The Phylogeny and Ontogeny of Autonomic Control of the Heart and Cardiorespiratory Interactions in Vertebrates

Dane A.Crossley, II *Author ([email protected]) for correspondence Texas, North Denton,TX76203-5220,USA. University of Paulista, Campus RioClaro, SãoPaulo 13506-900,Brazil. subsequent breathing. coordinated withtheonsetofcentralrespiratoryrhythmicityand immediately afterhatchingorbirth,suggestingthatitmaybe heart, exertedviathevagusnerve,isoftenseenshortlybeforeor delayed andfirstevidenceofafunctionalcholinergictonusonthe development. However, innervationofthecardiacreceptorsis control bycirculatingcatecholaminesseemsimportantthroughout 690 6 5 4 1 pacemaker, buttheprevailingheartrate ( Each contractionofthevertebrateheartisinitiatedbyamyogenic sinus arrhythmia,Ontogeny, Vertebrate Cardiorespiratory interaction,Heartratevariability, Respiratory KEY WORDS:Autonomicnervoussystem,Parasympathetictonus, and heart invertebrateembryospossessesbothmuscariniccholinergic and location,inmostspeciesareasyetlittleunderstood.The conserved throughvertebratephylogeny, theyaredifferent inkind generating respiratorymodulationoftheheartbeatseemtobehighly respiratory gasexchange.Althoughthecentralinteractions arrhythmia inmammals.Bothmayincreasetheeffectiveness of can generatecardiorespiratorysynchronyinfishandrespiratorysinus variability. Theseincluderespiratorymodulationoftheheartbeatthat frequency componentsobservedinspectralanalysisofheartrate responsible forbeat-to-beatchangesinheartratesuchasthehigh fast-conducting, myelinatedefferent fibresinthevagusnerve,isalso after aperiodofsubmersion.Parasympatheticcontrol,exertedvia breathers likeinactivereptilesorspeciesthatsurfacetoairbreathe at thefirstairbreathfollowingaperiodofapnoeaindiscontinuous responsible forinstantaneouschangesinheartrate,suchasoccur animals, inhibitoryparasympatheticcontrolispredominantand nervous system.Inspontaneouslyactiveorexperimentallyprepared Heart rateinvertebratesiscontrolledbyactivitytheautonomic Edwin W. Taylor and cardiorespiratoryinteractionsinvertebrates The phylogenyandontogenyofautonomiccontroltheheart REVIEW © 2014.PublishedbyTheCompanyofBiologistsLtd|JournalExperimentalBiology(2014)217,690-703doi:10.1242/jeb.086199 University of Birmingham, Birmingham B152TT, Birmingham Birmingham, University UK. of Biológicas, Universidade Federal deSãoPaulo, SãoPaulo 04021-001,Brazil. coordination of effectiveness ofgasexchange isalsoimprovedbytightbeat-to-beat allow forgrossmatchingofcardiacoutputtometabolism,but the excitatory sympatheticinfluencesontheheart.Thesemechanisms system (ANS),whichexertsinhibitoryparasympathetic and within thecentralnervoussystem(CNS)viaautonomic Introduction ABSTRACT Department of BiologicalSciences, Developmental Integrative of BiologyCluster,Department Bioscience, AarhusUniversity, of DK-8000Aarhus,Department Denmark. ScienceandTechnologyNational Instituteof inComparative Physiology, Brazil. deZoologia,InstitutoBiociências, Universidade Estadual Departamento β -adrenergic receptorsveryearlyindevelopment.Adrenergic f H to ventilationoftherespiratoryorgans, whether 1,2 , CleoA.C.Leite 6 3 f 3,4, Departamento deCiências Departamento H ) isdeterminedfrom *, MarinaR.Sartori 2 School of Biosciences, School of 2,4 (RSA). Inhumans, RSA isnormallywelldeveloped injuveniles related andthisrelationshipis termed respiratorysinusarrhythmia 2007) revealsapeakatrelatively highfrequencythatisrespiration neurones generatingtherespiratoryrhythmanddetermining receptors andcoordinatecentralinteractionsbetweenpoolsof These integrateafferent inputsfromarangeofcentralandperipheral baroreceptors andmechanoreceptorsaswellhigherbraincentres. activity canbeinfluencedbyafferent inputfromperipheral ANS arelocatedwithinthebrainstemorspinalcordwheretheir The cellbodiesofthepreganglionicneuronesinbothparts Control ofthesecardiorespiratoryinteractionsresidesintheCNS. the effectiveness ofrespiratorygasexchangeanditsmetaboliccosts. between thetworhythmswouldseemessentialinordertooptimize typically pulsatileandsometimesintermittent,closeco-ordination (Piiper andScheid,1977).Asbothventilationperfusionare among thelungfishesandamphibiansshowingvariableratios more inwaterbreathers,withthebimodal,air/waterbreathers ventilation-to-perfusion ratiovariesfrom1inairbreathersto10or according totheirrespectivecapacitiesforoxygensothatthe air orwaterandofbloodovertherespiratorysurfacesarematched 1999). Ithaslongbeenrecognizedthattheoverallratesofflow spectral analysisof during inspirationinmammals andslowsduringexhalation.Power typically revealedasarisein regular andrhythmicventilation,cardiorespiratoryinteractionsare acceleration immediatelyuponthefirstairbreath.Inanimalswith display bradycardiaduringapnoeaandapronouncedcardiac pattern suchasair-breathing fishordivingtetrapodstypically they aregillsorlungs.Animalswithadiscontinuousbreathing similarities intheneuralcontrolof of operationthesesystems,vertebratessharesomefundamental argue that,despitemajordifferences intheconstruction andmode cardiovascular andrespiratorysystemsinvertebrates,wewill variability (Taylor etal.,1999). f vagus isalsoresponsibleforinstantaneous, beat-to-beatcontrolof 2).The inhibitory vagaltonevariedbetween15and102%(Fig. 1), mammals, whileadrenergic tonevariedfrom4to30%(Fig. vagus (Taylor etal.,1999). Inarepresentativecollectionof parasympathetic armoftheANSviaXthcranialnerve, the operates underavariabledegreeofinhibitorytonus,imposedby the routinely activeorexperimentallypreparedvertebrateschiefly to activitylevels,includingfightorflightresponses,theheart in vertebrate groups. then describeandinterpretourcurrentknowledgeofthe other heart andofcardiorespiratoryinteractions(CRI)inmammals and description oftheoriginandnaturetonicnervouscontrolto the 1).We introducethereviewwithashort respiratory rhythm(Table H , Tobias Wang This reviewexploresthecentralcoordinationof While adrenergic influences ontheheartareimportantinrelation (Bootsma etal.,1994;Taylor etal.,1999).Theheartaccelerates 5 f , AugustoS.Abe H variability (HRV) (GrossmanandTaylor, f H during inspiration(Taylor etal., f H and itscoordinationwiththe 2,4 and f H

The Journal of Experimental Biology dorsal motornucleusofthevagus(DVN)(Ransonetal.,1993), of vagalpreganglionicneurones(VPNs)arelocatedwithinthe (feedback) thatgatebaroreceptorinputs(Spyer, 1994).While70% neurones andafferent inputfrompulmonarystretchreceptors both centrallygenerated(feed-forward)influencesfromrespiratory from thebraintoheartthroughvagusnerveinresponse 1993; Janszkyetal.,2004). disease ininfantsandadults(Cammetal.,1996;Thompson of HRV hasbeensuggestedasaclinicalindicator ofcardiovascular 2004). Thelackofhighfrequencycomponentsinspectralanalysis increasing theeffectiveness ofgasexchange(Yasuma andHayano, matching ofventilationwithincreasedperfusionthelung, 2003). IthasbeensuggestedthatRSA servestoprovidetemporal individuals, suchashigh-performanceathletes(Giardinoetal., then declineswithagebutthisdeclineisalleviatedinphysicallyfit REVIEW The symbols( Air-brea CVPNs inthenucleusambiguus(NA). hypothesize thatthismaybethecase inamphibiantadpoles.Ma cardiac vagalpreganglioni synchrony, CRS)areduetostimulation of We haveevidencethatthecentralcardiorespiratory interactions Table 1.Aschematicdiagramoftheputativ inhibition of CVPNs byrespiratorydrive.The question inhibition ofCVPNs indicate theputativelocation ofcentralin dashed rectangles gaps inour presentknowledge

In mammals,RSA ismediatedby fluctuations ininhibitoryinput P vagalpreganglionicneurone respiratorysinusarrhythmia respiratorymotorneurone nucleusambiguus VPN heartratevariability RSA RMN fetalheartratevariability NA HRV FHRV C electrocardiogram dorsalmotornucleusofthevagus f cardiacVPN cardiorespiratorysynchrony ECG cardiorespiratoryinteractions DVN centralnervoussystem CVPN autonomicnervoussystem CRS acetylcholine CRI air-breathing organ CNS ANS ACh ABO List of abbreviations List of H heart rate and ) denote the presence of vagal preganglionic neurones (VPNs) andC vagal preganglionicneurones(VPNs) ) denotethepresenceof Dipnoi Teleostii Elasmobranchii Mammalia Squamata Testudinata Crocodilia Aves Amphibia thing adult amphibians, reptiles andbirds thing adultamphibians, e influencesdeterminingautonomiccontrolof ? DVN and CVPN( Location ofVPN( marks indicate where data were not available. were not available. marks indicatewhere data ? ? ?

