Proprioceptors in extraocular muscles

Recei ed: 22 No embe 2022 Accep ed: 7 Feb ua y 2023 DOI: 10.1113/EP090765 REVIEW ARTICLE P op iocep o s in ex aocula muscles Roland Blume 1Géno a Ca e o-Rojas1Paula M. Cal o2Johannes S eiche 3 Rosa R. de la C uz2Angel M. Pas o 2 1Cen e o Ana omy and Cell Biology, Di ision o Ana omy, Medical Image Clus e , Medical Uni e si y Vienna, Vienna, Aus ia 2Depa amen o de Fisiología, Facul ad de Biología, Uni e sidad de Se illa, Se illa, Spain 3Depa men o Ana omy and Biomechanics, Di ision o Ana omy and De elopmen al Biology, Ka l Lands eine Uni e si y o Heal h Science, K ems an de Donau, Aus ia Co espondence Roland Blume , Cen e o Ana omy and Cell Biology, Medical Uni e si y Vienna, Waeh inge S asse 13, 1090 Vienna, Aus ia. Email: [email p o ec ed] Funding in o ma ion Aus ian Science Fund (FWF), G an /Awa d Numbe s: P15478, P20881, P32463-B; Ma e ials we e also suppo ed by p ojec s, G an /Awa d Numbe s: PGC2018-094654-B-100, PID2021-124300NB-I00; MCIN/AEI FEDER ‘A way o making Eu ope’ and by p ojec P20_00529 Conseje ía de T ans o mación Económica, Indus ia y Conocimien o, Jun a de Andalucía-FEDER. P.M.C. is a ‘Ma ga i a Salas’ ellow o he Uni e sidad de Se illaMa e ials we e also suppo ed by p ojec s This e iew was p esen ed a he ‘Mechano ansduc ion, Muscle Spindles and P op iocep ion’, which ook place a Ludwig-Maximilians Uni e si a , Munich, 25–28 July 2022. Handling Edi o : Ronan Be g Abs ac P op iocep ion is he sense ha le s us pe cei e he loca ion, mo emen and ac ion o he body pa s. The p op iocep i e appa a us includes specialized sense o gans (p op iocep o s) which a e embedded in he skele al muscles. The eyeballs a e mo ed by six pai s o eye muscles and binocula ision depends on ine- uned coo dina ion o he op ical axes o bo h eyes. Al hough expe imen al s udies indica e ha he b ain has access o eye posi ion in o ma ion, bo h classical p op iocep o s (muscle spindles and Golgi endon o gan) a e absen in he ex aocula muscles o mos mammalian species. This pa adox o moni o ing ex aocula muscle ac i i y in he absence o ypical p op iocep o s seemed o be esol ed when a pa icula ne e specializa ion ( he palisade ending) was de ec ed in he ex aocula muscles o mammals. In ac , o decades he e was consensus ha palisade endings we e senso y s uc u es ha p o ide eye posi ion in o ma ion. The senso y unc ion was called in o ques ion when ecen s udies e ealed he molecula pheno ype and he o igin o palisade endings. Today we a e aced wi h he ac ha palisade endings exhibi senso y as well as mo o ea u es. This e iew aims o e alua e he li e a u e on ex aocula muscle p op io- cep o s and palisade endings and o econside cu en knowledge o hei s uc u e and unc ion. KEYWORDS eye muscle, Golgi endon o gans, muscle spindles, palisade endings, p op iocep ion 1INTRODUCTION The e m p op iocep ion was in oduced by She ing on (1907), and i is bes desc ibed as a posi ion sense ha le s us be awa e o he loca ion and mo emen o body pa s. P op iocep i e This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. © 2023 The Au ho s. Expe imen al Physiology published by John Wiley & Sons L d on behal o The Physiological Socie y. sensa ions a ise in skele al muscles, skin and join s and hey a e he ounda ion o coo dina ed mo emen s (Bewick & Banks, 2015; Smi h e al., 2020). The alue o p op iocep ion is e iden in animal models wi h p op iocep i e de ici s (Chen e al., 2007)and in subjec s who ha e los hei p op iocep ion sense (Gallaghe Expe imen al Physiology. 2023;1–9. wileyonlinelib a y.com/jou nal/eph 1 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 2BLUMER ET AL. &Cole,1995; Go don e al., 1995). Wi hou p op iocep ion, mo emen s a e uncoo dina ed, and asks like s anding, eaching ou o a cup o co ee o walking a e impossible (Gallaghe & Cole, 1995). Specialized muscle ecep o s, he p op iocep o s, play a key ole in p op iocep ion (Bewick and Banks (2015). Two ypes o p op io- cep o s can be dis inguished in mammalian skele al muscles: muscle spindles and Golgi endon o gans (Figu e 1). Muscle spindles lie deeply embedded in he muscle and a e spindle-shaped, encapsula ed o gans. They con ain a bundle o muscle ib es (in a usal muscle ib es) which a e endowed wi h senso y ne e e minals in he muscle spindle’s mid- egion (equa o ial egion). The senso y ne e e minals a e s e ch-sensi i e and egis e changes in muscle leng