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Does the preoptic anterior hypothalamus receive

thermoafferent information?
Nancy J. Berner and H. Craig Heller
Am J Physiol Regul Integr Comp Physiol 274:9-18, 1998.

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Medicine .. Anesthesia

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Does the preoptic anterior hypothalamus
receive thermoafferent information?
NANCY J. BERNER1 AND H. CRAIG HELLER2
1Department of Biology, The University of the South, Sewanee, Tennessee 37383–1000; and
2Department of Biological Sciences, Stanford University, Stanford, California 94305–5020

Berner, Nancy J., and H. Craig Heller. Does the preop- perature (thermosensitive) and to Ts (thermorespon-
tic anterior hypothalamus receive thermoafferent informa- sive). There have been many single-unit studies of
tion? Am. J. Physiol. 274 (Regulatory Integrative Comp. POAH neurons on anesthetized and on unanesthetized
Physiol. 43): R9–R18, 1998.—The preoptic anterior hypothala- animals. These studies have demonstrated POAH units
mus (POAH) is considered the thermointegrative center of that are thermosensitive, either warm or cold sensitive.
the mammalian brain. Studies on anesthetized and unanes-
thetized animals have demonstrated neurons in the POAH
In addition, studies have reported units that respond to
that respond to changes in both POAH temperature (TPOAH ) changes in Ts (for reviews, see Refs. 3, 5). These data
and skin temperature (Ts ). In these studies, however, electro- seem to support models that place the integration of
encephalographic (EEG) activity was not monitored. Recent thermoafferent information in the POAH.
work has revealed the potential for arousal state selectivity of Recent investigations of putative thermoafferent
neurons combined with thermal influences on arousal state to pathways, however, have revealed a possible problem

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create the appearance that cells are thermosensitive or with the assumption that changes in firing rates of
thermoresponsive when in fact they may not be responding POAH cells that correlate with changes in peripheral
directly to temperature or to thermoafferent input. It is and/or POAH temperatures are reflecting thermointe-
therefore necessary to reexamine the influence of central and grative processes (12, 13). As reviewed in those papers,
peripheral temperature on POAH cells. In the present study, urethan-anesthetized animals show electroencephalo-
66 POAH cells were recorded from urethan-anesthetized rats
graphic (EEG) changes similar to those seen in unanes-
while EEG, TPOAH, and Ts were monitored. Seventy-five
percent (41 of 55) of the cells were EEG state responsive; 22% thetized animals changing arousal states. In addition,
(6 of 27) were TPOAH sensitive; and 33% (19 of 58) appeared to EEG state changes in anesthetized animals can be
be Ts responsive. However, when EEG state changes were induced by thermal and other stimuli. Units in many
taken into account, none of the cells that appeared to be Ts areas of the brain, including the hypothalamus, are
responsive were responding to Ts within any uniform EEG EEG state selective: they change their firing rates with
state. All changes in their firing rates were associated with changes in the EEG (12, 20, 22, 23, 28, 30). Therefore,
EEG state changes. This study raises a question as to changes in POAH unit activity recorded in anesthe-
whether or not peripheral temperature information is inte- tized preparations in response to thermal stimuli may
grated in the POAH. Consideration should be given to the be reflecting changes in cortical EEG state rather than
possibility that Ts information is integrated lower in the thermoregulatory integrative activities. To control for
neuroaxis. Monitoring EEG is essential in studies attempting
this possible confounding variable, it is necessary to
to characterize the integrative properties of POAH neurons of
anesthetized or unanesthetized animals. This caveat applies monitor EEG in single-unit studies, and this has not
not just to thermoregulatory studies but to investigations of been done in most studies of the thermosensitivity and
other integrative functions of the hypothalamus and many thermoresponsiveness of POAH cells.
other brain regions as well. If the POAH is a thermointegrative area, there
should be cells in this area that change firing rate
single-unit activity; thermoregulation; electroencephalo-
graph; thermointegration; urethan anesthesia
because of changes in local temperature, changes in
peripheral temperature, and changes in both tempera-
tures within EEG-defined arousal states. Although it
has been shown that some hypothalamic units are
THE PREOPTIC ANTERIOR hypothalamic area (POAH) is locally thermosensitive within an arousal state (10, 11,
considered the thermointegrative center of the mamma- 26, 27), there is no such unequivocal demonstration
lian brain. Cooling the POAH elicits appropriate heat- that POAH units respond specifically to peripheral
gain responses, and, conversely, heat loss responses are thermal stimulation independently of EEG changes.
activated when the POAH is heated. Changes in ambi- Such a demonstration was the purpose of this study,
ent, hence skin, temperature (Ts ) alter the threshold and to that end we searched the POAH for cells
POAH temperatures (TPOAH ) for thermoregulatory re- responding to changes in both local and peripheral
sponses or alter the gain of the responses. Simple temperature in urethan-anesthetized rats while moni-
neuronal models have been proposed as hypotheses for toring the EEG states of the animals.
how POAH neurons could interact and respond to
thermoafferent input to produce these system character- MATERIALS AND METHODS
istics that have been described in a number of mamma- Animals and surgical procedures. Experiments were con-
lian species (for reviews, see Refs. 3, 14–16). If any of ducted on 28 male Wistar rats weighing 250–350 g. Animals
these models for POAH thermointegration, or even were housed in a temperature-controlled room (22–24°C) on a
their basic assumptions, are correct, then there should 12:12-h light-dark photoperiod. They had access to food and
be POAH cells that respond both to local tem- water ad libitum.