(+)

(+) teractions generating respiration-related HRV. The plus andminus teractions generating HRV.Theplus respiration-related generating respiration-related generatingrespiration-related mmals have HRV (as respiratory sinus arrhythmia, RSA) generated respiratory sinusarrhythmia, mmals haveHRV(as ? NA ) ? ? ? c neurones (CVPNs) in the dorsal motor nucleusofthevagus inthedorsalmotor c neurones(CVPNs)

(–) )

heart isthereforewithdrawn,causing responsive tobaroreceptorstimulation.Theirinhibitoryinputonthe the NA,sothattheyareinactiveduringinspiration,beingnolonger accordingly silencesor‘gates’ thediscretepopulationofCVPNsin (Spyer, 1994;Jordan,1995).Respiratoryactivityduringinspiration baroreceptor afferents enteringviathenucleusofsolitarytract plus inputsfromlungstretchreceptorsthatinhibitactivityin inspiratory neuronesintheneighbouringventralrespiratorygroup, the NA arisesbecausetheyreceiveaninhibitoryinputfrom cardiac-related rhythms.ThisrespiratoryrhythmicityinCVPNs contrast, CVPNslocatedintheNA firewithrespiratory-relatedand activity oftheseneuronesisratherregularbutnotrhythmic.By et al.,1994;Jones1995;1998).Theongoing stimulation ofarterialbaroreceptorsortherespiratorycycle(Jones by stimulationofpulmonaryC-fibres,butareunaffected by 3).CVPNwithintheDVNareactivated (Jordan etal.,1986)(Fig. ambiguus(NA) outside oftheDVNinventro-lateralnucleus around 80%ofthecellbodiescardiacVPNs(CVPNs)arelocated and theconsequenteffects on the conductionvelocityoftheirefferent axons,theirefferent activity different functionalproperties,includingtheirafferent connections, the DVN(Table NA whencomparedwiththeactivity inslowfibresfromCVPNs heart byactivityinmyelinatedfibresfromCVPNslocatedthe 1995) clearlyshowedtheenhanceddegreeofcontrolexertedon In asophisticatedneurophysiologicalstudy, Jonesetal.(Jonesal., essential forthebeat-to-beatcontrolofheartthatgeneratesRSA. from theCVPNsinDVN.Thishighconductionvelocityis velocities, whichdiffer fromtheslowconductingC-fibrescoming (Table conducting myelinatedefferent axonsleavingtheCVPNsinNA responses areinstantaneousbecausetheyrelayedbyrapidly (Jordan andSpyer, 1987;Jordan,1995;Taylor etal.,1999).The RSA CRI/RSA? CRI CRI? RSA CRI CRI CRS CRS related HRV Respiration-

1), classifiedasB-fibresonthebasisoftheirconduction may share this characteristic. CRI, card may sharethischaracteristic. VPNs, respectively in the DVN or the ventro-lateral NA.The respectively intheDVNorventro-lateral VPNs, The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 heart rate variability (HRV) (i heart ratevariability(HRV) 1). SotherearetwopopulationsofCVPNthathave

heartrateinvertebrates,revealingt innervation innervation Parasympathetic Heart innervation

f H . ncluding cardiorespiratory f H signsindicatestimulation or ? ? ? ? ? ? ? vagal fibers Myelinated to riseduringinspiration

io-respiratory interactions. interactions. io-respiratory (DVN) infishand (DVN) by theinhibitionof – – innervation Sympathetic

he huge 691

The Journal of Experimental Biology Protopterus annectens Dicentrarchus labrax laevis al., 1996);mouse, Gottinger miniatureswine, et al.,2006).Birds:duck, tegu, Tupinambis merianae auratus unpublished). Reptiles:red-earedslider, ta. 04 Tbe2). et al.,2004)(Table asphyxia, wasastrongpredictor ofseverebrainsteminjury(George In fetalsheep,chronicsuppression ofFHRV, followinginduced when assessedasinfantsbyapplication ofstandardclinicalcriteria. often didnotsubsequentlydevelop RSA andshowedpooroutcomes, 2010). Babiesthatexperienced anasphyxicepisodeduringbirth developed at33–35 rate ofventilation,indicativeRSA,wasabsentat30 premature humanneonates,ahighfrequencypeakattherecorded gestation) newborninfants(Thompsonetal.,1993).However, in that RSA isamajorcontributortoHRV inhealthyterm(38–40 in thespectrumforHRV inhealthyhumanneonates,demonstrating and breathingmovementsdetectedaclearpeakattheventilation rate 692 REVIEW albus relation torestingvaluesfollowingpharmacologicalblockade.Fishes:sturgeon, Tones astheproportional changein werecalculatedasdetailedelsewhere(Altimiras etal.,1997).Exceptions,denotedbyasingleasterisk,werecalculated Fig. spectral analysisofrecordingsf the thirdtrimesterofpregnancy(Davidetal.,2007).Similarpower frequency component,indicativeofneuralorganization, appearedin in fetalheartrate(FHRV) ofhumanbabiesrevealedthatahigh et al.,1978).Time–frequency analysisofthebeat-to-beatvariation of thecholinergic antagonist atropine duringfetalmaturation(Walker progressive increaseinparasympathetictone,asrevealedbyinjection sheep wasunvaryingataround185 fetal brainstem(Windle, 1933).Although dorso-medial position,possiblytheequivalentofDVN,in as neuronesthatformtheNA migrate ventro-laterallyfromamore The separationofVPNsarisesduringembryologicaldevelopment

.Adrenergictone(%)ontheheartdetermined inrepresentativespeciesacrossdifferentvertebrategroupsandattemperatures. 1. (Iversen etal.,2011); pacu, (Taylor andIhmied,1995);bullfrog, (Cameron, 1979);antarcticfish1, Mus musculus A mphibians (Iversen etal.,2010);skipjacktuna, Mammals

Reptiles weeks orabout85%gestation(see Taylor etal., (Sandblom etal.,2010).Amphibians:axolotl, Fishes Birds Anas boscas Sus scrofadomestica (M.R.S., A.S.A.andE.W.T., unpublished); Asian swampeel(submerged) Asian swampeel(air-breath) (Ishii etal.,1996);goat, Piaractus mesopotamicus H (Johansen andReite,1964);greatcormorant, Jeju (postair-breath) Jeju (preair-breath) [as anelectrocardiogram(ECG)] Trachemys scripta Red-eared slider Lithobates catesbeianus Pagothenia bernacchii Great cormorant Miniature swine African lungfish Boa constrictor Antarctic fish1 Antarctic fish2 Yellowfin tuna Clawed toad Green iguana Skipjack tuna beatsmin Pepper frog Rattlesnake Guinea pig Sea bass Sturgeon (Kuwahara etal.,1999);Hartleyguineapig, Bullfrog Goldfish f H Mouse Axolotl Duck Tegu Pacu Goat Vole in fetalandnewborn *

20406080 100 0 120 140 160 Katsuwonus pelamis −1 Capra aegagrushircus 25°C 0°C (Overgaard etal.,2002);greeniguana, , therewasa (Leite etal.,2009);jeju, 25°C 25°C 26°C

weeks then , andantarcticfish2, (Taylor etal.,2012);pepperfrog, 22°C 30°C 20°C 5°C 30°C 0°C 22°C Ambystoma mexicanum 23°C 26°C Boa constrictor 25°C

5°C week 30°C 22°C 30°C 10°C 25°C 20°C , andyellowfintuna, 25°C Acipenser naccarii 26°C (Matsui andSugano,1989). that merittheattention ofcomparativephysiologists. Suchstudies changes intheircontrolsystems, whichattemptstoidentifyareas groups andendswithasummary oftheapparentevolutionary ontogeny ofautonomiccontrol of theheartineachvertebrate animals, somerelativelylittlestudied. Thereviewalsoconsidersthe reptile isanumbrellatermdescribing verydiversegroupsof have acomplexphylogeny;that istosaythatfish,amphibianor unlike mammalsandbirds,theso-called‘lowervertebrate’ groups limitations onourknowledgeanditmustbeemphasizedhere that, treatment ofeachgroupisnecessarilyunevenbecause the to themorethoroughunderstandingofmammalianpattern. The turn fromfish,throughamphibiansandreptilestobirds,inrelation comparative surveyoftheothervertebrategroups,considered in including humans(Taylor, 1989).Thisconsiderationunderpinsour remarkable degreeofhomologywiththosethatoperateinmammals, mechanisms thatoperateintheCNSofelasmobranchfishesshow a conserved throughoutevolution.Thusthecardio-regulatory circuitry ofthemammaliansystemseemtohavebeenhighly and Taylor (Grossmanand Taylor, 2007).Manyaspectsofthebrain the exclusivityofthismechanismhasbeencontestedbyGrossman ‘polyvagal theory’ propoundedbyPorges (Porges, 1995).However, conducting, myelinatedefferent nervefibres.Thisisthebasisfor discrete populationofCVPNsintheNA thatpossessfast generates RSA isnecessarilyrestricted tomammalsthathavethe 15°C It hasbeensuggestedthatbeat-to-beatmodulationof Hoplerythrinus unitaeniatus Phalacrocorax carbohanedae (Wang etal.,2001a); rattlesnake, Pagothenia borchgrevinki Adrenergic tone(%) Cavia porcellus (McKenzie andTaylor, 1996);Africanclawedtoad, The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 26°C Thunnus albacores (McKenzie etal.,1995);asianswampeel, Iguana iguana 26°C Leptodactylus labyrinthicus (Akita etal.,2002);vole, (Axelsson etal.,1992);seabass, (McKenzie etal.,2007);goldfish, (M.R.S., A.S.A.andE.W.T., unpublished); (Yamamoto etal.,2009).Mammals: (Keen etal.,1995);Africanlungfish, Crotalus durissusterrificus (M.R.S., A.S.A.andE.W.T., Microtus arvalis Monopterus Xenopus Carassius (Campbell (Ishii et f H that