h. Fine- uning o he muscle spindle’s sensi i i y is achie ed by mo o inne a ion (γ-mo oneu ons) a he spindle’s pole. Unlike muscle spindles, Golgi endon o gans lie a he muscle– endon in e ace. They ha e a capsule o pe ineu al cells and a e illed wi h collagen bundles and ne e e minals. Because Golgi endon o gans lie in se ies wi h he muscle ib es, hey egis e muscle con ac ion (Jami, 1992). The con inuous in o ma ion om he muscle spindles and Golgi endon o gans abou he changes in muscle leng h and ension enables he b ain o calcula e he body and limb posi ion (G ego y e al., 1987;Jami,1992;P oske, 2015). The eyeballs a e he mos mobile o gans o he body and a e mo ed by six pai s o ex aocula muscles (EOMs). Because ision is use ul only oge he wi h he awa eness o he di ec ion o iewing, i was pos ula ed (She ing on, 1918) ha , like he skele al muscles, he EOMs should be endowed wi h classical p op io- cep o s o posi ional in o ma ion. Su p isingly, he opposi e is he case and, wi h ew excep ions, he classical p op iocep o pai is absen in mos mammalian species (Maie e al., 1974). Despi e he lack o p op iocep o s, beha iou al and expe imen al s udies ha e p o ided e idence ha p op iocep i e signals om he EOMs each he b ain (Balsle & Miall, 2008; Balsle e al., 2022; Donaldson, 2000; Gau hie e al., 1990; S einbach & Smi h, 1981; Wang e al., 2007). This sugges s ha he b ain uses senso y eedback om EOMs o calcula e eye posi ion. The pa adox o moni o ing EOM ac i i y in he absence o ypical p op iocep o s seemed o be esol ed when a pa icula ne e specializa ion e med palisade ending was de ec ed in EOMs o mammals (Dogiel, 1906; Hube , 1900). In ac , o decades he e was consensus ha palisade end- ings subs i u e o muscle spindles and Golgi endon o gans and ha hey p o ide eye posi ion in o ma ion (Al a ado-Malla & Pincon- Raymond, 1979; Billig e al., 1997; Dogiel, 1906; Wang e al., 2007). Howe e , ecen s udies ha e called in o ques ion he senso y ole o palisade endings (Konakci, S eiche , Hoe zenecke , Blume , e al., 2005; Lienbache e al., 2011; Zimme mann e al., 2013). This e iew aims o ecapi ula e li e a u e including da a om ou esea ch g oup on EOM p op iocep o s and palisade endings and o conside cu en knowledge abou hei s uc u e, molecula cha ac e is ics and unc ion. New Findings ∙Wha is he opic o his e iew? This e iew aims o e alua e he li e a u e on p op iocep o s and pa icula ne e specializa ions (palisade endings) in mammalian ex aocula muscles (EOMs) and o econside cu en knowledge o hei s uc u e and unc ion. ∙Wha ad ances does i highligh ? Classical p op iocep o s (muscle spindles and Golgi endon o gans) a e absen in he EOMs o mos mammals. Ins ead, palisade endings a e p esen in mos mammalian EOMs. Fo many yea s, palisade endings we e conside ed o be senso y bu ecen s udies show ha hey combine senso y and mo o ea u es. The unc ional signi icance o palisade endings is s ill deba ed. 2MUSCLE SPINDLES IN EXTRAOCULAR MUSCLES Muscle spindles a e a ely ound in mammalian EOMs. Excep o e en- oed ungula es (pig, sheep, cal and camel) and p ima es (human and monkey), muscle spindles a e absen in he EOMs o mammals (Abuel A a e al., 1997; Blume e al., 2001;Ha ke ,1972; Maie e al., 1974; Rungaldie , Heiligenb unne e al., 2009; Ruskell, 1990). In pigs, he numbe o EOM muscle spindles is e y high and a ies be ween 148 and 310 muscle spindles pe muscle (in e io oblique muscle: 148; supe io oblique muscle: 310) (Blume e al., 2001; Maie e al., 1974). The ex emely high numbe o muscle spindles in he EOMs o ungula es is no equalled in he EOMs o p ima es. Speci ically, be ween 18 and 34 muscle spindles (18 muscle spindles in he medial ec us and 34 muscle spindles in he in e io ec us muscle) we e coun ed in human EOMs (Lukas e al., 1994), whe eas in monkeys only six muscle spindles we e coun ed in he ec us muscles bu none in he oblique muscles (G eene & Jampel, 1966). The occu ence o muscle spindles in he EOMs ac oss mammals is shown in Figu e 2a. De ailed s uc u al analyses o EOM spindles we e pe o med in sheep (Ha ke , 1972; Rungaldie , Heiligenb unne e al., 2009), pigs (Kubo a, 1988), cal es (Blume e al., 2003) and men (Blume e al., 1999; Lukas e al., 1994; Ruskell, 1989). Only he EOM muscle spindles o e en- oed ungula es (sheep, cal and pig) mo phologically con o med o skele al muscle spindles (Blume e al., 2003;Ha ke , 1972; Kubo a, 1988; Rungaldie , Heiligenb unne e al., 2009). In de ail, EOM muscle spindles o ungula es ha e a usi o m shape and a capsule o pe ineu al cells. Inside he spindle, wo ypes o in a usal muscle ib es wi h di e en nuclea a angemen s in he equa o ial egion can be dis inguished: nuclea chain ib es, which ha e a ow 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License BLUMER ET AL.3 FIGURE 1 Classical p op iocep o o gans in skele al muscles o mammals. (a) Schema ic d awing o a muscle spindle. The muscle spindle con ains nuclea bag and nuclea chain in a usal ib es. Bo h o hem a e inne a ed by Ia a e en axons (blue) ha o m annulospi al endings in he equa o ial egion. Some in a usal muscle ib es a e also inne a ed by II a e en axons (pu ple). Addi ionally, e e en γ-mo oneu ons (yellow) es ablish mo o con ac s on he in a usal muscle ib es in he muscle spindle’s pola egions. Ou side he muscle spindle, an α-mo oneu on (g een) es ablishes synap ic con ac s wi h he ex a usal muscle ib es. (b) Schema ic d awing o a Golgi endon o gan. This o gan is loca ed a he muscle– endon junc ion and is illed wi h collagen bundles. A single la ge Ib a e en axon ( ed) en e s he Golgi endon o gan and a e spli ing in o se e al b anches, ne e e minals es ablish con ac wi h he collagen ib es o he Golgi endon o gan. o cen ally a anged nuclei, and nuclea bag ib es, which show a clus e o nuclei. Bo h in a usal ib es ecei e senso y inne a ion in he equa o ial egion whe e axons spi al a ound he in a usal ib es. Whe he seconda y senso y endings, which a e common in skele al muscle spindles and lank he p ima y senso y endings, a e also p e- sen in EOM muscle spindles is unclea . Besides his senso y pa , EOM muscle spindles in ungula es also ha e a mo o inne a ion. Speci ically, hin mo o axons es ablish mo o e minals on in a usal muscle ib es in he pola egion and ou side he muscle spindle (Rungaldie , Heiligenb unne e al., 2009). Figu e 2b shows annulospi al ne e e minals in he equa o ial egion o a muscle spindle om pig EOM. Se e al s uc u al pa icula i ies we e unco e ed in he human EOM spindles (Blume e al., 2006; B uenech & Ruskell, 2001). Speci ically, he muscle spindles a e small in diame e and mos o hem lack equa o ial expansion. Addi ionally, nuclea bag ib es a e absen in human EOM spindles, and besides nuclea chain ib es, so-called anomalous ib es which esembled ex a usal muscle ib es a e egula ly p esen . Some in a usal ib es appea ac u ed and e mina ed close o he poles bu also a he le el o he equa o ial egion (Blume e al., 1999; Ruskell, 1989; B uenech & Ruskell, 2001). All nuclea chain ib es ecei e annulospi al senso y ne e e minals in he equa o ial egion, bu many anomalous ib es lack senso y inne a ion (Blume e al., 1999; Ruskell, 1989). Mo o inne a ion was obse ed in he pola egion o human EOM muscle spindles (Blume e al., 1999). The s uc u al pa icula i ies in human EOM spindles we e no only obse ed in aged pe sons (Lukas e al., 1994; Ruskell, 1989), bu we e also p esen in in an s (Blume e al., 1999; B uenech & Ruskell, 2001). Thus, he a ypical ea u es in human EOM muscle spindles a e no a ibu able o age- ela ed al e a ions bu migh ep esen a unc ional specializa ion. In mice skele al muscle spindles, molecula analyses ha e demons a ed ha he annulospi al senso y ne e e minals exhibi cha ac e is ics o choline gic synapses (Zhang e al., 2014, 2015). Speci ically, he annulospi al ne e e minals exp ess choline ace yl- ans e ase (ChAT), he syn hesizing enzyme o ace ylcholine, and a e associa ed wi h ace ylcholine ecep o s (Zhang e al., 2014, 2015). So a molecula analyses on EOM muscle spindles ha e only been pe o med in sheep (Rungaldie , Heiligenb unne e al., 2009). Di e en om he skele al muscle spindles, he annulospi al ne e e minals o EOM muscle spindles do no exp ess ChAT and do no ha e ace ylcholine ecep o s (Rungaldie , Heiligenb unne e al., 2009). These indings sugges ha skele al muscle spindles and EOM spindles exhibi di e ences a he molecula le el. The unc ion o EOM spindles was es ed in sheep (Manni e al., 1966). Following s e ching o he EOMs, signals which we e ypical o muscle spindle a e en s we e eco ded in he ipsila e al igeminal 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 4BLUMER ET AL. FIGURE 2 Classical p op iocep o s and palisade endings in he EOMs o mammals. (a) Hea map showing he p esence o absence o classical p op iocep