Social Behaviour and Oxytocin Secretion in the Brain ... - Wseas.us
Social Behaviour and Oxytocin Secretion in the Brain ... - Wseas.us
Social Behaviour and Oxytocin Secretion in the Brain ... - Wseas.us
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RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINE<strong>Social</strong> <strong>Behaviour</strong> <strong>and</strong> <strong>Oxytoc<strong>in</strong></strong> <strong>Secretion</strong> <strong>in</strong> <strong>the</strong> Bra<strong>in</strong>Regulated by CD38 <strong>in</strong> Human <strong>and</strong> MiceHARUHIRO HIGASHIDA, OLGA LOPATINA, ALLA B. SALMINA, YU A.PICHUGINA, ANDREI A. SOUMAROKOV <strong>and</strong> TOSHIO MUNESUEKanazawa University Research Center for Child Mental Development, 13-1 Takaramachi,Kanazawa 920-8640, Japan <strong>and</strong> Departments of Psychiatry, Biochemistry, Medical,Pharmaceutical <strong>and</strong> Toxicological Chemistry, Krasnoyarsk Medical University,Krasnoyarsk 660022, R<strong>us</strong>siaharuhiro@med.kanazawa-u.ac.jpAbstract: - <strong>Oxytoc<strong>in</strong></strong> (OXT) <strong>in</strong> <strong>the</strong> hypothalam<strong>us</strong> is <strong>the</strong> biological basis of social recognition,tr<strong>us</strong>t, love <strong>and</strong> bond<strong>in</strong>g. Previo<strong>us</strong>ly, we showed that Cd38, a proliferation marker <strong>in</strong> leukaemiacells, plays an important role <strong>in</strong> <strong>the</strong> hypothalam<strong>us</strong> <strong>in</strong> <strong>the</strong> process of OXT release <strong>in</strong> adult mice.Disruption of Cd38 (Cd38-/-) elicited impairment of maternal behaviour <strong>and</strong> male socialrecognition <strong>in</strong> adult mice (Nature, 446, 41, 2007), similar to <strong>the</strong> behaviour observed <strong>in</strong> Oxt <strong>and</strong>OXT receptor (Oxtr) gene knockout (Oxt-/- <strong>and</strong> Oxtr-/-, respectively) mice. Impairment was alsoprom<strong>in</strong>ent <strong>in</strong> Cd38-/- newborn mice. However, <strong>the</strong>se behaviours were much milder than thoseobserved <strong>in</strong> Oxt-/- <strong>and</strong> Oxtr-/- mice. These phenotypes seemed to be ca<strong>us</strong>ed by <strong>the</strong> high plasmaOXT levels dur<strong>in</strong>g development from neonates to 3-week-old juvenile mice. These resultssuggest that secretion of OXT <strong>in</strong>to <strong>the</strong> bra<strong>in</strong> <strong>in</strong> a Cd38-dependent manner plays an important role<strong>in</strong> <strong>the</strong> development of social behaviour. Based on <strong>the</strong>se results <strong>in</strong> animal experiments, OXTtreatment for autistic subjects as a restore method has been proposed, <strong>and</strong> its <strong>us</strong>e hasbegun <strong>in</strong> several hospitals.Key-words: - <strong>Oxytoc<strong>in</strong></strong>, <strong>Social</strong> recognition, Maternal behaviour, CD38, Autism1 Introduction<strong>Oxytoc<strong>in</strong></strong> (OXT), a nonapeptide <strong>in</strong>volved<strong>in</strong> reproduction, is syn<strong>the</strong>sised <strong>in</strong> <strong>the</strong>paraventricular nucle<strong>us</strong> <strong>and</strong> supraopticnucle<strong>us</strong> of <strong>the</strong> hypothalam<strong>us</strong>, <strong>and</strong> travelsdown neuronal axons to <strong>the</strong> posteriorpituitary. It is secreted <strong>in</strong>to <strong>the</strong> generalcirculation from <strong>the</strong> nerve end<strong>in</strong>gs of <strong>the</strong>neurohypophysis <strong>and</strong> <strong>in</strong>to <strong>the</strong> bra<strong>in</strong> fromdendrites. It is well known that OXT isl<strong>in</strong>ked to complex social behaviour [1-3].In humans, <strong>in</strong>tranasal OXT may promoteISSN: 1790-5125 304 ISBN: 978-960-474-165-6
RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINEtr<strong>us</strong>t, gaze or face recognition <strong>and</strong><strong>in</strong>f<strong>us</strong>ion of OXT can <strong>in</strong>crease generosity[2-4]. In rodents, OXT is highly <strong>in</strong>volved<strong>in</strong> social <strong>in</strong>teraction, social recognition,pair bond<strong>in</strong>g <strong>and</strong> maternal behaviour[1-3,5-8]. In addition, animal studies haveshown that <strong>in</strong>creased levels of OXT <strong>in</strong> <strong>the</strong>early postnatal period may affectbehaviour <strong>and</strong> last <strong>in</strong>to adulthood, <strong>and</strong> thatsubcutaneo<strong>us</strong> adm<strong>in</strong>istration of low dosesof OXT facilitates social recognition [5].Two types of mice with OXT (Oxt) orOXT receptor (Oxtr) gene knockout(Oxt-/- or Oxtr-/-) show profound socialamnesia [5-8]. <strong>Social</strong> amnesia can be fullyrescued by <strong>in</strong>jection of OXT <strong>in</strong>to <strong>the</strong>medial amygdale <strong>in</strong> Oxt-/- mice.Impairment of social behaviour is clearlyobserved even <strong>in</strong> pups. Theseobservations suggest that OXT plays animportant role <strong>in</strong> social behaviour byOXTR stimulation dur<strong>in</strong>g bra<strong>in</strong>development throughout <strong>the</strong> juvenile toadult stages [9].Recently, we reported that adult micewith a null mutation <strong>in</strong> Cd38, a “niceness”prote<strong>in</strong> with ADP-ribosyl cyclase activity,showed deficiency <strong>in</strong> social behaviour dueto <strong>the</strong> abnormality of central <strong>and</strong>peripheral OXT secretion [9-11]. We alsoshowed that decreased formation of cyclicADP-ribose (cADPR) results <strong>in</strong>dysfunction of Ca2+-<strong>in</strong>duced Ca2+-releasefor OXT secretion <strong>in</strong> hypothalamic OXTneurons (Fig. 1). Here, we report <strong>the</strong>relationship between social behaviour <strong>and</strong>OXT levels <strong>in</strong> Cd38 knockout mice, <strong>and</strong>compared <strong>the</strong> results among threedifferent genotypes: Oxt-/-, Oxtr-/- <strong>and</strong>Cd38-/-. And we disc<strong>us</strong>s on <strong>the</strong> <strong>us</strong>age ofOXT on treatment for autism patients.Fig. 1. A scheme show<strong>in</strong>g thatCD38-dependent cADPR- <strong>and</strong> NAADPsensitive<strong>in</strong>tracellular Ca 2+ mobilizationfrom ryanod<strong>in</strong>e receptors <strong>in</strong> microsomeshas a key role <strong>in</strong> oxytoc<strong>in</strong> (OT) release.This system of OXT is important <strong>in</strong> socialbehaviour.2 Critical time w<strong>in</strong>dow of plasmaOXT levels for adult from juvenilestagesThe decrease <strong>in</strong> OXT concentration afterwean<strong>in</strong>g dur<strong>in</strong>g development wasobserved only <strong>in</strong> Cd38-/- mice, suggest<strong>in</strong>gan important critical period to dist<strong>in</strong>guishdifferent plasma OXT switch<strong>in</strong>g from <strong>the</strong>ISSN: 1790-5125 305 ISBN: 978-960-474-165-6
RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINEjuvenile stage to <strong>the</strong> adult stage [11]. Asbreast milk is <strong>the</strong> only food source <strong>in</strong>lactat<strong>in</strong>g pups, we speculated that OXT is<strong>in</strong>evitably taken <strong>in</strong> from <strong>the</strong> breast milk.To confirm this, we performedquantitative analysis to determ<strong>in</strong>e whe<strong>the</strong>rOXT is present <strong>in</strong> <strong>the</strong> mammary gl<strong>and</strong>s oflactat<strong>in</strong>g dams <strong>and</strong> milk <strong>in</strong> pups. Milkcurd was found <strong>in</strong> <strong>the</strong> stomachs of <strong>the</strong>offspr<strong>in</strong>g born to Cd38-/- females,Fig. 2. Plasma OXT levels <strong>in</strong> twogenotyoes dur<strong>in</strong>g development.which was quite different from that <strong>in</strong>those of Oxt-/- <strong>and</strong> Oxtr-/- females. OXTwas abundant <strong>in</strong> <strong>the</strong> mammary gl<strong>and</strong>tissue <strong>and</strong> breast milk <strong>in</strong> lactat<strong>in</strong>g dams ofboth genotypes, with no significantdifference between Cd38+/+<strong>and</strong> Cd38-/-animals. . In <strong>the</strong> three stages of growth <strong>and</strong>development, <strong>the</strong> plasma OXT seems tobe controlled from different sources:Foetal stage, Infant nt stage (breastfeed<strong>in</strong>gstage) <strong>and</strong> Adult stage (wean<strong>in</strong>g stage). Inwild-type mice, dur<strong>in</strong>g all developmentalstages, OXT levels are kept high (Fig. 2).In contrast, <strong>in</strong> Cd38 knockout mice OXTlevels decreased significantly afterwean<strong>in</strong>g [10,11].3 Implications for developmentaldisordersA series of recent studies suggested thatOXT is related to autism [13,14]. It hasbeen reported that plasma OXT levels <strong>in</strong>autistic children are lower than those <strong>in</strong>age-matched normal controls, although<strong>the</strong> precise deviation is very small [15].Inf<strong>us</strong>ion of OXT reduces repetitivebehaviours <strong>in</strong> adults with autistic <strong>and</strong>Asperger’s disorders [16].. However, <strong>the</strong>sestudies have largely foc<strong>us</strong>ed on autism <strong>in</strong>older children <strong>and</strong> adults. There have beenonly a few studies <strong>in</strong> <strong>in</strong>fants dur<strong>in</strong>gbreastfeed<strong>in</strong>g <strong>and</strong> <strong>the</strong>period.early postnatalFig. 3. A scheme show<strong>in</strong>g that nasal OXT<strong>in</strong>f<strong>us</strong>ion or local CD38 expression <strong>in</strong> <strong>the</strong>hypothalam<strong>us</strong> can rescue socialimpairment <strong>in</strong> autistic subjects.ISSN: 1790-5125 306 ISBN: 978-960-474-165-6
RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINEAlthough <strong>the</strong> exact mechanism is unclear[18], based on our data, we proposed thatlack of adequate exogeno<strong>us</strong> OXT dur<strong>in</strong>gbreastfeed<strong>in</strong>g would affect <strong>the</strong> normaldevelopment of <strong>the</strong> bra<strong>in</strong> <strong>in</strong> geneticallys<strong>us</strong>ceptible <strong>in</strong>fants, <strong>the</strong>reby <strong>in</strong>creas<strong>in</strong>g <strong>the</strong>risk of autism (Fig. 3). OXT treatment as