The Journal of Experimental Biology hircus Ambystoma mexicanum pelamis Antarctic fish3,Paranototheniaangustata cod, Gadusmorhua Microtus arvalis cormorant, constrictor ancestral trait or theresultofsecondaryloss (Young, 1958). This conditionisuniqueamongst vertebratesandmaybeeitheran innervation oftheheartor branchial circulation(Taylor, 1992). cephalic andpharyngealregions sothereisnodirectsympathetic sympathetic nervoussystem does notextendrostrallyintothe Although theyhaveaninhibitory vagalinnervationoftheheart, earliest vertebrateswithawell-developed ANS(Young, 1958). period over300 Ancestors ofcontemporarysharkswerepresentduringtheSilurian 1956) (reviewedbyTaylor, 1992). of nicotinicratherthanmuscarinicreceptors(Augustinsson at el., stimulation inlampetroidsacceleratestheheartthroughactivation vagal innervation.Incontrasttoallotherchordates, vagal The heartofmyxinoidsisaneuralwhereasthelampreyreceives our understandingofmammalian,andthereforehuman,systems. are notonlyofgreatintrinsicinterestbutalsocanfurtherilluminate 2002); greeniguana, et al.,2012);pepperfrog, Fig. unitaeniatus anguilla pharmacological blockade.Fishes:dogfish, ratherthan in relationtorestingvaluesfollowingpharmacologicalblockade.Doubleasteriskdenotesproportionalchangesobservedaftervagotomy calculated asproportionalchange possible, tonewasrecalculatedasdetailedelsewhere(Altimirasetal.,1997).Exceptions,denotedbyasingleasterisk,were REVIEW Cyclostomes Fish Chondrichthyes (cartilaginousfishes–theElasmobranchs)

.Vagal tone(%)ontheheartdeterminedinrepresentativespeciesacrossdifferentvertebrategroupsandattemperatures. 2. (Matsui andSugano,1989). , andyellowfintuna, (Seibert, 1979);Asianswampeel, (Wang etal.,2001a); rattlesnake, Phalacrocorax carbohanedae (McKenzie etal.,2007);rainbowtrout, (Ishii etal.,1996);Hartleyguineapig,

million yearsagoandarethoughttorepresentthe A (McKenzie etal.,2009);Antarcticfish1, mphibians Mammals Iguana iguana Reptiles Fishes Birds (McKenzie andTaylor, 1996);Africanclawedtoad, Leptodactylus labyrinthicus Thunnus albacores Asian swampeel(submerged) Asian swampeel(air-breath) (M.R.S., A.S.A.andE.W.T., unpublished);tegu, Jeju (postair-breath) Jeju (preair-breath) Red-eared slider Antarctic fish3 (Yamamoto etal.,2009).Mammals:Gottingerminiatureswine, Great cormorant (Campbell andEgginton,2007);seabass, Monopterus albus Rainbow trout Miniature swine African lungfish Boa constrictor Scyliorhinus canicula Antarctic fish1 Antarctic fish2 Atlantic cod Yellowfin tuna Green iguana Crotalus durissusterrificus Skipjack tuna Clawed toad Rattlesnake Pepper frog Guinea pig Bullfrog Sturgeon (Keen etal.,1995);Africanlungfish, Sea bass Dogfish Goldfish Duck Pacu Mouse Axolotl

Oncorhynchus mykiss Goat Eel Tegu –10 40 90 140 90 190 –10 40 240 290 340 Vole (M.R.S., A.S.A.andE.W.T., unpublished).Reptiles:red-earedslider, ** ** ** ** * Cavia porcellus * *

10°C 23°C 20°C 30°C 7°C 26°C Pagothenia bernacchii 12°C 22°C (Iversen etal.,2011); pacu, 5°C 30°C 11°C 11°C 22°C 25°C 12°C 17°C 20°C (Taylor etal.,1977);sturgeon, 26°C (Akita etal.,2002);mouse, 25°C 30°C (Campbell etal.,2006).Birds:duck, 30°C 22°C (Wood andShelton,1980);goldfish, 5°C Xenopus laevis 26°C 25°C 15°C important modulatorof (Agnisola etal.,2003).Despitetheseadrenergic influences,themost proportional changein 1992). Inaddition,cholinergic vagaltone,assessedasthe stimulation ofvenousreceptors(BarrettandTaylor, 1984;Taylor, hyperoxia inducesasecondaryreflexbradycardia,possibly from whereas vagaltoneisreleasedduringhyperoxia,althoughextreme canicula cholinergic vagaltonuson theheart.Thedogfish, atropine (Taylor, 1992). Injectionofneuraltracersto identifyVPNs control, asitcanbeabolished by cardiacvagotomyorinjectionof normoxic fishexhibitedlongperiods ofCRS,whichisundervagal cardiorespiratory synchrony(CRS) indogfish.Unrestrainedand et al.,1999). (Butler andTaylor, 1975;Taylor etal.,1977;Taylor, 1992;Taylor the predominantmodeofnervouscardio-regulationindogfish variations intheoveralldegreeofcholinergic vagaltonusserveas increasing temperature(Fig. 1977) (seeTable Circulating catecholamineshaveadirecteffect on 0°C , andAntarcticfish2, Tupinambis merianae The cardiacvagusisalsoresponsible forthegenerationof Protopterus annectens 10°C Dicentrarchus labrax 25°C 0°C 25°C Vagal tone(%) Piaractus mesopotamicus (Taylor andIhmied,1995);bullfrog, , showsapronouncedreflexbradycardiaduringhypoxia 26°C The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 Acipenser naccarii Mus musculus 25°C 20°C 15°C

1) andalsomodulatevagalcontroloftheheart Pagothenia borchgrevinki Sus scrofadomestica (M.R.S., A.S.A.andE.W.T., unpublished); (Iversen etal.,2010);skipjacktuna, (Sandblom etal.,2010).Amphibians:axolotl, Anas boscas f H Carassius auratus f following atropinization,increaseswith H (Ishii etal.,1996);goat,

1). Collectively, thesestudiesshowthat (McKenzie etal.,1995);eel, in elasmobranchsisthedegreeof (Leite etal.,2009);jeju, (Johansen andReite,1964);great Trachemys scripta ihbtscatesbeianus Lithobates (Kuwahara etal.,1999);vole, 26°C (Cameron, 1979);Atlantic (Axelsson etal.,1992); 25°C Capra aegagrus Hoplerythrinus (Overgaard etal., f H Katsuwonus Anguilla Scyliorhinus (Short etal., When Boa (Taylor 693

The Journal of Experimental Biology al., 1986)(M.R.S.,A.S.A.andE.W.T., unpublished);bullfrog, (Table al., 1977;BarrettandTaylor, 1985c; Grossman andTaylor, 2007) conduction velocitiesthatresemble mammalianB-fibres(Shortet supplying theheartviaefferent cardiacnerves(Table primitive vertebrateisendowedwithtwolocationsforCVPNs and Taylor, 1985b;Taylor, 1992;Taylor etal.,2009b).Thus,this neurones supplyingrespiratorymusclesinthegillarches(Barrett where theyhaveanoverlappingrostro-caudaldistributionwith constitute about45%ofCVPNswiththerestlocatedinDVN, CVPNs, innervatingtheheartviabranchialcardiacnerve.They f units (Jonesetal.,1995),suggestingtheyinitiatereflexchanges in accompanied byamarkedbradycardia,powerfullystimulated these of capsaicinintotheventilatorystreamdogfish,which was sporadically andincreasedtheirfiringrateduringhypoxia.Injection Taylor, 1985a;BarrettandTaylor, 1985c).Someunitsfired attributed totwotypesofunit(Taylor andButler, 1982;Barrettand of spontaneous,centrallygeneratedefferent activitythatcouldbe of thevagusindecerebrate,paralyseddogfishrevealedhighlevels Anas platyrhynchos al., 2001);rattlesnake, A.S.A. andE.W.T., unpublished).Reptiles:red-footedtortoise, Amphibians: axolotl, instantaneous vagal branchescontainmyelinatedfibres(Table synchronize heartbeatwithventilation(Taylor, 1992).Thecardiac related activitywhichwasunaffected byhypoxia,mayserveto 1982; BarrettandTaylor, 1985a).Theseunits,showingrespiration- were synchronouswithventilatorymovements(Taylor andButler, heart. Other, typicallylarger unitsfiredinrhythmicalbursts,which 694 REVIEW (M.R.S., A.S.A.andE.W.T., unpublished);iguana, hermanni 8% ofthetotalpopulationVPNs(Fig. in scatteredventro-laterallocationsoutsideofDVNthatcomprise the DVN.However, thereisaclearlydistinguishablegroupofcells in thebrainstemofdogfishrevealedthatabout90%arelocated dogfish, Fig. DVN (Barrettand Taylor, 1985c).Thus,thereisclear evidencefor respiration-related activityasoriginating inCVPNslocatedthe antidromic stimulationofthe cardiacvagus,identifiedthis H , aswellcontributingtotheoveralllevelofvagaltoneon the Recordings fromthecentralcutendofabranchialcardiacbranch

3. Distribution of vagal preganglionic neurones (VPNs) and cardiac vagal preganglionic neurones (CVPNs) in representative species. Fishes: Distributionofvagalpreganglionicneurones(VPNs)andcardiac(CVPNs)inrepresentativespecies. 3.