o s and palisade endings in eye muscles in di e en mammals. Golgi endon o gans a e p esen in e en- oed ungula es. In monkeys (as e isk), hey a e p esen in some, bu no all, EOMs. The es o he species lack Golgi endon o gans. Muscle spindles a e only ound in humans, monkeys and e en- oed ungula es. Palisade endings a e p esen in all species, excep mice and guinea pigs. In abbi s and a s, he palisade endings di e om he canonical palisade endings o highe mammals. (b, c) Visualiza ion o classical p op iocep o s in pig EOMs by immuno luo escence. Ne e ib es ( ed) a e labelled wi h an an ibody agains neu o ilamen (NF), and ne e e minal (g een) wi h an an ibody agains synap ophysin (SYP). Muscle ib es (blue) a e coun e s ained wi h phalloidin (Phall). (b) The equa o ial egion o a muscle spindle. The axons ( ed) spi al a ound he in a usal muscle ib es (blue) and es ablish synap ophysin-posi i e con ac s (g een) on he in a usal muscle ib es. (c) A Golgi endon o gana he muscle– endon junc ion. The endon is no labelled and con inues o he igh o he muscle ib es (blue). The Golgi endon o gan is inne a ed by a single axon ( ed) which di ides in o se e al b anches inside he Golgi endon o gan. Axonal b anches es ablish synap ophysin-posi i e ne e e minals (g een). MF, muscle ib e; MTJ, muscle– endon junc ion; T, endon. (d–g) Palisade endings in ca EOMs a e shown ollowing (Con inues) 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License BLUMER ET AL.5 FIGURE 2 (Con inued) immuno luo escence s aining using he same s aining combina ion as o he muscle spindle and he Golgi endon o gan and in schema ic d awing (e). In he luo escence s aining (d, , g) he endon is no isible and con inues o he igh o he muscle ib es (blue). (d) Low magni ica ion image showing palisade endings a he muscle– endon junc ion. Palisade endings a e o med by ne e ib es ( ed) which come om he muscle and ex end in o he endon. The e, hey u n back o app oach he muscle– endon junc ion. By u he spli ing, axons es ablish synap ophysin-posi i e e minal a icosi ies (g een) a ound single muscle ib e ips. (e) Schema ic d awing o a palisade ending. Te minal a icosi ies (g een) o he palisade ending a e ound a he le el o he endon (T) and he muscle ib e (MF) ip. ( ) The palisade ending om he inse in (d) is shown a high magni ica ion. (g) The ne e ib e ( ed) ha o ms a palisade ending es ablishes mul iple synap ophysin-posi i e en g appe mo o e minals (g een) along he muscle ib e (blue). ( , g) F om he publica ion ‘Palisade endings ha e an exocy o ic machine y bu lack ace ylcholine ecep o s and dis inc ace ylcholine es e ase ac i i y’ (Blume e al., 2020). ganglion (Manni e al., 1966). This inding indica es ha he ungula e EOM spindles a e s e ch-sensi i e and egis e changes in muscle leng h. Suppo o he idea ha human EOM spindles espond o s e ch came om a ecen s udy ha used unc ional magne ic esonance imaging o isualize neu onal ac i i y (Balsle e al., 2022). I was shown ha he s e ch o he igh la e al ec us was associa ed wi h he inc eased neu onal ac i i y o he le oculomo o and le abducens nuclei. The au ho s (Balsle e al., 2022)ha especula ed ha ollowing muscle s e ch, a e en s om EOM spindles a e ansmi ed o he EOM mo o nuclei a he con ala e al side whe e hey e oke ac i i y o he EOM mo oneu ons. The pa hway by which a e en s om human EOM spindles each he b ains em a he con ala e al side is unknown. 3GOLGI TENDON ORGANS IN EXTRAOCULAR MUSCLES Like muscle spindles, Golgi endon o gans a e excep ional in mammalian EOMs. They a e only p esen in e en- oed ungula es (sheep (Rungaldie , Heiligenb unne e al., 2009; Ruskell, 1990), pigs (Blume e al., 2001), cal es (Blume e al., 2003) and camels (Abuel A a e al., 1997)) and in p ima es (monkeys) (Ruskell, 1979). Whe eas Golgi endon o gans a e nume ous in e en- oed ungula es (be ween 104 and 125 Golgi endon o gans we e coun ed in pig EOMs) (Blume e al., 2001), hey a e in equen in monkeys. Tha is, some monkey EOMs con ain one o wo Golgi endon o gans and o he muscles none (Ruskell, 1979). In he es o he mammalian species including humans, Golgi endon o gans a e absen . As signi ican numbe s o Golgi endon o gans a e exclusi ely ound in he EOMs o e en- oed ungula es, i seems ha hey a e only ele an o his animal g oup. The occu ence o Golgi endon o gans in EOMs ac oss mammals is shown in Figu e 2a. Golgi endon o gans in he EOMs o e en- oed ungula