arefill method has been proposed, <strong>and</strong> its<strong>us</strong>e has begun <strong>in</strong> several hospitals,<strong>in</strong>clud<strong>in</strong>g Kanazawa <strong>and</strong> KrasnoyarskUniversity Hospitals [19]. In some cases,we observed improvement <strong>in</strong> socialbehaviour, as might be suggested fromexperimental data <strong>and</strong> as it has beenreported previo<strong>us</strong>ly [13,17].4 Concl<strong>us</strong>ionWe concluded that different sources ofOXT seem to impact bra<strong>in</strong> development atdifferent stages of growth, <strong>and</strong> th<strong>us</strong>ma<strong>in</strong>tenance of high OXT level is securedfor development <strong>and</strong> social behaviour.OXT treatment with a nasal spray hasbeen proposed, <strong>and</strong> its <strong>us</strong>e has begun <strong>in</strong>several hospitals.Reference1 Neumann ID. Bra<strong>in</strong> oxytoc<strong>in</strong>: a keyregulator of emotional <strong>and</strong> socialbehaviours <strong>in</strong> both females <strong>and</strong> males. JNeuroendocr<strong>in</strong>ol 2008; 20: 858-865.2 Donaldson ZR, Young LJ. <strong>Oxytoc<strong>in</strong></strong>,vasopress<strong>in</strong>, <strong>and</strong> <strong>the</strong> neurogenetics ofsociality. Science 2008; 322: 900-904.3 Lee HJ, Macbeth AH, Pagani JH,Young WS 3rd. <strong>Oxytoc<strong>in</strong></strong>: <strong>the</strong> greatfacilitator of life. Prog Neurobiol 2009;88: 127-151.4 Kosfeld M, He<strong>in</strong>richs M, Zak PJ,Fischbacher U, Fehr E. OXT <strong>in</strong>creasestr<strong>us</strong>t <strong>in</strong> humans. Nature 2005; 435:673-676.5 Nishimori K, Young LJ, Guo Q, WangZ, Insel TR, Matzuk MM. <strong>Oxytoc<strong>in</strong></strong> isrequired for nurs<strong>in</strong>g but is not essentialfor parturition or reproductive behavior.Proc Natl Acad Sci USA 1996; 93:11699-11704.6 Ferg<strong>us</strong>on JN, Aldag JM, Insel TR,Young LJ. OXT <strong>in</strong> <strong>the</strong> medial amygdalais essential for social recognition <strong>in</strong> <strong>the</strong>mo<strong>us</strong>e. J Neurosci 2001; 21:8278-8285.7 Pedersen CA, Vadlamudi SV, BocciaML, Amico JA. Maternal behaviordeficits <strong>in</strong> nulliparo<strong>us</strong> OXT knockoutmice. Genes Bra<strong>in</strong> Behav 2006; 3:274-281.8 Takayanagi Y, Yoshida M, Bielsky IF,Ross HE, Kawamata M, Onaka T,Yanagisawa T, Kimura T, Matzuk MM,Young LJ, Nishimori K. Pervasivesocial deficits, but normal parturition, <strong>in</strong>OXT receptor-deficient mice. Proc Natl.ISSN: 1790-5125 307 ISBN: 978-960-474-165-6
RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINEAcad Sci USA 2005; 102: 16096-16101.9 Higashida H, Salm<strong>in</strong>a AB,Olovyannikova RY, Hashii M,Yokoyama S, Koizumi K, J<strong>in</strong> D, LiuHX, Lopat<strong>in</strong>a O, Am<strong>in</strong>a S, Islam MS,Huang JJ, Noda M. Cyclic ADP-riboseas a universal calcium signal molecule<strong>in</strong> <strong>the</strong> nervo<strong>us</strong> system. Neurochem Int2007; 51: 192-199.10 J<strong>in</strong> D, Liu HX, Hirai H, Torashima T,Nagai T, Lopat<strong>in</strong>a O, Shnayder NA,Yamada K, Noda M, Seike T, Fujita K,Takasawa S, Yokoyama S, Koizumi K,Shiraishi Y, Tanaka S, Hashii M,Yoshihara T, Higashida K, Islam MS,Yamada N, Hayashi K, Noguchi N,Kato I, Okamoto H, Mats<strong>us</strong>hima A,Salm<strong>in</strong>a A, Munesue T, Shimizu N,Mochida S, Asano M, Higashida H.CD38 is critical