Document DvbDBKNJ2noGOq9EJze9EYy15

BT 1e0S Cran ke, mili) of ado moa e pai ih dlr sss. mrygous for r(aers se is), dil fleing P'P~ . Birth ave 22 IEE Pe of x. mocos of date Y-?r Y-is Ton Few New ow W Won fas 8 genera anfenne no onyfo pi. Mean Rang~ N T wm ow VEr R n il verbraes nclL adiog man. Th 2/27/7t :28 1 sm ws oma 2 PeHTter Has ynaodme ormasyhod ecamet.he an. Isentms pcoornttarnotl 6/25/?1 24.5 23-2.6 2 AE OBE 3 OB BW 8 WF enducin severe 1d oi 9130171 22.i 19-25 5 yom x y rEeteT01A7 Oto LaboraariKsloofsMDa.riKneain 2115/72 25 1 3N/1E7/.72 B 22,7 aa21-. 23.5 88 9/20[7! ion BORD OM BNL] sewn 10/20/71 van EER oom an Murr. Sense !/26172 a Varn xv WoExxa & 5 BET opfeoNteiwnYcoortkerrs oofoCtiv1U1n3b1e0rsiy 1/26/72 b X-Y-It wim -- wr m-- us wn "BE Pin wu OCoaLaNboorrantokriVoeaflMaeanrmiBeorsoses 1!11/71 24.7 23-26.5 13 l~-pt Y-Is Y-Br Mean Ran~ At P~dtgree 2828 32 30-34 Pedigree 2918 31 28-33.5 6 27,3 24.5-30 2 Pedigree 29.3 2H7L,4 Pde Pedigree 30.5 25,5 25.8 24.1 3030 Sea 28.5-31 3 27-29 4 2954 29,5-31 3 22.5-27 3 24-28 6 22-26 6 X-Y-Br Pedigree 2974 29,9 27.5 32 15 ptp~ Y-Br Y-Br Mean Range 36.6 31.8 28.3 29 35-38 28.--34.5 24.5-32 27.5-30.5 mozygoas t:or pl (large size), differing completely in breeding structure and appearance. The P locus of X, macnlatzty is O[ generaI significance not only for pitullacy gland function in teleosts, but for all vertebrates including man. This system may become an important model for studying the genetic control of endocrine structnre and function. KLAUS D. KALLMAN SOSccsiibeenoncrceness,,LaNNbeeowwratYYooorirrekks AAo]qquuMaarraiiruuimnme,, NNeeww YYoorrkk ZZoooollooggiiccaall SSoocciieettyy,, Brooklyn 11224 BrooMyn College of C~ty UniForMly of New York. Brooklyn 11210 YALERIE B oRKOSKI O~born Laboratories el Marine Science~, New York Aquarium may city wn poo iio Simi vainions fn sk ad ge" id pl may specify, two proteins differing ininththeeiirr eeffffiicciieennccyy iinnininititiiaattiinnggmmororppbhoo-- seni hans The P locus probably pare for + numer of abe secs 2 Smeg ni 5syn m fo genie changes. The P Ideas probably exes is lst dil a the pa oF Xihophorss U1), bo Tle bv Ro SE ba he A exerts its elfeet directly oa the pitui- ary gland, allough the role of the known shou the genetics of these dif. 197 00Ui Be Saxe an tary gland, although the role of the pth hou ao be evs, ferns. Th poopie hs TShirt at 5 oh Beg The P gene aso has a0 indirect of. hypothalamus should also be evaluated. The P gene also has an indirect ef- fet on the dit se of mle pay vein of he sen, ace vas} Sec fo hk SSfeiincnccteeonggrrthooewwttahhdurrlaatttseeizeddeeoccfrreemaassaeelsse platyfish, wwiitthh iinn. rela nose prodction 5 say Lrg mls, for xan, tho af X. S55Yoh Bg eee creasing androgen production (9), early maturing males agr nibeanstmallleyr ppm, nok ony stedmenst Bi maturiag males are significantly smaller ih Ite matuiog ones. Sue ifer: Babi, bu ako' devlop smitures GmsUn,Caf. Pt 1 than late maturing ones. Size differ- encesbetweenthe woclues ofmals 101 present in the smaller morphs 3 5 suit Toh were ences were absotc within between the two absolute within seven cla~ses seven broads, of males broods, hess Jn one (/30/71) the largest diflecntinion has becom ted in + 45 SER SE h Fork lr male surpassed the smallest IiBr whereas in one (9/30/7I) the largest lrlr maIe surpassed the smallest lrBr mle by 0S mn (Table 2). The ex. An, ad ha ed(08 