NeuroscienceandBiobehavioralReviews51(2015)1–14 ContentslistsavailableatScienceDirect Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev Review Developmental programing of thirst and sodium appetite AndreS.Mecawia,b,AnaF.Macchionec,d,PaulaNun˜eze,CarmenPerillane, LuisC. Re isa,LauraV ivas c,f ,JuanArguelle se,∗ aDepartmentofPhysiologicalSciences,InstituteofBiology,FederalRuralUniversityofRiodeJaneiro,Seropedica,Brazil bDepartment of Physiology,Fa cultyofM edicine, U niversity ofMala ysia,K ualaLump ur ,M ala ysia cInstituteofM ed icalInvesti gationM er cedesand MartínFer re yra,INIME C-CON ICET-Na tionalUniversityofCordoba,Cordoba,Argentina dDepartm en tofCellu larBiology,F acultyofD enti stry,Na tionalUn iversityofCordoba,Córdob a,Argentin a eDepartment of Function alBiolog y,Neur os cienceInst ituteofA sturias(INE U ROPA),Fa cultyofM edicineandHealthSciences,UniversityofOviedo,Oviedo, Spain fDepartmentofPhysiology,FacultyofExact,PhysicalandNaturalSciences,NationalUniversityofCordoba,Córdoba,Argentina a r t i c l e i n f o a b s t r a c t Articlehistory: Thirstandsodiumappetitearethesensationsresponsibleforthemotivatedbehaviorsofwaterandsalt Receiv ed10July2014 intake ,res pectivel y,andbo tha ree ssentialres ponsesforth em ain tenanceof hydromin er alhom eost asis AReccceepivteedd i9n D reevcies medb eforr2m0 154 December 2014 in anim als. These se nsat ions and their rela ted behav iors de velop very ea rly in the postna tal period in animals.Manystudieshavedemonstratedseveralpre-andpostnatalstimulithatareresponsibleforthe Availableonline17December2014 developmentalprogramingofthirstandsodiumappetiteand,consequently,thepatternofwaterandsalt intakeinadulthoodinneed-freeorneed-inducedconditions.Theliteraturesystematicallyreportsthe Keywords: involvementofdietarychanges,hydromineralandcardiovascularchallenges,renin–angiotensinsystem Thirst andsteroidhormonedisturbances,andlifestyleinthesedevelopmentalfactors.Therefore,thisreview Sodiumappetite RDeenvienlo–pa nmgeiontteanl spirnogsyrastmeming awnidll hadudmraensss ,haosww perlela- sawndh picohstnneautraol ecnhdalolecrnigneess cuabns ptrraotgersaamre liifnevloolnvge tdh.iIrnsta danddit isoond,ituhme papospseitbiltee einp iagneinmeatilcs Lifestyle mol ecularme ch anis ms respo nsibleforthede velopment alp rogramin go fdrinkin gbe havior,t heclinical Epigenetic implicationsofhydromineraldisturbancesduringpre-andpostnatalperiods,andthedevelopmental Neuroendocrine originsofadu lt hydromineral behaviorwill bediscu ssed . ©2014ElsevierLtd.Allrightsreserved. Contents 1. Introduction............................................................................................................................................ 2 2. Ontogenyofthirstandsodiumappetite............................................................................................................... 2 3. Thirstandsodiumappetiteprograming............................................................................................................... 3 3.1. Dietarymanipulationandtheprogramingoffluidintake..................................................................................... 3 3.2. Hydromineralchallengesandtheprogramingoffluidintake................................................................................. 4 3.3. Therenin–angiotensinsystemandtheprogramingoffluidintake........................................................................... 5 3.4. Steroidhormonesandtheprogramingoffluidintake......................................................................................... 7 3.5. Otherdevelopmentalinfluencesontheprogramingoffluidintake.......................................................................... 8 4. Epigeneticmechanismsandhydromineralbalance................................................................................................... 8 Abbreviations: ACE, angiotensin converting enzyme; ALD, aldosterone; ANG II, angiotensin II; ANP, atrial natriuretic peptide; AP, area postrema; AT1, angiotensin receptor type 1; AT2, angiotensin receptor type 2; AVP, vasopressin; CVO, circumventricular organ; DRN, dorsal raphe nucleus; HSD2, 11 beta-hydroxysteroid dehydrogenase type 2enzyme;ICV,intracerebroventricular;LPBN,lateralparabrachialnucleus;LT,laminaterminalis;MnPO,medianpreopticnucleus;NTS,nucleusofthesolitarytract;OVLT, organumvasculosumofthelaminaterminalis;PEG,polyethyleneglycol;PVN,paraventricularnucleus;RAAS,renin–angiotensin-aldosteronesystem;SFO,subfornicalorgan; SHR,spontaneouslyhypertensiverats;SON,supraopticnucleus. ∗ Correspondingauthor.Tel.:+34985106245;fax:+34985106285. E-mailaddress:[email protected](J.Arguelles). http://dx.doi.org/10.1016/j.neubiorev.2014.12.012 0149-7634/©2014ElsevierLtd.Allrightsreserved. 2 A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 5. Clinicalaspectsofthedevelopmentalprogramingoffluidintake................................................................................... 10 6. Conclusions........................................................................................................................................... 11 Acknowledgments.................................................................................................................................... 11 References............................................................................................................................................ 11 1. Introduction that each individual might have in relation to its surroundings (Brakefieldetal.,2005). Thelossorgainofbodywaterandsodium,whichoccursduring Thehydroelectrolytehomeostaticsystemsthatregulatethirst differentstatesoffluiddisturbance,elicitsreflexiveandbehavioral andsodiumappetitearenotexemptfromdevelopmentalprogram- responsesthatequilibratetherateoffluiddepletionorexpansion, ingeffects.Manystudiesindicatethatduringsensitiveperiodsof ultimatelyrestoringbodyfluidlevels.Toactivatetheappropriate ontogeny,differentpre-and/orpostnatalchallengesmodifyfluid homeostaticresponses,thecentralnervoussystemmustreceive intake patterns of offspring during development and in adult- and integrate multiple types of sensory input from specialized hoodinneed-freeand/orneed-inducedconditions(Arguellesetal., receptors that monitor the body fluid status. These signals are 2000;Perillanetal.,2007;Mecawietal.,2009;Leshem,2009a,b; detected by ta ste recep tors, perip heral osmo/N a+-rec eptors, vol- Macch ioneeta l., 201 2). umereceptorsandarterial/cardiopulmonarybaroreceptors,which Inviewofthesefindings,theliteratureregardingtheontogeny activatethenucleusofthesolitarytract(NTS;Vivasetal.,2013), of the mechanisms related to ingestive behavior, i.e., thirst and thelaminaterminalis(LT),andoneofthesensorycircumventricu- sodiumappetite,andhowdevelopmentalchallengescanalterthe lar organs (CVOs), the area postrema (AP). The LT comprises the lifelong patterns of water and salt intake will be reviewed. The medianpreopticnucleus(MnPO)andtwoothersensoryCVOs:the potentialneuroendocrineandmolecularmechanismsresponsible subfornicalorgan(SFO)andtheorganumvasculosumofthelam- for the programing of drinking behavior, as well as the possible inaterminalis(OVLT;Antunes-Rodriguesetal.,2004).TheSFOand clinicalimplications,willalsobeaddressed. OVLTaredevoidoftheblood–brainbarrier,andbothcontaincells that are sensitive to humoral