0363-6119/98 $5.00 Copyright r 1998 the American Physiological Society R9


R10 THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH

Each animal was anesthetized with 4% halothane (Halocar- polygraph records in 10-s epochs (13). In urethan-anesthe-
bon Laboratories) followed by an intraperitoneal injection of tized rats, five EEG states can be distinguished as previously
1.0 g urethan/kg body wt. The anesthetic effect of the urethan described (13). State 1 EEG is a low-amplitude, high-
injection lasted for the duration of the experiment. The frequency pattern similar to the EEG of an awake animal.
animal was shaved, and the scalp and body trunk were State 3 EEG is a high-amplitude, low-frequency pattern
treated with a depilatory cream. The animal was placed in a similar to the EEG of non-rapid eye movement sleep. State 2
Kopf stereotaxic instrument. A midline incision was made, EEG consists of rapid alternations between states 1 and 3
the skin was deflected, the top of skull was scraped, bleeding EEG patterns, and it can vary from being almost all state 1 to
vessels were cauterized, and the skull surface was treated being almost all state 3. States 4 and 5 are mostly seen in
with hydrogen peroxide (3%). Five EEG electrodes were animals that are hypothermic. State 5 EEG is characterized
implanted into the skull. Four electrodes recorded frontal- by alternating high spikes and very low amplitude waves. State 4,
occipital and occipito-occipital EEG activity, and one served like state 2, is a transition state and consists of alternations
as the common electrode for single-unit recordings. A pair of between state 3 and state 5 activity in varying proportions.
thermodes, each consisting of stainless steel concentric inner Temperatures stored on the computer were TPOAH, Ts,
and outer cannulas (the outer one closed at the bottom) rectal temperature, and the water-perfused blanket tempera-
allowing one-way circulation of water, were implanted 11.5– ture. Inputs from thermocouples were processed by a custom-
2.0 mm from bregma, 62.0 mm lateral of midline, and 9.0 mm made signal conditioner, which converted the temperature
deep. The thermodes and a thermocouple reentrant tube were signal to a voltage input for the computer. A time code
glued into a Plexiglas block that was drilled to allow unidirec- generator was synchronized with the computer time clock,
tional perfusion of the thermodes. The block was anchored to and 10-s intervals were recorded on the polygraph paper.
the skull with bone screws and dental acrylic. The POAH was Histology. At the end of an experiment the animal was

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made accessible to electrode penetration through a 4.0-mm euthanized by an intracardial injection of a general anes-
hole in the skull centered 1.0 mm off midline and 1.0 mm thetic (50 mg/kg ketamine, Parke-Davis; 10 mg/kg aceproma-
behind bregma, and the dura was removed. A reentrant tube zine, Tech-American; and 5 mg/kg xylazine, Miles Laboratories).
was situated on the opposite side of midline so that the center The brain was removed, quickly frozen in 2-methylbutane at
of the recording area and the reentrant tube were equidistant 240°C, and mounted for sectioning. The brain was sectioned
from the thermodes. into 30-µm sections on a cryostat (Hacker Instruments), and
Experimental protocol. Immediately after surgery, the ani- the sections were dried and stained with cresyl violet. The
mal, still in the stereotaxic device, was placed in the experi- anterior/posterior and lateral position of the electrode track
mental setup. A thermocouple was inserted into the hypotha- was easily distinguishable from the slides. The recorded
lamic reentrant tube to measure TPOAH. An integrated Ts was depth of the electrode, as determined stereotaxically during
obtained from six thermocouples, wired in parallel, attached the recording session, was used to pinpoint the actual record-
to various skin areas about the animal’s trunk. A thermo- ing site.
couple was inserted 2.0–3.0 cm into the rectum to monitor Data analysis. One-way analysis of variance (ANOVA) was
core temperature. The animal was wrapped in a water- used to determine whether there was a significant (P # 0.01)
perfused blanket to control skin and core temperatures. effect of EEG state on the firing rates of the individual POAH
Because changes in scrotal temperature are known to have units. Scheffé’s F test with an error rate set at P # 0.01 was
strong effects on the EEG (19, 20), we were careful that the used following a significant overall ANOVA to make pairwise
water-perfused blanket did not extend to the scrotal area. The comparisons between EEG state groups.
rate of change of both TPOAH and Ts was ,0.5–1.0°C/min. To determine the TPOAH sensitivity of a cell, its thermal
TPOAH was maintained at ,37–38°C during Ts manipula- coefficient (Tc; impulses per second per degree Celsius) was
tions, and Ts was maintained at ,36–38°C during TPOAH determined by linear regression (frequency vs. TPOAH ) over
manipulations. the temperature range of maximum slope (7, 8). A minimum
A glass microelectrode, previously pulled to a resistance of temperature range of 2°C was used for calculating the slope.
10–15 MV using a model P-87 Flaming Brown Micropipette As in previous studies, a cell was classified as warm sensitive
Puller (Sutter Instrument) and filled with a 3.0 M NaCl if the slope was $10.80 and cold sensitive if the slope was
solution, was stereotaxically advanced through the target #20.60 (for review, see Ref. 5). All others were classified as
area with the use of a Trent Wells hydraulic microdrive until insensitive. Responsivity of POAH cells to changes in Ts was
a cell was detected. Single-unit firing detected by the elec- also determined by linear regression (frequency vs. Ts ), and
trode was passed to a Grass high-impedance probe. The the same criteria were used for classifying the cells as were
signal was amplified and filtered by a Grass preamplifier and used for TPOAH sensitivity.
viewed on a Tektronix S113 oscilloscope. Action potentials In the cases of cells with Tc values that classified them as
with a signal-to-noise ratio greater than 3:1 were passed TPOAH sensitive or Ts responsive, further analyses were
through a window discriminator (our design). The discrimina- performed to determine whether each cell was TPOAH sensi-
tor output was digitized and stored on a personal computer as tive or Ts responsive independent of EEG changes. These
firing rate frequency averaged over 10-s epochs. The raw additional analyses were threefold. 1) The Tc of each cell was
single-unit firing data were also stored on polygraph paper. determined within the states characterized by uniform EEG
After a cell was discriminated it was recorded for up to 1 h patterns (states 1 and 3; Ref. 13). If the Tc within EEG state 1
while Ts and TPOAH were manipulated. The microelectrode or 3 met the criteria as outlined above, the cell was classified
was then advanced until another cell was located. A recording as TPOAH sensitive or Ts responsive. However, if the Tc within
session lasted several hours, during which the microelectrode both EEG states 1 and 3 did not meet with the above criteria,
was moved to different POAH sites. the cell was classified as appearing to be TPOAH sensitive or Ts
Data recording and EEG analysis. EEG, single-unit activ- responsive. EEG state 2 was not used in this analysis because
ity (SUA), and four temperatures were recorded continuously it consists of varying percentages of state 1 and state 3
throughout the experiments. The EEG signal was recorded on activity. States 4 and 5 were not used for this analysis because
paper by a Grass model 7 polygraph at a chart speed of 5 they are associated with body temperatures outside of a
mm/s. EEG state analysis was done manually by scoring the normal range (13). 2) For a cell to be classified as only
THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH R11