1) sothattherespiration-related efferent activitycanaffect Scyliorhinus canicula (Cruce andNieuwenhuys,1974);red-earedslider, f H . CentralrecordingsfromCVPNs, identifiedby (Taylor etal.,2001);Mammals:ferret, Ambystoma mexicanum A mphibians Crotalus durissusterrificus Mammals Reptiles Fishes Birds (Taylor, 1992);pacu, Axolotl (post-metamorphosis) Axolotl (pre-metamorphosis) Dhub (Saudi Arabian lizard) Red-footed tortoise Hermann’s tortoise (Taylor etal.,1999);Africanclawedtoad, Red-eared slider Snapping turtle (Campbell etal.,2006);caiman, Clawed toad Rattlesnake Iguana iguana Pepper frog Piaractus mesopotamicus Cane toad

Ferret/cat 3). Thesearesolely Caiman Bullfrog Dogfish Iguana Pacu Duck Cod Mustela putoriusfuro

Trachemys scripta 10 20 304050607080 0 Lithobates catesbeianus 1) withhigh

1). Chelonoidis carbonaria (M.R.S., A.S.A.andE.W.T., unpublished),dhub, (Leite etal.,2009);Atlanticcod, (M.R.S., A.S.A.andE.W.T., unpublished);snappingturtle, and M.vison consequently inthecardiacvagi, affecting mechanoreceptors onthegillsmay generateactivityinCVPNsand fish, normalbreathingmovementsthatstimulateperipheral activity inthecardiacvagus(Young etal.,1993).Thus,intheintact central stimulationofabranchialbranchthevagusaffected phasic activityrecordedfromthesenervesindetermining than itsintrinsicrate(Taylor etal.,2006),identifyingaroleforthe drove thedenervatedheartofdogfishatratesbothslowerand faster 1985a; Taylor, 1992).Phasicelectricalstimulationofcardiacvagi response tomechanicalstimulationofgillsepta(BarrettandTaylor, the decerebrated,paralyseddogfishbutsameunitsfired in cardiac vagusorcentrallyfromCVPNswasgenerated in DVN arereversed.Activityrecordedfromthecentralcutendof the characteristics ofCVPNswithintheDVNandthoseoutside the resembles thesituationdescribedinmammals,exceptthat identified byneuroanatomicalstudies(Taylor, 1992).Thisagain cardiac nerveindogfisharisefromseparategroupsofCVPNs,as mammals. Thus,thetwotypesofefferent activityrecordedfromthe activity resemblesthatdescribedforCVPNsintheDVNof regularly orsporadicallybutneverrhythmically, orweresilent.This laterally outsidetheDVNwereeitherspontaneouslyactive,firing CVPNs (Taylor, 1992;Taylor, 2011). Neuroneslocatedventro- operates bothonrespiratorymotorneurones(RMNs)andthe equally possiblethatadirectdrivefromcentralpatterngenerator excitatory ratherthaninhibitoryasdescribedformammalsanditis the burstsaresynchronous,innervationofCVPNsislikelytobe located togetherintheDVN(Taylor etal.,2009b;Taylor, 2011). As by centralinteractionsbetweenrespiratoryneuronesandCVPNs the generationofphasicefferent activityincardiacvagigenerated ventilation, branchial mechanoreceptors.This is reminiscentof,but stimulation ofperipheralchemoreceptors plus,viaincreased reflex bradycardiainresponse tohypoxiamayarisefrom DVN andfromstimulationofmechanoreceptors, andthatthetypical arises fromcentralinteractions betweenCVPNsandRMNsinthe Caiman latirostris Cells outsidetheDVN(%) (Taylor etal.,2012);pepperfrog, (M.R.S., A.S.A.andE.W.T., unpublished),Hermann’s tortoise, Xenopus laevis (Ranson etal.,1993);cat, The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 (M.R.S., A.S.A.andE.W.T., unpublished).Bird:duck, (Wang etal.,1999); canetoad, Gadus morhua Uromastyx aegyptiusmicrolepis Leptodactylus labyrinthicus Felis catus CVPN VPN (Withington-Wray etal.,1986). f H (Jordan etal.,1986). . ThisimpliesthatCRS Bufo marinus Chelydra serpentina (Taylor et (M.R.S., Testudo (Innes et f H . Also,

The Journal of Experimental Biology hypoxic and Smith,1967)wereabletodemonstrate1:1synchronizationof were abolishedbyatropine.Inaddition,RandallandSmith(Randall beat (RandallandSmith,1967).Boththebradycardiasynchrony development ofanexactsynchronybetweenbreathingandheart the genesisofCRS.Introut,hypoxicbradycardiaresultedin has stressedtheimportanceofinputsfromperipheralreceptorsin HRV thatincludedCRI(Campbelletal.,2004).Work onteleosts In thesculpin,Myoxocephalusscorpius,cardiacvagotomyabolished supplying thebranchial arteries(Taylor, 1992)(Fig. many oftheseareCVPNs,others innervategillarches,possibly are locatedinaventro-lateralnucleus outsidetheDVN.Although VPNs inthislocation(Fig. scattered laterallyoutsideofthe DVN.Theyconstituteonly10%of bodies. Inaddition,asmallnumber ofCVPNs(about2%)are 60% ofcellbodiesandadorsal groupcontainingabout40%ofcell separate nucleiwithintheDVN,aventralgroupcontaining about (Taylor etal.,2009a).Pacu hasCVPNsdistributedintopologically wide rangeoffrequencies,bothbelowandabovetheintrinsic rate branches ofcranialnervesVII,IXandXentrainedtheheartover a stimulation ofthecardiacvagusorcentralrespiratory heart (Leiteetal.,2009).Asinthedogfish,peripheral,phasic bursts ofactivityinthecardiacvagus,whichappearedtorecruit the increase inventilatoryamplitudeaccompaniedbyrespiration-related cardiac vagusandanassociatedbradycardia.Hypoxiacaused an Spontaneous coughsgeneratedaburstofefferent activityinthe the cardiacvaguswassilentinlightlyanaesthetized,normoxic fish. mechanoreceptors onthegills.Inpacu, generated byreflexpathways,presumablyarisingfrom overall se(Fig. than totemperatureper Antarctic fishesisattributabletohighlevelsofvagaltonusrather Taylor etal.,1999;Perry2004)(Table degree ofsympatheticcontrolvariesconsiderably(Taylor, 1992; The teleostheartreceivesdualautonomicinnervation,althoughthe stimulation oflungstretchreceptorscausesanincreasein opposite inkindto,thehypoxicresponsemammals,where other intrinsicandextrinsicfactors(Fig. values from2to180%dependingonoxygenlevels,temperatureand (Fig. this controliscomplicatedbytheroleofcirculatingcatecholamines temperature withinspecies,butidentifyingtheneuralcomponentof normoxic fishvariesfrom5to30%amongstspeciesandwith excitatory adrenergic toneontheheartofsubmerged, inactive, REVIEW Burgh DalyandScott,1962). Osteichthyes (bonyfishes–chieflytheTeleosts) onset of respiratory drive. onset ofrespiratorydrive. Table 2.Aschematicdiagramoftheputativedevelopmentautonomicinfl adrenergic receptorsappearon Cholinergic and attributable tocirculatingcatecholamines.In Embryos closeto Late stage Early stage A dult vertebrate dult vertebrate

hatching/birth hatching/birth embryos embryos 1). Also,cardiacvagaltoneinsubmerged fishvarieswith f H f , thevagalefferent supplytotheheartalsogeneratesHRV. H with pulsatileforcedventilation,whichwasclearly 3). Incod,Gadusmorhua A – Ch receptor Vagal innervation Cholinergic tonus Ventilatory drive Ventilatorydrive Cholinergictonus Vagalinnervation Ch receptor

2). Aswellaslargely determining manyspeciesaninhibitorycholinergic

Piaractus mesopotamicus 2). Thelowf the heart early in development but their innervation is delayed.Adrenergictone the heartearlyindevelopmentbuttheir

1). Thus,thedegreeof

, 12%ofVPNs 3). H recorded in f H

– – – (De

, increase in 1995). Thisevidenceforstretch receptorfeedbackinducingthe occurring duringspontaneous airbreathing(e.g.Grahametal., in determiningthesechangeshasrecentlybeenstudied. (Rombough, 1997;PelsterandBemis,1991).TheroleoftheANS embryogenesis, followedbyadeclineimmediatelypriortohatching neurones. Airbreathing intheAsianswampeel, for centralinteractionsbetween respiratoryandcardiacmotor taking anairbreath.Forexample, enormously, allair-breathing fishshowamarkedrisein within fishes.Eventhoughthestructuresusedforairbreathing differ Air breathinghasevolvedindependentlyonnumerousoccasions tonus ontheheartmaycorrespondtoonsetofgillventilation. 1971). Ifthatassumptioniscorrect,establishmentofacholinergic of theheartviavagusnerve,asspeculatedbyHoleton(Holeton, cholinoceptors andtheestablishmentofinhibitorynervouscontrol hatching islikelytostemfromtheappearanceofmuscarinic after hatching(Milleretal.,2011), sothatslowingoftheheartupon heart bytheadditionofacetylcholine(ACh)wasineffective until circulating catecholamines.Incontrast,cholinergic inhibitionofthe throughout developmentasaresultofincreasinglevels antagonist earlyindevelopmentandtheadrenergic toneincreased trout, buccopharyngeal cavityelicitschanges in Graham etal.,1995;Skals al., 2006).Manualinflationofthe use thebuccopharyngealcavityforgasexchange(Johansen, 1966; in theelectriceelandtworelatedspeciesofsynbranchideels that 1996). Typically, thereisaprogressiverisein early duringdevelopmentinlarvalfish(PelsterandBurggren, diffusion directlyoverthebodysurface,abeatingheartappears conduction ratesbetweenthesenervescannotyetberuledout. elasmobranchs (Taylor etal.,2009a).However, arolefordifferent may beimplicatedinthegenerationofCRSbothteleostsand respiratory musclesinthejaw, suggestingthatcentralinteractions synchronous withactivityintheVthcranialnervethatinnervates related activityinthecardiacvagiofbothgroupsfishis intriguing datafromourcurrentstudiessuggestingthatrespiration- generated reflexlybyincreasedvagaltone.Thereis,however, some branchial mechanoreceptorsduringforcedventilation,andis appears duringhypoxia,perhapsasaresultofstimulation hyperoxic fishwhencardiacvagaltoneislow;whileinteleosts,it primarily generatedbycentralinteractionsininactive,normoxicor mode ofgenerationCRS,whichinelasmobranchsmaybe Air-breathing fish tonus on the heart appears close tohatch tonus ontheheartappearsclose Even thoughrespiratorygasexchangecanbesatisfiedby Thus, weareleftwithanapparentconflictofevidenceonthe uences onheartrateinvertebrates Oncorhynchus mykiss,wasreducedbyaβ