signals, plasma and cerebrospinal 2. Ontogenyofthirstandsodiumappetite fluid (CS F)sodium co ncentratio ns(Viva setal., 1990 ;Noda,2006), osmolality(SladekandJohnson,1983)andangiotensinII(ANGII) Earlydevelopmentisconsideredacrucialperiodfortheestab- levels(Sim psonet al.,1 978).The LT,A Pand NTSmodul at eneu ral lishment ofbehavior. In therat,the m echan ismsre spo nsi blefor circuit ry,which inc lud esinteg rati vea rea ssuc hast heparave ntricu- drinking ma ke their firs t ap pea ranc e abruptly a nd sequenti ally lar(PVN) ,supra optic(SO N),lateralp arabr achia l( LPB N)anddorsal at critica l ages. Wirt h and Epstein (19 76) show ed t hat newborn rap he(DR N)nuclei.I nthis context ,themodula tionof wat erand ra tscould notb emad eto drinkwa terinr esponse toan yknown sodium intak e invol ve s int eractions be tween the C VO recep tive stim ulus o f th irst but th at drink ing co uld be induc ed by cellular areas(L T,AP,a ndNTS), theserotone rgicpathw ays from theDRN, dehydrat ion atpo stna tald ay2,byh ypovo lem iaatpo stn atalday thegu stat ory infor matio nfr omtheLPBN andtheOT ergic/ AVP ergic 4,andbyiso pr oterenola tpos tn ata lday6.ANGI I-i nducedin take path wayswit hintheSON andP VN (Fig. 1).O nce thesesignalsact un derg oe sasimilaronto ge neticprog ress io n.Dri nkinginre sponse ontheabo ve-men tion edn euro chem ical net works ,they trigger the tointracran i alANGI Ioccursatpo stnatalday2 ,butatth is stage,the app rop riate sympathetic , endocrine and behavior al re sponses to pu pscannotdi sting u ishbetw e enmilkan dw at er(E lli set al.,198 4). restoretheh ydromineral balance(Vi vase tal.,2013). Howe ver,by postnatald ay8,the adult resp onseh asap pe are d,and In p regn ancy, several adaptat ions in m ate rnal hemodynamic, thepups dri nkmorew ate rt han milk inrespon se tointracra nial horm onalandbio chemic alvariables occ urthatal lowfornormal ANG IIad minis tration (Ellis etal. ,1984 ). Thirstelic ite dbyactiva- fetalgrow than ddevelopme nt.Studies condu cted inrec entd ecades tion of thebrainrenin –angi ote nsi nsyste m(RAA S)inth es uckling have produc ede videncetosup portthe importanc e ofthee nviron- ratb ec ome smo respecifictowate rafter1 6days (Le she metal., ment duringse nsitivepe rio dsofge stat ionandearl yp ostn atallife. 198 8),andth emec hanism so fthirst arous ed byre ninorint rac el- Thec onsequ encesoft hedeve lop mentale nvir onme ntmightp er- lulard ehyd rati onarefullyde ve loped beforew ea ning( Les hemand sist untiladulthood ,a ffec tingtissuestruc tureandfunct ion.In fact, Epste in,1988). rese arch has shown that this proce ss, known as “develop me ntal Accor dingly, rat pups develop the thirst mechanism during a program ming ,” migh t res ult i n adult d iseases ; th is hypothesis is periodwhenthe yar estill complet elyd epend entontheir mother ’s oftencalled“de velopm entalo rig insof adultdise ase” (Barkereta l., milk a nd bef ore t hey nee d these me chanisms b ec ause maternal 2002) .Barke randcolleagues formu lat edthi shypoth esisbas ed on milk ensu res the pup ’s hyd ration and nutritio n. When rat pups observ ationsc olle ctedfrome conomically poo rregionso fEngla nd exhib it thirst dur ing th eir life, the y lap and swa llow, re pea tedly with(i)theh ighestra tesof infantmortal itydu etoma ln utrition, opening their mouths inad iffere ntm otor patt ernfromt hatofsuck- main ly in t he early 20th c entury , and (ii) the hig hest rates of ling.Thu s,iti sclearth a tt heneura lmech anisms forth irst an dthe mortali ty from coron aryh eartdisea seso me deca deslate r(Bark er acto fdrink in g arein nate (Fit zsimon s,1998). and Osmo nd, 1 986). Mo re rec ently, a large amoun t of r esearch At present, the re are no experime ntal data investigating the has been carr ied out to ev aluate ho w the a dult phe no type is a postn atalonto genyo fthi rst inhumans,soi tiscu rrentlyunkno wn con seque nceofe nviro nm entalsig nals oper ating ongenesdu rin g towhatex tentthirs tis “hard -w ired”atb irt h .O neunexpl oredpos- development . sib ility is that there is little differen tia tion betw een hunger and Itispossiblethattheso-called“programmingphenomenon”isa thirstin n ewb ornan im als,at leastinmamm als,given thatin this type of “phenot ypic plas ticity”for theexpression ofdifferentph en - case,t he developm entalsy ste mof foo d/fluidint akein volve sb oth otyp es fromthesam egenotyp e.T hus ,thisphen om enonisd ueto need sbe ingmetsimulta neously v iatheinge stiono fbreast milk. pre-exi sting gen eticv ariationsa ndist her esultofthein ter acti on Ifthis isthe case ,thenbecauset hef ood /fluidinta ke seems tobe ofavarietyo fenviro nmentale vent ss uch asada pt atio n,develop- de velo pe din newb orns (Elliset al.,1 984),mam malsm ightha ve to m en talprog ra mingandepigen eticalt erati ons .Theultima tegoalof learntodif fer entiatehu ngera nd th irstlate rindevelo pmen t,eith er thistyp eofprocess isto provideas trategytoa dap ttoacon stant ly durin go rpostweanin g,whe nbo thsup plies ar edifferentiated (Hall fluct uatin g environ m en t,minim iz ingtheg en otypi cd is advantage etal.,2 00 0). A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 3 Fig.1. Schematicrepresentationoftheneurochemicalcircuitsinvolvedinfluidbalanceregulation[AdaptedfromVivasetal.,2013]. Akeydifferencebetweenbreastmilk(provideddirectlyfrom Humansdonotstartlifewithanobvioussaltpreference.There the breast) and substitutes is that breast milk changes its nutri- has been sufficient research to suggest that human neonates do tionalcompositionduringfeeding(Hall,1975).Theforemilkisthin notdifferentiallyingestsaltandwatersolutions(Beauchampetal., andwateryandhasrelativelylittlenutritionalcontentcompared 1986; Harris et al., 1990; Zinner et al., 2002), and earlier stud- with the hindmilk, available later in the feed (if the infant con- ies have concluded that babies are indifferent to salt or reject it tinues to feed from the same breast), which contains far greater (Nowlis, 1973; Crook, 1978; Desor et al., 1975). In fact, human quantitiesoffatsandothernutrients(Bisharaetal.,2008).There- infants of less than 4 months of age ingest water and moderate fore,itispossiblethatthenutritionaldifferencesbetweenforemilk concentrationsofsodiumchloridesolutioninequalamounts,and and hindmilk allow for the differential satisfaction of thirst and thedifferentiationbetweenthembeginsat4–24monthsofage,at hunger in breast-fed infants, something that is not possible for whichpoint,theinfantsexhibitaheightenedacceptanceofsaline bottle-fed infants, who consume a relatively homogenous mix- solutionrelativetowater.However,at31–60monthsofage,chil- ture. For slightly different reasons, Hall (1975) argued that the drentendtorejectsalinesolutioninfavorofwater(Beauchamp foremilk/hindmilk nutritional difference might be important for et al., 1986). Thus, those changes in salt preference might also thedevelopmentofappetiteregulation,providingapotentialcon- reflect,atleastinpart,theeffectsofpreviousexperiences(Harris nection between bottle-feeding and the development of obesity. et al., 1990; Stein et al., 2012). As reviewed by Leshem (2009a), However,asthereislittleempiricaldatainvestigatingthepostna- humansdonotseemtohavearobustsodiumappetitecompared taldevelopmentofthirstinhumans,thishasyettobesubstantiated