appearing to be TPOAH sensitive or Ts responsive, the cell also a power analysis using confidence intervals of 99%. This
had to show statistically significant changes in firing rate resulted in the ability to determine whether or not the
with changes in EEG according to criteria as stated above. 3) numbers of cells within each classification group in the
If a cell only appeared to be TPOAH sensitive or Ts responsive present study were significantly different (P # 0.01) from
by the first two tests stated above, a third analysis was those of previous studies.
performed. This analysis was a determination of the effect of
TPOAH or Ts on the EEG state of the animal. It was done by a RESULTS
one-way ANOVA for each cell to determine whether there was
a significant (P # 0.01) effect of TPOAH or Ts on the EEG state A total of 66 cells from 28 urethan-anesthetized rats
of the animal for data used to determine the Tc of the cell. was characterized in terms of responsivity to changes
Scheffé’s F test with an error rate set at P # 0.01 was used in EEG state and Ts and sensitivity to TPOAH. Figure 1
following a significant overall ANOVA to make pairwise
comparisons between EEG state groups. Although a positive summarizes the anatomic distribution of these cells.
correlation was not considered necessary for classification of a Most of the cells in this study were recorded in the
cell as only appearing to be TPOAH sensitive or Ts responsive, it lateral and medial preoptic areas.
was considered to be further evidence that the changes in SUA responses to EEG states. Changes in EEG state
EEG were brought about by the changes in either TPOAH or Ts were elicited while recording from 55 of the 66 cells. Of
and that the firing rate of the cell was primarily reflecting these 55 cells tested, 41 (75%) showed significant (P #
these EEG changes rather than a thermoregulatory process. 0.01) changes in firing rate with changes in the cortical
Because of the nature and results of the study, it was EEG state of the animal.
deemed necessary to compare our data with data from

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SUA responses to TPOAH manipulations. TPOAH was
previously published studies. The question to be asked was
whether our data set was equivalent to the data sets on which
manipulated while recordings from 27 of the 66 cells
previous studies based their interpretations. To make this were made. Of the 27 cells tested, 5 cells (18%) were
possible, we analyzed our data using the most stringent warm sensitive, 1 (4%) was cold sensitive, and 21 (78%)
criteria used in previous studies (5). Statistical comparisons were temperature insensitive. The warm- and cold-
of the numbers of cells within each classification group in the sensitive cells were thermosensitive within EEG states
present study with those from previous studies were done by 1 and/or 3. Figure 2 shows one cell (cell 1911) that had

Fig. 1. Anatomic distribution of cells recorded. Dots indicate approximate locations of cells recorded. AC, anterior
commissure; AHA, anterior hypothalamic area; AVPO, anterioventral preoptic nucleus; BST, bed nucleus of the
stria terminalis; HLDBB, horizontal limb of the diagonal band of Broca; LAH, lateral anterior hypothalamic
nucleus; LHA, lateral hypothalamic area; LPOA, lateral preoptic area; MPOA, medial preoptic area; MPON, medial
preoptic nucleus; PVN, paraventricular nucleus; StH, striohypothalamic nucleus; 3V, third ventricle; ZI, zona
incerta.
R12 THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH

Table 1 shows the data for the 12 cells that were or


appeared to be TPOAH sensitive (had Tc values of #20.60
or $10.80 for TPOAH ). This table gives the overall Tc for
the cell, the Tc for the cell in each EEG state during
which it was recorded, the EEG responsivity, the
influence of TPOAH on EEG state for each cell, and the
resulting classification of each cell. Because the Tc for
each cell was determined over the temperature range of
maximum slope, the TPOAH in each EEG state was
determined for those data used to determine the Tc. The
EEG state responsivity, on the other hand, was deter-
mined for the entire time the cell was being recorded.
Closer inspection of Table 1 shows that our methodol-
ogy not only enabled us to detect cells that appeared to
be TPOAH sensitive when they were actually EEG state
responsive (e.g., cell 612, Fig. 3), but we were also able
to detect TPOAH-sensitive cells that would not have been
so classified if data from all EEG states were combined.
Fig. 2. Preoptic anterior hypothalamus (POAH) warm-sensitive cell One such cell was cell 1041. The overall Tc of this cell

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(cell 1911). Each point is average firing rate of the cell over a 10-s
epoch. Symbols denote electroencephalographic (EEG) state of the was 20.18. However, in state 1 its Tc was 10.92, and
animal during each 10-s recording epoch. (For details of analysis see within this state it was clearly TPOAH warm sensitive.
Table 1.) SUA responses to Ts manipulations. Ts was manipu-
lated while recordings from 58 of the 66 POAH were
made. When EEG was not taken into account, 11 of
Tc values $10.80 for all EEG states during which it these 58 cells (19%) appeared to be warm responsive, 6
was recorded. Because these EEG states include 1 and (10%) appeared to be cold responsive, 2 (3%) appeared
3, this cell was classified as TPOAH sensitive. In addition, to be both warm and cold responsive, and 39 appeared
this cell did not show significant changes in firing rate nonresponsive. However, when EEG was taken into
with changes in EEG states, supporting the conclusion account, none of these cells were thermoresponsive in
that this cell was indeed responding to TPOAH, not to the uniform EEG states 1 or 3. All of the cells that
changes in EEG states brought about by changes in appeared to be responsive to Ts were also responsive
TPOAH. (P # 0.01) to EEG state changes, possibly indicating
Six of the 21 temperature-insensitive cells appeared that these cells could have been responding not to Ts,
to be TPOAH sensitive if EEG state changes were ig- but to the EEG state changes (Table 2). Most of these
nored. Five appeared warm sensitive, and one ap- cells also showed significant effects of Ts on EEG state
peared cold sensitive. Within EEG states 1 and 3, all of (Table 2). There were no cells recorded in this study
these cells were insensitive to changes in TPOAH or there that responded to changes in Ts without a concomitant
were not enough data to make that determination change in EEG.
(either the cell was not recorded during EEG state 1
and/or 3, or data within state 1 and/or 3 did not span
2°C). It is important to note that whenever state 1
and/or 3 Tc determinations were not available, appar-
ent thermosensitivity was dependent on data from
states 2 and/or 4. Because states 2 and 4 consist of
continuous, temperature-dependent mixtures of EEG
activity characteristic of the other states, the assump-
tion of EEG dependence of the apparent thermosensitiv-
ity was warranted. For example, Fig. 3 presents data
from a cell that appeared to be warm sensitive to TPOAH.
This apparent warm sensitivity was due to Tc values
$10.80 during EEG states 2 and 4. This cell had
significantly different firing rates in states 1 and 3 at a
TPOAH of ,38°C. Because state 2 in this cell consisted of
predominantly state 3 activity at the highest TPOAH and
mostly state 1 activity at the lowest TPOAH, the cell
appeared to be thermosensitive in state 2. Similarly,
state 4 in this cell consisted predominantly of state 3
activity at 38°C and the amount of state 3 activity
Fig. 3. POAH cell (cell 612) that appears warm sensitive. Each point
declined with temperature. The conclusion was that is average firing rate of the cell over a 10-s epoch. Symbols denote
this cell was responding to EEG changes and was not EEG state of the animal during each 10-s recording epoch. (For
intrinsically thermosensitive. details of analysis see Table 1.)
THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH R13

Table 1. Data from cells with thermal coefficients (either overall or within EEG state 1 or 3)
to classify them as TPOAH sensitive
Cell Number (Tc , Classification) EEG State Tc Frequency, spikes/s n TPOAH , °C n

Cell 611 (Tc 5 10.90, appear warm sensitive) 1 ND 13.5 6 1.2 37.4 6 0.7 5
3 10.65 15.7 6 1.5 35.1 6 1.1 4
4 10.90 11.5 6 4.3 35.5 6 4.5 139
Cell 612 (Tc 5 10.90, appear warm sensitive) 1 ND 6.5 6 0.7 6 34.1 6 4.6 0
2 10.89 14.8 6 3.7* 63 38.4 6 0.1 15
3 ND 18.8 6 1.8*† 12 33.4 6 4.0 4
4 10.79 15.0 6 3.2* 10 10
Cell 831 (Tc 5 10.82, appear warm sensitive) 3 ND 4.0 6 1.0 37.2 6 0.6 19
4 10.74 2.7 6 1.3‡ 36.2 6 1.4‡ 43
Cell 911 (Switch: off TPOAH , 35°C, warm sensitive) 2 10.13 0.8 6 0.8 36.8 6 2.4 63
3 10.15 1.0 6 1.3 36.2 6 2.3 60
Cell 1025 (Tc 5 11.23, appear warm sensitive) 1 ND 9.7 6 2.5 73 36.9 6 0.2 40
2 11.35 6.3 6 2.1* 73 34.3 6 1.3* 27
3 10.20 3.4 6 1.0*† 91 35.2 6 1.2*† 39
Cell 1041 (Tc 5 20.18, warm sensitive) 1 10.92 15.8 6 3.1 33.5 6 3.0 18
2 20.01 13.4 6 1.8* 34.0 6 2.6 75
3 20.22 10.8 6 1.6*† 35.9 6 1.0*† 76
Cell 1222 (Tc 5 10.86, warm sensitive) 1 11.0 9.7 6 4.1 34.1 6 2.6 80