– – – – f The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199

H associated withanairbreathdoes notexcludearole

A receptor receptor drenergic

f H increases duringairbreathing ing/birth, possibly related to the possiblyrelatedto ing/birth, is established earlybutis isestablished f

innervation innervation Sympathetic H –

that aresimilartothose Monopterus albus , f H -adrenergic throughout f tonus Adrenergic H

in larval f H after 695

The Journal of Experimental Biology et al.,2007).Thesef a briefbradycardiathenfollowedbytachycardia(McKenzie with asignificantincreaseinHRV. Eachairbreathwasprecededby breathing increasedtenfoldindeephypoxiaandthiswasassociated swim-bladder asanair-breathing organ (ABO),thefrequencyofair Hoplerythrinus unitaeniatus cholinergic vagaltonus(Iversenetal.,2011) (Figs cardiac output,thatwasprimarilymediatedbywithdrawalofa f Within 20heartbeatsofeachairbreath,abeat-to-beatvariabilityin associated withbreathinginunimodalair-breathing vertebrates. 696 REVIEW increased often inintermittentpatterns,wherelunginflationisassociatedwith Adult amphibiansuseabuccalpumptoforce-ventilatetheirlungs caused aninstantaneousrisein branch in amphibians. Allbranchesofthe vagusnerveincludingthecardiac and thedegreeofparasympathetictonusonheart some et al.,1999). the brainstemwheretheyareincloseproximitytoCVPNs(Wang cranial nerves,includingthevagus,whichhavetheircellbodies in muscles inamphibians,aswelltheirairways,areinnervated by generating theseresponsesareunknown,themajorrespiratory tone ontheheartandpulmonaryartery. Althoughthemechanisms receptors duringboutsofbreathingmayresultintherelease vagal anaesthesia orinjectionofatropine.So,stimulationlungstretch normally breathinganimals,whichwereabolishedby deep toads elicitedcardiovascularresponsessimilartothoseobserved in However, artificialinflationofthelungsinanaesthetizedfrogsand cardiorespiratory interactions(Wang etal.,1999;Wang etal.,2004). through-ventilated toads,indicatingcentralcontrolof during boutsoffictivebreathingindecerebrate,paralysedand cardiorespiratory coupling. vagotomy orinjectionofatropinereducesabolishesthe release ofvagaltoneontheheartandpulmonaryarteryascardiac et al.,1999).Thesecardiovascularchangesareprimarilyduetoa reduced from300%to80%(Figs air-breath bothadrenergic andcholinergic tonefell,withthelatter established. Pharmacologicalblockaderevealedthatfollowingan constriction inthemammalianlung(Taylor etal.,1996). wall, comparablewiththevagalefferents controllingreflexbroncho- may provideefferent axonstosmoothmuscleintheswimbladder (i.e. occipitalandanteriorspinalnerves)plusVPNsintheDVNthat outside theDVN.TheABOwassuppliedbyhypobranchialnerve VPNs weredistributedintheDVNandventro-laterallocations breathing infish.Inafacultativeairbreather, thebowfin, derived fishes. of thef Changes incholinergic toneseemtodominatetheefferent regulation do notpossesssympatheticinnervationoftheheart(Table each airbreath,asdescribedformammals.Thelungfishes(Dipnoi) Amphibians – the transition toairbreathing Amphibians –thetransition Cardiac andpulmonary vagalmotoneurones showalargely the NA andcontainsabout30%ofVPNs(Wang etal.,1999)(Fig. outside thecentralgrey, whichmaybetheamphibianequivalent of equivalent tothemammalianDVN, orinaventro-lateralnucleus, their cellbodieseitherinamedial nucleus,withinthecentralgrey, of HRV, includingtheprecisebeat-to-beatmodulationof inhibitory cholinergic tonewasresponsibleforthemajorproportion H There isanapparentcorrelationbetweenthedistributionofVPNs At presentverylittleisknownaboutthecentralcontrolofair typical ofwater-breathing fish(seeCampbelletal.,2004)wasre- H changes associatedwithairbreathinginbothprimitiveand Xenopus f H and ariseinpulmonarybloodflow(reviewedbyWang are suppliedwithefferent axonsbyneuroneswith H changes werequalitativelysimilartothose f H , ateleostfishthatusesmodified and pulmonarybloodflowincreased

f 1, 2).Furthermore,modulationof H from 28to41 bpm, doubling

1, 2).Injeju, Amia calva f H around

1). 3). , associated withanincreaseinapparentvariabilityof temperature, amelioratingthetemperaturedependencyof whereas by thefactthatithasnegligiblerestingtoneonadultheart the studyofdevelopmentcardiacvagaltoneiscompromised Fritsche, 1999).However, theutilityofbullfrogasamodelfor Xenopus cholinergic toneontheheartduringlarvaldevelopmentwhile investigations revealedadichotomy, withthebullfrogexhibiting knowledge ofthechangesin and itscontrol.However, therehasbeenlittleadvancementinour organ systems,includingdevelopmentofthecardiovascularsystem earliest celldivisionstotheformationofCNSandothermajor of embryologicaldevelopmentinamphibians,extendingfromthe mechanisms forthemodulationof cardiorespiratory adaptationstobestudied,includingthe adult ventilatingandperfusinglungsenablestheassociated from alarvalwater-breathing formwithgillstoanair-breathing breathing invertebratesbecausetheirtransitionatmetamorphosis changes associatedwiththedevelopmentandevolutionofair single nucleusinthemedialDVN(Taylor etal.,2012)(Figs moderate levelsofadrenergic tone,hasallofitsVPNslocatedina bullfrog, whichhasnegligiblenormoxicvagaltoneontheheartand and Ihmied,1995;Taylor etal.,2012)(Figs temperature andwas4–6timeshigherthanadrenergic tone(Taylor inhibitory vagaltoneontheheartinnormoxiathatvariedwith overlapping distribution.Thisamphibianexhibitedhighlevelsof have aribcage but nodiaphragm.Thethoracic respiratorymuscles Reptiles ventilatetheirlungsusing anaspiratorythoracicpumpand in Burggren andFritsche,1997;1997).Thecourseofchanges since previousreviews(Burggren andDoyle,1986;Burggren, 1995; amphibian NA (Taylor etal.,2001)(Fig. in thewhitematteroutsideDVNthatcouldbedesignated as an number ofVPNsintheDVN,with15%nowlocatedanovel area 2001). Theseovertchangeswereaccompaniedbyadoublingofthe voluntary migrationontoland(Taylor etal.,1999;Taylor etal., injection ofthyroidhormone,thisledtolosslarvalgillsand metamorphosis. Whenaxolotlswereinducedtometamorphoseby CVPNs, associatedwiththeswitchtoairbreathingat revealed changesinthelocationofVPNs,possiblyincluding et al.,2012)(Fig. occurs aroundmetamorphosisis clearlymerited. for CVPNsinduallocations thebrainstemofamphibiansthat of theheartandinparticular possibilityofaseparationroles following metamorphosis.Furtherdetailedstudyofneuralcontrol latter groupthatisco-locatedwithCVPNsintheputative NA nerve root(McLeanetal.,1995;Wilson et al.,2002).Itmaybethis VIIth andIXthcranialnerves,theotheratlevelofvagus formation ofbullfrogs.Onewaslocatedbetweentheorigins the activity, havebeenidentifiedwithintheventralmedullaryreticular appear tobeinvolvedinthegenerationofendogenousrespiratory and E.W.T., unpublished).Two specificrhythmogenicsites,which clawed toads, Lithobates catesbeianus ontogeny ofcardiaccontrolhavebeenconductedinbullfrogs, followed byadecline(Burggren andFritsche,1997).Studiesofthe progressive decline,aincreaseoraninitial Reptiles The amphibiansareakeygroupforstudyingthefunctional Work ontheneotenousaxolotl, f H during ontogenyisspeciesspecific.Patternsincludea Xenopus lacks it(Burggren andFritsche,1997;Jacobsson The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 Xenopus laevis

2). has highlevelsofvagaltonethatincreasewith (Burggren andFritsche,1997),African (Jacobsson andFritsche,1999).These f H during developmentinamphibians f H . Therearedetaileddescriptions Ambystoma mexicanum,has