withthirst,unlikeallothermammalsthathavebeenstudied.How- (Harshaw,2008). ever,likeotheranimals,humansalsolovetoeatsalt,abehavior Sodiumpreferenceisahedonicresponsedirectlydependenton thathasimportantculturalandhedoniccomponentsandprobably thesodiumconcentrationinthesolutionbeingoffered(Bare,1949). varieswithgenes,gender,hormones,healthstatusand,aswewill Italsoplaysanimportantroleintheamountofsodiumconsumed reviewhere,severalperinatalfactors. bymammals,includinghumans,inneed-freeconditionsinwhich physiologicalrequirementsareabsent.Betweenpostnataldays10 3. Thirstandsodiumappetiteprograming and 15, the p reference for hig hly hyp ertonic N aCl soluti ons ( 2% orgreater)prevails,whereasafterweaningandduringadulthood, During pregnancy and early lactation, the developing animal th eprefere ncevalue sapproa chiso toniccon cent rations (near0.9% iscomplet elydepend ento nitsm otherfor all nutritionalr equire- NaC l)inrats(M idkiff andBerns tein,19 83;Moe,1986) .Thus ,the m ents.Theref ore,itisno tsu rp risingth at ma ternalnutri tionand sodium p refe rence-av ersio ncurveis age-de pend ent,wh ichm ight hydrom ineralvari at ion sca ninfluenc efeta lhealtha ndwellbe ing. be due to maturational chan ges in t he development of the taste Additionally,t hoseinflue nces canpersi stint oadulth ood andmight sys tem (Fa rbman,1965) andthe ch orda tympaninerv er esp onses resultinanin creas edriskfor hyd romine rald isordersa ndc ardio- (Hillan dAlmli,198 0).Pre viou sre searcho ntheont ogeny ofsodium vascul ar dis ease(Bark eran dO smond,1986;B arker,200 2;M cArdle appe tite has sh own t hat a so dium defi cit ca used by a dr enalec- etal.,20 06). tomy or furo semide adm in istration induce s sodium in take at 12 Bo thanimalmodelsandhumanstudieshaveprovidedvaluable dayso fa ge(Moe,19 86).However,d irectstim ulation ofthe br ain informa tionfor clarifyi ngth edevel opmen talpr ograming ofthirst RAAS b y in tracran ial inje ction of r enin in creases the in take of a andsaltappe tite .Thisrevi eww illhighlightinv estigationst ha thave NaCl solu tion,rather thanmilk ,a searly as3day spo stnatal ly in stud ied the relat ionsh ip bet wee n altered prenatal and post natal rats( Lesheme tal.,19 94).D uring th iscrit ica ld evelo pmentalwi n- environ men tsandthepr ograming offluid intakeus inga varietyof dow ,thereni n- ind ucedso diuma ppet iteisdi ssociatedfromt hirst nutritional,hy drom ine ralandendo cr inem anipu lation s. becau se( i)hypertonicN aClisp referred to water,(ii)t heap petite develops faster than thirst and (iii) 3-day-old renin-stimulated 3.1. Dietarymanipulationandtheprogramingoffluidintake pupsavid lylick dryN aCl.Th eser esult sshowtha ttheactivationof brainANGIIin3-day-oldratpupsevokesaprecociousandspecific Maternalmalnutritionmodelshavebeendevelopedwithsev- sodiu map pe tit e. eralexperim entalprotoco ls.When ratd ams arefedahy poca loric 4 A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 diet,theiroffspringdisplayrestrictedgrowthandhyperphagia,as 3.2. Hydromineralchallengesandtheprogramingoffluidintake well as the development of hypertension, hyperleptinemia and obesityinadultlife(Vickersetal.,2000).Specifically,changesin Becausedietaryfoodalterationsduringthefetalandneonatal kidney morphophysiology (and more specifically, nephron num- periodscanalterthepatternoffluidintakeinadulthood,itseems ber)mightplayanimportantroleinhypertensionoriginatingfrom plausibletosuggestthathydromineralchallengesduringsensitive fetalundernutrition.Ratsexposedtointrauterinefoodrestriction periodsofontogenymightalsomodifytheoffspring’spatternof exhibitareducednephronnumber,decreasedglomerularfiltration fluidintakeinneed-freeandneed-inducedconditions(Mouwetal., rateandincreasedbloodpressureinadulthood(Reginaetal.,2001; 1978; Contreras and Kosten, 1983; Crystal and Bernstein, 1995, Chouetal.,2008;Hoppeetal.,2007;Langley-Evansetal.,1999; 1998;Galavernaetal.,1995;ContrerasandRyan,1990;Curtisetal., Moritz et al., 2003). Thus, fetal undernutrition leads to lifelong 2004). morphofunctional-renalabnormalitiesandhypertensionprogram- Inthiscontext,ithasbeenshownthatepisodesofextracellu- ing(Langley-Evansetal.,1999).Inthiscontext,importantissues lardehydrationduetotheadministrationofpolyethyleneglycol thatneedtobeevaluatedinkidneydeficiencyandhypertension (PEG) in pregnant rats (which mimics human vomiting episodes programingbymaternalundernutritionaretherolesandconse- duringpregnancy)leadstoanincreasedsaltappetiteamongadult quences of these changes on fluid intake by those offspring in offspring (Nicolaidis et al., 1990). In fact, salt preference stud- adulthood. iesperformedinhumansrevealthatoffspringfromwomenwho Smart and Dobbing (1977) demonstrated that maternal food experiencedmoderatetoseverevomitingduringpregnancywere restrictioninducesaneonatalgrowthreductioninoffspring,which, more likely to prefer and to consume foods high in salt than when placed in a Skinner box test, drank more frequently dur- those whose mothers experienced little or no such symptoms ingingestivebehaviortestsinresponsetowaterdeprivationand (Crystal and Bernstein, 1995; Leshem, 1998). Other studies have tendedtorunmorequicklydownanalleywayforwatercompared alsodemonstratedthat16-week-oldinfantswhosemothersvom- with control rats. Additionally, Hoppe et al. (2007) showed that itedexcessivelyduringearlypregnancydrankmoreconcentrated protein restriction during pregnancy and lactation did not influ- saltsolutionsthantheircontrolcounterpartsandshowedlessaver- enceneed-freewaterintakeinadultoffspring;however,Alwasel sivefacialreactionstosaltysolutions(CrystalandBernstein,1998), etal.(2012)observedanintenseincreaseinneed-freewateringes- indicatingthatmaternaldehydrationcanleadtoanenhancedsalt tionamongtheoffspringofmothersfedalow-proteindietwhen preferenceinoffspring(Malagaetal.,2005). waterwastheonlyfluidoffered.Interestingly,whenbothwaterand Galavernaetal.(1995)alsoobservedanenhancedsaltappetite isotonicsalinesolutionswereoffered,thelow-protein-programed in rat offspring from dams submitted to acute and repeated offspringdemonstratedanelevatedpreferenceforsodium,which mineralofluid losses during pregnancy after diuretic-natriuretic could have been related to their increased sodium excretion treatment.Inthiscontext,areportedhistoryofmineralofluidloss (AlwaselandAshton,2009).Thesedataareconsistentwiththose such as that from hemorrhage, exercise-induced dehydration, or observedbyLangley-EvansandJackson(1996),whodemonstrated neonatal diuretic therapy might increase the avidity for salt and that rats from mothers fed a low-protein diet were resistant to theattendanthealthrisks(Leshem,1998).Thesefindingsarerel- hypertensioncausedbysaltoverloadover7days,probablyduetoa evant considering that nearly two-thirds of all pregnant women renalsodiumwastingphenotype.Additionally,whereasthecontrol experiencenauseaand/orvomitingduringthisperiod(Whitehead animalsavoidedthemandatoryintakeofhypertonicsalineduring etal.,1992). thefirstdayofsaltoverload,theanimalsfrommothersfedalow- In rats, Mansano et al. (2007) observed that maternal water proteindietshowedanincreasedintakeofthissolutioncompared restriction over an 11-day period increased natremia and osmo- withtheirpreviousintakeofwater. lalityandwasassociatedwithanincreaseinaldosteroneplasma Several studies have found that an increased salt sensitivity concentrationsinoffspringat21daysold.Theseresponsescould isassociatedwithcompromisedintrauterinefetalgrowthleading facilitateoffspringsurvivalunderexpecteddroughtconditionsand to low birth weight in human babies (Simonetti et al., 2008). In predispose these animals to suffer from diseases such as hyper- accordance with this finding, salt taste preference was inversely tension in adulthood (Mansano et al., 2007). In fact, maternal correlatedtobirthweightoverthefirst4years(Steinetal.,2006) waterdeprivationduringthelast3daysofpregnancyresultedin andwasabsentat10–15yearsofage(Shirazkietal.,2007).These asignificantincreaseinANGIItype1(AT ),ANGIItype2(AT ) 1 2 dataindicatethatdevelopmentalundernutrition(fromproteinor andangiotensinogenexpressionintheforebrainandinintracere- food restriction) and a low birth weight could lead to changes broventricular(ICV)angiotensinII-inducedthirstinmaleoffspring inrenalfunctionandsodiumexcretion,which,inturn,mightbe (Zhangetal.,2011). responsiblefortheexpressionofanatriophilicphenotype.Thus, Mouwetal.