BMC Neuroscience | |
Absence of M-Ras modulates social behavior in mice | |
John W. Schrader1  Marie J. Leung1  Bin Wang1  Annette Ehrhardt1  | |
[1] The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver V6T 1Z3, Canada | |
关键词: Behavior heatmap; Anxiety; VNO; Social recognition; R-Ras3; | |
Others : 1229740 DOI : 10.1186/s12868-015-0209-8 |
|
received in 2015-03-06, accepted in 2015-10-08, 发布年份 2015 |
【 摘 要 】
Background
The molecular mechanisms that determine social behavior are poorly understood. Pheromones play a critical role in social recognition in most animals, including mice, but how these are converted into behavioral responses is largely unknown. Here, we report that the absence of the small GTPase M-Ras affects social behavior in mice.
Results
In their interactions with other males, Mras−/−males exhibited high levels of territorial aggression and social investigations, and increased fear-related behavior. They also showed increased mating behavior with females. Curiously, increased aggression and mating behaviors were only observed when Mras−/−males were paired with Mras−/−partners, but were significantly reduced when paired with wild-type (WT) mice. Since mice use pheromonal cues to identify other individuals, we explored the possibility that pheromone detection may be altered in Mras−/−mice. Unlike WT mice, Mras−/−did not show a preference for exploring unfamiliar urinary pheromones or unfamiliar isogenic mice. Although this could indicate that vomeronasal function and/or olfactory learning may be compromised in Mras−/−mice, these observations were not fully consistent with the differential behavioral responses to WT and Mras−/−interaction partners by Mras−/−males. In addition, induction of c-fos upon pheromone exposure or in response to mating was similar in WT and Mras−/−mice, as was the ex vivo expansion of neural progenitors with EGF. This indicated that acute pheromone detection and processing was likely intact. However, urinary metabolite profiles differed between Mras−/−and WT males.
Conclusions
The changes in behaviors displayed by Mras−/−mice are likely due to a complex combination of factors that may include an inherent predisposition to increased aggression and sexual behavior, and the production of distinct pheromones that could override the preference for unfamiliar social odors. Olfactory and/or social learning processes may thus be compromised in Mras−/−mice.
【 授权许可】
2015 Ehrhardt et al.
Files | Size | Format | View |
---|---|---|---|
Fig.5. | 10KB | Image | download |
Fig.4. | 80KB | Image | download |
Fig.3. | 31KB | Image | download |
Fig.2. | 20KB | Image | download |
Fig.1. | 42KB | Image | download |
Fig.5. | 10KB | Image | download |
Fig.4. | 80KB | Image | download |
Fig.3. | 31KB | Image | download |
Fig.2. | 20KB | Image | download |
Fig.1. | 42KB | Image | download |
【 图 表 】
Fig.1.
Fig.2.
Fig.3.
Fig.4.
Fig.5.
Fig.1.
Fig.2.
Fig.3.
Fig.4.
Fig.5.
【 参考文献 】
- [1]Robinson GE, Grozinger CM, Whitfield CW: Sociogenomics: social life in molecular terms. Nat Rev Genet 2005, 6:257-270.
- [2]Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci 2004, 7:847-854.
- [3]Rankin CH: From gene to identified neuron to behaviour in Caenorhabditis elegans. Nat Rev Genet 2002, 3:622-630.
- [4]Stowers L, Cameron P, Keller JA: Ominous odors: olfactory control of instinctive fear and aggression in mice. Curr Opin Neurobiol 2013, 23:339-345.
- [5]Ihara S, Yoshikawa K, Touhara K: Chemosensory signals and their receptors in the olfactory neural system. Neuroscience 2013, 254:45-60.
- [6]Boulet M, Charpentier MJ, Drea CM: Decoding an olfactory mechanism of kin recognition and inbreeding avoidance in a primate. BMC Evol Biol 2009, 9:281. BioMed Central Full Text
- [7]Karlson P, Luscher M: Pheromones’: a new term for a class of biologically active substances. Nature 1959, 183:55-56.
- [8]Perez-Gomez A, Stein B, Leinders-Zufall T, Chamero P: Signaling mechanisms and behavioral function of the mouse basal vomeronasal neuroepithelium. Front Neuroanat 2014, 8:135.
- [9]He J, Ma L, Kim S, Nakai J, Yu CR: Encoding gender and individual information in the mouse vomeronasal organ. Science 2008, 320:535-538.
- [10]Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, Cross JC, Weiss S: Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 2003, 299:117-120.
- [11]Sakamoto M, Imayoshi I, Ohtsuka T, Yamaguchi M, Mori K, Kageyama R: Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. Proc Natl Acad Sci USA 2011, 108:8479-8484.