es ha e a usi o m shape and a capsule o pe ineu al cells. Typically, a single myelina ed ne e ib e en e s he Golgi endon o gan and a e di iding in o se e al b anches, ne e e minals es ablish in ima e con ac wi h he collagen bundles o he Golgi endon o gans (Figu e 2c shows a Golgi endon o gan om pig EOM). EOM Golgi endon o gans exhibi some ea u es ha a e no ound in Golgi endon o gans o skele al muscles (Blume e al., 2001; Ruskell, 1989). Speci ically, EOM Golgi endon o gans ha e a la ge luid- illed space be ween he collagen and he capsule, and only one o h ee muscle ib es a e a ached ou side o he Golgi endon o gan. Addi ionally, in some cases, up o h ee muscle ib es en e he Golgi endon o gan, and a e en ance, he muscle ib es ei he e mina e in collagen bundles o he Golgi endon o gan o pass h ough he o gan (Blume e al., 2001). So a , physiological s udies on EOM Golgi endon o gans a e missing. Conside a ions abou hei possible unc ion a e based on ana omical s udies. As an analogue o he classical Golgi endon o gan in skele al muscles, EOM Golgi endon o gans lie in se ies wi h he muscle ib es, and i is he e o e mos likely ha hey egis e muscle ib e con ac ion. Because only a e y ew muscle ib es a e a ached o he EOM Golgi endons o gans, hey would egis e he con a- c ions o e y ew muscle ib es. Such indi idual moni o ing o muscle ac i i y indica es ha he b ain ecei es eedback abou e y delica e eye mo emen s. The e ec o muscle ib es passing h ough he Golgi endon o gans is unclea a he momen . 4PALISADE ENDINGS IN EXTRAOCULAR MUSCLES A he beginning o he 20 h cen u y, Hube (1900), Dogiel (1906) and Toze and She ing on (1910) we e he i s o desc ibe a pa icula ne e specializa ion in he EOMs o abbi s, ca s and monkeys. This s uc u e was e med he palisade ending, la e also known as he inne a ed myo endinous cylinde . Mo e ecen s udies in single species (Al a ado-Malla & Pincon-Raymond, 1979; Ebe ho n e al., 2005; Lukas e al., 2000; Richmond e al., 1984; Ruskell, 1978; Rungaldie , Pomikal e al., 2009) and ou sys ema ic s udy o 13 mammalian species ac oss six di e en o de s ( oden s, lagomo phs, ca ni o es, pe issodac yls, a iodac yls and p ima es) (Blume e al., 2016) con i med ha palisade endings a e p esen in mos mammals. Speci ically, among on al-eyed mammals, palisade endings a e egula ly p esen in humans (Lukas e al., 2000; Richmond e al., 1984), monkeys (Ruskell, 1978; Toze & She ing on, 1910), ca s (Al a ado-Malla & Pincon-Raymond, 1979), e e s (Blume e al., 2016) and dogs (Rungaldie , Pomikal e al., 2009). Among la e al-eyed mammals, hey a e p esen in e en- oed ungula es (pigs and sheep), odd- oed ungula es (ho ses), lagomo phs ( abbi s) and a s (Ebe ho n e al., 2005), and a e absen only in mice and guinea pigs (Blume e al., 2016). Coun s e ealed ha he numbe o palisade endings is highe in on al-eyed species han in hose la e al-eyed species equipped wi h palisade endings (Blume e al., 2016). The wide dis ibu ion o palisade endings ac oss mammals sugges s ha hey migh subs i u e classical 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 6BLUMER ET AL. p op iocep o s al hough hey migh be mo e ele an o he on al- eyed han he la e al-eyed species. The occu ence o palisade endings in EOMs ac oss mammals is shown in Figu e 2a. Palisade endings a e p esen in all ec us EOMs al hough, in on al- eyed species, many mo e palisade endings a e ound in he medial ec us han in he o he ec us muscles (Blume e al., 2016, 2017; Lienbache e al., 2018). In ca s, monkeys, and humans, palisade endings we e also ound in he oblique EOMs (Al a ado-Malla & Pincon-Raymond, 1979; Lukas e al., 2000; Lienbache e al., 2011). As demons a ed in a on al-eyed species (ca ), palisade endings a e imma u e a bi h and de elop du ing he i s 3 mon hs o li e in a muscle-speci ic sequence (Blume e al., 2017). The p ope de elopmen o palisade endings elies on eye mo emen s in he ea ly pos na al pe iod as he block o eye mo emen s by bo ulinum neu o- oxin subs an ially delays he palisade ending ma u a ion (Ca e o- Rojase al.,2022). Palisade endings a e exube an axonal e mina ions a he muscle– endon junc ion o he global laye (inne laye ) o he EOMs (Figu e 2d, and gshow palisade endings in ca EOMs). So a , no palisade endings ha e been ound in he o bi al laye (ou e laye ) o he EOMs which aces he bony wall o he o bi . Palisade endings a e o med by myelina ed ne e ib es ha