(1978)foundthatalthoughprenatalandearlypost- somereportshavedescribedthegreaterriskofdevelopinghyper- nataldietarysodiumdeprivationhadnoeffectonsaltpreference, tension in low-protein diet-programed offspring (Sahajpal and itdidinduceapersistentincreaseinwaterintake,whereaspre- Ashton, 2003; Eriksson et al., 2007) as being closely related to andpostnataldietarysodiumoverloadreducedwaterintakeand intense sodium retention d uet othein cre asedN a+–K+– 2Cl−tran s- incr easedsodi umpref erenceb othinnee d-freeco ndition sanda fter portersontheascendinglimboftheloopofHenle(Manningetal., 10daysofdietarysodiumdeprivation(ContrerasandKosten,1983; 2002)ortheincreasedsensitivitytocomponentsfromtheRAAS Curtisetal.,2004).Averysimilarresponsewasobservedintheoff- (ManningandVehaskari,2005a,b).Recently,DeLimaetal.(2013) springofewesfedwithahigh-saltdietandofewesthatgrazedon demonstratedthatmaternalproteinrestrictionledtoreducedAT saltbushduringpregnancyandlactation;theseoffspringdisplayed 1 receptorandAVPexpressioninthehypothalamusofadultoffspring reducedfoodandwaterintakeinadulthood(Chadwicketal.,2009). thatwasassociatedwithanattenuationofthethirstresponsetoICV Dietary sodium restriction in postnatal life in rats also inhibited ANGIIadministration.Additionally,theseanimalsshowedreduced thenormalremodelingofthechordatympaninervestructureby fractional sodium excretion related to increased systolic blood increasingitsterminalfieldsintheNTSinadulthood(Sollarsetal., pressure.Therefore,thereareclearlyconflictingviewsregarding 2006).Theabsenceofremodelingchordatympaninerveterminals theinfluenceofalow-proteindietduringfetalandneonatallife insodium-restrictedratsmightberesponsibleforthechangesin onfluidintake.However,ingeneral,perinatalproteinrestrictionis sodiumtaste,leadingtochangesinsodiumappetite/satietyinadult relatedtochangesinsodiumexcretionandsensitivityandresults animals.Recently,Haraetal.(2014)showedthatoffspringfrom inthepredispositiontodevelophypertension. salt-sensitiveDahlratdamsfedahigh-saltdietduringpregnancy A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 5 hadasignificantreductioninsaltintakeintheiryounglife.Onthe lactationperiodsasaprogramingmodel(Macchioneetal.,2012). otherhand,offspringfromDahldamsfedahigh-saltdietduring Atthebehaviorallevel,theresultsshowedthattheoffspringthat lactation had an increased salt appetite, demonstrating that the developed in a sodium-rich environment (PM–Na group) drank effectofaperinatalhigh-saltdietonsodiumappetiteprograming reduced amounts of water not only during furosemide–sodium is dependent on the stage of development. A high-salt environ- depletionbutalsoduringneed-freeconditionsasadultscompared mentinuterowasalsoresponsibleforahypertensivephenotype withthemanipulatedcontrolanimals(PM–Ctrolgroup).Thisstudy inadultrats,increasingpressorresponsivenesstoANGIIandbeta- showedhowtheavailabilityofarichsourceofsodiumcouldmodify adrenergic stimulation (Arguelles et al., 1996, 2000; Contreras, thebrainpatternofcellactivity,inducingacomparativelyhigher 1989,1993;Contrerasetal.,2000;Vidonhoetal.,2004).Further- braincellactivityaftersodiumdepletioninkeyareasinvolvedwith more,amaternalhigh-saltdietinewesinmid-to-latepregnancy osmoreceptionandosmoregulationsuchastheSFOandAVPneu- programstheoffspringtooverexpressthekeyelementsofrenal rons from the hypothalamic magnocellular SON and PVN nuclei, RAAS,includingangiotensinogen,angiotensinconvertingenzyme accompanied by an inverse effect in the NTS (Macchione et al., (ACE),andAT andAT receptors,at90daysold,thusindicating 2012,Fig.2).Thefactthatsodium-exposedanimalshaveincreased 1 2 changesinrenaldevelopmentandphysiology(Maoetal.,2013). activityintheseareasmightreflectasensitizationoftheosmosen- Thesefindingssuggestthathighsaltintakeduringpregnancypro- sitive circuits in these animals as a result of plasticity changes gramstheRAAStobeoveractiveinadulthood,perhapsleadingto induced by perinatal manipulation. Moreover, in the case of the exaggeratedwaterandsaltintakeandthepossibleriskofdevelop- SONs of PM–Na animals, we found a greater number of vaso- ingrenalandcardiovasculardiseases(Maoetal.,2013).However,it pressinergiccellsactivatedbybothfurosemidedoses(20%and35% isnotonlylong-termmanipulationofdietarysodiumthatcanlead increases in the response to low and high doses of furosemide, toalterationsinsodiumpreference.Leshemetal.(1996)demon- respectively)comparedwithPM-Ctrolanimals,suggestingacom- stratedthatin12-day-oldsucklingratssubjectedtoacutesodium parativelymajoractivationofthevasopressinergicsystem.Because depletion,thesubsequentadults’avidityforhypertonicsalinewas thissystemismainlyinvolvedinrenalwaterrecapture,minimiz- substantially enhanced. Additionally, in humans, a large body of ingthedropinbloodpressureasaresultofhypovolemiacaused evidencesuggeststhatbothcongenitalandexperimentalfactors bysodiumdepletion,ourresultsshowincreasedvasopressinergic influencethesaltpreference(Kochlietal.,2005;Leshem,2009b). activity and decreased thirst during the test. These observations Accordingly,Steinetal.(1996,2012)proposeapersistenteffectof mightbeexplainedbyanSFO–SONpathwaysensitizationinduced earlyexperienceonhumansaltpreferences.Perhapssomeunder- byperinatalsodiumavailabilitythatallowsPM–Naanimalstohave lyingmechanismscouldbecoincidentwiththeoneproposedby a larger anticipatory response, thereby reabsorbing more water Roitmanetal.