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2 ND 10.9 6 2.5 36.4 6 1.8* 20
3 ND 11.5 6 2.4 36.7 6 0.1* 21
Cell 1911 (Tc 5 10.80, warm sensitive) 1 10.84 21.7 6 3.1 33 31.8 6 1.8 18
2 10.98 22.6 6 3.2 40 33.1 6 2.6 28
3 10.95 23.4 6 3.0 51 35.0 6 2.5*† 29
4 10.88 22.7 6 2.6 122 35.9 6 2.5*† 58
Cell 2911 (Tc 5 21.24, appear cold sensitive) 1 ND 9.4 6 2.6 5 35.4 6 3.1 0
2 21.25 11.3 6 3.8 274 36.7 6 0.3 92
3 ND 8.4 6 2.1† 64 2
Cell 2915 (Tc 5 11.18, appear warm sensitive) 2 11.03 5.2 6 1.0 43 31.4 6 0.9 5
3 ND 5.2 6 0.4 3 30.1 6 1.1† 0
4 20.03 0.8 6 0.2†‡ 9 7
Cell 3121 (Tc 5 22.40 cold sensitive) 2 ND 3.2 6 1.3 196 30.5 6 0.3 4
3 22.85 2.3 6 1.8† 104 29.7 6 0.8† 10
Cell 3132 (Tc 5 11.57 warm sensitive) 2 10.60 7.1 6 5.2 108 30.1 6 1.2 5
3 12.20 11.9 6 4.1† 128 29.8 6 1.1 12
Included are overall thermal coefficient (Tc ) for each cell, Tc of each cell within each electroencephalographic (EEG) state, mean 6 SD firing
rate of each cell in each EEG state (for all data), mean 6 SD preoptic anterior hypothalamus (POAH) temperature (TPOAH ) during each EEG
state (for all data), the classification of each cell, and number of 10-s epochs during which the cell was recorded. ND means there are no data to
determine a Tc for that cell in that EEG state for 1 of 2 reasons: none of the data used to determine overall Tc (temperature range of maximum
slope with a minimum temperature range of 2°C) was in a particular EEG state or the temperature range within an EEG state was not 2°C.
n 5 No. of 10-s epochs averaged to obtain mean 6 SD. Number in one 10-s epoch is average firing rate (or temperature) for the cell (or POAH)
during that 10-s epoch. n Values at right are the number of 10-s epochs used for determination of Tc of the cell in each EEG state as described in
MATERIALS AND METHODS. These values were also used to determine effect of TPOAH on EEG state. n Values in middle are for the entire time that
the cell was being recorded (where different from time used to determine Tc ) and were used to determine significant differences between EEG
state and firing rate. * Significantly different from EEG state 1, P # 0.01. † Significantly different from EEG state 2, P # 0.01. ‡ Significantly
different from EEG state 3, P # 0.01.

Figure 4 shows data for one cell that appeared to be temperature, and the EEG is state 2 dominated by
warm responsive to Ts. During the recording of this cell, state 3-like activity. In response to the lowering of
the EEG state of the animal was strongly related to Ts. blanket temperature, Ts falls and the EEG shows an
The firing rate of the cell was significantly higher in increasing amount of state 1-like activity until it is
state 3 than in state 1. Once again, state 2 consists of a finally all state 1. The firing rate of the cell increases as
temperature-dependent mixture of state 1 and state 3 Ts falls and EEG state 1 activity increases. Thus the
activity, with state 3 activity predominant at the high- cell appears to be cold responsive with a Tc of 24.4
est temperature and state 1 activity predominant at (Table 2). In contrast, Fig. 5B is a 2.0-min recording of
the lowest temperature. Therefore, the apparent ther- the same cell, which begins with blanket and skin
moresponsiveness of this EEG state-selective cell is due temperatures at high levels. Under these thermal
to the temperature dependence of the EEG state of the conditions the animal is in EEG state 1 and the cell has
animal. a high firing rate. As blanket temperature is returned
Figure 5 shows an interesting case in which a cell to a neutral temperature, Ts falls, and the EEG
could appear to be both warm sensitive and cold progresses from state 1 to state 2 to state 3, and the
sensitive. Cell 1044 had a higher firing rate in state 1 firing rate of the cell declines. Now the cell appears to
than in state 3. State 1 could be stimulated by either be warm responsive with a Tc of 9.24 (Table 2).
high or low Ts. Thus, in Fig. 5A, a 2.5-min segment of Table 2 shows the data for all 19 of the 58 cells that
recording begins with a neutral blanket and skin had Tc values of #20.60 or $10.80 for Ts. This table
Table 2. Data from cells with thermal coefficients to classify them as Ts responsive
Cell Number (Tc , Classification) EEG State Tc Frequency, spikes/s n Ts , °C n