come om he muscle and ex end in o he endon. The e, he axons make a u-shaped u n o app oach he muscle– endon junc ion. By u he b anching, axons es ablish e minal a icosi ies a he le el o he endon and a ound single muscle ib e ips (Figu e 2e and ). In e es ingly, palisade end- ings in abbi s and a s di e om he palisade endings in highe mammals. Speci ically, palisade endings in abbi s and a s lack e minal a icosi ies a he endon le el and only e minal a icosi ies a ound he muscle ib e ips a e ound (Blume e al., 2016; Ebe ho n e al., 2005). The muscle ib es associa ed wi h palisade endings possess se e al en g appe e minals along hei leng h. They a e consequen ly classi ied as mul iply inne a ed muscle ib es (MIFs) (Al a ado-Malla & Pincon-Raymond, 1979; Ruskell, 1978). This is opposed o he singly inne a ed muscle ib es (SIFs) in EOMs which co espond o he classical skele al muscle ib es and ecei e a single and la ge mo o endpla e. SIFs and MIFs a e ound in bo h he global and he o bi al laye o he EOMs (May e al., 1975). The MIFs exhibi a non- wi ch o m o con ac ion and he cell bodies o MIF mo oneu ons a e loca ed a he bo de o he EOM nuclei al hough he speci ic pa e n o a angemen is di e en ac oss species (Bohlen e al., 2016; Bu ne Enne e e al., 2001; Ca e o-Rojas e al., 2021; He nandez e al., 2019). Al hough he senso y inne a ion o EOMs is a con en ious issue, he e has been a consensus o decades ha palisade endings a e senso y s uc u es and ha e p op iocep i e unc ion. The eason is ha palisade endings lie in se ies wi h muscle ib es and i has been assumed ha hey a e in an ideal posi ion o egis e muscle ib e con ac ion (Al a ado-Malla & Pincon-Raymond, 1979). Suppo o he idea ha palisade endings a e p op iocep o s came om ine s uc u al analyses which we e ca ied ou almos simul aneously in monkeys (Ruskell, 1978) and ca s (Al a ado-Malla & Pincon-Raymond, 1979). In bo h animal species, he e minal a icosi ies o palisade endings es ablish con ac wi h he collagen ib ils o he endon. Such neu o- endinous con ac s esemble senso y ne e e minals o Golgi endon o gans. As opposed o he common neu o endinous con ac s, ew e minal a icosi ies o palisade endings es ablish con ac wi h he muscle ib es. These neu omuscula con ac s lack a basal lamina in he synap ic cle , a ea u e ypical o senso y ne e e minals in muscle spindles. Al oge he , mo phological s udies e ealed ha he palisade endings exhibi s uc u al cha ac e is ics in common wi h he classical p op iocep o s. Findings in a single neu onal acing expe imen ein o ced he senso y na u e o palisade endings (Billig e al., 1997). Following he injec ion o neu onal ace in o he igeminal ganglion, h ee kinds o ace -labelled ne e e mina ions we e ound in he EOMs, one ype esembling he palisade ending (Billig e al., 1997). Because he igeminal ganglion is a senso y ganglion, his inding p o ided di ec e idence ha palisade endings a e senso y s uc u es. Indi ec indica ions ha palisade endings a e senso y came om o he s udies (S einbach & Smi h, 1981; S einbach e al., 1987; Wang e al., 2007). Speci ically, a single physiological expe imen in monkeys demons a ed ha he neu onal ac i i y in a ea 3 o he soma osenso y co ex inc eased when he animal mo ed i s eyes (Wang e al., 2007). This inding p o ed ha he EOMs a e endowed wi h senso y o gans o egis e muscle con ac ion and o send his in o ma ion o he b ain. In monkey EOMs, muscle spindles and Golgi endon o gans a e a e o absen whe eas palisade endings occu in e y high numbe s (Ruskell, 1978). Consequen ly, he palisade ending is he only possible candida e o ansmi eye posi ion in o ma ion o he b ain’s soma osenso y co ex whe eby he exac ou e o his in o ma ion is unclea , ye . Clinical s udies in squin pa ien s (S einbach & Smi h, 1981; S einbach e al., 1987) showed ha pa ien s unde going ma ginal myo omy o co ec ion o he eye posi ion exhibi ed de ici s in spa ial pe cep ion. Because palisade endings we e pa ly o comple ely emo ed by he ma ginal myo omy, i was assumed ha he spa ial pe cep ion de ici s we e a esul o missing senso y eedback om palisade endings a e su ge y (S einbach & Smi h, 1981; S einbach e al., 1987). In his con ex , i is impo an o no e ha he spa ial pe cep ion de ici s in pa ien s we e obse ed a sho ime a e he ope a ion (be ween 7 and 48 h), and i would be o in e es o know i he de ici s disappea o a e p esen o e a longe pe iod o ime. In 