(2002),whodescribedneuronalalterationscommon afterfurosemidetreatmentanddrinkinglesswater,resultingina tosaltanddrugsensitization. morehypertoniccocktailduringtheintaketest.Anotherexplana- Accumulatingevidenceindicatesthattheabilitytotastesaltis tionofourresultsinvolvesplasticitychangesintheosmosensitive inborn,althoughresponsestosaltyfoodsarestronglyinfluenced mechanismsthatmightaltertheosmoticthresholdforAVPrelease byenvironmentalfactorsinhumans(Mattes,1997).Veryrecently, and subsequent water drinking. Previous studies from the Ross GoldsteinandLeshem(2014)suggestedthattheattractiontosalt laboratorydemonstratedthattheplasmaosmolalitythresholdfor isconditionedbythepostingestivebenefits.Theyfoundsomeevi- AVP release was increased in offspring exposed in utero to an denceofbeneficialeffectsofdietarysodiumthatmightcontribute 8–10mEq/L increase in maternal hypernatremia in response to tothepredilectionforsaltorsalt-flavor-enhancedfoodsbycon- maternalwaterrestriction.Inthesamemodel,theauthorsdemon- ditioning for the increased requirement during growth. In this stratedalterationsinthepituitaryAVPcontentandinhypothalamic context, dietary experiences during development and increased AVPsynthesis(Ramirezetal.,2002;Desaietal.,2003). physical activity during childhood (7–12 years of age) might be responsible for greater salt preference and intake (Verma et al., 3.3. Therenin–angiotensinsystemandtheprogramingoffluid 2007). Additionally, the relationship between parental and off- intake spring food preferences seems generally weak (Rozin, 1991). Measuresofsaltconsumptionandsaltusageobtainedfrommoth- Typically,treatmentsthatactivatetheRAASinadulthoodinduce erswereunrelatedtoindividualdifferencesintheacceptabilityof thirstandsodiumappetite(Fitzsimons,1998).However,challenges saltyfoods(BeauchampandMoran,1984).However,healthydiets tooralterationsoftheRAASduringontogenybyexperimentalor dependonenvironmentalfactors,includingfoodavailabilityand external factors have profound and long-lasting effects; ANG II, thechild-feedingpracticesoftheadults(BirchandDavison,2001; in particular, appears to play a critical role in thirst and sodium KralandRauh,2010). appetite programing. For example, ANG II contributes to kidney The evidence presented here suggests that exposure to an development,atleastintherat(Langley-Evans,2009),becausethe altered osmotic environment during ontogeny can program the effectofRAASblockadeduringthedevelopmentalperiodcaused adultsystemsthatgovernthirstandsodiumappetite,andifper- long-termchangesinwaterandsaltintakeinadultratsthatwere sistent through adulthood, these alterations might have adverse atleastpartiallyattributabletochronicalterationsinrenalmor- clinical effects such as that on the incidence of hypertension. In phophysiology(Butleretal.,2002;Mecawietal.,2010;Marinetal., addition,thesedataindicateadirectalterationofintakepatterns 2011).Infact,RAASblockadewithenalaprilfrombirthuntil24–28 and, therefore, adjustments in the means of balancing the fluid daysofageinducedevidentabnormalitiesinneonatalratsat3or4 and hydroelectrolyte states. However, there is little information weeksofage.Theseratsexhibitedimpairedrenalhemodynamics regarding how these stimuli might provoke the behavioral and withareducedfiltrationrate,and,withrespecttoeffectiverenal endocrine alterations found throughout development and what plasmaflow,theyshowedelevatedrenalvascularresistanceand modifications occur at the neuronal and/or brain circuit levels. impairedtubularreabsorptionofwaterandsodium(Guron,2005). Assumingthatinmammals,theperiodsofpregnancyandlactation Thus,theRAASisclearlyinvolvedinkidneyorganogenesisapart arecharacterizedbyhydroelectrolyteandosmoregulatoryremod- fromitsclassicroleinmaintainingcardiovascularandhydromin- eling, resulting in an increase in sodium appetite (Barelare and eralhomeostasis(Guron,2005;Cooperetal.,2006;Gomezetal., Richter,1938;Leshemetal.,2002;Deloofetal.,2000;Macchione 1993;Fribergetal.,1994;Shanmugametal.,1994). et al., 2012), Vivas’s group used a rat model of voluntary access Waterdrinkingresponsivenesstodipsogenicstimulihasawell- tohypertonicsodiumchloridesolutionduringthepregnancyand knownsequentialactivationpattern,andchangesintheontogeny 6 A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 Fig.2. Effectsoffurosemide-inducedsodiumdepletion(2doses:low-furoandhigh-furo)onthenumberofFos-immunoreactive(Fos-ir)cellsin(A)thesubfornicalorgan (SFO),(B)thenucleusofthesolitarytract(NTS),and(C)thesupraopticnucleus(SON)andthelateralmagnocellularsubdivisionoftheparaventricularnucleus(PaLM)ofthe twoperinatalmanipulated(PM)groups.ThePM–Nagrouphadvoluntaryaccesstoahypertonicsodiumchloridesolution(0.45MNaCl),waterandastandarddiet,whereas thePM–Ctrolgrouphadfreeaccesstowaterandastandarddietonly.(D)TheaveragenumberofFos/vasopressin-immunoreactive(Fos/AVP-ir)double-labeledcellsinthe SON andtheP aLMsu bdiv ision ofthe pa ravent ricu la rnucleus ofbo thPM gro ups afterinje ctionwi th thetwodifferentdosesoffurosem ide.Valuesar ethemeans±S E.*p <0 .05, significantlydifferentfromthePM–Ctrolgroup.(E)PhotomicrographsshowingthepatternofFos-immunoreactivityinthesubfornicalorgan(SFO,I–II)andimmunoreactive double-labeledcells(Fos–AVP)inthesupraopticnucleus(III–IV)amongPM–Ctrol(IandIII)andPM–Na(IIandIV)animalsaftertheinjectionofahighdoseoffurosemide. Thesmallsquar esin platesCan d Dsh owhigher magnific ations( 40×)of cellsin10 × plat es. Scal ebar=1 00 (cid:2)m [Ad aptedfro mM acch ioneeta l.,2 0 12]. A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 7 ofdrinkingbehavioraftermanipulationoftheRAASduringpreg- In view of the diversity of the experimental results, it seems nancyhavealreadybeenreported(Perillanetal.,2004,2007,2008). obvious that the RAAS is involved in several aspects of the Inthiscontext,offspringexposedtoextracellulardehydrationin development of mechanisms that are responsive to hydrosaline uterodidnotrespondtoeithercellulardehydrationat2daysofage imbalances.Theapparentdiscrepanciesmightbeduetothevari- orextracellulardehydrationat4daysofage(Perillanetal.,2008). ety of experimental protocols used, thus highlighting the need Additionally, rats that developed in a hyperreninemic ambiance forfurtherstudies.Thesefindingssuggestthatahydrosaline-and duringgestationweremoresensitivetothirstinducedbyisopro- RAAS-alteredenvironmentduringpregnancymightmodifysome terenol ((cid:3)-adren ergic agoni st); this s ee ms to be indep en dent of thirstandsod iumappetite respons eslaterinl ife. theRAASsystembecausecaptoprilpre-treatmentdidnotalterthe increased water intake induced by isoproterenol (Perillan et al., 3.4. Steroidhormonesandtheprogramingoffluidintake 2004). On the other hand, according to Mecawi et al. (2010), RAAS Very few studies have directly assessed the effects of gluco- blockadeduringallofpregnancyandlactationviamaternaloral corticoids and mineralocorticoids on thirst programing. Perillan administrationofanACEinhibitordidnotchangethespontaneous etal.(2007)demonstratedtherewerenoeffectsontheoffspring waterandsaltintakeinadultmalerats(despitetheapparentrenal of rat dams treated with deoxycorticosterone on thirst induced injury).Incontrast,Butleretal.(2002)foundthatblockageofthe by hypertonic saline at two days old, by PEG at four days old, AT receptorsinratdamsonlyduringpregnancy(fromgestational or by isoproterenol at six days old. In adulthood, the offspring 1 day 2 to 19) resulted in female offspring displaying significantly from dams treated with cortisol or dexamethasone showed no increasedwaterintakeandhypertonicsalineunderbasalcondi- significantdifferencesinneed-freewaterintakecomparedtothe tionsinadulthood.Thisapparentdiscrepancybetweentheresults controls.Additionally,whensubmittedtosodiumoverload,prena- obtainedbyButleretal.(2002)andMecawietal.(2010)mightbe tallycortisol-treatedoffspringshowedatendencytoincreasetheir duetothedurationoftreatment,theRAASinhibitorusedineach waterintakeandurinaryvolumecomparedwithcontrols(Moritz protocol,ordifferencesbygender.Moreover,Mecawietal.