form pap. 4 &. Re PA Comba male by 0.5 mm (Table 2). The ex- ceplonsl Br ual 96411) tht lon of small mle. Homers X. 1, ETLgee ree vt 1 matursd ceptional .matured at 18 BrBr at 18 wesks male weeks (Table 1), I (2964-11) that (Table 1), is aobbioitnheedsm0llefosrt. hSoolml oryBgromualse 1 polymorphic a th Plows reign Fos Ep or also the smallest homozygous Br maIe end Inge fh wo, Kins of males (13). Elmina, , SzeHo (0 oe obtained so far. Small and large fish Siow st the sa rt, bt the foes Gn of 7 from he Ro Choy wontd "4 158 grow at the ~ame rate, hot the former 0p at av carr ago when they be lewe two popuions: J. gmosus 13K, 5Kmwant mi stop at an earlier age when they be- cseormvea sexually maar. Soe thes 5 prgmaces homangon for Gal CHAS come sexually mature. Since these oh- ions 64 net die thuoughont Le) 4nd XK. prgmacs ren Bo 1 mes 7 es Ao 0 servati~ns did not differ throughout he Yer, sar oki, whi ws the year, natural daylight, which was ok Sotelo, cant acco or the not ontrolled, cannot account for the illin grrowths42dasg ocf sal `mdmaitfafuteurriretintyyc..es in growth and age of sexuaI "The 7 fcr have mani them The P factors have manifested them- sive bh in the ofbping of In. Abit Perfuarinaed ergo uid re sofa as high cupcly oven selves both iu the offspring of intra- nmd erin. cross This pol. andcarbon ose sven. Aer nyeverins bon os of st po and interstraict crosses. This polyiodrphis i 8 aaturl Sompooeit of Reed erubion re posted in he ner and seen 4 eos f an morphism is a natural component of populion sud is apparel thy renin or he fine of he anne: Force whieh mn. we wild populations and is apparently ideprad, Wo ave found i 1 platy 15 sled arse prion mei he vee ov rice Bind be liter 4 widespread. We have found it in platy- oh sick colled from four iver sys. Jail of prfuerocubons hs rom bee dseoveed, wHeh, crap dapoied fish.stocks collected from four river sys- tSemis (10). The sx chromosome con. in she ier afer chvalaion in he loud love he Ter 0 be nomsnen re tems (!0). The sex chromosome con- n of he ma, XY or XY, be uns and ki 8 marr of dys wiht sport ro he nl stitution of the males, XY or YY, has Doig 1 do wih ada se sod ape nothing to do with adult size and age oofohseXu.lanmdatVuislitnokne.PedPlanbe Sie 1966, when organ lun physiologist rsarch. Thee inclde of sexual maturation. P~ a~d pl can be some with Pe r An X chrome. breathing wis fist epi, hrs have rors of, Iie. besting ( both X- and Y-linked. An X chromo- fled fr eceny ben dei. bon ove 100 pubicaions sovcening organ. pefiion (1) of loseosn. oifn some with pl has recently been identiom the Blas populaon (10), the wi. nc Taorochmias. (13 whole sae 9), do olonph fied from the Belize population (10). S~milar variations in size and age ooff sseexxuuaali mmaattuurraattiioonn hhaavvee bbeeeena re- ported for a number of other species of Xiphophorus (11), but little is known about the genetics of these dif- locus may ferences. loons may have The have been important polymorphism been important orthe at this for the bbevoododylyuptpiaoarrntss ossfhhootwhwe aallglleoonmmueestt,rriisccigngrcroeowwtvthahraiaonnudds large males, for example, those of X. pygmaeua, not only assume a different fb t, K. D. KU Kallmaa, ZuTtoglca New Yorf 55, 2. Xioh~phorux macutatu~ is pol~morph[~ for ~x htomoso~ ~r~ kinds of [gmal~ (XX,. WX. ~ nab two kinds of mal~ (~. ~) may occur ~ithl~ the same n~tu~l ~OpUIg~oll, ~ males are not t~ ~s~lt of 50 o bp10C,8 opi ks [1 s~elal In.rotary crosses as are t~ mals of t~ rice ~h. O~zim ~tlpex Vamamoto, Gneffcs ~. 