Berner Heller 98 Cortex Not Poa Important

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Does the preoptic anterior hypothalamus

receive thermoafferent information?

NANCY J. BERNER1 AND H. CRAIG HELLER2

1Departm ent of Biology, Th e Un iversity of th e S outh , S ewan ee, Tenn essee 373831000; and2Departm ent of B iological S ciences, S tanford University, S tanford, California 943055020

Be r ne r, Nanc y J. , and H . Cr ai g H e l l e r. Does the preop-tic anterior hypothalamus receive thermoafferent informa-tion? A m. J . P h ysi ol . 2 74 ( Regulatory Integrative Comp.Physiol. 43):R9 R18, 1998.The preoptica nt erior hypotha la-mus (POAH) is considered the thermointegrative center oft he m a mma l i a n bra i n. St udi es on a ne st he t iz ed a n d u na ne s-t he t i ze d a n i ma ls ha ve de monst ra t e d ne urons i n t he POAHthat respond to changes in both POAH temperature (T POAH )and skin temperat ure (Ts ). In th ese stu dies, however, electro-encephalographic (EEG) activity was not monitored. Recentwork ha s revealed th e potential for a rousa l stat e selectivity ofneur ons combined with th ermal influences on a rousal state t ocr e a t e t h e a p p ea r a n ce t h a t ce ll s a r e t h e r m os en s it iv e orthermoresponsive when in fact they may not be respondingdi rect l y t o t e mpera t ur e or t o t h e rmoa ffe re nt i nput . I t i s

therefore n ecessary to r eexamine the influence of centra l an dperipheral temperat ure on P OAH cells. In the pr esent stu dy,66 POAH cells were recorded from urethan-anesthetized ratsw h il e E E G , TPOAH , a nd Ts were monitored. Seventy-fivepercent (41 of 55) of the cells were EEG sta te r esponsive; 22%(6 of 27) were T POAH sensitive; and 33% (19 of 58) appea red t obe Ts responsive. However, when EEG state changes weretaken into account, none of the cells that appeared to be T sresponsive were responding to T s wit hi n a ny uni form EEGstate. All changes in their firing rates were associated withE E G s t a te ch a n ge s. T h is s t u dy r a is es a q u es t ion a s t owhether or not peripheral temperature information is inte-gra t e d i n t he POAH. Conside ra t i on shoul d be given t o t hepossibility th at Ts i nforma t i on i s i nt e gra t e d l owe r i n t heneuroaxis. Monitoring EEG is essential in studies attempting

to cha ra cterize th e integra tive properties of POAH neu rons ofanesth etized or un anesth etized anima ls. This caveat appliesnot just to therm oregulatory studies but to investigations ofot her i nt e gra t i ve funct i ons of t he hypot ha l a mus a nd ma nyother br ain r egions as well.

si ngle -uni t a c t i vi t y; t he rm ore gul a t i on; e l ect roe nce pha l o-graph; thermointegration; uretha n an esthesia

T H E P R E O P T IC A NT E R IOR hypotha lamic area (POAH) isconsidered the ther moint egrative center of the ma mma -lian bra in. Cooling the POAH elicits appr opriate hea t-gain responses, and, conversely, heat loss responses are

activated when the POAH is heated. Changes in ambi-ent, hence skin, temperature (Ts ) alter the thresholdPOAH temperatures (TPOAH ) for thermoregulatory re-s p on s e s or a l t er t h e g a in of t h e r e s pon s e s. Sim p leneur ona l models h ave been pr oposed a s hypotheses forh ow POAH n e u r on s cou l d i n t er a ct a n d r e s pon d t otherm oafferent inpu t to produce these system char acter-istics tha t ha ve been described in a n umber of mam ma-lian species (for reviews, see Refs. 3, 1416). If any ofthese models for POAH thermointegration, or eventheir basic assumptions, are correct, then there shouldb e P O AH ce ll s t h a t r e sp on d b ot h t o l oca l t e m -

perature (thermosensitive) and to T s (thermorespon-s iv e). Th e r e h a v e b ee n m a n y s in g le -u n i t s t u d ie s of POAH neurons on anesthetized and on unanesthetizedanima ls. These studies have demonstra ted POAH unitstha t a re th ermosensitive, eith er war m or cold sensitive.In addition, stud ies have reported units th at r espond tochan ges in Ts (for reviews, see Refs. 3, 5). These da taseem to support models that place the integration of ther moafferent information in th e POAH.

Recent investigations of puta tive therm oafferentpathways, however, have revealed a possible problemwi t h t h e a s s u m p t i o n t h a t c h a n g e s i n fir i n g r a t e s o f POAH cells tha t correlate with changes in peripheraland/or POAH temperatur es ar e reflecting th ermointe-grative processes (12, 13). As reviewed in those papers,urethan-anesthetized animals show electroencephalo-graph ic (EE G) cha nges similar t o those seen in un anes-thetized a nimals changing arousal stat es. In addition,EEG s t a t e c h a n g es i n a n e s t h et i ze d a n i m a ls ca n b einduced by thermal and other stimuli. Units in manya r e a s o f t h e b r a i n , i n c l u d i n g t h e h y p o t h a l a m u s , a r eEE G stat e selective: they change th eir firing rat es withcha nges in th e E EG (12, 20, 22, 23, 28, 30). Therefore,changes in POAH unit activity recorded in anesthe-tized preparat ions in response t o thermal st imuli maybe reflecting changes in cortical EEG state rather thanther moregulatory int egrative activities. To cont rol for

this possible confounding var iable, it is necessary tomonitor EEG in single-unit studies, and this has notbeen done in most stu dies of the th ermosensitivity an dthermoresponsiveness of POAH cells.

I f t h e P O AH is a t h e r moin t e gr a t iv e a r e a , t h e r es h ou l d b e c el ls i n t h i s a r e a t h a t ch a n g e fir i n g r a t ebecause of changes in local temperature, changes inperipheral temperatu re, and changes in both tempera-tures within EEG-defined arousal states. Although ith a s b ee n s h ow n t h a t s om e h yp ot h a la m ic u n it s a r elocally therm osensitive within a n arousa l sta te (10, 11,26, 27), there is no such unequivocal demonstrationt h a t POAH u n i t s r e s pon d s p eci fica l ly t o p e r ip h e r a lthermal stimulation independently of EEG changes.

Such a demonstration was the purpose of this study,a n d t o t h a t e nd w e s ea r ch ed t h e P OAH for ce llsr e s pon d in g t o ch a n g e s i n b ot h l oca l a n d p e r ip h e r a ltemperatur e in ur ethan-anesthetized ra ts while moni-toring the EEG states of the animals.

MATERIALS AND METHODS

Animals and surgical procedures. Experiments were con-ducted on 28 m ale Wistar rat s weighing 250350 g. Animalswere housed in a temper atu re-controlled room (22 24C) on a12:12-h light-dark photoperiod. They had access to food andwater ad libitum .