Cell 612 (Tc 5 11.92, appear warm responsive) 1 10.65 6.5 6 0.74 6 32.3 6 0.9 6
2 11.91 14.8 6 3.7* 63 36.0 6 2.2* 32
3 ND 18.8 6 1.8*† 12 37.3 6 0.9* 12
4 ND 15.0 6 3.2* 10 38.4 6 0.1*† 10
Cell 714 (appears warm responsive Ts . 34.5, Tc 5 14.43, nonrespon- 1 20.24 3.7 6 1.7 31.1 6 2.3 14
sive Ts , 34.5, (Tc 5 10.09) 2 10.99 13.1 6 1.8* 37.4 6 0.9* 19
3 20.29 16.0 6 3.6* 37.4 6 0.7* 11
4 11.97 12.2 6 4.5* 37.4 6 1.2* 22
Cell 821 (Tc 5 15.91, appear warm responsive) 1 10.07 27.1 6 2.8 36.5 6 0.5 35
2 ND 9.4 6 6.1* 33.5 6 0.6* 3
3 ND 4.2 6 2.4* 34.7 6 0.7* 5
Cell 1025 (Tc 5 21.40, appear cold responsive) 1 20.58 9.7 6 2.5 73 33.8 6 1.7 32
2 20.30 6.3 6 2.1* 73 35.8 6 0.6* 68
3 10.20 3.4 6 1.0*† 91 36.0 6 1.1* 31
Cell 1041
Overall Tc 5 20.62 1 ND 15.8 6 3.1 35.0 6 0.4 18
2 10.65 13.4 6 1.8* 37.1 6 0.6* 75
3 ND 10.8 6 1.6*† 36.6 6 0.3*† 76
Ts , 36.5°C, Tc 5 22.77 1 ND 18.5 6 1.4 35.0 6 0.4 8
2 ND 13.3 6 1.4* 36.9 6 0.1* 33
3 ND 10.1 6 1.9*† 36.4 6 0.3*† 32
Ts . 36.5°C, Tc 5 12.82, appears both warm and cold responsive 2 12.06 13.2 6 2.0 37.4 6 0.7 28

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3 ND 10.8 6 1.7† 36.8 6 0.3† 51
Cell 1044
Overall Tc 5 10.63 1 10.75 12.9 6 2.1 36.9 6 1.5 27
2 20.85 4.5 6 2.0* 36.6 6 0.9 28
3 ND 2.8 6 0.8* 36.9 6 0.2 15
Ts , 36.6°C, Tc 5 24.40 1 ND 11.8 6 2.0 34.6 6 0.2 8
2 22.88 5.8 6 2.2* 35.3 6 0.7 7
3 ND 2.5 6 0.4* 36.4 6 0.3* 2
Ts . 36.6°C, Tc 5 19.24, appears both warm and cold responsive 1 ND 13.7 6 1.7 37.8 6 0.3 19
2 ND 4.1 6 1.8* 37.0 6 0.3* 21
3 ND 2.8 6 0.8* 36.9 6 0.1* 13
Cell 1532 (Tc 5 12.07, appear warm responsive) 1 ND 4.4 6 1.6 23 31.7 6 0.4 3
2 12.59 7.9 6 3.0* 21 34.8 6 0.8* 16
3 ND 12.2 6 1.0*† 10 37.0 6 0.2*† 10
Cell 1534 (Tc 5 11.15, appear warm responsive) 1 10.35 27.0 6 3.0 38.0 6 2.2 20
2 ND 26.7 6 1.9 38.9 6 0.3 6
3 10.37 20.8 6 1.9*† 35.7 6 1.0*† 20
Cell 2473 (Tc 5 20.60, appear cold responsive) 2 20.28 5.9 6 1.2 35.4 6 0.6 16
3 20.50 4.3 6 2.0† 35.9 6 1.0 54
Cell 2761 (Tc 5 12.74, appear warm responsive) 2 12.69 11.8 6 3.6 35.8 6 0.5 76
3 ND 14.6 6 2.7† 36.9 6 0.1† 40
Cell 2831 (Tc 5 21.55, appear cold responsive) 2 ND 43.5 6 1.3 34.8 6 0.4 20
3 ND 41.7 6 1.2† 35.6 6 0.4† 47
Cell 2913 (appears to be a warm responsive switching cell that is off 1 ND 1.9 6 1.8 40.3 6 0.2 22
Ts , 40°C) 2 ND 2.0 6 1.5 40.1 6 0.1 8
3 10.06 0.2 6 0.8*† 36.5 6 4.0*† 30
Cell 2914 (appears to be a warm responsive switching cell that is off 1 ND 2.5 6 1.0 40.1 6 1.0 16
Ts , 40°C) 2 ND 2.6 6 1.0 40.2 6 0.4 18
3 10.07 0.2 6 0.6*† 35.5 6 3.7*† 44
Cell 3023 (Tc 5 15.05, appear warm responsive) 2 ND 5.1 6 20 104 36.5 6 0.4 43
3 ND 12.6 6 0.9† 23 37.3 6 0.4† 20
Cell 3031 (Tc 5 16.09, appear warm responsive) 1 ND 7.2 6 1.3 34.6 6 0.6 18
2 16.68 13.6 6 9.9* 34.3 6 1.4 63
3 ND 32.7 6 1.7*† 37.7 6 0.9*† 24
Cell 3121 (Tc 5 21.01, appear cold responsive) 2 20.38 3.2 6 1.3 196 35.8 6 0.5 138
3 20.27 2.3 6 1.8† 104 36.4 6 0.4† 72
Cell 3132 (Tc 5 21.68, appear cold responsive) 2 22.16 7.1 6 5.2 36.6 6 0.7 108
3 20.42 11.9 6 4.1† 36.5 6 0.5 128
Cell 3532 (Tc 5 13.52, appear warm responsive) 3 ND 11.8 6 2.8 36 37.5 6 0.3 9
4 ND 8.4 6 1.6‡ 17 36.4 6 0.4‡ 17
5 ND 14.3 6 4.1§ 17 37.1 6 0.3§ 13
Cell 3811 (Tc 5 20.90, appear cold responsive) 2 10.54 4.0 6 0.8 36.7 6 0.9 58
3 20.37 8.6 6 1.1† 34.7 6 1.4† 29
4 20.35 6.3 6 1.1†‡ 34.7 6 1.2† 18
Included are overall Tc for each cell, Tc of each cell within each EEG state, mean 6 SD firing rate of each cell in each EEG state, mean 6 SD
skin temperature (Ts ) during each EEG state (for data corresponding to the Tc ), the classification of each cell, and number of 10-s epochs
during which the cell was recorded. n 5 No. of 10-s epochs averaged to obtain mean 6 SD. Number in one 10-s epoch is average firing rate (or
temperature) for the cell (or skin) during that 10-s epoch. n Values at right are the number of 10-s epochs used for determination of Tc of the cell
in each EEG state as described in MATERIALS AND METHODS. These values were also used to determine effect of Ts on EEG state. n Values in
middle are for the entire time that the cell was being recorded (where different from time used to determine Tc ) and were used to determine
significant differences between EEG state and firing rate. * Significantly different from EEG state 1, P # 0.01. † Significantly different from
EEG state 2, P # 0.01. ‡ Significantly different from EEG state 3, P # 0.01. § Significantly different from EEG state 4, P # 0.01.
THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH R15