45 (19~)]. Beemer utah, Ey. Fas mabe 4. M. Gordon, The C~ and Br~edlng Labomto~ Animals. E. I. Farris, Ed. (Wiley. New York, 1950). p. 345. ~. K. O. Kall~n, ~ologica Hew ~ork 50, habitus, but also develop s~ructures 6. C, Grobste~e, Unlv. Cali/. Publ. Z~I. ~7, not present in the smaller morphs (12).The all for arly gonadotrop 2be seyGdofFs(Yok (12). The allele for early gonadotrop differentiation has become fixed in X. pygmaeus pygmacus inhabiting the Rio, 3 02% pygmaeus pygmaeus inhabiting the Rio Axtla, and has led to a uniform popu- 0940): J. ~xp. Zool. l~, 215 7. G- Pickgord ~a ~, W, Atz, ~h PhFalalog) ~] the FittdtaO, Gland o] FL~hes (New York Zoological Society, New York~ 195~. 8. M. P. ~hre~bman, Z~logiea N~w Fork 2t7 (19~). " 9, H. Cehcn~ ibid, 31~ 121 HL K. D. Kal~maa and M. P~ Sehreibman, pygmaeus lation of pygmaeua nigrnss in small males. nigi'ensis in the Rio Choy However, X. the Rio Choy is polymorphie at the P locus resulting unpublithed results. Gi akSony, Hend8y1 11. K, D. Kallmaa, Z~lo~ieu New Fork 56, 77 f197D; and R, B0rowsky, ~e~alt~ ~7 (1972)~ G. Pe~, Z. Zaol. SyM. Brolu~ tion.~ Forsch. 2, 185 (I9~; C. D. Zander, Z. in two kinds of males (13). Elminalion of P~ from the Rio Choy would 12. D. E. gose~, Bull Fin, Slate Man. Biol. leave two populations: X. pygmaeus pygmaeus homozygous for pe (small 13. K. D. Kallmaa~ uRpublishcd !4. Supoorted in part by h'IH grant ~ RO* size) and X. pygmaeu$ nigrenMs he ~ Janua~ 1~3; revved 5 April 1973 PPeerrfliluuoorrooccaarrbboonnss HHaav~iinngg aa .SShhoorrtt DDwweellll Tiimme iinn tthhe LLiiver Abstract. Perfluorinated organic liquids are useful as high capacity" oxygen and carbon dioxide solvents. A/err intravenous in/usion room o] these perfluorinoted emulsions are deposited in the liver and spleen in a matter o[ days, where they remain ]or the lifetime el the anhnaL Hence, wlrile they may be use[u1 as isolated organ perfection media their value as artificial blood is limited. A ]amity el perfluorocarboJ,s hay now been dizmvered, which, although deposited in the liver after cirtulaHon in the blood, leave the liver to be excreted via the !ungs and skin in a matter of days without apparent harm to the animal Since 1966, when organic liquid breathing was first reported, there have been over 100 publications oncemlag tim use of inert fluorochemieals (1) in physiological research r These include reports of liquid breathing (2), of organ perfusion (3), of infusion ia / / / Exhibit Exhibit ~mals (4), and as radiographic /_ SCIENCE, Vt~t. llll 3028 / ." 33002288..00000011 aMAc0B31101 3MA00631101 se). A yes bl in 1960 ag~. ~ts. ~3). A symposium held in 1969 dof of ht gave the sly.re of the nr~ ~s o~ th~ lime 1()6).. Nit of thes pctoriasd orgie M~st of these p~rflu~rinated organic bass me pine for og liquids ar~ synthesized ~o~ industrial of swat or coy us~ ~use of lheir value as ele~lr[eally soonteie hemi soon nonconductiw, chemically nonreactive~ hk sae bd es xm and heat slabie liquid heat ex~haage~, a a a leak 6erectors, and hydraulic fluids. To beh by tor pte 3 0 Thck hig~ solubility for gases, a auioe aes, 3 HE dad sanc~ ia commerce, ~s a hig~iy ~esired ery in ey. Is oe se mers present there properW in biology. mers present 1here ace hundreds Including lh are