(2010) etal.,2011).Thus,thereseemstobenosignificanteffectsoftreat- observedadecreasedresponsetostrongstimulisuchascellular mentwithadrenalcorticoidshormonesduringthedevelopmental dehydration(hypertonicsodiumchloride),extracellulardehydra- period on thirst programing, although some reports described tion(PEG),(cid:3) -adrenergicR AASstim ulation( isoproterenol ),orbrain hypert ensi vepat ternsinthea dultoffspr ingof damstr eatedwith ANG II production stimulation (with a low dose of an oral ACE glucocorticoids(Wyrwolletal.,2007;Tangetal.,2011). inhibitor).Usingthesameapproach,Mecawietal.(2009)demon- In humans, a congenital deficiency of the 21-hydroxylase stratedthatACEinhibitionduringpregnancyandlactationcould enzyme,whichisinvolvedincortisolandaldosterone(ALD)syn- lead to changes in other behavioral patterns such as locomotor thesis,isresponsibleforaseverereductioninplasmacortisoland activity,painperception,andsocialinteraction,allofwhichmight ALDlevels,leadingtotheearlydevelopmentofadrenalhyperplasia berelatedtotheobservedchangesinfeedingbehaviorinadult- and,inthemostseverecases,renalsaltwasting.Kochlietal.(2005) hood. evaluated the salt appetite of young patients with a salt wast- As previously discussed, maternal dehydration during preg- ingformofcongenitaladrenalhyperplasia.Theydemonstratedan nancy has been associated with homeostatic changes in sodium increased salt appetite in non-therapeutic normalized salt wast- appetite(Nicolaidisetal.,1990),thirst(Zhangetal.,2011),andthe ingpatientscomparedwithhealthycontrolsubjects.Theseauthors pressorresponsetoANGII(Gomezetal.,1993)inadultoffspring. suggestedthattheincreasedsaltappetiteinsaltwastingpatients Inallcases,theeffectshavebeenattributedtoalterationsofthe isduetothreefactors:(i)anadaptiveresponsemediatedbythe RAAS components, suggesting that the development of the fetal RAAStomaintainthebodilysodiumbalance,(ii)aninnatepredis- RAASissensitivetomaternal-fetalhydration.Thisissupportedby positiontoeatsalt,and(iii)animprintingbyhyponatremicevents Guanetal.(2009)andZhangetal.(2011),whoseworksdescribe duetotheabsenceofALD.However,moreexperimentalandclini- increasedexpressionoftheAT andAT receptorsintheoffspring calstudiesareneededtounderstandtheimpactofdevelopmental 1 2 ofdehydratedmothers.Thus,maternaldehydrationalterstheRAAS alterationsofadrenalhormonesontheprogramingofbehavioral sensitivityofadultoffspring. responsesrelatedtothehydromineralbalanceinadulthood. Follow-up RAAS studies focusing on hypertensive mothers Inadditiontotheroleofandrogens,estrogensandprogestogens showed that total aortic ligation between the renal arteries insexualdifferentiation,behaviorandreproduction,theinfluence producesasharpriseinreninsecretion,generallyaccompaniedby of gonadal steroid hormones on cardiovascular and hydromin- adeleterioussideeffectontherat’shealth(Rojo-OrtegaandGenest, eral homeostasis in adult life is well established (Mecawi et al., 1968).Thus,partialaorticligation(Costalesetal.,1984)isamodi- 2007, 2008; Dalmasso et al., 2011; Caeiro et al., 2011; Antunes- fiedmodelthatproducesanimalswithpolydipsiaandnatriophilia Rodriguesetal.,2013;Dadametal.,2014).Inviewofthis,SWR/J along with adequate health. This experimental pathophysiologi- mice are known to develop nephrogenic diabetes insipidus, with cal paradigm provides the opportunity to study the influence of a higher polydipsia in females than in males. Schmalbach and environmental factors such as an endogenously modified RAAS Kutscher (1975) performed a gonadectomy in SWR/J male and during pregnancy on the hydromineral homeostasis of the off- femalemicebeforepubertytoverifywhethergonadalhormones spring. In this context, progeny from dams subjected to partial wereresponsibleforprogramingsexualdifferencesinfluidintake. aortic ligation showed a long-term modification in their inges- Theyshowedthatthatanovariectomysignificantlyreducedpoly- tivebehavior,exhibitinganincreasedappetiteforhypotonicsaline dipsia in females, whereas castration had no effect in males. solutions compared with control rats and an increase in their Moreover,thecastrationofSWR/Jmalesresultedinalowerintake salt/water intake ratio following two different thirst challenges ofisotonicNaClsolution,whereasfemalesshowednosignificant (24hoffluiddeprivationorsodiumdepletionbyfurosemidetreat- differencesinsaltintake. ment;Arguellesetal.,2000).Thus,itwasshownthatwhilepups Similarly,aneonatalfemaleratovariectomymarkedlyreduced fromdamswithhypocaloric-inducedhypertensionwereinsensi- need-free saline drinking in adulthood, with intake values com- tivetothehypertensiveeffectsofsodiumchloride(Langley-Evans parable to those found in male rats. Moreover, the treatment andJackson,1996;Arguellesetal.,2000;Perillanetal.,2004,2012), of male newborn rats with estradiol led to increased intake of theoffspringofhyperreninemic,hypertensiveandnatriophilicrat hypertonicsalineinadulthoodinrelationtovehicle-treatedani- mothershadmodifiedingestivebehaviors. mals (Krecek, 1978). Additionally, Alan Epstein’s group showed 8 A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 thatnewborngonadectomizedmaleratsdrank3%NaClinadult- mellitusinducesincreasedplasmaaldosteroneconcentrationsin hood in both need-free and need-induced states, whereas the dams as well as in newborn (Cugini et al., 1987). Future studies ovariectomizedfemaleratsthatweregivenneonataltestosterone are necessary to more closely investigate the influence of these showedadecreasein3%NaClintakeinneed-freeconditions(Chow disturbancesonbodyfluidhomeostasis. et al., 1992). On the other hand, when newborn ovariectomized Anotherissueofconcernishypoxiaduringgestation,acommon ratsweretreatedwithnonaromatizableandrogen(dihydrotestos- complicationduringpregnancythatcouldleadtoseveralmorpho- terone,thebiologicallyactiveformoftestosterone),changeswere logical and functional changes related to cardiovascular diseases notobservedineitherneed-freeorneed-induced3%NaClintakein in adult life (Rueda-Clausen et al., 2009). Fetal hypoxia induces adulthood(Chowetal.,1992).Thisresultsuggeststhattheeffect changesintheneed-inducedsodiumappetiteinadultlife.Ratoff- oftestosteroneonsodiumintakeseemstobegovernedbythecon- springfrommothersaffectedbyhypoxiaduringpregnancyshowa versionoftestosteronetoestrogeninthebrain. reducedexpressionofAT (butnotAT )ANGIIreceptorsinthefore- 2 1 Althoughusinganon-invasiveapproach,Fergusonetal.(2003, brain, associated with an increased sodium appetite in response 2009)confirmedtheabovementionedfindings,showingthatestro- to subcutaneous hypertonic saline or ICV ANG II injection (Yang genduringthedevelopmentalperiodleadstoincreasedsaltintake etal.,2010).Additionally,ICVANGIIinjectioninducedhigherc- inadulthood.Theresearchshowedthatmaleandfemaleoffspring FosexpressionintheSFO,MnPO,PVNandSONnucleiamongrats frommothersthatreceivedchowwithethinylestradiol(asemisyn- submitted to fetal hypoxia compared with control animals, sug- theticestrogen)aftergestationalday7consumedmore3%sodium gestingahighersensitivityamongthoseanimalstotheRAASand, chloride-flavored solution than same-sex controls (Scallet et al., consequently,totheadjustmentstochallenges(Yangetal.,2010). 