3). Thischangewas 1, 2).Incontrast,the f H (A. Narshi f H

1–3). (Taylor

The Journal of Experimental Biology durissus a cardiacvagaltonus.Inthetortoiseandinrattlesnakes evidence indicatedthattheresponsewasmediatedbywithdrawalof respiratory andcardiacneuronesinthemedulla.Furtherexperimental ventilation tachycardiaresultedfromcentralinteractionsbetween tone predominatesindetermining vagotomy (Burggren, 1975;Wang etal.,2001b).Overall, cholinergic receptors waswithouteffect on receptors, arterialchemoreceptorsandbaroreceptorsorwater tachycardia (Burggren, 1975).Asstimulationofpulmonarystretch onset oflungventilationwasaccompaniedbyanimmediate In theturtle, termed CRSbutthisisnottheone-to-onesynchronydescribedinfish. with intermittentlungventilationindiscontinuousbreatherswere (Wang andHicks,1996a).Thesecardiovascularchangesassociated blood flowincreasedmorethanthreefoldattheonsetofbreathing coupling. Inthefreedivingturtle, et al.,2006).Reptilesshowclearexamplesofcardiorespiratory Hicks, 1996a;Wang andHicks,1996b;Wang etal.,2001b;Campbell single breathsinotherspeciesofreptiles(Burggren, 1975;Wang and pronounced changesinf typically exhibitintermittentbreathingpatternsaccompaniedbyvery to experimentallunginflation(Al-Ghamdietal.,2001).They pump withabuccalthatfurtherinflatesthelungsandresponds brainstem bydescendingfibres.Somespeciesreinforcethethoracic are innervatedbyspinalnerveswithrhythmicityrelayedfromthe REVIEW (Ariens Kappersetal.,1936)(Table divisions (medialandventro-lateral)ofthevagalmotorcolumn seems tovaryamongspeciesthoughearlystudiesdescribed two neuranatomy. Thesomatotopicorganization ofthevagus in reptiles of patternscardiorespiratoryinteractioninreptilesto their abolished byatropinization(Campbelletal.,2006). rattlesnakes, identifiedinthespectrumofitsHRV thatwas flavomarginata in spontaneouslybreathing,anaesthetized pondturtles caused apronouncedbradycardia, aswellvasomotorresponses, have beenconfirmedbyelectrical stimulationofthebrainstemthat them astwoseparatenuclei.These neuroanatomicalobservations lateral. Thecellshapesaswell astheseparatelocationsidentify located twogroupsofVPN,one medialintheDVNandother determines resting rattlesnake, oscillation (DeVera andGonzales,1997).IntheSouthAmerican decreased thelowfrequencypeaksandabolishedhigh respiratory pattern(DeVera etal.,2012).Atropineinjection appeared wheneverthelizardsexhibitedapronouncedregular antagonists (DeVera andGonzález,1999).A highfrequencypeak oscillations atlowfrequencythatwereabolishedbyadrenergic HRV inthelizard adrenergic toneontheheart(Figs but unrestrainedgreeniguanahassimilarlevelsofcholinergic and such asturtles,f (Figs consisting ofnumerousbreaths,whereas group (Fig. chelonians suggeststhatthishighproportionischaracteristicof the sinensis VPNs arereportedlylocatedintheNA oftheterrapin hermanni of VPNswerelocatedintheventro-lateralNA oftheturtle There ispresentlyapaucityofdatarelatingthecentralintegration A seriesofexperimentsusingpower spectralanalysistoanalyse 1, 2).However, therewasclearrespiratorymodulationof (Leong etal.,1984)andourcurrentstudiesonarangeof the tachycardiaduringventilationwasabolishedby (Cruce andNieuwenhuys,1974)whileupto50%of Crotalus durissus,vagal,parasympathetictonelargely 3). Inhatchlingturtles Pseudemys scripta,andthetortoise, . Thecardioinhibitory responsedependedon the H f remains elevatedthroughoutventilatorybouts H (Wang etal.,2001b;Campbell2006) Gallotia galloti H and cardiacshuntpatterns.Insomespecies,

1, 2). f H f

H 1, Fig. Trachemys scripta,pulmonary in reptilesthoughtheprepared ; itwasconcludedthatthis Trachemys scripta showed thatitincluded f 3). Between36and50% H also increasesduring Testudo graeca,the Cyclemys we have Crotalus Trionyx Testudo f H in study ofitscontrol. changes incardiacoutputaccompanying development,enabling in combinationwithmeasurement of 1996; CrossleyandAltimiras, 2000) sothatchangesinheartmass, stroke volumeduringreptiliandevelopment(BirchardandReiber, 2011a). Embryonicheartmasshasbeensuggestedtobeanindexof flow haveonlybeenconductedinembryonicalligators(Eme et al., 4),butmeasurementsofblood clades, excludingSphenodontia(Fig. described inrepresentativespeciesfromeachofthemajorreptilian birds andmammals.Changesin representing theevolutionarylinkbetweenancestralamphibians, because oftheirphylogeneticdiversity, withseparatelines poorly understoodthoughthegroupprovidesinterestingmodels this willbethefocusoffuturework. Specific labellingofCVPNshasremainedelusiveinreptiles and distribution ofVPNsoutsidetheDVNseemstoberule(Fig. unpublished) (Fig. containing about5%ofcellbodies(M.R.S.,A.S.A.andE.W.T., band intherostro-caudalextentofvagalmotornucleus brain revealedthatthelateralnucleuswasrestrictedtoanarrow development. Anincompleteplotofthedistributioncellsin nucleus, implyingthatVPNsmigratefromtheDVNduring juveniles VPNswerelocatedbothintheDVNandalateral restricted toadiscreteDVNclosethefourthventricle,whilein an earlyembryoofthegreeniguana, neuroanatomical basisofcentralintegrationanditsdevelopment.In juvenile andembryonicreptilesinanattempttorevealthe location ofVPNsandpathwaystheiraxonsinarangeadult, respiration-related HRV. not ruleoutaroleforcentralinteractionsinthegenerationof from thevagusnerveinrattlesnakes(Sundinetal.,2001),thisdoes associated withstimulationoflungstretchreceptors,wasrecorded peripheral reflexeswasnotdetermined.Althoughafferent activity, Whether thisrelationshipisgeneratedcentrallyorasaresultof low power spectrumofHRV thatwasrespirationrelated, developedat the rattlesnakeshowedaclearhighfrequencycomponentin Campbell etal.,2006)(Fig. ventrolateral locationsoutsidetheDVN(Taylor etal.,2001; are intheDVNwhile~4%ofVPNslocatedscattered DVN atobex.Intherattlesnake neurone cellbodiesinscatteredventrolaterallocationsoutsidethe discrete DVNrostralofobexwithasmallnumber(about10%) constrictor, themajorityofVPNsareagainconcentratedina up about13%ofthewhole(Taylor etal.,2001).Intheboa, the DVNintotwodistinctgroupswithamorelateralgroupmaking the NA (Fig. the DVNwithasmallproportion(2–6%)ventrolaterallylocatedin lizard, designated astheNA (Taylor etal.,2010)(Fig. group outsidetheDVNcontainingabout12%ofVPNsand majority ofVPNsareintheDVNbutthereisadiscretelateralcell of reptileshasrevealedthatinthecaiman, and DVN(Hsiehetal.,1988). stimulation ofareasinthecaudalmedullacorrespondingtoNA integrity ofthevagusnervesandwasparticularlymarkedupon turtles. Two maincharacteristicshave emerged. Embryonic investigated primarilyinAmerican alligatorsandcommonsnapping The ontogeneticdevelopment ofregulation Functional maturationofthereptiliancardiovascularsystem is We arecurrentlyusingfluorescentneuraltracerstodeterminethe An exploratorystudyofthecentrallocationVPNsinarange f H Uromastyx microlepis, themajorityofVPNsarelocatedin and wasabolishedbyatropine(Campbelletal.,2006). The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 3). However, therewasaclearseparationofVPNsin 3). So,insquamatereptilesarelativelysparse

3). DespitethelackofadiscreteNA, f Crotalus durissus H during developmenthavebeen f H , mayprovideanindexofthe Iguana iguana,VPNswere Caiman latirostris

3). Intheagamid , 95%ofVPNs f H has been , the Boa 697

3).

The Journal of Experimental Biology Burggren 2009); Chelonoidis carbonaria indicating theestablishmentofaneffective vagaltonusontheheart, markedly afterhatchinginthesnappingturtle, sympathetic nervousoutflow(Fig. longicollis 698 merianae REVIEW Crocodilians (Figs suggesting thismaybeacommonfeatureofdevelopmentin findings intheParaguayancaiman(D.A.C.,unpublished)(Fig. Crossley andAltimiras,2005).We haverecentlyobtainedsimilar limited hypertensivebaroreflexresponse(Crossleyetal.,2003a; central nervouscontroloff 6).Alligatorembryosalsolack hatching (Emeetal.,2011b) (Fig. Cholinergic receptor-mediated regulationisabsentuntilthetimeof circulating catecholaminesratherthatadrenergic innervation. 5)throughoutthefinal40%ofincubationthatisattributableto (Fig. alligators maintainaconstantandpronounced Fig. al., 2010); duperreyi tone onf Galliformes Teleosts Squamates Chelonian Crocodilian Sphenisciformes Charadriiformes Ratites A nseriformes Like alligators,embryonicturtlespossessamarked

.Heartrate( 4. h d e

i (open squares), (open triangles).(C)Crocodilianembryosincluding (Crossley andBurggren,2009); (open diamonds)and H

at 70%ofincubationthatdoesnotderivefrom

b (Crossley etal.,2013); f

06 8 90 80 50 60

H ) atdifferentpointsofincubationinrepresentativespecies. 5, 6). b –1 (open circles), fH (beats min ) 100 120 140 Pogona henrylawsoni 20 40 60 80 0 20406080 100 0 H A Pelodiscus sinensis in responsetohypoxiaandexhibita etdns Testudines Incubation (%) 70 Chelydra serpentina c

(Eme etal.,2013); 5). j (Crossley andBurggren,2009); f H i fell slightlybeforeand (open circles), f Chelydra serpentina (open triangles).(B)Squamateembryosincluding β -adrenergic tone c (crosses), Trachemys scripta d M.R.S., unpublished; Alligator mississippiensis β 20406080 100 0 B -adrenergic Lamprophis fuliginous qaae Squamates H Oncorhynchusmykiss (brown house snake) Lamprophisfuliginosus(brown Iguanaiguana Chelydraserpentina Gopherusagassizi Chelonoidiscarbonaria Trachemys scripta Trachemys dorbigni(D’Orbigny’s sliderturtle) mississippiensis Alligator Caimanyacare(Paraguayancaiman) Spheniscushumboldti(Humboldtpenguin) Leucophaeuspipixcan(Franklinsgull) Dromaius novaehollandiae(emu) Anas platyrhyncho Branta canadensis(Canadagoose) Anser anserdomesticus Gallus gallus Gallus gallus(redjunglefowl) Gallus gallusdomesticus Gallus gallusdomesticus Colinus virginianus(bobwhitequail) Incubation (%)

5), k (Crossley andBurggren,2009). , markedly reduced atropine alonehadnoeffect on (M.R.S., A.S.A.andE.W.T., unpublished).However, injectionof topical applicationofACh,whichcouldbeblockedwithatropine time) astheyexhibitedacleardose-dependentreductionin present intheheartofearlyiguanaembryos(10%incubation green iguanas(Table hatching (Table of acardiacvagaltonuswasdelayeduntilimmediatelybefore undergone morethan90%ofdevelopment,indicatingthattheonset (Alvine etal.,2013)(Fig. during thefinal30%ofembryonicincubationinsnappingturtles until thetimeofhatchingalthoughcholinergic tonuswasverified 1996). A numberofturtlesandtortoises lackcholinergic toneon coincident withtheonsetoflungbreathing(BirchardandReiber, (black Sumatrachicken) e (Spencer, 2012); Data fromSquamateembryosarelimited. (green iguana) (A) Testudine embryosincluding: s (mallardduck) j (red-earedsliderturtle) (deserttortoise) k (filled circles), (snappingturtle) (filled squares)and d (red-footedtortoise) (rainbow trout) (filled square), (domestic goose) (leghornchicken) (broiler chicken) (American alligator) The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 a,c g

C 20406080 100 0 e c

Crocodilians 2; Fig. d c i f Iguana iguana (Zhao etal.,2013); c j f c

k c H Bassiana duperreyi

2; Fig. in allstagesofembryologicaldevelopment Trachemys dorbigni a,c d g b c h Caiman yacare 6). A similarresultwasreported forthe f g i

6; Table 1). Thecholinergic receptorsseemtobe Burggren, 2009); 2014); al., 2011b); tone. Thefigureisbasedonthefollowing: bars indicatethepresenceof course ofembryonicdevelopment. reptilian andfishspeciesduringthe k h a of β Fig. 1999); (Miller etal.,2011). (Crossley etal.,2013); (Crossley andAltimiras,2012);

d (filled triangles)and Gopherus agassizi

-adrenergic toneonf .Timeline indicatingthepresence 5.