0363-6119/98 $5.00 Copyright 1998 th e Am er ica n P h ysiologica l Society R9


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Each anima l was anesth etized with 4% halotha ne (Ha locar-bon Laboratories) followed by an intraperitoneal injection of1.0 g ur etha n/kg body wt. The an esth etic effect of th e uret ha ni nje ct i on l a st ed for t he dura t i on of t he e xpe rime nt . Thea n i m a l w a s s h a v ed , a n d t h e s ca l p a n d b od y t r u n k w er etreat ed with a depilatory cream. The animal was placed in aKopf stereotaxic instrument. A midline incision was made,the skin was deflected, the top of skull was scraped, bleeding

vessels were cauterized, and the skull surface was treatedwit h hydrogen pe roxide (3%). Fi ve EEG e le ct rodes wereimplanted into the skull. Four electrodes recorded frontal-occipital an d occipito-occipital EEG activity, a nd one s ervedas the common electrode for single-unit recordings. A pair ofth ermodes, each consistin g of sta inless steel concentr ic inn era nd out e r ca nnul a s (t he out e r one cl ose d a t t he bot t om)allowing one-way circulation of water, were implant ed 1.52.0 mm from bregma ,2.0 mm later al of midline, and 9.0 mmdeep. The therm odes and a therm ocouple reentra nt t ube wereglued into a P lexiglas block tha t wa s drilled to allow un idirec-tional perfusion of the thermodes. The block was anchored toth e skull with bone screws an d dent al acrylic. The POAH wasmade accessible to electrode penetration through a 4.0-mmhole i n t he skul l ce nt e red 1.0 mm off mi dli ne a nd 1.0 mmbehind bregma, and th e dura was removed. A reentra nt t ubewas situ ated on t he opposite side of midline so tha t th e centerof the r ecording area and t he reentr ant tube were equidistan tfrom t he th ermodes.

Experim ental protocol. Immediately after sur gery, the ani-mal, still in the stereotaxic device, was placed in the experi-menta l setup. Ath ermocouple was inserted into the h ypotha -lamic reentra nt tu be to measur e TPOAH. An integrated Ts wa sobtained from six thermocouples, wired in parallel, attachedt o va ri ous ski n a r e a s a bout t he a ni ma l s t runk . A t he rmo-couple was inserted 2.03.0 cm into the rectum to monitorcor e t e m pe r a t u r e. T h e a n i m a l w a s w r a p pe d i n a w a t er -pe rfuse d bl a nke t t o c ont rol ski n a nd core t e mpe ra t ure s.Be ca use c ha nge s i n scrot a l t e mpe ra t ure a re known t o ha vestrong effects on th e EE G (19, 20), we were careful tha t thewater -perfused blan ket did not extend to the scrotal ar ea. The

ra t e of c ha nge of bot h TPOAH a n d Ts wa s 0.51.0C/min.TPOAH w a s m a i n t a i n e d a t 3738 C duri ng Ts ma ni pul a -t i o n s , a n d Ts w a s m a in t a i n ed a t 3638 C duri ng TPOAHmanipulations.

A glass m icroelectr ode, previously pu lled to a resista nce of1015 M using a model P-87 Flam ing Brown MicropipetteP u l le r (S u t t er I n s t r u m en t ) a n d fi ll ed w it h a 3 .0 M N a C lsolution, was st ereotaxically advanced thr ough th e ta rgetarea with the use of a Trent Wells hydraulic microdrive untila cell was detected. Single-unit firing detected by the elec-t rode wa s pa sse d t o a Gra ss hi gh-impe da nce probe . Thesignal was am plified and filtered by a Grass pream plifier andviewed on a Tektr onix S113 oscilloscope. Action potentia lswit h a si gna l -t o-noise r a t i o gre a t e r t ha n 3:1 were pa ssedth rough a window discrimina tor (our d esign). The discrimina-

tor output was digitized and stored on a personal computer asfiri ng ra t e fre que ncy a ve ra ge d over 10-s e pochs. The ra wsingle-unit firing data were also stored on polygraph paper.After a cell was discriminated it was recorded for up to 1 hwhile Ts a n d TPOAH were manipulated. The microelectrodewas then advanced until another cell was located.Arecordingsession lasted several hour s, durin g which th e microelectr odewas m oved to different P OAH sites.

Data recording and EEG analysis. EEG, single-unit activ-ity (SUA), and four temperatures were recorded continuouslythroughout the experiments. The EEG signal was recorded onpa pe r by a Gra ss mode l 7 pol ygra ph a t a c ha rt spe e d of 5mm/s. EEG stat e ana lysis was done manu ally by scoring th e

polygraph records in 10-s epochs (13). In urethan-anesthe-tized rats, five EEG states can be distinguished as previouslyd e scr i be d (1 3). S t a t e 1 E E G i s a l ow -a m p l it u d e , h i gh -fre quenc y pa t t e rn simi la r t o t he EEG of a n a wa ke a ni ma l .St a t e 3 EEG i s a hi gh-a mpli t ude, l ow-fre que ncy pa t t e rnsimilar to the EEG of non-rapid eye movement sleep. State 2EEG consi st s of ra pi d a l t erna t i ons be t we en st a t e s 1 a nd 3EEG pat terns, an d it can vary from being almost all state 1 to

bei ng a l most a l l s t a t e 3. St a t e s 4 a nd 5 a r e most ly se e n i nanimals that are hypothermic. State 5 EEG is characterizedby alternat ing high spikes and very low amplitude waves. State 4,like state 2, is a transition state and consists of alternationsbetween state 3 and state 5 activity in varying proportions.

Te m pe r a t u r es s t or e d on t h e com p u t er w er e TPOAH, Ts,rectal temperat ure, and t he water-perfused blanket tempera-tu re. Inpu ts from ther mocouples were processed by a cust om-made signal conditioner, which converted the temperaturesigna l t o a vol t a ge i nput for t he comput e r. A t i me c odegenerator was synchronized with the computer time clock,an d 10-s inter vals were recorded on th e polygraph paper.

Histology . At t h e e n d of a n e xp er i m en t t h e a n im a l w a se ut ha ni z e d by a n i nt ra c a rdi a l i nj e c t i on of a ge ne ra l a ne s-th etic (50 mg/kg ketam ine, Par ke-Davis; 10 mg/kg aceproma -zine, Tech-American ; an d 5 m g/kg xylazine, Miles Labora tories).The brain was removed, quickly frozen in 2-methylbutane at40C, and mounted for sectioning. The brain was sectionedinto 30-m sections on a cryostat (Hacker Inst rum ents), andthe sections were dried and stained with cresyl violet. Theant erior/posterior and lateral position of the electrode t rackwa s e a sil y di st i ngui sha ble from t he sli des. The re cordeddepth of the electrode, as determined st ereotaxically duringthe recording session, was used to pinpoint the actual record-ing site.

Data analysis . One-way analysis of variance (ANOVA) wasused to determine whether th ere was a significant (P 0.01)effect of EEG sta te on th e firing r ates of the individua l POAHu n it s. Sch effes F t e st wit h a n e rror ra t e se t a t P 0.01 wasused following a significan t overa ll ANOVA to mak e pa irwisecomparisons between EEG state groups.

To de t e rmi ne t he TPOAH sensitivity of a cell, i ts thermalcoefficien t (Tc; impulses per second per degree Celsius) wasdetermined by linear regression (frequency vs. T POAH ) overthe temperat ure ran ge of maximum slope (7, 8). A minimumtemperatu re r ange of 2C was used for calculating t he slope.As in pr evious st udies, a cell was classified as wa rm sensitiveif the slope was 0.80 and cold sensitive if th e slope was0.60 (for r eview, see Ref. 5). All oth ers were classified asinsensitive. Responsivity of POAH cells to chan ges in Ts wa salso determined by linear regression (frequency vs. T s ), andthe same criteria were used for classifying t he cells a s wereused for TPOAH sensitivity.