- [12]Mak GK, Enwere EK, Gregg C, Pakarainen T, Poutanen M, Huhtaniemi I, Weiss S: Male pheromone-stimulated neurogenesis in the adult female brain: possible role in mating behavior. Nat Neurosci 2007, 10:1003-1011.
- [13]Walker TL, Vukovic J, Koudijs MM, Blackmore DG, Mackay EW, Sykes AM, Overall RW, Hamlin AS, Bartlett PF: Prolactin stimulates precursor cells in the adult mouse hippocampus. PLoS One 2012, 7:e44371.
- [14]Kaur AW, Ackels T, Kuo TH, Cichy A, Dey S, Hays C, Kateri M, Logan DW, Marton TF, Spehr M, et al.: Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors. Cell 2014, 157:676-688.
- [15]Wacker DW, Ludwig M: Vasopressin, oxytocin, and social odor recognition. Horm Behav 2012, 61:259-265.
- [16]Skuse DH, Gallagher L: Genetic influences on social cognition. Pediatr Res 2011, 69:85R-91R.
- [17]Gabor CS, Phan A, Clipperton-Allen AE, Kavaliers M, Choleris E: Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition. Behav Neurosci 2012, 126:97-109.
- [18]Matsumoto K, Asano T, Endo T: Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton. Oncogene 1997, 15:2409-2417.
- [19]Ehrhardt GR, Leslie KB, Lee F, Wieler JS, Schrader JW: M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line. Blood 1999, 94:2433-2444.
- [20]Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C: M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem 1999, 274:23850-23857.
- [21]Kimmelman AC, Osada M, Chan AM: R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 2000, 19:2014-2022.
- [22]Fernandez-Medarde A, Santos E: Ras in cancer and developmental diseases. Genes Cancer 2011, 2:344-358.
- [23]Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE, Stark GR: Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 2005, 65:939-947.
- [24]Nunez Rodriguez N, Lee IN, Banno A, Qiao HF, Qiao RF, Yao Z, Hoang T, Kimmelman AC, Chan AM: Characterization of R-ras3/m-ras null mice reveals a potential role in trophic factor signaling. Mol Cell Biol 2006, 26:7145-7154.
- [25]Roubertoux PL, Guillot PV, Mortaud S, Pratte M, Jamon M, Cohen-Salmon C, Tordjman S: Attack behaviors in mice: from factorial structure to quantitative trait loci mapping. Eur J Pharmacol 2005, 526:172-185.
- [26]Kulikov AV, Osipova DV, Naumenko VS, Popova NK: Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains. Genes Brain Behav 2005, 4:482-485.
- [27]Chamero P, Marton TF, Logan DW, Flanagan K, Cruz JR, Saghatelian A, Cravatt BF, Stowers L: Identification of protein pheromones that promote aggressive behaviour. Nature 2007, 450:899-902.
- [28]Frisch C, Dere E, Silva MA, Godecke A, Schrader J, Huston JP: Superior water maze performance and increase in fear-related behavior in the endothelial nitric oxide synthase-deficient mouse together with monoamine changes in cerebellum and ventral striatum. J Neurosci 2000, 20:6694-6700.
- [29]Dere E, De Souza-Silva MA, Frisch C, Teubner B, Sohl G, Willecke K, Huston JP: Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes. Eur J Neurosci 2003, 18:629-638.
- [30]Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL, Silver DL: Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 2014, 509:503-506.
- [31]Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda S, Harada N, Shah NM: Estrogen masculinizes neural pathways and sex-specific behaviors. Cell 2009, 139:61-72.
- [32]Juntti SA, Tollkuhn J, Wu MV, Fraser EJ, Soderborg T, Tan S, Honda S, Harada N, Shah NM: The androgen receptor governs the execution, but not programming, of male sexual and territorial behaviors. Neuron 2010, 66:260-272.
- [33]Xu X, Coats JK, Yang CF, Wang A, Ahmed OM, Alvarado M, Izumi T, Shah NM: Modular genetic control of sexually dimorphic behaviors. Cell 2012, 148:596-607.
- [34]Yang CF, Chiang MC, Gray DC, Prabhakaran M, Alvarado M, Juntti SA, Unger EK, Wells JA, Shah NM: Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 2013, 153:896-909.
- [35]Hurst JL, Payne CE, Nevison CM, Marie AD, Humphries RE, Robertson DH, Cavaggioni A, Beynon RJ: Individual recognition in mice mediated by major urinary proteins. Nature 2001, 414:631-634.
- [36]Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T, et al.: CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 2007, 446:41-45.
- [37]Mak GK, Weiss S: Paternal recognition of adult offspring mediated by newly generated CNS neurons. Nat Neurosci 2010, 13:753-758.
- [38]Isogai Y, Si S, Pont-Lezica L, Tan T, Kapoor V, Murthy VN, Dulac C: Molecular organization of vomeronasal chemoreception. Nature 2011, 478:241-245.