2). g e c f (Radder andShine,2006); D.A.C., unpublished; (Crossley etal.,2003b); H g d (filled squares), (open squares). d of embryosuntiltheyhad g (open square), M.R.S., unpublished; j β (Alvine etal.,2013); -Adrenergic blockade a Tupinambis (filled circles), i (Crossley and Bassiana H a (Crossley and Chelodina in avian, d β (Swart etal., -adrenergic b f (Eme et (Crossley, h f (Du et H Filled upon f H

The Journal of Experimental Biology of VPNsoutside theDVNbut30%ofCVPNs are inaventro-lateral cholinergic mechanisms.Theduck (Yamamoto etal.,2009),indicatingthat itisgeneratedby frequency ofthepowerspectrum thatislikelytoincludeRSA Atropine reducedHRV inthecormorant,particularlyhigh flight andlungventilation(Boggs, 1997)remainunresolved. addition, thecardiacchronotropiceffects oftherelationshipsbetween sacs ratherthanchangesinlungvolume(ScheidandPiiper, 1986).In affected bytheventilatorymechanics ofbirdlungsthatinvolveair generating thislattercomponentinHRV areunknown,andmaybe Cyr etal.,2009;KjaerandJørgensen, 2011). Themechanisms frequency componentrelatestoventilation(Khandokeretal., 2004; be relatedtothermoregulationandarealteredbystress,whilethe high calculated fromR–Rintervals.Lowfrequencyoscillationsappear to and highfrequencycomponentsonthepowerspectrumsignal several birds.SimilartomammalianHRV, therearelowfrequency bpm (Yamamoto etal.,2009)(Figs whereas sympatheticblockadecausedadecreasefrom178to 142 increased from178to359 determining inhibitory parasympatheticcontrolisoftenpredominantin Although birdshavedualautonomicinnervationoftheheart, respiratory rhythmicityandactiveventilation(Table tonus athatchingmaybecorrelatedwiththeonsetofcentral 1982). We suggestthattheestablishmentofacholinergic cardiac necessary toprovideeffective conductionvelocities(Fosteretal., delay inthemyelinationofefferent fibressupplyingtheheart, within theCNSorperipherallyonheart.Itmayalsorelatetoa may indicatealackofestablishmentappropriateconnections innervation fromtheCNSofmuscarinicreceptorsonheart.This cholinergic controlcanbeattributedtotheabsenceofeffective Burggren, 2009)(Fig. African brownhousesnake,Lamprophis fuliginosus REVIEW Birds Squamates Chelonian Crocodilian Sphenisciformes Charadriiformes Galliformes Ratites Anseriformes Teleosts Central controlofHRV inbirdsisrelativelypoorlystudied.

f

H . Inthegreatcormorant,

06 8 90 80 50 60

6). Thesedataimplythatthelackof

bpm followinginjectionofatropine Incubation (%) 70

Aythya fuligula 1, 2).HRV hasbeenrecordedin Phalacrocorax carbo, has lessthan5%

2). (Crossley and H Leucophaeuspipixcan(Franklinsgull) (brown house snake) Lamprophisfuliginosus(brown Iguanaiguana Chelydraserpentina(snappingturtle) Gopherusagassizi(deserttortoise) Chelonoidiscarbonaria(red-footedtortoise) Trachemys scripta(red-earedsliderturtle) Trachemys dorbigni Alligator mississippiensis Caimanyacare(Paraguayancaiman) Spheniscushumboldti(Humboldtpenguin) Dromaiusnovaehollandiae(emu) Anas carolinensis Anas platyrhyncho Brantacanadensis Anser anserdomesticus Gallusgallus Gallusgallus(redjunglefowl) Gallusgallusdomesticus Gallusgallusdomesticus Oncorhynchusmykiss Colinusvirginianus(bobwhitequail) f H abolition ofrespiration-relatedoscillationsin evoke adivingapnoea,inducedbradycardiaresultingfrom airways ofanaesthetizedandforce-ventilatedducks,inorderto described inmammals.Stimulationofwaterreceptorstheupper have evolvedasimilarfunctionalseparationofCVPNstothat distribution ofCVPNsoutsidetheDVNsuggeststhatbirdsmay and Shideman,1968),theinhibitory vagalcontrolof noradrenaline arealsopresentduring thistime(Zacks,1954;Ignarro mechanisms forproduction and degradationofACh chickens duringthefirstquarter ofincubation(Barry, 1950),and the muscarinic andadrenergic receptorsarefoundinembryonic other species(CrossleyandAltimiras,2000).Althoughcardiac of circulatingcatecholaminesinembryonicchickensandpossibly is derivedprimarilyfromhumoralcontrol,asaresultofhighlevels 30% ofdevelopmentthatwasobserved(Fig. control oftheheartthroughoutdevelopmentorforatleast final atropine abolishedspectralpoweroverthewholefrequencyrange. RSA, wasmediatedbytheparasympatheticsystem.Injection of majority ofhighfrequencyvariability, whichconstitutedanavian species (Khandokeretal.,2004).Inchickenhatchlings, Taylor etal.,2001). bird mayshowcentralgenerationofRSA (ButlerandTaylor, 1983; f sympathetic andparasympatheticsystemsexertatonicinfluence on et al.,1999).Shahal.(Shah2010)reportedthatboth breaking throughtheeggshellduringhatching)inchicks(Tazawa onset ofRSA wasassociatedwith external ‘pipping’ (theprocessof frequency oscillationidentifiedasRSA (Moriyaetal.,1999).The Taylor etal.,2001)(Table nucleus thathasbeenidentifiedastheNA (Bloggetal.,1998; but theyhavebeen subjecttolongperiodsof selectivebreeding extensive cholinergic controlhasbeenobservedinsomechickens until closetohatchinginsome species(Table substantially morearrhythmicthanembryonic H (black Sumatrachicken) Several birdspeciesstudiedexhibitanexcitatory HRV relatedtorespirationispresentfromhatching inseveral in theemuhatchling (green iguana) (green-winged teal) s (mallardduck) (Canada goose) (D’Orbigny’s sliderturtle) (rainbow trout) (leghornchicken) (domestic goose) (broiler chicken) (American alligator) The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 a,c g e c c d i c c c j c c a,c d b h c . i Spectral analysisofHRV revealedthatthe i g f i d b a of cholinergictoneon Fig. present. Figureisbasedonthefollowing: indicates thatcholinergictonewasnot cholinergic tone.Theopenportion Filled barsindicatethepresenceof course ofembryonicdevelopment. reptilian andfishspeciesduringthe unpublished; 2003b); (Alvine etal.,2013); (Swart etal.,2014); (Crossley, 1999); (Crossley andAltimiras,2012);

1; Fig.

.Timeline indicatingthepresence 6. f (Eme etal.,2011b); 3). Thisdisproportionate h (Crossley etal.,2013);

5). Thisexcitatorytone f H c D.A.C., unpublished; , suggestingthatthis j e (Miller etal.,2011). (Crossley etal.,

2; Fig. f f H H , withahigh in avian, β g f M.R.S., -adrenergic H 6). More is absent f H 699 was