In the cases of cells with T c values that classified them asTPOAH se nsit i ve or Ts re sponsi ve , furt he r a na l yse s wereperformed to determine whether each cell was TPOAH sensi-

t i ve or T s responsive independent of EEG chan ges. Theseadditional analyses were threefold. 1 ) The Tc of each cell wasdetermined within the states characterized by uniform EEGpat tern s (states 1 a nd 3; Ref. 13). If th e Tc within EEG state 1or 3 met th e criteria a s outlined a bove, the cell was classifieda s TPOAH sensitive or Ts responsive. However, if th e T c withinboth E EG stat es 1 and 3 did not meet with t he above criteria,th e cell was classified as appea ring to be TPOAH sensitive or Tsresponsive. EEG state 2 was not used in this analysis becausei t c onsi st s of va ryi ng pe rce nt a ges of st a t e 1 a nd st a t e 3activity. States 4 a nd 5 were n ot used for th is ana lysis becauset he y a re a ssoci a t ed wit h body t e mpera t ur e s out si de of anorma l ra nge (13). 2 ) F or a ce ll t o b e cl a ss ifi ed a s on l y

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appearing to be T POAH sensitive or Ts responsive, the cell alsoha d t o show st a t i st i c a l l y si gni fic a nt c ha nge s i n firi ng ra t ewith changes in EEG according to criteria as stated above. 3 )If a cell only appeared to be T POAH sensitive or Ts responsiveb y t h e fi r s t t w o t e s t s s t a t e d a b o v e , a t h i r d a n a l y s i s w a sperformed. This analysis was a determination of the effect ofTPOAH or Ts on the EE G state of the an imal. It was done by aone-way ANOVA for ea ch cell to determine wh ether th ere wasa significant (P 0.01) effect of T

POAHor T

son t h e EEG st a t e

of t he a ni ma l for da t a use d t o de t e rmine t h e T c of the cell.Sch effes F t e st wit h a n e rror ra t e se t a t P 0.01 was usedfollowing a significant overall ANOVA to make pairwisecomparisons between EEG state groups. Although a positivecorr elation was n ot considered necessary for classification of acell as only appear ing to be TPOAH sensitive or Ts responsive, itwa s consi dere d t o be furt he r e vi dence t ha t t he cha nge s i nEEG were brought a bout by th e chan ges in either T POAH or Tsa nd t ha t t he firi ng ra t e of t he ce ll wa s pri ma ri ly re fle ct i ngthese EEG changes rather than a thermoregulatory process.

B e c a u s e o f t h e n a t u r e a n d r e s u l t s o f t h e s t u d y , i t w a sd ee m ed n e ce ss a r y t o com p a r e ou r d a t a w it h d a t a fr ompreviously published studies. The question to be asked waswhether our data set was equivalent to the data sets on whichpre vi ous st udi es ba sed t he i r i nt e rpret a t i ons. To m a ke t hi s

possible , we a na l yze d our da t a usi ng t he most st ri nge ntcriteria used in previous studies (5). Statistical comparisonsof th e nu mbers of cells with in each classificat ion gr oup in t hepresent study with those from pr evious studies were done by

a power a na l ysi s usi ng confide nce i nt e rva l s of 99%. Thisr e su l t ed in t h e a b il it y t o d e t er m i n e w h e t h er or n ot t h enumbe rs of ce ll s wit hi n e a ch cl a ssi fica t i on group i n t hepresent study were significantly different (P 0.01) fromth ose of previous s tu dies.

RESULTS

A total of 66 cells from 28 u reth an -anesthet ized r atswas characterized in terms of responsivity to changesi n EEG s t a t e a n d T s and sensitivity to TPOAH . Figure 1summarizes the anatomic distribution of these cells.Most of the cells in this study were recorded in thelatera l and medial preoptic area s.

S UA responses to EEG states. Changes in EE G statewere elicited wh ile recordin g from 55 of the 66 cells. Ofthese 55 cells tested, 41 (75%) showed significant (P 0.01) cha nges in firing ra te with cha nges in th e corticalEEG sta te of the a nimal.

SUA responses to TPOAH manipulations. TPOAH wa smanipulated while recordings from 27 of the 66 cellswere made. Of the 27 cells tested, 5 cells (18%) were

war m s ensit ive, 1 (4%) was cold sens itive, an d 21 (78%)we r e t e m p e r a t u r e i n s e n s i t i v e . Th e wa r m - a n d c o l d -sensitive cells were th ermosensitive within E EG st ates1 an d/or 3. Figure 2 sh ows one cell (cell 1911 ) t h a t h a d

Fig. 1. Anatomic distribution of cells recorded. Dots in dicat e a pproximat e locations of cells recorded. AC, anter iorcommissure; AHA, anterior hypothalamic area; AVPO, anterioventral preoptic nucleus; BST, bed nucleus of thestria terminalis; HLDBB, horizontal limb of the diagonal band of Broca; LAH, lateral anterior hypothalamicnucleus; LHA, later al hypothala mic area; LPOA, latera l preoptic area; MPOA, medial preoptic area; MPON, medialpreoptic n ucleus; P VN, para ventricular nucleus; StH, striohypothalamic nucleus; 3V, third ventricle; ZI, zonaincerta.

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Tc values 0.80 for all EEG states during which itwas recorded. Because these EEG states include 1 and3, this cell was classified a s TPOAH sensitive. In addition,this cell did not show significant changes in firing ratewith chan ges in E EG st ates, supporting t he conclusionthat this cell was indeed responding to TPOAH , n o t t oc h a n g e s i n EEG s t a t e s b r o u g h t a b o u t b y c h a n g e s i nTPOAH .

Six of the 21 temper atu re-insensitive cells appear edt o b e TPOAH sensitive if EEG state changes were ig-n or e d . Fi ve a p p ea r e d wa r m s e n si t iv e, a n d on e a p -

peared cold sensitive. Within E EG st ates 1 an d 3, all ofth ese cells were insen sitive to chan ges in TPOAH or therew er e n ot e n ou g h d a t a t o m a k e t h a t d et e r mi na t ion(either the cell was not recorded during EEG state 1and/or 3, or data within state 1 and/or 3 did not span2 C) . I t i s i m p o r t a n t t o n o t e t h a t wh e n e v e r s t a t e 1and/or 3 Tc determinations were not available, a ppar-e n t t h e r m os e n si t iv it y wa s d e pe n d en t on d a t a fr oms t a t e s 2 a n d / o r 4 . Be c a u s e s t a t e s 2 a n d 4 c o n s i s t o f continuous, temperature-dependent mixtures of EEGactivity characteristic of the other states, the assump-tion ofE EG dependence of the appa rent t hermosensitiv-ity was warranted. For example, Fig. 3 presents datafrom a cell that appear ed to be warm sen sitive to TPOAH.