2005, he molecula pheno ype o he palisade endings was unco e ed by ou esea ch g oup (Konakci, S eiche , Hoe zenecke , Blume , e al., 2005; Konakci, S eiche , Hoe zenecke , Habe l, e al., 2005). Because he e minal a icosi ies o palisade endings a e ull o clea esicles which a e ypical o choline gic mo o e minals, we hypo hesized ha palisade endings a e po en ially choline gic o gans. We es ed di e en choline gic ma ke s in palisade endings including an ibodies agains ChAT, esicula ace ylcholine ans- po e (VAChT) and choline anspo e (ChT). We obse ed ha , like mo o e minals, palisade endings in ca s and monkeys we e immuno eac i e o ChAT (Konakci, S eiche , Hoe zenecke , Blume e al., 2005; Konakci, S eiche , Hoe zenecke , Habe l, e al., 2005). Addi ional expe imen s in monkeys e ealed ha palisade endings also exp essed VAChT and ChT. Un o una ely, he an ibody agains 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License BLUMER ET AL.7 VAChT and ChT did no wo k in ca s. La e , he choline gic pheno ype o palisade endings was con i med in o he mammals including humans (Rungaldie , Heiligenb unne , e al., 2009; Rungaldie , Pomikal, e al., 2009; Lienbache e al., 2018a,2019). The no el insigh in o he molecula iden i y o palisade endings eopened he deba e abou he unc ional signi icance o his EOM-speci ic s uc u e. Tha palisade endings exhibi a choline gic pheno ype was no easily compa ible wi h he p e ious no ion ha hey o igina e in he senso y igeminal ganglion (Billig e al., 1997). Doub s ha he sou ce o he palisade endings lies in he igeminal ganglion came om wo olde s udies (Sas & Scháb, 1952; Toze & She ing on, 1910). Speci ically, ollowing a lesion o he oculomo o nucleus o se e ance o he c anial mo o ne es (oculomo o , ochlea and abducens ne e) inne a ing he EOMs, degene a ion o he palisade endings was obse ed. These indings sugges ed ha palisade endings o igina e in he EOM mo o nuclei and no in he igeminal ganglion. Because o hese disc epancies ega ding he sou ce o he palisade endings, he cen al connec ions o he palisade endings we e ein es iga ed. These in es iga ions we e independen ly ca ied ou by he esea ch g oup o P o . Ho n and ou esea ch g oup. Following he injec ion o neu onal ace in o he EOM mo o nuclei, ace -labeled palisade endings we e ound in he EOMs o monkeys (Lienbache e al., 2011; Zimme mann e al., 2011) and ca s (Zimme mann e al., 2013). Addi ionally, i was obse ed ha he axons o ming palisade endings es ablish mul iple mo o e minals along he muscle ib es associa ed wi h palisade end- ings (Blume e . al. e al., 2020; Zimme mann e al., 2013). These indings con i med ha palisade endings o igina e in he EOM mo o nuclei, mos likely, om he MIF mo o neu ons o which hey a e he pe iphe al expansions (Figu e 2g). Because molecula and neu onal acing s udies sugges ed ha palisade ending a e e ec o s, we es ed whe he palisade endings ha e exocy o ic machine y o neu o ansmi e (ace ylcholine) elease (Blume e al., 2020). Key p o eins in neu onal exocy osis a e SNAP25, synap o agmin, syn axin, complexin and synap ob e in (Fe nandez- Chacon e al., 2001; Su on e al., 1998). Using immunohis ochemis y, we con i med ha hese exocy o ic p o eins a e also exp essed in he palisade endings. This indica es ha palisade endings ha e he molecula p e equisi e o neu o ansmi e (ace ylcholine) elease. Su p isingly, o he key ea u es o choline gic synapses we e no ound in palisade endings. Speci ically, he enzyme ace ylcholine es e ase (AChE), which deg ades ace ylcholine o e mina e neu onal ans- mission, was absen in mos palisade endings and in o he s i was only p esen a low concen a ions as demons a ed by an i-AChE immuno- his ochemis y (Blume e al., 2020). Addi ionally, we did no ind ecep o s o ace ylcholine on muscle ib es associa ed wi h palisade endings as demons a ed by he absence o α-bunga o oxin (a snake enom ha binds o ace ylcholine ecep o s) and an i-ace ylcholine ecep o signals. Excep ions a e only he palisade endings o abbi s and a s, whe e, di e en om he canonical palisade endings o highe mammals, ace ylcholine ecep o s we e ound (Blume e al., 2016). 