2003).Thisgroupalsodemonstratedasimilareffectonsaltintake Prenatal exposure to the abuse of drugs such as alcohol and usingphytoestrogengenistein,butonlyinhigherdosesandwith nicotinecanprogramtheoffspring’shydromineralbalanceinadult- anuncleartransgenerationaleffect(Fergusonetal.,2003). hood.Ratsexposedtoalcoholduringpregnancyshowedseven-fold These studies have shown that developmental exposure to greaterAVPplasmaconcentrationsthancontrolanimals,aswellas gonadalsteroidhormonesleadstoanincreasedsodiumappetite significantlyelevatedlevelsofneed-freewaterconsumption(Dow- inadultlife,whichisincontrasttoadulthoodexposure,forwhich Edwardsetal.,1989).Theseresultsindicatethatprenatalalcohol adultfemaleovariectomizedratstreatedwithestradiolfor2weeks exposurecausesalong-termdisruptioninthecentralmechanisms showedasignificantreductioninhypertonicsalineintakeinneed- regulatingAVPreleaseandwaterintakeinrats.Conversely,male freeandneed-inducedconditionscomparedwithvehicle-treated andfemalepupsfrommothersexposedtonicotineduringgesta- rats(Mecawietal.,2007,2009;Dalmassoetal.,2011).Thisoppo- tion or during both gestation and lactation showed a significant site effect of gonadal hormones given during development or in increaseinhypertonicsalineintakeafter24hofwaterdeprivation adulthoodmightrevealapossibledifferenceintheepigeneticpro- inadulthood,withoutasignificantalterationinsaltintakeinneed- gramingeffectsofgonadalhormonesduringdevelopmentversus free conditions (Hui et al., 2009). On the other hand, female but inamaturedandsexuallydimorphicphaseoflife. notmaleratsexposedtonicotineduringdevelopmentshoweda significantincreaseinwaterintakeandadecreaseinAT andAT 1 2 3.5. Otherdevelopmentalinfluencesontheprogramingoffluid receptorexpressionintheforebrainafterwaterdeprivation(Hui intake etal.,2009).Furthermore,offspringofdamsexposedtonicotine hadasignificantlyincreasedrenalAT /AT ratio(Maoetal.,2009). 1 2 Several other changes during ontogeny influence drinking Becausetheavailableresultsarescarceordiscrepant,morestudies behavior.Partialmaternalseparationduringlactation,forexam- arenecessarytoelucidatetheconsequencesofthegestationaluse ple,impactsadultfluidintake.Leshemetal.(1996)demonstrated ofillicitandlicitdrugsonthehydromineralbalanceofoffspring. that rats separated from their dams for 24h on the 15th day of lactationonlyincreasedneed-freesalineintakewhentheyhadno accesstosalineduringtheseparationperiod.Theseresultsindi- 4. Epigeneticmechanismsandhydromineralbalance catethatmaternalseparationaffectssaltintakeinadulthoodonly as a secondary outcome when there is also sodium deprivation. Several studies have been conducted to understand how Furthermore,itshouldnotbeoverlookedthatsaltingestionduring changesduringthebiologicaldevelopmentalstagesofmammals sucklingdeprivationmightattenuatethestresseffectsofmaternal couldleadtoseverephenotypemodificationsinadulthoodwith- separation. out individual DNA sequence alterations (for review, see Fig. 3). The overconsumption of sugar throughout pregnancy might The increase in our knowledge of the epigenetic control of gene causemetabolicandcardiovascularproblemsinoffspringinadult- expressionprovidesabroaderviewofourcurrentunderstanding hood (Grande, 1975). Likewise, high sugar exposure during fetal ofdevelopmentalplasticityandtherelationshipsbetweentheenvi- development can also program fluid intake in adult life. Studies ronmentandchangesingeneexpression(Hochbergetal.,2011). haveshownthatfetalexposuretoahighsucrosesolutionatthe Spontaneouslyhypertensiverats(SHR)drinkmorewaterand endofpregnancyinducedincreasedexpressionoftheAT andAT hypertonicsalinethanWistarrats,andthisphenotypealsoseems 1 2 receptorproteinsintheforebraininadultanimals,althoughthere toberelatedtoincreasedexpressionofRAAScomponentsinthe werenosignificantdifferencesinwaterorhypertonicsalineintake brain and periphery (Harrap et al., 1984). Erkadius et al. (1996) comparedwithcontrolsinneed-freeconditions(Wuetal.,2011). andDiNicolantonioetal.(2005),usinganelegantmodelofSHR However,afterwaterdeprivation,theanimalsexposedtoahigh embryotransferfromanSHRfemaledonortoaWistarfemalerecip- sucrosesolutioninearlylifeshowedincreasedwaterand1.8%NaCl ient,demonstratedthatthedevelopmentofanexaggeratedsodium intake,asaresultoftheirextracellularvolumelosses(asindicated appetiteinSHRratsisdependentonprenatalSHRfetalenviron- by the higher hematocrit), and c-Fos protein expression in neu- mentalprograming.Inaddition,someresearchhaddemonstrated ronsfromtheSFO,PVNandSONcomparedwithcontrolrats.Thus, thatepigeneticchangesinSHRratscorrelatedwithincreasedRAAS theexcessiveconsumptionofsugarduringpregnancycanalteroff- activity.Forexample,inthekidneysofSHRrats,pro-reninmRNA springhydromineralbalanceregulationinadulthoodinresponse and protein are overexpressed compared with their expression tohomeostaticchallenges,includingessentialneuroendocrineand inWistarrats;thisoverexpressionwasassociatedwithincreased renalchanges,andcausegreatersensitivityoftheforebrainRAAS histone acetylation, increased methylation in activating histone mechanismsthatcontrolbodyfluids.Inaddition,maternaldiabetes codes, and decreased methylation of suppressive histone codes A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 9 Fig.3. Epigeneticprogramingofthemorphofunctionalphenotypebyenvironmentalfactors.(1)Severalexternalorinternalenvironmentalfactorsareabletointeractwith biologicalsystemsandchangetheexpression/activityoftheenzymaticmachineryresponsibleforcatalyzingcovalentchangesinDNAandhistones,remodelingchromatin andmodulatinggeneexpression.(2)Theenzymesthatmediatechangesinthehistoneacetylation(Ac)patternarehistoneacetyltransferases(whichcatalyzetheacetylation) thatpromotechromatinunpackingandhistonedeacetylases(whichcatalyzethedeacetylation)thatpromotechromatinpackaging.(3)DNAmethylation(M)iscatalyzedby DNAmethyltransferases(therebyreducinggeneexpression),whereasDNAdemethylationcouldbepassiveoractive;inthelattercase,demethylationismediatedbyDNA demethylaseenzymes(therebyincreasinggeneexpression).(4)BothincreasedchromatinpackingandincreasedDNAmethylationreducegeneexpressionbyhinderingthe interactionoftranscriptionfactors(TF)andRNApolymerasewithtargetgenes,whereaschromatinunpackingandDNAmethylationreductionfacilitategeneexpression.(5) Thus,theseepigeneticchangesinspecificgenesareabletoincreaseordecreasetheexpressionofmRNAanditsrelatedproteins,inducingthemorphofunctionalprograming ofphysiologicalsystems. (Lee et al., 2012b). Additionally, several tissues from SHR rats 1998).Booijetal.(2013)andAlbertandBenkelfat(2013)arguethat alsoshowhigherlevelsofACEmRNAandproteinexpressioncor- theDNAmethylationstatusatseveralkeygenesoftheserotonergic related with ACE gene promoter hypomethylation and histone system,accompaniedearlylifestress,constitutesariskfactorfor codemodifications(Leeetal.,2012a).Therefore,RAASinhibition depression.TheoriginoftheserotonergicsystemintheDRNhas by peripheral and central ACE administration decreases sodium beenshowntobeanimportantneuronalcircuitthatisimplicated intakeandbloodpressureinSHRrats(Antonaccioetal.,1979;Di in renal sodium excretion and sodium appetite regulation (Reis, Nicolantonioetal.,1982). 2007;Mecawietal.,2013).Overall,thedevelopmentalepigenome Inthiscontext,SHRratsdisplaylowerserotoninturnoverinthe of the serotonergic system might be an early critical program- forebrainandmidbrainstructures(KimandKo,1998;Kuboetal., ingeffectimplicatedintheefficiencyofadultcardiovascularand 1990). Additionally, reduced serotonergic activity is commonly hydromineralphenotypecontrolwhenfacedwithenvironmental associatedwithdepressioninadulthood(BlieranddeMontigny, challenges. 