hundreds of Compound of th sper ope. t compounds of Ihi~ general ~yoe, over himired of which we have sated, a hundred of which we have studied. eval spin. thos pula Generally speaking, these oerfluoriaid ComEpEounts (PEC) ae xen noted compounds (PFC) are excellent E133503) r3,t Tee 3 Jo Emulion, worn gated Fig. t. Emulsion absorbancz plotted against ultrasonieation time. Emulsions Jk Sn Gog Bovis were circulated Ihrough a Branson autohk ek ie Ese timed sonicx~tor cell at 10C, sample [-- Perfluorodccalin and perfluorometh- tau Le es i ar yldecalin left lhe ddaayyss wwhhiillee PPIllIDD rlievmearininedafomr amttoenrthosf remained for months (Fy.3) Ala one parca (Fig. 2). Afler 5 months the petcet~lage SEFC oft pd dre rag of PFC of the injected dose remaining for LID, PPS. and PP wa 30 230 for PliD, PP5, and PP9 was 34, 2.3, ee ia hat ov et ak and 1.3- We think that at teast part Ee eal PEC wa ho of this residual PFC was due to im- iis nthe ls, Obs PC th, purities in the liquid. Other PFC tested, Bing FET FCAT PID, oh E5 including FC75, FC47, PID, E4, Fonols by nd Fomlin 2 reine Fomblin L~ and Fomblin Z remained hn of the animal. We stl have dogs with for months, probabty ~or the lifetime of the animal. We still have dogs with meni moh PFC i th Its apparently as much PFC in their livers JTC SCE CNN as was there 4 years ago when the 110 fa Sy -PFC was first administered. | ExB um be bs mi io of Examination by gas chromatography solvents for a large variety of gases (7), as sonmeabolzable, and are POSIT Sows hand acre is bruh of mie having PPS or PPD (7), arc aonmetabolizable, and are as sop. al ae, LF eit i we tt Set Toso ahnosl completely insoluMe in waler. ey re very po sone So oo i ot enh af se bans 1 mors of As a class they arc very poor solvents ort = on ep ane lo ox Wn for te appre for all hut a few organic suhslances, od fox hs smo a oo Be vk Uh re shown n Fi 3 Th rath and for Ihese reasons can only ~ ~ed streams were flowed thlough Sl:~Ctro0hotometer cuveues having appropriate light paths, and the optical densily was recorded. The optlcu[ denshy was cal- culated to acconnt for the lenglh el the cell a am Sra a oF ries ok ted wi FOP, what for intravascu~ar gas transport orotate sven. ae 2 in Th mic were il hs somomeeion te vod wis Bh form of oR-in-water emuhions. Eons re ving made i varios a ross merle heats ond (ha 3pcm by vlano)r rn Efforts are being made in variods rate of 2 ml!mia. The mice were killed in groups at intervaN thereafter, and rua 1 Soin sete via Ih os 208 ons wie ied et be. ed on laboratories to develop artificial blood, their Iivers and spleens were analyzed En of mens BEC for PFC ty pete pvin Uy ds pos wes nynd 0 ps chrom. based on the use of oil-in-water PFC for PFC by specific gravity, by direct tion. whores mon ve sombtn.1s Moib on wilh 1h. _togphy snd me asec PEC ms emulsions, where the emulsion is made oneligi ud hon. oo ody Shr (vs a olin found he salon aout of FOI wilh an emulsifying ag~nI and mechanL combustion to fluoride ion with the use of sodium biphenyl (8), and often ar Se tim. eso beans ton a to hora, sb wh he mt st ~1 energy. Such emulsions have re by hexane extraction and gas chroma- a ow omepae 10. ogre The Tae a sneer 300 pi. markaNy low toxicily~we ~ave 10 per. tography. The fluoride ion concentra- | Cont (by volume) Raorocubon emul. Yon was messured with an Orion In addition, we Rave found that per cent (by ~olume) fluorocarbon emul- tion was measured with an Orion Soe cre he mado ten bars Foo decode Tho PF Beinn peor ph sions where the median letfial dose in lanlhaaum fluoride electrode. The PFC a Br mice after a single intravenous inj~tion liquids were stoiehiometrically' con- ES iia eed home etd 10 Boi oh bon nent ed 5 oo pon iz 200 ml/kg, with the blood volume verted to fluoride ion by tl~e blphenyl i aay sone moat: Sroican nd pth (1-345 of the mouse being probably about 60 method. UR. On of th win plo, et eperme ove Tot ml/kg. One of the main problems, ot in rom wih hw of ea Tn ths ful of pn not the main problem, wi~h the use Toren ovis es beh Tot fretiviatipuipiiceg ~oo~car~ou qm[sio~s has been that Dy a Srp nthe og a hs Roig the her vigor press they are deposited in the li~er and en whan es mai of Be le em i ms pa I aly dm spleen, where th@ remain for the life om ima, vow tnt het SLL oe ee bec ep of the animal. We now report the dis~ ppe ol BG LL te of oes eh i riontot fs te br ard Ef AT cove~ of a number of closely related ~uorrooccaarrbboonnss tt~haatt lleeaavvee tt~hee lliivveerr aannd d} I spleen of the mous~ ia a matter of MA +. he spac 20d aman gas days. Elson are made wi5 terhn Vim amor ws or Em~ls~ons are made with 5 peceeni re pn Le iy Pluronic F68 in the water phase, ~ith 10 porn by vob onto 5 pic ih mare of te ot of 2 mow 10 percent by volume (abont 19 perSn welt) PRC pt a oP. 2. Perrin cot of 1h hep ried (ot Kg f pop cent by weight) PFC liquid and with tthhee mmiixxttuurree bbeoinngg ssuubbjjeecctteedd t1o0 aa b~rriiee~f Loic or 1a 3 presare of abow Smo of PRCexmese2d ferent (G2 of 77) 5 mami evr sonication or [o a prc~Hg~ o~ 530 Fajen ns Gaon momogenner UF SAE ose Be [0 en of 31 prem 550 ks/cae in a Gaalin homogenizer. Foray gnc staan comune PC eas hl Ph of FCAT (oy ames. Te Wt was For any given sur~actaat concentration, CUTEC av charac rs ok TO ed svi rl Sond 10 4 for4 dos on aka each PFC has a characteristic rate at wich it beaksdown fo panics when Sr incon plod. Gros 6 4X el, Anayss of the gas shove the wNch it breaks down In particles when continuously soncaied and 3 chame. Tce ree Kil aL howe aS dae "00 hes vp ce of FCAT eonfimmusly soniczled an~ a charac- Se pn wht poi ca 8 Sb Set onl fr ThE Ie wh ene, pod a 3 teristic poim at which the particles can roman my op BR he Sn Coe pm, morn, 10 md for FEV I be made no smaller, as judged by optiCimon i 13, To on. Eh el tins 3 ng rd ids pace FC(33 oho cal measurements (F~g. 1). The emuISons centeredby trot te Sabin 0S SG fe Fs ha si~ was centrifuged to remove parce. and cath emion oe tated 950s fora mi.Appromwely 8 $2 2 Vol SSS Fo particles, and each emulsion to be tested Ca cd meno ma hal Bi Shas a il LE Ba cur PID wih vapor rie was injected intravenously into the taiI EE a Se tn TRC dh Tor FES TE S15 ond Bre veins of 200 albino Swi~s mice at a o o i~[g. 2. Perfluorochemitd conten~, of the Mmoowusee lliivveerr pplloottteedd aaggaaiinnsstt ttiimmee. TThhee +mnnnt of PFC expressed as th~ percentnge of initial dose remaining in the liver of Swiss albino mice injected with l0 percent PFC emulsion in 5 percent Plurunic F68 and killed at vmions ime~wals after injection is plotted. Groups of six mice were killecl at 1 hour, I a~d 5 days, and 7., 3, 4, 8, 12, and 20 weeks. Livers and spleens were ~nalyzed in duplicate for PFC by the sodiura biphenyl procedure. Each poin~ rept'esents the average, and the