for social behaviour byregulat<strong>in</strong>g OXT secretion. Nature 2007;446: 41-45.11 Liu HX, Lopat<strong>in</strong>a O, Higashida C,Tsuji T, Kato I, Takasawa S, OkamotoH, Yokoyama S, Higashida H.Locomotor activity, ultrasonicvocalization <strong>and</strong> oxytoc<strong>in</strong> levels <strong>in</strong><strong>in</strong>fant CD38 knockout mice. NeurosciLett 2008; 448: 67-70.12 Lopat<strong>in</strong>a O, Liu HX, Am<strong>in</strong>a S, HashiiM, Higashida H. <strong>Oxytoc<strong>in</strong></strong>-<strong>in</strong>ducedelevation of ADP-ribosyl cyclaseactivity, cyclic ADP-ribose or Ca(2+)concentrations is <strong>in</strong>volved <strong>in</strong>autoregulation of oxytoc<strong>in</strong> secretion <strong>in</strong><strong>the</strong> hypothalam<strong>us</strong> <strong>and</strong> posteriorpituitary <strong>in</strong> male mice.Neuropharmacology 2010; 58: 50-55.13 He<strong>in</strong>richs M, von Dawans B, Domes G.<strong>Oxytoc<strong>in</strong></strong>, vasopress<strong>in</strong>, <strong>and</strong> humansocial behavior. Front Neuroendocr<strong>in</strong>ol2009; 30: 548-557.14 Yamasue H, Kuwabara H, KawakuboY, Kasai K. <strong>Oxytoc<strong>in</strong></strong>, sexuallydimorphic features of <strong>the</strong> social bra<strong>in</strong>,<strong>and</strong> autism. Psychiatry Cl<strong>in</strong> Neurosci2009; 63: 129-140.15 Modahl C, Green L, Fe<strong>in</strong> D, Morris M,Waterho<strong>us</strong>e L, Fe<strong>in</strong>ste<strong>in</strong> C, Lev<strong>in</strong> H.Plasma oxytoc<strong>in</strong> levels <strong>in</strong> autisticchildren. Biol Psychiat 1998; 43:270-277.16 Holl<strong>and</strong>er E, Novotny S, Hanratty M,Yaffe R, deCaria C, Aronowitz B.<strong>Oxytoc<strong>in</strong></strong> <strong>in</strong>f<strong>us</strong>ion reduces repetitivebehaviors <strong>in</strong> adults with autistic <strong>and</strong>Asperger’sdisorders.Neuropsychopharmacol 2003; 28:193-198.17 Macdonald K, Macdonald TM. Thepeptide that b<strong>in</strong>ds: a systematic reviewof oxytoc<strong>in</strong> <strong>and</strong> its prosocial effects <strong>in</strong>humans. Harv Rev Psychiatry 2010; 18:1-21.18 Ebste<strong>in</strong> RP, Israel S, Lerer E,Uzefovsky F, Shalev I, Gritsenko I,ISSN: 1790-5125 308 ISBN: 978-960-474-165-6
RECENT ADVANCES <strong>in</strong> CLINICAL MEDICINERiebold M, Salomon S, Yirmiya N.Arg<strong>in</strong><strong>in</strong>e vasopress<strong>in</strong> <strong>and</strong> oxytoc<strong>in</strong>modulate human social behavior. AnnNY Acad Sci 2009; 1167: 87-102.19 Munesue T, Yokoyama S, NakamuraK, Anitha A, Yamada K, Hayashi K,Asaka T, Hong-Xiang Liu, J<strong>in</strong> D,Koizumi K, Islam MS, Huang JJ, MaWJ, Kim UH, Kim SJ, Park KW, KimDS, Kikuchi M, Ono Y, Nakatani H,Suda S, Miyachi T, Hirai H, Salm<strong>in</strong>a A,Pichug<strong>in</strong>a YA, Soumarokov A, Takei N,Mori N, Tsujii M, Sugiyama T, Yagi K,Yamagishi M, Sasaki T, Yamasue H,Kato N, Hashimoto R, Taniike M,Hayashi Y, Hamada J, Suzuki S, Ooi A,Noda M, Kamiyama Y, Kido M,Shimizu N, Yoshikawa T, Mats<strong>us</strong>himaLopat<strong>in</strong>a O, Hashii M, Am<strong>in</strong>a S,Malavasi F, Huang EJ, Zhang JS,Shimizu N, Yoshikawa T, Mats<strong>us</strong>himaA, M<strong>in</strong>abe Y, Higashida H. Two geneticvariants of CD38 <strong>in</strong> subjects withautism spectrum disorder <strong>and</strong> controls.Neurosci Res In prpeparation.ISSN: 1790-5125 309 ISBN: 978-960-474-165-6