5FUNCTIONAL CONSIDERATIONS ON PALISADE ENDINGS Neu onal acing and immunohis ochemical s udies ha e shown ha palisade endings a e he pe iphe al expansion o MIF mo o axons (Blume e al., 2017, 2020; Zimme mann e al., 2013). Because o his s uc u al uni , he exci a ion o MIF mo o axons would induce neu o ansmi e elease a he si e bo h o he en g appe mo o e minals and o he palisade endings. En g appe mo o e minals a e endowed wi h ace ylcholine ecep o s and neu o ansmi e elease would induce con ac ion o he muscle ib e body, whe eas palisade endings lacking ace ylcholine ecep o s would exe no e ec on he e minal po ion o he muscle ib e opposi e o he palisade ending. Mo eo e , due o he low concen a ion o absence o AChE, he as emo al o ace ylcholine is insu icien . Consequen ly, he e ec o ace ylcholine elease om palisade endings is di icul o p edic , bu is possible ha ace ylcholine se ee om palisade endings binds o hi he o unknown ecep o s o se es as a ecep o - independen , modula o y unc ion. Al hough he unc ional signi icance o palisade endings is s ill deba ed, he e a e indica ions ha he palisade endings migh be ele an o con e gence eye mo emen s, which a e c ucial o ocusing on close objec s o pe o ming nea -wo k ac i i ies. Du ing con e gence eye mo emen s, bo h eyes mo e inwa ds equi ing he coo dina ed ac i i y o bo h medial ec us muscles. I has been shown in on al-eyed species ha many mo e palisade endings a e p e- sen in he medial ec us muscle han in he o he ec us muscles (Blume e al., 2016; Lienbache e al., 2018). Mo eo e , in a on al- eyed species (ca ) i has been demons a ed ha palisade endings a e ully de eloped signi ican ly ea lie in he medial ec us muscle han in he o he ec us muscles (Blume e al., 2017). Finally, in p ima es (monkey and man), many palisade endings o he medial ec us exp ess cal e inin, and i is hypo hesized ha he cal e inin-posi i e palisade endings ep esen a specialized, p obably mo e exci able ype o palisade ending equi ed o con e gence eye mo emen s (Lienbache e al., 2018, 2019). 6CONCLUSION The p esen e iew has shown ha he occu ence o classical p op io- cep o s in EOMs a ies widely ac oss mammalian species. Exclusi ely in he EOMs o e en- oed ungula es, muscle spindles and Golgi endon o gans a e p esen . In he EOMs o p ima es (monkey and man), only muscle spindles wi h a simpli ied mo phology a e p esen , and in he emainde o species, muscle spindles and Golgi endon o gans a e lacking a all. Because he classical p op iocep o pai is only p esen in he EOMs o e en- oed ungula es, only his animal g oup is equipped wi h a adi ional p op iocep i e eedback sys em o moni o he EOM ac i i y. Whe he his co ela es wi h any eye mo emen p ope ies in e en- oed ungula es is cu en ly unknown. Mos mammalian species 1469445x, 0, Downloaded om h ps://physoc.onlinelib a y.wiley.com/doi/10.1113/EP090765 by Uni e sidad De Se illa, Wiley Online Lib a y on [20/03/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 8BLUMER ET AL. possess palisade endings in he EOMs, and he e was an ag eemen o many yea s ha palisade endings subs i u e o classical p op io- cep o s and p o ide eye posi ion in o ma ion. Today we a e aced wi h he ac ha palisade endings combine senso y as well as mo o cha ac e is ics. Because o his ambigui y, i is challenging o so ou he unc ion o palisade endings. In he u u e, u he molecula p o iling and elec ophysiological expe imen s a e needed o cla i y he unc ional ole o palisade endings. AUTHOR CONTRIBUTIONS Roland Blume concep ualized and w o e he manusc ip . All au ho s made c i ical e isions and app o ed he inal e sion o he manusc ip . All au ho s ag ee o be accoun able o all aspec s o he wo k in ensu ing ha ques ions ela ed o he accu acy o in eg i y o any pa o he wo k a e app op ia ely in es iga ed and esol ed. All pe sons designa ed as au ho s quali y o au ho ship, and all hose who quali y o au ho ship a e lis ed. ACKNOWLEDGEMENTS The au ho s wish o hank Syl ia Ge ges o hei help ul echnical assis ance. We u he wan o hank he Associa ion o Resea ch in Vision and Oph halmology o he pe mission o euse igu es om ou p e ious publica ion en i led ‘Palisade Endings Ha e an Exocy o ic Machine y bu Lack Ace ylcholine Recep o s and Dis inc Ace yl- cholines e ase Ac i i y’ by Roland Blume , Johannes S eiche , Géno a Ca e o-Rojas, Paula M. Cal o, Rosa R. de la C uz and Angel M. Pas o , In es Oph halmol Vis Sci. 2020 Dec 1;61(14);31. h ps://doi.o g/10. 1167/io s.61.14.31. CONFLICT OF INTEREST None decla ed. ORCID Roland Blume h ps://o cid.o g/0000-0001-5048-4865 REFERENCES Abuel A a, A. A., DeSan is, M., & Wong, A. (1997). 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