vertical bars represent the standard deviation for sin mice. Approximately 8 percent of the initial dose appeared in 1be spleen, a.nd at fimilar [ate of decrease in PFC was observed for PP5 and PPg_ and a t~Ni electron capture detector of the breath of mice having PP5 or PP9 in their livers revealed the presence of enough of these substances to more or less account for their disappearance at the rate shown in Fig. 2. The breath of mice jnst injected with FC47, where the concentration in the blood was high (about 5 percent by volume), or from mice that had been injected months before, was analyzgd by gas chromatography and no delectable PFC was fonnd. The smallest amount of FC47' detectable with this instrument is about 20O pg. In addition, we have found that perfluorod imet hyldecalln perfluoro- (1,3-dimcthyl)cyclohexa~e, perfluoromethylcyclohexane, and a mixture of perfh,orodccalin and perfluoro-(I-3-dimethyl)cycIohexane leave the liver rapidly, la this unique family of perfluorinated decalins and eyclohexanes, lhose having the higher vapor pressures leave the most rapidly. It is easily demonstrated that these substances are pres- ina cup on he anvkai lsamypli'ng leargne t incotnhceenbtrreaattihonso.f Fmurlctehera,ndbycaptslacin- large concentrations. Further, by placing a cup on the animals' skin, sampling the gas space, and analyzing by gas chromatography we can shcw that it is diffusing through the skin. Anarysis of the liver of a mouse wwweehiiiggchhhtt))rect10e0i00vedmmlt(pooe~fr 11k00iloppgeerrarccmeennttofFFbCCoA4dT7y (0.2 ml of FC47) 8 m~nths earlier revealed the presence of 5.1 percent of FC47 (by volume). The liver was allowed to dry for 4 days over silica gel. Analysis of the gas above the silica gel showed no trace of FC47. The liver was removed, powdered in a mortar, and reanalyzed for FC47. It contained 8 percent PFC (by volume) per gram of dried liver. FC47 has a vapor pressure of only about 2 torr.. But even P1D wilh a vapor pressure of 13 tort remained ia the liver in. AUGUST 1973 681 33002288..00000022 swAGoBat102 3MA00631102 deny, The vapor press of per , Pt Smal eu wi eemeth Bein definitely. The vapor pressure of permin To nd ed ASCE BEI Sa fluorodecaIin is 14 tort and that of petcromethydeciin is tr. PRR perflueromethyldecalln is 5 torr. Ou le sho tht there sre SOTNVE SE SE ER he 5H Our results show that there are issof PRC whieh form some kina oriJ Be oot Sel SLT LT classes of PFC which form some kind oF Sms ond wih or Ei rs Py A re of chemical bond with the liver subStance. Suh PRC comin stoms over Pent SERN 10 Rol vom, tenm,t stance. Such PFC contain atoms olher cron a too AR om rset ain coe HEL IER i than carbon and fluorine. All of them consi iter 3 COC or a CNC * Rig Mition opr pf cig Hohe Bor Tl 40 coutahl either a C-O-C or a C-N-C tage. One ply for meh 3 SERA BAT CY mi Ban Sa EE linkage. One possibility for such a coup in a he hurd ccton 5 6 Bk Fo, Gh Gh Ue eb ls BTA coupling is that the unshared electron ys on gt SEE Er TRE pair on the oxygen or nitrogen atom TTay sEively foor e`bonh WWihbfhthee TBLb ns te SbTeUtEsRee em nt 0 nn may passively form bonds with the substance of the liver. If the binding rs fo pti then pia thr was lo protein lhen it is surprising that vas ot band 30 an to 14, it was not bound as much to, say, le, Ulich odie (5 ta por ; ' ; muscle. UlIrieh's finding (9) that per- roronstane & aonSdo ae ot 