- [39]Chamero P, Katsoulidou V, Hendrix P, Bufe B, Roberts R, Matsunami H, Abramowitz J, Birnbaumer L, Zufall F, Leinders-Zufall T: G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice. Proc Natl Acad Sci USA 2011, 108:12898-12903.
- [40]Ehrhardt A, David MD, Ehrhardt GR, Schrader JW: Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. Mol Cell Biol 2004, 24:6311-6323.
- [41]Louahed J, Grasso L, De Smet C, Van Roost E, Wildmann C, Nicolaides NC, Levitt RC, Renauld JC: Interleukin-9-induced expression of M-Ras/R-Ras3 oncogene in T-helper clones. Blood 1999, 94:1701-1710.
- [42]Serguera C, Triaca V, Kelly-Barrett J, Banchaabouchi MA, Minichiello L: Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy. Nat Neurosci 2008, 11:949-956.
- [43]Kudryavtseva NN, Lipina TV, Koryakina LA: Effects of haloperidol on communicative and aggressive behavior in male mice with different experiences of aggression. Pharmacol Biochem Behav 1999, 63:229-236.
- [44]Miczek KA, Fish EW, De Bold JF, De Almeida RM: Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems. Psychopharmacology 2002, 163:434-458.
- [45]Couppis MH, Kennedy CH: The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice. Psychopharmacology 2008, 197:449-456.
- [46]Roberts SA, Simpson DM, Armstrong SD, Davidson AJ, Robertson DH, McLean L, Beynon RJ, Hurst JL: Darcin: a male pheromone that stimulates female memory and sexual attraction to an individual male’s odour. BMC Biol 2010, 8:75. BioMed Central Full Text
- [47]Li Q, Korzan WJ, Ferrero DM, Chang RB, Roy DS, Buchi M, Lemon JK, Kaur AW, Stowers L, Fendt M, et al.: Synchronous evolution of an odor biosynthesis pathway and behavioral response. Curr Biol 2013, 23:11-20.
- [48]Takahashi A, Miczek KA: Neurogenetics of aggressive behavior: studies in rodents. Curr Top Behav Neurosci. 2014, 17:3-44.
- [49]Brain P, Poole A: Some studies on the use of “standard opponents” in intermale aggression testing in TT albino mice. Behaviour 1974, 50:100-110.
- [50]Guillot PV, Carlier M, Maxson SC, Roubertoux PL: Intermale aggression tested in two procedures, using four inbred strains of mice and their reciprocal congenics: Y chromosomal implications. Behav Genet 1995, 25:357-360.
- [51]Miczek KA, Maxson SC, Fish EW, Faccidomo S: Aggressive behavioral phenotypes in mice. Behav Brain Res 2001, 125:167-181.
- [52]Francois MH, Nosten-Bertrand M, Roubertoux PL, Kottler ML, Degrelle H: Opponent strain effect on eliciting attacks in NZB mice: physiological correlates. Physiol Behav 1990, 47:1181-1185.
- [53]Ogawa S, Choleris E, Pfaff D: Genetic influences on aggressive behaviors and arousability in animals. Ann N Y Acad Sci 2004, 1036:257-266.
- [54]Kolunie JM, Stern JM, Barfield RJ: Maternal aggression in rats: effects of visual or auditory deprivation of the mother and dyadic pattern of ultrasonic vocalizations. Behav Neural Biol 1994, 62:41-49.
- [55]Fish EW, Faccidomo S, Miczek KA: Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT(1B) receptor agonist CP-94,253. Psychopharmacology 1999, 146:391-399.
- [56]Takahashi A, Quadros IM, de Almeida RM, Miczek KA. Behavioral and Pharmacogenetics of Aggressive Behavior. Curr Top Behav Neurosci. 2012.
- [57]Nakamura K, Kikusui T, Takeuchi Y, Mori Y: Influences of pre- and postnatal early life environments on the inhibitory properties of familiar urine odors in male mouse aggression. Chem Senses 2008, 33:541-551.
- [58]Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R: Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 1994, 265:1875-1878.
- [59]Cools R, Roberts AC, Robbins TW: Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci. 2008, 12:31-40.
- [60]Celada P, Bortolozzi A, Artigas F: Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 2013, 27:703-716.
- [61]Wiedenmayer C: Stereotypies resulting from a deviation in the ontogenetic development of gerbils. Behav Processes 1997, 39:215-221.
- [62]Ödberg FO. Abnormal behaviours: stereotypies. In: First World Congress on Ethology Applied to Zootechnics. Madrid: Industrias Grafices Espana; 1978: 475-480.
- [63]Canteras NS, Simerly RB, Swanson LW: Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat. J Comp Neurol. 1995, 360:213-245.