This apparent warm sensitivity was due to T c values0 . 8 0 d u r i n g E E G s t a t e s 2 a n d 4 . T h i s c e l l h a dsignificantly different firing rat es in stat es 1 and 3 a t aTPOAH of38C. Because st at e 2 in th is cell consisted ofpredominant ly sta te 3 activity at th e highest TPOAH a n dm o s t l y s t a t e 1 a c t i v i t y a t t h e l o we s t T POAH, t h e c e l lappeared to be thermosensitive in state 2. Similarly,state 4 in this cell consisted predominantly of state 3a c t i v i t y a t 3 8 C a n d t h e a m o u n t o f s t a t e 3 a c t i v i t ydeclined with temperatur e. The conclusion was thatthis cell was r esponding to EEG chan ges a nd was n otintr insically th ermosensitive.

Table 1 shows the data for the 12 cells that were orappear ed to be TPOAH sensitive (had Tc values of0.60or 0.80 for TPOAH ). This t able gives th e overa ll Tc forthe cell , the Tc for the cell in each EEG state duringwh ich i t wa s r e cor d e d, t h e EEG r e s pon s iv it y, t h einfluence of TPOAH on EEG state for each cell , and t heresulting classification of each cell. Because the Tc foreach cell was determ ined over the tem perat ur e ran ge of

m a x im u m s lop e , t h e TPOAH i n e a c h E E G s t a t e w a sdetermined for th ose dat a used to determine th e Tc. TheEEG state responsivity, on th e other h and, was deter-mined for the entire time the cell was being recorded.

Closer in spection of Table 1 shows tha t our met hodol-ogy not only enabled us t o detect cells tha t a ppeared t obe TPOAH sensitive when they were actually EEG sta terespons ive (e.g., cell 612, Fig. 3), but we were a lso ableto detect TPOAH-sensitive cells that would not have beenso classified if data from all EEG states were combined.One such cell was cell 1041. The overall Tc of this cellwa s 0.18. However, in state 1 its T c wa s 0.92, andwithin th is stat e it was clearly TPOAH warm s ensitive.

S UA responses to Ts manipulations. Ts was manipu-lated while recordings from 58 of the 66 POAH werem a d e . W h e n EEG wa s n o t t a k e n i n t o a c c o u n t , 1 1 o f these 58 cells (19%) appeared to be warm responsive, 6(10%) appeared to be cold responsive, 2 (3%) appearedto be both warm and cold responsive, and 39 appearednonresponsive. However, when EEG was taken intoaccount, none of these cells were t herm oresponsive int h e u n i f o r m EEG s t a t e s 1 o r 3 . Al l o f t h e c e l l s t h a tappeared to be responsive to T s were also responsive(P 0.01) to EEG state chan ges, possibly indicatingthat these cells could have been responding not to T s,but to the EEG state changes (Table 2). Most of thesecells a lso showed significant effects of Ts on EE G s t a t e(Table 2). There were no cells recorded in this studythat responded to changes in T s without a concomitan tcha nge in EEG.

Fig. 2. Preoptic anter ior hypothala mus (POAH) warm -sensitive cell(cell 1911 ) . Each point is average firing ra te of the cell over a 10-sepoch. Symbols denote electroencephalographic (EEG) state of theanim al du ring each 10-s recording epoch. (For deta ils of ana lysis seeTable 1.)

Fig. 3. POAH cell (cell 612 ) that appears warm sensitive. Each pointis average firing rate of the cell over a 10-s epoch. Symbols denoteEEG state of the a nimal during each 10-s recording epoch. (Fordetails of analysis see Table 1.)



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Figure 4 shows data for one cell that appeared to bewarm responsive to Ts. Dur ing th e recording of th is cell,the E EG sta te of the a nimal was str ongly related to Ts.The firing rate of the cell was significantly higher insta te 3 tha n in sta te 1. Once again, stat e 2 consists of atemperatur e-dependent m ixtur e of state 1 an d stat e 3

activity, with state 3 activity predominant at the high-e s t t e m p e r a t u r e a n d s t a t e 1 a c t i v i t y p r e d o m i n a n t a tthe lowest temperatu re. Therefore, the a pparent ther-morespons iveness of th is EE G sta te-selective cell is dueto the t emperature dependence of the EE G stat e of theanimal.

Figure 5 shows an interesting case in which a cellcou ld a p pe a r t o b e b ot h w a r m s en s it ive a n d coldsensitive. Cell 1044 h a d a h i gh e r fir i n g r a t e in s t a t e 1than in state 3. State 1 could be stimulated by eitherhigh or low T s. Thus, in F ig. 5A , a 2.5-min segment ofr e cor d in g b egi n s w it h a n e u t r a l b l a n ke t a n d s k in

t e m p e r a t u r e , a n d t h e E E G i s s t a t e 2 d o m i n a t e d b ystate 3-like activity. In response to the lowering of blanket temperature, Ts f a l l s a n d t h e EEG s h o ws a nincreasing a mount of stat e 1-like activity unt il i t isfinally all state 1. The firing ra te of the cell increases a sTs falls and EEG state 1 activity increases. Thus the

cell appears to be cold responsive with a T c of 4.4(Table 2). In contrast, Fig. 5B is a 2.0-min recording oft h e s a m e ce ll , wh i ch b eg in s wit h b la n k e t a n d s k int e mp er a t u r e s a t h ig h l ev els . U n d er t h e se t h e r m a lconditions th e anima l is in EE G stat e 1 and t he cell hasa h igh firing rat e. As blanket temperatu re is return edt o a n eu t r a l t e m pe ra t u r e, Ts fa lls , a n d t h e E E Gp r og r es s es f r om s t a t e 1 t o s t a t e 2 t o s t a t e 3 , a n d t h efiring rate of the cell declines. Now the cell appears tobe warm r esponsive with a T c of 9.24 (Table 2).

Table 2 shows the data for all 19 of the 58 cells thath a d Tc values of0.60 or 0.80 for Ts. This ta ble

Table 1. Data from cells with therm al coefficients (either overall or with in E EG state 1 or 3)to classify them as TPOAH sensitive

Cell Number (T c, Cla ssifica t ion ) E E G St a t e Tc Frequ ency, spikes/s n TPOAH , C n