55, Impaired Learning and Decreased Cortical Norepinephrine fluorohexane is bound to, or at least interacts wih, cyechrone P50 3. air Bilateral Locus Coeruleus Lesions interacts with, cytochrome P450 sugoe ht ssn EC ry fom com gests that certain PFC may form comlees wih cts ko<ontnlBaIOs Apu, Brel eson of the ces locus corns in as deple he plexes with certain iron-containing pro- tteeiinns.. TThhee ssttrrasiigghhtt-cchhaaiinn fBl0uoOrroOcCarAbDoOnMs iui so or,on theether band. 010-1 runnin for food reward in a simple Lohaped runway. A aered in hs studied so far, on the other hand, rapid- iene eer of th aes Sel 2 rn tn shen ly leave the liver of the intact animal. etAnhoithcerprpoosclebsililtyoisvhaet wn active he locus coenleus, although thse ratsrasthhowweidhrtahramleewesighegpain saintdinoosrmaolf Another possibility is that an active not ay tie lccoc aout metabolic process is involved not only in the binding, it the rls from in the Mnding, but in .the release from 4. L. C. Clark, 3r., Edmund Hall L~lu~, Uni'~rsity ot LauisVil~ .Sigma Xi, lg Ma~ 1967 (W. WelcIt. Louisville ~lme$ 20 May 1967); R. P, Geyer, R. O. Mon~e, K. Taylor, Ceo~lr~'~tofB, ~w York, 196~)~ pp, H. A. S)ovitcr. M. Petkovie, S. Ogoshl, L, ~, Clark, Jr.. P. Becatti~i, ~. $. D, M. ~g, M.-S. LIe, P. S. Szamo, D. P. Alrunga, M. M. Patel. M, V. Rips. L. Nyhau~ Radiologist 1~, 323 (1972). 6. L ~. Clark, Jr., Fed. P~oc. ag~ 1696 acmic Pr~, New York, 19~)~ voL ~, pp. I ~3-23 L biphny[ ragent, where the fluorine oo,Ll~ ~d ~ith an Orion elect~o~. ~e me~od bn~d m part upon lhat o( P_ P, Wheeler and M. L Fauth [Ao~. ~Itetn. ~, 1~ V. Oarich and H. DMM, Eut. 1. so, ~ (197tL Supported ia part by grants HL]~419 nnd HJ~522] from the National [nstitute~ ~ciation. Dr. D. Steibk and Mrs. we ~re es~eially indebted ~o the Chemical Company. April 1973; rviscd II ~lay I973 Impaired Learning and Decreased Cortical Norepinephrlne after Bilateral Locus Coeruleus Lesions o cerAef bbrsatrlaccctoo.rrttBeexxilaootef[rannloorrIeeepp.riiionnnee~pphhorrilfnneethaaennddnussciilggennuiisffiicclaoanncsatlllysy cddoiiemmriitnntliiessthhts tthihnee rrraaatttsee dooef]piilnentccerreeaathsseee o/ rtmning !or jood reward in a ~imple L-shaped rtmway. As assessed in this situation, learnin~ war absent in those rats with the most ~omplete ablations o] the locus coendeus, althoagh these rats showed normal weight gain and normal motor and exploratory activity. tthhee lliivveerr. IItt mmaayy bbee,, ffoorr eexxaammppllees, Uth3at the perfluorocyclocarbons are actively he peruoroeyloBcICaAbSonAsI xecxrceireedted bbyytthhee lilvieverr becaubecsauese ththeeyy 1re%:- de semble steroid fragments. This new family of compounds eon- Haangigioris ioonllwy achmolonfsndCompOUMsRavine 1C5n0.. taining only carbon and fluorine and stuers maTyUKEv having cyclic st.ructures may make posle VEC emiion Opi of D508 sible PFC emulsions capable of being ly ed safely used in intact animals. TeLtEADHCO C,Ignr, LEt~NO C. Ct2,ar, Sore Kare V0 BIOATTN FI~RNANDO BECATTINI on Kar, Vans OURO SAMUEL K^PLAN, VIRGINIA OBROCK a MR EA ater Heap " Children's Hospital RReessseaarrraccnhhuls psBzEaCgKER ts st St Foundation, * Cincinnati, OhioOka! 