- [64]Brennan PA, Zufall F: Pheromonal communication in vertebrates. Nature 2006, 444:308-315.
- [65]Kang N, Baum MJ, Cherry JA: A direct main olfactory bulb projection to the ‘vomeronasal’ amygdala in female mice selectively responds to volatile pheromones from males. Eur J Neurosci 2009, 29:624-634.
- [66]Kavaliers M, Choleris E, Colwell DD: Learning from others to cope with biting flies: social learning of fear-induced conditioned analgesia and active avoidance. Behav Neurosci 2001, 115:661-674.
- [67]Kavaliers M, Colwell DD, Choleris E: Kinship, familiarity and social status modulate social learning about “Micropredators” (Biting Flies) in deer mice. Behav Ecol Sociobiol 2005, 58:60-71.
- [68]Dias BG, Maddox SA, Klengel T, Ressler KJ: Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci 2015, 38:96-107.
- [69]Ferguson JN, Aldag JM, Insel TR, Young LJ: Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 2001, 21:8278-8285.
- [70]Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ: The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron 2005, 47:503-513.
- [71]Tobin VA, Hashimoto H, Wacker DW, Takayanagi Y, Langnaese K, Caquineau C, Noack J, Landgraf R, Onaka T, Leng G, et al.: An intrinsic vasopressin system in the olfactory bulb is involved in social recognition. Nature 2010, 464:413-417.
- [72]Winslow JT, Insel TR: The social deficits of the oxytocin knockout mouse. Neuropeptides 2002, 36:221-229.
- [73]Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ: Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 2004, 29:483-493.
- [74]Bielsky IF, Hu SB, Young LJ: Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav Brain Res 2005, 164:132-136.
- [75]Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y, Tsujimoto G, Mishima K, Iwasaki K, Fujiwara M: Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav Brain Res 2007, 178:123-127.
- [76]Lee HJ, Caldwell HK, Macbeth AH, Tolu SG, Young WS 3rd: A conditional knockout mouse line of the oxytocin receptor. Endocrinology 2008, 149:3256-3263.
- [77]Wersinger SR, Ginns EI, O’Carroll AM, Lolait SJ, Young WS 3rd: Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry. 2002, 7:975-984.
- [78]Gobrogge KL, Liu Y, Young LJ, Wang Z: Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. Proc Natl Acad Sci USA 2009, 106:19144-19149.
- [79]Veenema AH, Beiderbeck DI, Lukas M, Neumann ID: Distinct correlations of vasopressin release within the lateral septum and the bed nucleus of the stria terminalis with the display of intermale aggression. Horm Behav 2010, 58:273-281.
- [80]Kavaliers M, Agmo A, Choleris E, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW, Ogawa S: Oxytocin and estrogen receptor alpha and beta knockout mice provide discriminably different odor cues in behavioral assays. Genes Brain Behav. 2004, 3:189-195.
- [81]Roberts SA, Davidson AJ, McLean L, Beynon RJ, Hurst JL: Pheromonal induction of spatial learning in mice. Science 2012, 338:1462-1465.
- [82]Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M: Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem 2000, 275:20020-20026.
- [83]Drake NM, DeVito LM, Cleland TA, Soloway PD: Imprinted Rasgrf1 expression in neonatal mice affects olfactory learning and memory. Genes Brain Behav. 2011, 10:392-403.
- [84]Robles Y, Vivas-Mejia PE, Ortiz-Zuazaga HG, Felix J, Ramos X: Pena de Ortiz S. Hippocampal gene expression profiling in spatial discrimination learning. Neurobiol Learn Mem 2003, 80:80-95.
- [85]Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW: Ras and relatives–job sharing and networking keep an old family together. Exp Hematol 2002, 30:1089-1106.
- [86]Molosh AI, Johnson PL, Spence JP, Arendt D, Federici LM, Bernabe C, Janasik SP, Segu ZM, Khanna R, Goswami C, et al.: Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 2014, 17:1583-1590.
- [87]Blaustein JD, Feder HH: Cytoplasmic progestin receptors in female guinea pig brain and their relationship to refractoriness in expression of female sexual behavior. Brain Res 1979, 177:489-498.
- [88]Clark CR, MacLusky NJ, Parsons B, Naftolin F: Effects of estrogen deprivation on brain estrogen and progestin receptor levels and the activation of female sexual behavior. Horm Behav 1981, 15:289-298.
- [89]Phelps SM, Lydon JP, O’Malley BW, Crews D: Regulation of male sexual behavior by progesterone receptor, sexual experience, and androgen. Horm Behav 1998, 34:294-302.
- [90]Radonic A, Thulke S, Mackay IM, Landt O, Siegert W, Nitsche A: Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun 2004, 313:856-862.