Cell 611 (Tc0.90, a ppea r wa r m sen sit ive) 134

ND0.650.90

13.51.215.71.511.54.3

37.40.735.11.135.54.5

54

13 9Cell 612 (Tc0.90, a ppea r wa rm sensit ive) 1

234

ND

0.89ND0.79

6.50.7

14.8

3.7*18.81.8*15.03.2*

6

631210

34.14.6

38.4

0.133.44.0

0

15410

Cell 831 (Tc0.82, a ppea r wa rm sensit ive) 34

ND0.74

4.01.02.71.3

37.20.636.21.4

1943

Cell 911 (Switch: off TPOAH35C, wa rm sen sit ive) 23

0.130.15

0.80.81.01.3

36.82.436.22.3

6360

Cell 1025 (Tc1.23, a ppea r wa rm sen sit ive) 123

ND1.350.20

9.72.56.32.1*3.41.0*

737391

36.90.234.31.3*35.21.2*

402739

Cell 1041 (Tc0.18, wa r m sen sit ive) 123

0.920.010.22

15.83.113.41.8*10.81.6*

33.53.034.02.635.91.0*

187576


1.0NDND

9.74.110.92.511.52.4

34.12.636.41.8*36.70.1*

802021


234

0.84

0.980.950.88

21.73.1

22.6

3.223.43.022.72.6

33

405112 2

31.81.8

33.1

2.635.02.5*35.92.5*

18

282958

Cell 2911 (Tc1.24, a ppea r cold sen sit ive) 123

ND1.25

ND

9.42.611.33.8

8.42.1

527 4

64

35.43.136.70.3

092

2Cell 2915 (Tc1.18, a ppea r wa rm sen sit ive) 2

34

1.03ND0.03

5.21.05.20.40.80.2

4339

31.40.930.11.1

507

Cell 3121 (Tc2.40 cold sen sit ive) 23

ND2.85

3.21.32.31.8

19 610 4

30.50.329.70.8

410

Cell 3132 (Tc1.57 wa r m sen sit ive) 23

0.602.20

7.15.211.94.1

10 812 8

30.11.229.81.1

512

Included are overall thermal coefficient (T c) for each cell, Tc of each cell within ea ch electroencephalograph ic (EEG) sta te, mea n SD firingrat e of each cell in each EE G sta te (for all data ), mean SD preoptic anterior hypothalamus (POAH) temperature (T POAH ) during each EEGstat e (for all dat a), the classification of each cell, and nu mber of 10-s epochs during which th e cell was recorded. ND mea ns t here a re no dat a t odetermine a Tc for th at cell in tha t E EG sta te for 1 of 2 reasons: none of the dat a used t o determine overall T c (temperature range of maximumslope with a m inimum temperat ure ra nge of 2C) was in a particular EEG sta te or the temperature range within an EEG sta te was not 2C.n No. of 10-s epochs averaged to obtain mean SD. Number in one 10-s epoch is a verage firing ra te (or tempera tur e) for the cell (or P OAH)during th at 10-s epoch. n Values at rightare the number of 10-s epochs used for determination of T c of the cell in each EEG state as described inMATERIALS AND METHODS. These values were also used to determine effect of TPOAH on EEG state. n Valu es in mi d d l e are for th e entire time tha tthe cell was being recorded (where different from t ime used to determ ine T c) and were used t o determine significant differences between EE Gstate and firing rate. *Significantly different from EEG state 1, P 0.01. Significant ly different from EE G sta te 2, P 0.01. Significantlydifferent from EEG st ate 3, P 0.01.

R1 3THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH


7/11

Table 2. Data from cells with therm al coefficients to classify them as Ts responsive

Cell Number (Tc, Cla ssifica t ion ) E E G St a t e Tc Frequ ency, spikes/s n Ts , C n

Cell 612 (Tc1.92, a ppea r wa r m r espon sive) 1234

0.651.91

NDND

6.50.7414.83.7*18.81.8*15.03.2*

6631210

32.30.936.02.2*37.30.9*38.40.1*

6321210

Cell 714 (appears war m responsive Ts34.5, Tc4.43, nonrespon-sive Ts34.5, (Tc0.09)

1234

0.240.990.291.97

3.71.713.11.8*16.03.6*12.24.5*

31.12.337.40.9*37.40.7*37.41.2*

14191122


0.07NDND

27.12.89.46.1*4.22.4*

36.50.533.50.6*34.70.7*

3535

Cell 1025 (Tc1.40, a ppea r cold r esponsive) 123

0.580.300.20

9.72.56.32.1*3.41.0*

737391

33.81.735.80.6*36.01.1*

326831

Cell 1041Overall Tc0.62 1

23

ND0.65

ND

15.83.113.41.8*10.81.6*

35.00.437.10.6*36.60.3*

187576

Ts36.5C, Tc2.77 123

NDNDND

18.51.413.31.4*10.11.9*

35.00.436.90.1*36.40.3*

83332

Ts36.5C, Tc2 .8 2, a p pe a r s b ot h w a rm a n d col d r e sp on s ive 23

2.06ND

13.22.010.81.7

37.40.736.80.3

2851

Cell 1044Overall Tc0.63 1

23

0.75

0.85ND

12.92.1

4.52.0*2.80.8*

36.91.5

36.60.936.90.2

27

2815Ts36.6C, Tc4.40 1

23

ND2.88

ND

11.82.05.82.2*2.50.4*

34.60.235.30.736.40.3*

872

Ts36.6C, Tc9 .2 4, a p pe a r s b ot h w a rm a n d col d r e sp on s ive 123

NDNDND

13.71.74.11.8*2.80.8*

37.80.337.00.3*36.90.1*

192113


ND2.59

ND

4.41.67.93.0*

12.21.0*

232110

31.70.434.80.8*37.00.2*

31610


0.35ND0.37

27.03.026.71.920.81.9*

38.02.238.90.335.71.0*

206

20Cell 2473 (Tc0.60, a ppea r cold r esponsive) 2

30.280.50

5.91.24.32.0

35.40.635.91.0

1654


3

2.69

ND

11.83.6

14.62.7

35.80.5

36.90.1

76

40Cell 2831 (Tc1.55, a ppea r cold r esponsive) 23

NDND

43.51.341.71.2

34.80.435.60.4

2047

Cell 2913 (appears t o be a warm responsive switching cell that is offTs40C)

123

NDND0.06

1.91.82.01.50.20.8*

40.30.240.10.136.54.0*

228

30Cell 2914 (appears t o be a warm responsive switching cell that is off

Ts40C)123

NDND0.07

2.51.02.61.00.20.6*

40.11.040.20.435.53.7*

161844


NDND

5.12012.60.9

10423

36.5 0.437.30.4

4320


ND6.68

ND

7.21.313.69.9*32.71.7*

34.60.634.31.437.70.9*

186324


0.380.27

3.21.32.31.8

196104

35.80.536.40.4

13 872


3

2.16

0.42

7.15.2

11.94.1

36.60.7

36.50.5

10 8

12 8Cell 3532 (Tc3.52, a ppea r wa r m r espon sive) 345

NDNDND

11.82.88.41.6

14.34.1

361717

37.50.336.40.437.10.3

91713

Cell 3811 (Tc0.90, a ppea r cold r espon sive) 234

0.540.370.35

4.00.88.61.16.31.1

36.70.934.71.434.71.2

582918

Included are overall Tc for each cell, Tc of each cell within ea ch EEG st ate, mea n SD firing rat e of each cell in each EEG st at e, mean SDskin temperature (T s ) during each EEG state (for data corresponding to the Tc), the classification of each cell, and number of 10-s epochsduring which t he cell was recorded. n No. of 10-s epochs averaged to obtain mean SD. Number in one 10-s epoch is average firing rate (ortempera tur e) for the cell (or skin ) during th at 10-s epoch. n Values at rightare the number of 10-s epochs used for determination of T c of the cellin each EEG sta te as described in MATERIALS AND METHODS. These values were a lso used to deter mine effect of Ts on EEG state. n Values inmi d d l e are for the entire time that the cell was being recorded (where different from time used to determine T c) and were used to determinesignificant differences between EEG state and firing rate. *Significantly different from EEG state 1, P 0.01. Significantly different fromEEG state 2, P 0.01. Significant ly different from EE G sta te 3, P 0.01. Significant ly different from EE G sta te 4, P 0.01.