45229 + DE ems iGFs m,ael, he SEhSSbEunIES hSE RE EELTRRhsIRIhAmE P t E A T IR a Ei, WOR PRSEEESEEE im a E r RE y E SP E PEEED TI ERE STESNR ETS FEooSrt ERIS ES LESTN SGutuadgieess wwiitthh tthheeFFaallcckk-HHililllaarrpp hhiissttoo-- chanical echnique () reveal thepres. focuscoeruleus function 8 3 "reinforce. cchoeymiocfal atencehtnwiqourke (o1f) rneovreeaplintehpehrpirnees.ence of a network of norepinephrineTn me on 8 at mort rt containing nerve lerminals in the r corhrln core.Sud wih Our Sypris ware sg 10 mammalian cerebral cortex. Studies with oocel L mtuion 0 how tes th ther ht th norepmegites lesions (2) and stimulation (3) show tse emis rs dened fom conning oeuron neraing. that these terminals ar~ derived from 2 py stated 0. te meee Jom seu Stn for 4 amepln Son cell bodies situated in the nucleus locus COSTRiLhSefcc ofthe fourth ven ponentof the mechanms of ering. coeruleus in the floor of the fourth vensia lfaimutsion co Sie hooded Lief ay Gael eth, tricle. Electrical self-stimulation Call be yed gh code ps in Ss 300.2 101) wre sshd wih obtained through electrode tips in close is aoe and pesabrhion, moa a 3 Kept proximity to this nucleus (43, and this nnoorraaddrreenneerrggilcc ssyysstteemm mmaayy bbeeoonnee ooff WO catecholamine containing systems holes dulled biltecaly in the skull two catecholamine-con|Mni~g systems tthhaatt wwiillll ssuuppppoorrtt tthhiiss bbeehhaavviioorr ((55,, 66)).. On the a of orate consign. of si i ao ones Pouce wort On the basis of theoretical consideralos tha hen ropes fy card ou aor he woundwhpe tions, it has been proposed (5, 6a). fh he nerpimsine conan es. srl In sre futher rou. of that the noreplnephrine-eonta[ning neu5AS0se SWU ES El lCmiTalloadyaieorintpbtlyonaTrcthepneiudson,sweipechonsing0o3tss0cchsmtihnaCyhrdBtee)hoeoodftfnaacr1ees24r5e0%dbtepowowlele2toael)fr = rruonnss aarriissiinngg ffrroomm tthhee cceellll bbooddiieess ooff tthhee lmoecnuts"coseyrsutleenms iinnactthieon saesnsae"rtehinatfortchei-s ment" system in the sense that this term is used in theories of learning. Our experiments were designed to test the theory that the norepinephrine. containing neurons innervating the cerebral cortex form an essential component of the mechanisms of learning. Male hooded Lister rats (initial weight, 200---10 g) were anesthetized with pentobarbitone, immobilized in a Kopf sstteerreeoottaaxxiiec aappppaarraattuuss,, aanndd hhaadd bbuurrrr holes dallied bilatetaUy in the skull oovveerrtthhee cceerreebbeelllluumm.. IInn oonnee ggrroouupp ((BBIHT)) of six rats, no further procedures were carried out before the wound was resutured. In three further groups of rats, bilateral eleetrolytle lesions were made by passing a charge of 15 to 20 milUeoulombs through the bar~ tip of a varnished steel electrode to an anal ctthaheethoeelldeeecc.ttrrIoonddeeonwweaassgrolloouccpaatt(eeCddBa)attossfyysmmimxmetrearttr-sL, rally placed points in the cerebellar LWoLr cae a Fir 1. Hisclogcl preparation of the Fig. I. Histological p[eparalion~ of the of en i Sl region of the locus coeru]eus in the floor 5 EL ho a) Th of the fourth venalcle. (A) The locus mm Se Sch Se bs en Sts coeralees on each sMc has been ablated, allhough cells of the me.~ncephalie tract a BESS: nel of the trlgcmfval nerve (mesV), situated a, aagme TEN ena, fr rast lalerally to the locus coetuleus, have been wv pe To Rn BERET spaced. This rat showed no increase ia mei Se BIita a sae running speed in the CourSe of behavioral SOT BEy L ChimAay] inR e (he laon chorl (16n)3 testing. (B) The locus eo~ruleus (LC) iS intact on both s~des in a rat in group BH. 682 33002288..00000033 3SMMAA00D0B63311110033