10 A.S.Mecawietal./NeuroscienceandBiobehavioralReviews51(2015)1–14 ExposuretonicotineduringpregnancyreducesAT expression 5. Clinicalaspectsofthedevelopmentalprogramingof 2 inassociationwithincreasedAT genepromotermethylationinthe fluidintake 2 brainsofoffspring(Lietal.,2012).Relatedly,pre-and/orpostnatal nicotineexposurealsoincreasessodiumintakeinadulthoodafter Aspreviouslymentioned,muchinformationisbeingcollected water deprivation (Hui et al., 2009). Another example of mater- about the developmental programing of hydromineral balance nal environmental epigenetics changing RAAS compounds is the (Curtisetal.,2004;Galavernaetal.,1995;ContrerasandKosten, maternalproteinrestrictionapproach,inwhichincreasedadrenal 1983;ContrerasandRyan,1990;Mouwetal.,1978;Butleretal., AT receptorexpressionanddecreasedgenepromotermethylation 2002; Nicolaidis et al., 1990), and several studies have shown 1 occurinadulthood(Bogdarinaetal.,2007).Additionally,offspring evidence of these programing effects in humans (Crystal and from mothers fed a low-protein diet show increased ACE and Bernstein, 1995, 1998; Leshem, 2009a,b; Shirazki et al., 2007). reducedAT receptorexpressionassociatedwithhypomethylation Imprintingresearchinhumans,therefore,acquiresagreaterimpor- 2 oftheACEgenepromoterandreducedexpressionofthemiRNA tance, considering the high frequency of maternal and offspring mmu-mir-330,whichputativelyregulatesAT translation(Goyal sodiumstatusalterationsthatresultfrommorningsickness,high 2 etal.,2010). sodiumintakeand/orhyponatremiaevents,amongothers. The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 Takingintoaccountthediversemodificationsthatmightoccur (HSD2) is expressed only in ALD target cells, in which it confers inthesodiumstatusofthebodyduringtheprenatalandpostnatal ALD selectivity to the mineralocorticoid receptor, thereby inac- periods caused by environmental alterations and the implica- tivating glucocorticoids (Geerling et al., 2006). The differential tions of these modifications for development, it is interesting to expressionofHSD2isalsocorrelatedtotherangeinHSD2gene evaluatetheeffectsof(i)neonataldiuretictherapyand(ii)dehy- promotermethylationlevels.Thetissuesthatshowhighexpression dration/hypernatremiaininfantsorneonatesfedbybreastfeeding ofHSD2alsoshowlessmethylationofthesamegenethantissues alone. thatshowlittleornoexpressionoftheHSD2enzyme(Alikhani- Forexample,studiesperformedinchildrenwhohadreceived Koopaei et al., 2004). Because the central classical ALD action neonatal diuretic therapy found that they have, together with of inducing sodium appetite is dependent on HSD2 expression an increased salt preference, a greater fractional excretion of (Geerling et al., 2006), epigenetic changes to the gene encod- sodium than their matched controls, suggesting that neonatal ing this enzyme might also be responsible for sodium appetite serum sodium loss might be related to a greater salt appetite in programing. children8–15yearslater(Leshemetal.,1998). In addition to the RAAS, other systems related to hydromin- Ontheotherhand,sodiumlossinprematureinfantsisdefined eralbalanceareepigeneticallymodulated.Murgatroydetal.(2009) ashyponatremiaifserumsodiumfallsbelow130mmol;thiscan showedthatearlylifestressinmiceleadstohighcorticosterone naturallyoccurinthefirstpostnataldaysduetodecreasedfluid plasmalevelsandPVNAVPmRNAexpressionandisrelatedtoAVP deliverytothedistalnephron-dilutingsegments,oftencausedby gene hypomethylation in adulthood. In humans, disturbances in thedecreasedglomerularfiltrationrateoftheunderdevelopedkid- volume-regulatingmechanismsareassociatedwitheatingdisor- neys.Additionally,hyponatremiainthelatterhalfofthefirstmonth dersandalcoholabstinence;theAVPandANPhavebeenpossibly oflife(lateonset)ismostcommonlyduetoexcessiverenallosses implicatedinthisallostericstate(Frielingetal.,2008;Hillemacher relatedto(i)thehighfractionalexcretionofsodium,particularlyin etal.,2009).Frielingetal.(2008)demonstratedthatwomenwith infantsbornbefore28weeksofgestation,(ii)inadequatesodium bulimicdisordersalsohadsignificantlylowerANPmRNAexpres- intake,(iii)theretentionoffreewaterfromexcessiveAVPrelease, sion accompanied by hypermethylation of the promoter region (iv)renalfailureor,lesscommonly,(v)edematousdisorders(Al- of the ANP gene in peripheral blood cells. Furthermore, alcohol- Dahhanetal.,2002;FanaroffandMartin,2000). abstinentpatientssubmittedtoadetoxificationtreatmentshowed Inadditiontotheevidenceoftheprogramingeffectsofhypona- decreased ANP mRNA expression and increased methylation of tremicandvomitingepisodesduringpregnancy(Nicolaidisetal., theANPgenepromoterregion.Thisstudyalsorevealeddecreased 1990;CrystalandBernstein,1995,1998;Galavernaetal.,1995),it methylationoftheAVPgenepromoterregionbutnochangesinAVP ispossibletoexpectandassumethattheseeventscouldalsomodel mRNAexpression(Hillemacheretal.,2009).BecauseAVPandANP thefluidintakebehaviorandcentralcircuitactivityresponsiblefor affectthehydromineralbalance,theseepigeneticchangescaused hydromineralbalancemaintenance. bydevelopmentaloradultlifeeventscouldalsoleadtochangesin Anotherpossiblesituationistheoccurrenceofahypernatremic- osmoticandvolumeregulation,whichmightinturnaffectthirst dehydration event during the first days of life caused by andsodiumappetite. breastfeeding alone. There is no doubt that breastfeeding is the Thus, it is reasonable to assume that pre- and postnatal best and safest way of nurturing infants, and its advantages are challenges associated with changes in chromatin structure and, well-recognized;however,dehydrationcausedbyespeciallybad therefore,intheexpressionofadifferentiatedepigenomemight breastfeeding might occur in the first weeks of life (American beresponsiblefortheexpressionofanewphenotypeinadulthood, AcademyofPediatrics,1997).Reportsofdehydrationandhyper- especiallyforhydromineralbalance.Somestudieshaveshownthe natremia in exclusively breastfed term infants have appeared in importance of epigenetic modulation in several systems impli- the literature (Sofer et al., 1993; Paul et al., 2000). It has been catedinhydromineralhomeostaticcontrol.Manystudieshavealso demonstratedthatgoodbreastfeedingestablishesadecreaseinthe explored the phenomenon of the developmental programing of sodiumconcentrationinbreastmilktonormalphysiologicallev- drinkingbehavior,butonlyrecentlyhavewehadabreakthroughin els.However,ifawomanfailstoestablishgoodbreastfeeding,the understandingthemolecularmechanismspotentiallyresponsible normalphysiologicaldecreaseinthebreastmilksodiumconcen- forthisphenomenon.Thus,itisextremelyimportanttoassociate trationdoesnotoccur(Morton,1994),resultingintheoccurrence molecular biology techniques that allow for the study of epige- of mild hypernatremia in the mother and, consequently, in the netic alterations with the study of physiological and behavioral babies, as well. Moreover, observations made by Kusuma et al. mechanismsthatareprogramedbydevelopmentalenvironmen- (2009)showedaninterestingcorrelationbetweenahighersodium talchanges.Thisapproachwillallowustoexplainwhichsystems concentrationinbreastmilkandhypernatremicbabies;forevery areinvolvedintheprogramingoftheadultphenotypeandatwhat 1mEq/Lofbreastmilksodiumlevelenhancement,thereisa1.8- leveloforganization(genetic,epigenetic,cellularorsystemic)these foldincreaseinthebaby’snatremia.Additionally,hypernatremiain changesareoccurring. thesebabiesisduenotonlytothehighsodiumcontentinthebreast