8/11

gives th e overa ll Tc for each cell, the Tc for each cell ineach EEG st at e during which it was r ecorded, the E EGresponsivity, the influence of T s on EEG state for eachcell, and the resulting classification of each cell. Be-c a u s e t h e Tc for each cell was determined over thetemperature range of maximum slope, the T s in each

E E G s t a t e w a s d et e r min e d f or t h os e d a t a u s ed t od e t er m i n e t h e Tc. The EEG state responsivity, on theother hand, was determined for the entire time the cellwas being recorded.

D IS C U S S ION

If the POAH is the thermointegrative center of the

brain, it sh ould be possible to record from POAH cellstha t respond to cha nges in both T POAH and Ts. A n u m b e rof investigators have un dertaken such studies in ur e-t h a n - a n es t h e t iz ed a n i m a ls , a n d t h e s e s t u d i es h a v eyielded results that seem to support the basic premisethat peripheral temperat ure informat ion is integratedin the POAH (4, 17, 18, 31, 34; see Ref. 3 for a review).There was an un ant icipated confounding var iable, how-e ve r, wh ich u n d e r m in e s i n t er p r e t a t ion s of t h e d a t aobtained in t hese excellent stu dies. This confoun d h asthree components: 1 ) urethan-anesthetized rats showEEG state changes, some of which are similar to thosewhich chara cterize chan ges in ar ousal states in un an es-th etized an imals (12, 13, 19, 20, 22 24, 28, 30); 2 ) these

EEG state changes can be spontaneous (2224, 30),induced by thermal stimulation (12, 19, 20, 22) or avariety of other sensory modalities (22, 24, 28, 30); and3 ) m o s t ( 5 0 7 6 % ) POAH n e u r o n s a r e a r o u s a l s t a t eselective and vary their firing rates with changes inEEG activity (12, 13, 20, 22, 23, 28, 30). Therefore,u n l e s s EEG s t a t e i s m o n i t o r e d , i t i s n o t p o s s i b l e t odetermine whet her or not POAH SUA reflects a specific

Fig. 4. POAH cell (cell 3031 ) that appears responsive to increases inskin temperature (Ts ). Ea ch point is average firing ra te of the cellover a 10-s epoch. Symbols denote EEG state of the animal during

each 10-s recording epoch. (For deta ils of an alysis see Table 2.)

Fig. 5. Recordings of firing of a POAH cell(cell 1044 ) and th e simulta neous recordings ofthe EE G, Ts (in C), and water-perfused blan-k e t t e m p er a tu r e (Tbl; in C). A: 2.5-min seg-ment of the recording during which T bl a n d Tsbegan at a n eutr al level and were lowered. AsTs falls, EEG sta te chan ges from being mostlystate 3-like activity to being all state 1 activ-ity. Firing rat e of this cell was higher in st at e 1than in stat e 3, and therefore it a ppears to becold sensitive. B : 2.0-min segment of the re-cording during which Tbl a n d Ts b e g in a t ahigh level and are lowered to neutra l. At thebeginning of this recording the EEG state is 1

and the cell has a high firing rate.As tempera-tures fall, EEG state changes through 2 to 3a n d th e ce ll h a s a low er fi r in g r a te . D u r in gthis segment the cell, therefore, appears to bewar m sensit ive. F-F, fronta l-front al; F-O, fron-ta l-occipita l; SUA, single-unit activit y.



9/11

stimulus modality independently of changes in EEGactivity, which in t ur n a re driven by th e applied stimu-lus. Therefore, our goal was to test wh ether ther e werePOAH cells that were thermosensitive and/or thermore-sponsive independen t of EE G st at es. Such cells wouldbe candidates for playing r oles in thermoregulatoryintegration.

Our results are in agreement with previous studieson two counts. First , there are POAH cells that havefiring rates th at are a function of EEG state. Of the 55POAH cells we recorded in different EEG states, 75%were EEG state selective. This is within the range (5076%) of, and is not significantly different from, thenumbers of EEG state-responsive neurons recorded inprevious st udies (12, 19, 20, 2224, 28 30). Second, ourstudy also shows POAH neurons that are sensitive tol oca l t e m p er a t u r e ch a n g e s w it h i n u n i for m , E E G -defined ar ousa l states. Pr evious studies show a ran ge of8 70% of POAH neu rons as TPOAH sensitive, dependingon t he ar ousal stat e of the a nimal, with more neuronstemperatur e sensitive during wake th an non-rapid eye

movement sleep (10, 11, 26, 27). The number of T POAH-sensitive cells found in this stud y (22%) is not signifi-cantly different from the numbers of TPOAH-sensitiveneur ons recorded in previous st udies.

The present study is not in agreement with previousstudies that reported T s-responsive cells in the POAH.These various studies on a number of species usingdifferent meth ods of therma l stimulat ion h ave foun d anaver age of 22% of th e POAH cells responsive t o cha ngesin periphera l tempera tu re, with a r an ge of 339% (for areview, see Ref. 3). In the present study done on rats,using a water-perfused blanket for manipulating T s,3 3% o f t h e POAH ce ll s r e cor d e d a p p ea r e d t o b e Tsresponsive if EEG state changes were ignored. This

33% is not significantly different from the 22% averagein pr evious report s. However, of the 19 cells recorded int h i s s t u d y t h a t a p p ea r e d t o r e s p on d t o ch a n g e s i n T swith changes in firing rate, none responded to changesin Ts independently of EEG st ate changes. All of thesecells were EEG state selective, and none showed Tcvalues of0.60 or 0.80 within th e un iform EEGstates 1 and 3. Most showed significant effects of T s onE E G s t a t e, w h ich in d ica t e s t h a t t h e ch a n g es in Tsdetermined the EEG state, which in turn determinedthe firing rates of the cells. Although all of these cellsshowed significant differences in firing ra tes with achange from a t least one EE G stat e to another, in someca s es t h e m e a n Ts between the corresponding E EG

sta tes were n ot significantly different (e.g., cell 2473 ),indicating again that firing rate was correlated withEEG s t a t e ch a n g e s r a t h e r t h a n ch a n g e s in Ts. There-fore, there were no POAH cells found in the presentstu dy tha t were un equivocally Ts responsive.

There is the possibility that cells that respond to T swere simply missed in this study. However, statisticalanalysis showed that enough cells were recorded (givent h e a v e r a g e n u m b e r o f p u r p o r t e d T s-responsive cellsfound in pr evious studies), so tha t there is only a 1%chance tha t actual Ts-responsive cells were m issed. It isalso possible that some of the cells we recorded may

ha ve been foun d to be Ts responsive in EEG st ates 1 or 3i f we h a d b ee n a b le t o m a n i p u la t e Ts over a broaderran ge with out disrupt ing the st at e. It is very difficult t ocha nge Ts of an an esthet ized an imal significan tly with-out producing EEG state chan ges. Pr esumably, th iswou l d h a v e b ee n t r u e of p r e v iou s s t u d ie s a s wel l.Apparent thermoresponsiveness was associated in vir-t u a l l y a l l c a s e s wi t h EEG s t a t e 2 o r 4 . Th e s e s t a t e s

consist of temperat ur e-dependent, cont inuously vari-able proportions of states 1 an d 3 or sta tes 3 an d 5 EEGactivity, respectively. Close inspection of the EEG andunit activity recordings reveal a very close associationof moment-to-moment changes in EEG activity and cellfiring rates, indicating that the primary effect of T s inthese experiments was to alter EEG activity, which inturn determined firing rates.