The Journal of Experimental Biology progression. In somebonyfishes12%of VPNsarelocated fishes andmammalsisbridged byanintriguingphylogenetic and haverelativelyhighconduction velocities. possess sympatheticinnervationoftheheart,itsinfluenceon Although allbutthecyclostomes,elasmobranchsanddipnoi the vertebrategroups,manyofthemsummarizedinTable factors inthenatureofthiscontrolthatareheldcommonacross 700 REVIEW control off This reviewhasconsideredthefactorsdeterminingautonomic onset ofairbreathing(Table particular theonsetofRSA isoftendelayeduntilhatchingandthe heart throughoutdevelopmentbutcholinergic controlandin embryos showamaintainedrelianceonadrenergic controlofthe under artificialconditions(Fig. influence instantaneous respiration-related efferent activityinthecardiacvagiis able to activity inneighbouringrespiratory neurones.Theresultant in theDVNshowrespiration-relatedactivitythatisdriven by neighbouring respiratoryneurones,whileinelasmobranchsCVPNs located intheNA ofmammalsresultsfromtheinhibitionexertedby elasmobranchs inthattherespiration-relatedactivityCVPNs fundamental functionaldifferences betweenmammalsand fundamental totheircontrolfunctions.However, thereare neurones thatgenerateRSA.Thesetopographicalseparations are receive inhibitoryinputsfromtheventralgroupofrespiratory high proportion(80%)ofCVPNsarefoundintheNA wherethey majority (70%)ofVPNsarefoundintheDVNmammals but a CVPNs hasalsobeenfoundinthebrainstemofmammals. The located intheDVN.Thistopographicalandfunctionalseparation of CRS duetocentral,excitatoryinteractionswithRMNsthatarealso in theDVNshowrespiration-relatedactivitythatseemstogenerate of thehearttoexternalstimuli,suchashypoxia,whereasCVPNs ventro-lateral groupofcellsseemtodeterminethereflexresponses account for45%ofthetotalCVPNs,withrestinDVN.The lateral locationoutsidetheDVNbuttheyareallCVPNsand In elasmobranchfish,only8%ofVPNsareinascatteredventro- locations equivalenttothemammalianNA variesbetweengroups. the distributionofVPNsbetweenDVNandventro-lateral example, comparativeneuroanatomicalstudieshaverevealedthat of preganglionicandvisceralmotorneuronesinthebrainstem.For projections andthespecific,sometimesoverlapping,distribution appear tooriginatepartiallyasaresultoftheconvergence ofsensory have beenacentralthemeofthisreview. Thecentralinteractions of theinstantaneouschangesin from allmajorgroupsofvertebratesaroleforcholinergic control instantaneous beat-to-beatcontroloftheheart.We provideexamples parasympathetic inhibitorycontrolextendstoitsuniqueroleinthe innervation viathevagusnerve.Thispredominanceof proportionally smallerthantheinfluenceofparasympathetic routinely activeorexperimentallymanipulatedanimalsis fluctuations inthe on surfacingafteraperiodofsubmergence. Inaddition,theregular apnoea, whetherthisisattheterminationofarespiratorypauseor breathers whentakingtheirfirstairbreathfollowingaperiodof and theconsequentvariabilityof vagus infishandmammals. shown tobecontrolledbyphasicefferent activityinthecardiac shown bypowerspectralanalysistoberespirationrelatedhavebeen Conclusions This apparentfunctionallink between primitiveelasmobranch The centraloriginsofthesefluctuationsinvagaltoneontheheart, H in themajorgroupsofvertebrates.Thereareimportant f H of animalsthatbreatheregularlycanbe f H because theefferent axonsaremyelinated

2). 6). So,incommonwithreptiles,bird f H f in thedifferent vertebrategroups H that occurindiscontinuous f H

in 1. air breathing.The amphibiansshouldbethe primarytarget for development andevolutionof the controlsystemsassociatedwith interest andofimportance toourunderstandingofthe juvenile andadultanimal. optimize theeffectiveness ofrespiratorygasexchange inthe generate thecardiorespiratory interactionsthatmayserveto terrestrial speciestheonsetofairbreathing.Together, theywill respiratory systemattheonsetofanindependentexistenceand in muscarinic cholinergic and this review. Thereisevidencethatvertebrateembryoshave heart. this isanimportantfeatureenablinginstantaneouscontrolofthe ultrastructure todeterminewhethertheiraxonsaremyelinatedas species fromthesevariousgroupsandalsoexaminetheir measure conductionvelocitiesinthecranialnervesofarange of specificamphibians,reptilesandbirds.Inaddition,weneedto be assignedtotheCVPNsfoundinduallocationsbrainstems CVPNs inourrangeofreptilesandseparatefunctionshaveyetto resembling RSA.We haveyettodeterminethedistributionof CVPNs andthereisabundantevidencethatbirdsshowCRI duck. Interestingly, though,alarge proportionoftheseVPNsare dinosaurs, thebirds,withonly3%ofVPNsfoundinNA ofthe distribution ofVPNscharacterizesthosenear-ancestors ofthe physiological basisofthisrelationshipismerited.Thisalternative scattered locationsoutsidetheDVN,andfurtherworkon mammalian RSA,despitehavingnegligiblenumbersofVPNsin VPNs inthislocation.RattlesnakesshowCRIthatresemble 20%, whilesquamates(snakesandlizards)haveonlyaround5%of with turtleshavingupto40%ofVPNsintheNA andcrocodilians neat progressionisconfusedinthemarkedlypolyphyleticreptiles, in mammals,butthisincludesupto80%ofCVPNs.However, this responses. TheproportionofVPNsintheNA stabilizesat30–40% the onsetofepisodiclungbreathingandcentralchemoreceptor DVN hasbeenshowntooccuratmetamorphosis,concurrentwith as high300%.Theventro-lateralrelocationofVPNsoutsidethe 30% indifferent classesofamphibians.Cardiacvagaltonecanbe the proportionofVPNsoutsideDVNrisesto15,20andeven negligible vagaltoneontheheart.However, thisistheexceptionas investigation. ThebullfroghasallofitsVPNsintheDVNand the motorcentressupplyingthesecranialnervesmeritsfurther centrally. Thepossibilitythat therearecentralinteractionsbetween with activityintheVthcranialnerveandthatbothmaybedriven respiration-related activityinthecardiacvagioffishissynchronous hypoxia. However, therearesomeintriguingdatasuggestingthat generate CRSsothatitcharacteristicallyonlyoccursduring peripheral inputsfromgillchemoreceptorsandmechanoreceptorsto the DVN.Presentevidencesuggeststhatbonyfishesrelyon ventrolaterally outsidetheDVNbutonly2%ofCVPNsare being establishedbetween If thishypothesisprovescorrectthenittiesintotherelationship onset ofrespiratoryrhythmicityorphysicalmovements. after hatchingorbirth,wehypothesizethatthismayrelateto the cholinergic toneisoftennot detectable untilclosetoorimmediately tone canfirstbedetectedbypharmacologicalblockade(Table development andinmanyspeciesitisatthisstagethatcholinergic cardiac receptorsareinnervatedbytheANSlaterinembryonic circulating catecholaminesratherthansympatheticinnervation. The earlier than50%)butthisseemsdependentonhighlevels of β very earlystageofdevelopment(10%iniguana).Theyalsoshow -adrenergic toneontheheartatarelativelyearlystage(often Further studyofthisareaseems likelytobeofverygreat The ontogenyofautonomiccontroltheheartisalsofeaturedin The JournalofExperimentalBiology(2014)doi:10.1242/jeb.086199 β -adrenergic receptorsontheheartata f H variability andactivityinthe

2). As

The Journal of Experimental Biology Science Foundation[IOS-0845741toD.A.C.]. 2012/06938-8 toA.S.A./E.W.T., 2012/16537-0toA.S.A./M.R.S.];andNational de SãoPaulo[INCT 2008/57712-4,2010/51995-4,2008/00107-1 toC.A.C.L., Tecnológico [INCT 573921/2008-3];FundaçãodeAmparoàPesquisa doEstado This workwassupportedbyConselhoNacionaldeDesenvolvimentoCientífico e T.W. manuscript wasconductedbyE.W.T. withmajorcontributionsfromC.A.C.L.and with helpinthepreparationoffiguresfromM.R.S.Comprehensiverevision the C.A.C.L. andD.A.C.TheoriginalmanuscriptwaspreparedbyE.W.T. andD.A.C. student inthelaboratoryofA.S.A.andhasworkedcollaborationwithE.W.T., unpublished workcitedinthereviewarisesfromofM.R.S.whoisa of ourpresentunderstandingthebackgroundtostudies.Much conducted inthelaboratoriesofeachauthorsthatisdiscussedcontext this review. Itisfocusedon anoverviewofdataarisingfromexperiments All authorsmadesignificantandsubstantialcontributionstothesubjectmatter of The authorsdeclarenocompetingfinancialinterests. pre-eminent amongstthem. origins backtoGrahamShelton,myteacherandonetimementor. Chrisremains generation ofCanadianbiologistswasaspecialbreed;manytracingtheirscientific have crossedinbarsandworkplacesoneithersideoftheAtlanticOcean.His physiology. Oneofus(E.W.T.) rememberswithaffection themany timesourpaths appreciation ofhishugecontributiontocomparativeandappliedanimal marking thecareerofChrisWood. Theauthorsareunanimousintheir original submissionandhissoundadvice.Thismanuscriptispartofacollection editor ofthiscollectionpapers(StevePerry)forhisconstructivetreatmentour anonymous refereesandthehelpfulsuggestionsofathird.We aregratefultothe The compositionofthismanuscriptbenefittedfromthecriticalevaluationtwo variety oftemporalrelationshipsbetween transition toairbreathingatmetamorphosis,hatchingorbirth.The the controlsystemsandinparticulartheirresponsesduring and larvaeofchosenspeciesinordertodeterminetheontogeny CNS. Thesefundamentalstudieswillbeextendedtotheembryos their conductionvelocitiesandtheoriginsofanyactivityin with neurophysiologicalstudyoftheactivityincardiacnerves, CVPNs andthenumbercompositionoftheirefferent axons, work, andinparticularthestudyofcentraldistribution on thesegroups.Futurestudieswillcombineneuroanatomical embryos andthisreviewhasdescribedsomeofourpresentwork similarly provideexcellentopportunitiesforworkontheir appropriate regionsoftheCNS.Theoviparousreptilesandbirds this processisaccompaniedbytopographicalchangesin breathers tofacultativelungbreathers,andwealreadyknowthat these studiesbecausetheymetamorphosefromcommittedgill REVIEW ontogeny, atleastinpart,recapitulatestheirvertebratephylogeny. insights intothisexcitingareaofstudyasamphibianandreptilian approach alongtheselinesshoulduncovernewandfascinating activity suchasswimming,runningordiving.A combined cardiorespiratory variablesandtheirresponsestospontaneous animals willultimatelyexplorediurnalchangesin environmental hypoxiaorapnoea.Fieldstudiesonunrestrained feeding ortemperaturechangerestrictionofoxygensupplyby of animalstoincreasedmetabolicrateengenderedbyexercise, studies willincludelaboratory-basedcardiorespiratoryresponses cardiovascular controlwillneedtobemeasured.Functional and chemoreceptorsresponsibleforreflexrespiratory the responsestoafferent inputsfromperipheralmechanoreceptors gioa . adl,D .adTyo,E.W. 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