AL, Quackenbush CR, van den Oord EJ, Moy SS, et al.: Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice. Pharmacogenomics J 2012, 12(2):147-55.
• [44]Moy SS, Nadler JJ, Young NB, Nonneman RJ, Segall SK, Andrade GM, et al.: Social approach and repetitive behavior in eleven inbred mouse strains. Behav Brain Res 2008, 191(1):118-29.
• [45]Corriveau RA, Huh GS, Shatz CJ: Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 1998, 21(3):505-20.
• [46]Corvin A, Morris DW: Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol Psychiatry 2014, 75(4):276-83.
• [47]Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al.: The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131(6):1164-78.
• [48]Bialas AR, Stevens B: TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 2013, 16(12):1773-82.
• [49]Michailidou I, Willems JG, Kooi EJ, van Eden C, Gold SM, Geurts JJ, et al. Complement C1q-C3 associated synaptic changes in multiple sclerosis hippocampus. Annals of neurology. 2015. doi: 10.1002/ana.24398.
• [50]Bernard G, Vanderver A: Pol III-related leukodystrophies. In GeneReviews(R). Edited by Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH. Stephens K, Seattle (WA); 1993.
• [51]Daoud H, Tetreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, et al.: Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J Med Genet 2013, 50(3):194-7.
• [52]Tetreault M, Choquet K, Orcesi S, Tonduti D, Balottin U, Teichmann M, et al.: Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet 2011, 89(5):652-5.
• [53]Ansoleaga B, Jove M, Schluter A, Garcia-Esparcia P, Moreno J, Pujol A, et al.: Deregulation of purine metabolism in Alzheimer’s disease. Neurobiol Aging 2015, 36(1):68-80.
• [54]Kusek GK, Wahlsten D, Herron BJ, Bolivar VJ, Flaherty L: Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse. Genes Brain Behav 2007, 6(4):359-63.
• [55]Clapcote SJ, Roder JC: Deletion polymorphism of Disc1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function. Genetics 2006, 173(4):2407-10.
• [56]Tangye SG, Bryant VL, Cuss AK, Good KL: BAFF, APRIL and human B cell disorders. Semin Immunol 2006, 18(5):305-17.
• [57]Karpova NN, Lindholm JS, Kulesskaya N, Onishchenko N, Vahter M, Popova D, et al.: TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury. Front Behav Neurosci 2014, 8:315.
• [58]Bale TL: Neuroendocrine and immune influences on the CNS: it’s a matter of sex. Neuron 2009, 64(1):13-6.