An important conclusion from this study is that it isessential to monitor EEG when recording the activity ofneurons in the POAH to determine their responsive-ness t o various m odalities of stimulat ion. Th is is not anew conclusion; th e point was made 30 years ago. In1967, while investigat ing th e effects of progester one onneur al activity, Komisaruk an d co-workers (22) wrote,...we were impres sed by th e str iking tem poral corr ela-tion between chan ges in activity of single neur ons an dalterations in the arousal level of the cortical EEG.Since elevated activity of the majority of the neuronswe observed was closely correlated with cortical arousal,it was imp era tive to distinguish th e effects of progester-one that might be produced indirectly by an inducedchange in arousal from the effects on particular neu-rons independent of changes in brain arousal. Thisconclusion has been reiterated by other investigators(10, 23, 24).

Other studies of thermoregulatory integration havealso called attention to the EEG state selectivity of neur ons as being a confoun ding variable that ha s led toprobably false conclusions tha t cells ar e involved inthermoregulatory processing of informat ion. Grahnand colleagues (12, 13) investigated the ther morespon-siveness of cells in the rostra l ventromedial medullaand in the subceruleus area that were purported to beinvolved in ther moafferen t informa tion processing. Theconclusion of those studies was that virtually none ofth ese cells responded t o Ts within an EEG-defined state(one rostral ventromedial medulla cell was thermore-sponsive without a change in EEG activity). Rather,most cells were arousal state selective, and thermalstimulation of the skin altered arousal states. Kanosuea n d col le a gu e s (1 9, 2 0) e xa m i n ed t h e r e s pon s e s of diencephalic cells to therma l stimulation of t he scro-tum, and they also concluded that the cell responseswere not specific to the thermal stimulus but reflectedEEG activation caused by the thermal stimulation aswell as other modalities of stimulation.

Perspectives

The dat a from this stu dy have profound implicationsfor views of t he thermointegrative processes of t hemammalian central nervous system. Those views arebased on observed thermosensitive and thermorespon-



10/11

sive properties of cells. For a cell to qualify for inclusionin a model of thermointegrative processes, i t shouldhave thermal properties that are independent of EEGstate changes. This is not to say that such a cell couldnot be EE G stat e selective in a ddition t o being ther mo-responsive or ther mosensitive, but its chan ges in firingr a t e s h ou l d n o t b e s ol el y d e pe n d en t on EEG s t a t echange. In the unanesthetized animal, thermoregula-tion occurs cont inuously during wake or non-rapid eyemovement sleep. The activity of cells involved in ther-m o r eg u la t o r y i n t e gr a t i on s h ou l d , t h e r e for e , r e flectchanges in peripheral temperature without changes inEEG s t a t e . A ce ll t h a t on l y c h a n ge s fir i n g r a t e wit hchanges in EEG state cannot be responsible for continu-ous regulatory processes within a state. Because wefou n d n o POAH ce ll s t h a t r e s pon d e d t o Ts withoutcor r e s pon d in g EEG ch a n g e s, we h a v e t o con cl u de ,contra ry to current models of th ermointegration, tha tthe POAH is probably not the site of integration of peripheral temperatur e informat ion for purposes of thermoregulation.

Yet, we kn ow t hat peripheral temperatur e informa-tion is used in thermoregulation. The threshold T POAHfor activating thermoregulatory responses shift in re-s p o n s e t o c h a n g e s i n Ts. Th is observation, h owever,involves thermal stimulation in the POAH and in theperiphery while systemic thermoregulatory responsesa r e m e a su r e d. T h u s t h e in t e gr a t ion of ce n t r a l a n dperipheral temperature information could occur at anylocation between the POAH and the ultimate motoroutput neuron.

O u r in t e r pr e t at ion i s s u pp or t e d b y a n u m b er of experiments th at have examined therm oregulatory re-sponses t o Ts after partial or complete transections ofthe spinal cord. Many older studies showed th at after

complet e tra nsection of th e spinal cord at t he cervical orth oracic level, mam mals r egain th e ability to respond tocooling of the skin with vasoconstriction and shivering(for a review, see Ref. 33). Clinical observations ofparaplegic patients (9) report that spinal cord injuriesdo not prevent thermoregulatory responses (vasodila-tion and sweating) in areas innervated by the spinalcord below the level of the lesion. Cats (1, 6), monkeys(25), and rat s (2) ha ve been sh own t o regain th e abilityto respond to peripheral cooling eliminated by high-level transection (at the level of the superior colliculusto the mamm illary bodies) by subsequent low-leveltra nsection (at the inferior colliculus to the lowerone-third of the pons) in the same animal. Although

these responses are much reduced in comparison withintact animals and are not sufficient to maintain bodyt e m pe r a t u r e, it is im p or t a n t t o r e cogn iz e t h a t a lld e sce n d in g p a t h s i n t h e s e p r e pa r a t i on s h a v e b ee ns ev er e d, a n d e ve n if t h os e p a t h s a r e n ot d ir e ct lyinvolved in temperature regulation, they may play arole in modulating the general level of excitability ofspinal circuits. In a difficult series of experiments,Klussmann (21) selectively cut the ventr olateral fu-niculi of the spinal cord at th e cervical level in ra bbitsan d demonstrat ed no deficiencies in met abolich eat pr oduc-tion responses to sk in cooling. Because m ost a scending

thermosensitive fibers are found in the ventrolateral fu-niculi, it must be concluded that the peripheral thermoaf-ferent informa tion need n ot be communicated to th e hypo-thalamus to stimulate thermoregulatory responses.

The resu lts reported in th is paper, combined with th eresults of spina l tra nsection st udies, support a model ofthe thermoregulatory system in which hypothalamicther mosensitivity results in descending comma nds t ha tmodulate communication between peripheral thermo-sensors a nd th ermoregulatory effectors at lower levelson t he n eura l axis. This conclusion su pports th e earlierview of Sa tinoff (32) who wrote, I suggest tha t th ehypotha lamu s is not the sole integra tor of body tempera -ture. Rather, i t is the most important among many int h a t i t coor d in a t e s t h e a ct i vi t y o f o t h e r i n t eg r a t in gmecha nism s at lower levels of th e neu roaxis.

We are greatly indebted t o Dr. Dennis Grah n for his valu able helpand a dvice at a ll stages of this research.

Address reprint requests to N. J. Berner.

Received 31 July 1996; accepted in final form 10 September 1997.

R EFER EN C ES

1. A min i- S eresh k i, L. Brainst em contr ol ofshivering in th e cat. II.Facilitation. Am. J. Ph ysio l. 232 ( Regulatory Integrative Comp.Physiol. 1): R198R202, 1977.

2. A min i- S eresh k i, L. , an d M . R . Zarrin d ast . Brain stem tonicinhibition of thermoregulation in the rat. Am. J. Ph ysi o l. 247(Regulatory Integrative Comp. Physiol . 16): R154R159, 1984.

3. B o u l a n t , J . A . Hypothalamic control of thermoregulation. In: Handbook of the Hypothalmus, edited by P. J. Morgane and J.Panksepp. New York: Dekker, 1980, p. 182.

4. B o u l a n t , J . A . , a n d K . E . B i g n a l l . Hypothalamic neuronalresponses to peripheral and deep-body temperatures. A m . J .Physiol. 225: 13711374, 1973.

5. B o u l a n t , J . A ., a n d J . B . D e a n . Temperature receptors in t hecentral nervous system. Annu . Rev. Physiol. 48: 639654, 1986.

6. C h a m b e r s , W. W. , M. S . S e i g e l , J . D . L i n , a n d C . N . L i n .Thermoregulat ory responses of decerebrate a nd spinal cats. Exp .Neurol. 42: 282299, 1974.

7. D e a n , J . B ., a n d J . A. B o u l a n t . In vitro localization of th ermo-sensitive neur ons in th e ra t diencephalon. Am. J. Ph ysi o l. 257(Regulatory Integrative Comp. Physiol . 26): R57R64, 1989.

8. D e a n , J . B ., a n d J . A. B o u l a n t . Effects of synapt ic blockade onthermosensitive neurons in rat diencephalon in vitro. A m . J .Physiol. 2 5 7 (Regulatory Integrative Comp. Physiol. 26): R65R73, 1989.

9. D o w n e y , J . A . The spinal patient and thermoregulation. In:Therm al Physiology, edited by J . R. S. Ha les. New York: Raven,1984, p. 225228.

10. Fin d lay, A. L. R . , an d J. N . Hayw ard . Spontaneous a ctivity ofsingle neurons in hypothalamu s of rabbits during sleep a ndwaking. J. Physiol. (Lond.) 201: 237258, 1969.

11. G l o t z ba c h , S . F ., a n d H . C . H e l l e r . Ch a n g e s in th e th e r m a l

characteristics of hypothalamic neurons during sleep and wake-fulness. Brain Res. 309: 1726, 1984.

12. G ra h n , D . A ., a n d H . C . H e l le r. Activity of most rostralventromedial medulla n eurons reflect E EG/EMG pattern changes.

Am. J. Physiol. 257 ( Regulatory Integrative Comp. Physiol. 26):R1496R1505, 1989.

13. Grah n , D . A ., C . M. R ad ek e, an d H. C . Helle r. Arousal stat evs. temperature effects on neuronal activity in the subcoeruleusa r e a . Am. J. Physiol. 256 (Regulatory Integrative Comp. Physiol.25): R840R849, 1989.

14. Hamm el, H. T. Regulation of internal body temperature. A n n u .Rev. Physiol . 30: 641710, 1968.

15 . H a m m e l , H . T. , H . C . H e l l e r, a n d F. R . S h a r p . Probing th erostral brains tem of anest hetized, unanest hetized and exercising



11/11

dogs and of hibernat ing and eut herm ic ground squirrels. Federa-tion Proc. 32: 15881597, 1973.

16 . H e l l e r , H . C . Central nervous mechanisms regulating bodytemperature. In: Microwaves and Thermoregulation , edited by E.Adair. New York: Academ ic, 1983, p. 161190.

17 . H e l l o n , R . F . The st imulation of hypothalamic neurons bych a n g es in a m b ie n t te m p er a tu r e . Pfl u gers Arch . 321: 5666,1970.

18. Hellon , R . F. Hypothalamic neurons responding to changes inhypothalamic and a mbient temperatu res. In: Physiological an d

Behavioral Temperature Regulation, edited by J. D. Hardy, A. P.Gagge, and J. A. J. Stolwijk. Springfield, IL: Thomas, 1970, p.463471.

19. K a n o s u e , K . , T. N a k a y a m a , Y. I s h i k a w a , a n d T. H o s o n o .Threshold temperatures of diencephalic neurons responding toscrotal warming. Pfl u gers A rch . 400: 418423, 1984.

20. K a n o s u e , K ., T. N a k a y a m a , Y. I s h ik a w a , T. H o s o n o , T.K a m i n a g a , a n d A . S h o s a k u . Responses of thala mic and h ypo-thalamic neur ons to scrotal warming in rats: n on-specific re-sponses? Brain Res. 328: 207213, 1985.

21. Kluss ma nn , F. W. Ener gy production of rabbits before a nd a ftertransection of both ventro-lateral funiculi of the spinal cord. J .Therm . Biol. 8: 133135, 1983.

22. K o m i s a r u k , B . R ., P . G . M c D o n a l d , D . I . Wh i t m o y e r , a n dC . H . S a w y e r. Effects of progesterone and sensory stimulationon E E G a n d n e u ron a l a ct i vi t y i n t h e r a t . Exp . N eu rol. 1 9 :494507, 1967.

23. Linc oln , D. W. Correlation of unit activity in the hypothalamuswith EEG patterns associated with the sleep cycle. Exp. N eurol.24: 118, 1969.

24. Linc oln , D. W. Response of hypotha lamic units to stimu lation ofth e vagina l cervix: specific versu s non-specific effects. J . Endocri-n ol. 43: 683684, 1969.

25. L i u , J . C . Tonic inhibition of therm oregulat ion in t he decer-e b r a te m o n k e y (Saimiri sciureus ). E xp . Neurol . 64: 632648,1979.

26. P a r m e g g i a n i , P . L . , A . A z z a ro n i , D . C e v o l a n i , a n d G . F e r -r a r i . Responses of ant erior hypothalam ic-preoptic neur ons todirect thermal stimulation during wakefulness and sleep. Brain

Res. 269: 382385, 1983.27. P a r m e g g i a n i , P . L ., D . C e v o l a n i , A . Az z a r o n i , a n d G . F e r -

rari. Thermosensitivity of anterior hypothalamic-preoptic neu-rons during the waking-sleeping cycle: a study in brain func-tional sta tes. Brain Res. 415: 7989, 1987.

28 . Pf af f , D . W. , an d E. Grego ry. Correlation between pre-opticarea unit activity and the cortical electroencephalogram: differ-ence between normal and castrated male rats. Electroencepha-logr. Clin. Neurophysiol . 31: 223230, 1971.

29 . P f a ff , D . W. , a n d C . P f a ff m a n n . Olfactory and hormonalinfluences on the basal forebrain of the male rat. Brain Res. 15:137156, 1969.

30 . R amire z, V. D . , B. R . Komis aru k , D . I. Wh it moy er, an d C . H.S a w y e r . Effects of hormones an d vaginal stimulation on theE E G a n d h yp ot h a la m i c u n i t s i n r a t s . A m . J . P h ys iol. 212:13761384, 1967.

31 . R e a v e s , T. A ., J r . G a in of th e r m os e n sit iv e n e u r o n s in th epreoptic area of the rabbit, Oryctolagus cuniculu s. J . T h e r m .

Biol. 2: 3133, 1977.32 . S a t i n o f f , E . N e u r a l or g a n iz a tion a n d e volu tion of th e r m a l

regulation in mammals. Science 201: 1622, 1978.33 . S i m o n , E . Temperature regulation: the spinal cord a s a site of

extrahypothalamic thermoregulatory functions. Rev. Physiol. Biochem . Pharm acol. 71: 176, 1974.

34 . Wi t , A ., a n d S . C . Wa n g . Temperature sensitive neurons inpreoptic/anterior hypothalam ic region: effects of increasing ambi-ent temperature. Am . J. Physiol. 215: 11511159, 1968.


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