EEG state was determined for those data used to


determine the Tc. The EEG state responsivity, on the
other hand, was determined for the entire time the cell
was being recorded.
DISCUSSION

If the POAH is the thermointegrative center of the


brain, it should be possible to record from POAH cells
that respond to changes in both TPOAH and Ts. A number
of investigators have undertaken such studies in ure-
than-anesthetized animals, and these studies have
yielded results that seem to support the basic premise
that peripheral temperature information is integrated
in the POAH (4, 17, 18, 31, 34; see Ref. 3 for a review).
There was an unanticipated confounding variable, how-
ever, which undermines interpretations of the data
obtained in these excellent studies. This confound has
three components: 1) urethan-anesthetized rats show
EEG state changes, some of which are similar to those

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Fig. 4. POAH cell (cell 3031) that appears responsive to increases in
skin temperature (Ts ). Each point is average firing rate of the cell which characterize changes in arousal states in unanes-
over a 10-s epoch. Symbols denote EEG state of the animal during thetized animals (12, 13, 19, 20, 22–24, 28, 30); 2) these
each 10-s recording epoch. (For details of analysis see Table 2.) EEG state changes can be spontaneous (22–24, 30),
induced by thermal stimulation (12, 19, 20, 22) or a
gives the overall Tc for each cell, the Tc for each cell in variety of other sensory modalities (22, 24, 28, 30); and
each EEG state during which it was recorded, the EEG 3) most (50–76%) POAH neurons are arousal state
responsivity, the influence of Ts on EEG state for each selective and vary their firing rates with changes in
cell, and the resulting classification of each cell. Be- EEG activity (12, 13, 20, 22, 23, 28, 30). Therefore,
cause the Tc for each cell was determined over the unless EEG state is monitored, it is not possible to
temperature range of maximum slope, the Ts in each determine whether or not POAH SUA reflects a specific

Fig. 5. Recordings of firing of a POAH cell


(cell 1044) and the simultaneous recordings of
the EEG, Ts (in °C), and water-perfused blan-
ket temperature (Tbl; in °C). A: 2.5-min seg-
ment of the recording during which Tbl and Ts
began at a neutral level and were lowered. As
Ts falls, EEG state changes from being mostly
state 3-like activity to being all state 1 activ-
ity. Firing rate of this cell was higher in state 1
than in state 3, and therefore it appears to be
cold sensitive. B: 2.0-min segment of the re-
cording during which Tbl and Ts begin at a
high level and are lowered to neutral. At the
beginning 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 3
and the cell has a lower firing rate. During
this segment the cell, therefore, appears to be
warm sensitive. F-F, frontal-frontal; F-O, fron-
tal-occipital; SUA, single-unit activity.
R16 THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH

stimulus modality independently of changes in EEG have been found to be Ts responsive in EEG states 1 or 3
activity, which in turn are driven by the applied stimu- if we had been able to manipulate Ts over a broader
lus. Therefore, our goal was to test whether there were range without disrupting the state. It is very difficult to
POAH cells that were thermosensitive and/or thermore- change Ts of an anesthetized animal significantly with-
sponsive independent of EEG states. Such cells would out producing EEG state changes. Presumably, this
be candidates for playing roles in thermoregulatory would have been true of previous studies as well.
integration. Apparent thermoresponsiveness was associated in vir-
Our results are in agreement with previous studies tually all cases with EEG state 2 or 4. These states
on two counts. First, there are POAH cells that have consist of temperature-dependent, continuously vari-
firing rates that are a function of EEG state. Of the 55 able proportions of states 1 and 3 or states 3 and 5 EEG
POAH cells we recorded in different EEG states, 75% activity, respectively. Close inspection of the EEG and
were EEG state selective. This is within the range (50 unit activity recordings reveal a very close association
276%) of, and is not significantly different from, the of moment-to-moment changes in EEG activity and cell
numbers of EEG state-responsive neurons recorded in firing rates, indicating that the primary effect of Ts in
previous studies (12, 19, 20, 22–24, 28–30). Second, our these experiments was to alter EEG activity, which in
study also shows POAH neurons that are sensitive to turn determined firing rates.
local temperature changes within uniform, EEG- An important conclusion from this study is that it is
defined arousal states. Previous studies show a range of essential to monitor EEG when recording the activity of
8–70% of POAH neurons as TPOAH sensitive, depending neurons in the POAH to determine their responsive-

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on the arousal state of the animal, with more neurons ness to various modalities of stimulation. This is not a
temperature sensitive during wake than non-rapid eye new conclusion; the point was made 30 years ago. In
movement sleep (10, 11, 26, 27). The number of TPOAH- 1967, while investigating the effects of progesterone on
sensitive cells found in this study (22%) is not signifi- neural activity, Komisaruk and co-workers (22) wrote,
cantly different from the numbers of TPOAH-sensitive ‘‘...we were impressed by the striking temporal correla-
neurons recorded in previous studies. tion between changes in activity of single neurons and
The present study is not in agreement with previous alterations in the arousal level of the cortical EEG.
studies that reported Ts-responsive cells in the POAH. Since elevated activity of the majority of the neurons
These various studies on a number of species using we observed was closely correlated with cortical arousal,
different methods of thermal stimulation have found an it was imperative to distinguish the effects of progester-
average of 22% of the POAH cells responsive to changes one that might be produced indirectly by an induced
in peripheral temperature, with a range of 3–39% (for a change in arousal from the effects on particular neu-
review, see Ref. 3). In the present study done on rats, rons independent of changes in brain arousal.’’ This
using a water-perfused blanket for manipulating Ts, conclusion has been reiterated by other investigators
33% of the POAH cells recorded appeared to be Ts (10, 23, 24).
responsive if EEG state changes were ignored. This Other studies of thermoregulatory integration have
33% is not significantly different from the 22% average also called attention to the EEG state selectivity of
in previous reports. However, of the 19 cells recorded in neurons as being a confounding variable that has led to
this study that appeared to respond to changes in Ts probably false conclusions that cells are involved in
with changes in firing rate, none responded to changes thermoregulatory processing of information. Grahn
in Ts independently of EEG state changes. All of these and colleagues (12, 13) investigated the thermorespon-
cells were EEG state selective, and none showed Tc siveness of cells in the rostral ventromedial medulla
values of #20.60 or $10.80 within the uniform EEG and in the subceruleus area that were purported to be
states 1 and 3. Most showed significant effects of Ts on involved in thermoafferent information processing. The
EEG state, which indicates that the changes in Ts conclusion of those studies was that virtually none of
determined the EEG state, which in turn determined these cells responded to Ts within an EEG-defined state
the firing rates of the cells. Although all of these cells (one rostral ventromedial medulla cell was thermore-
showed significant differences in firing rates with a sponsive without a change in EEG activity). Rather,
change from at least one EEG state to another, in some most cells were arousal state selective, and thermal
cases the mean Ts between the corresponding EEG stimulation of the skin altered arousal states. Kanosue
states were not significantly different (e.g., cell 2473), and colleagues (19, 20) examined the responses of
indicating again that firing rate was correlated with diencephalic cells to thermal stimulation of the scro-
EEG state changes rather than changes in Ts. There- tum, and they also concluded that the cell responses
fore, there were no POAH cells found in the present were not specific to the thermal stimulus but reflected
study that were unequivocally Ts responsive. EEG activation caused by the thermal stimulation as
There is the possibility that cells that respond to Ts well as other modalities of stimulation.
were simply missed in this study. However, statistical Perspectives
analysis showed that enough cells were recorded (given
the average number of purported Ts-responsive cells The data from this study have profound implications
found in previous studies), so that there is only a 1% for views of the thermointegrative processes of the
chance that actual Ts-responsive cells were missed. It is mammalian central nervous system. Those views are
also possible that some of the cells we recorded may based on observed thermosensitive and thermorespon-
THERMOSENSITIVITY AND THERMORESPONSIVENESS OF THE POAH R17

sive properties of cells. For a cell to qualify for inclusion thermosensitive fibers are found in the ventrolateral fu-
in a model of thermointegrative processes, it should niculi, it must be concluded that the peripheral thermoaf-
have thermal properties that are independent of EEG ferent information need not be communicated to the hypo-
state changes. This is not to say that such a cell could thalamus to stimulate thermoregulatory responses.
not be EEG state selective in addition to being thermo- The results reported in this paper, combined with the
responsive or thermosensitive, but its changes in firing results of spinal transection studies, support a model of
rate should not be solely dependent on EEG state the thermoregulatory system in which hypothalamic
change. In the unanesthetized animal, thermoregula- thermosensitivity results in descending commands that
tion occurs continuously during wake or non-rapid eye modulate communication between peripheral thermo-
movement sleep. The activity of cells involved in ther- sensors and thermoregulatory effectors at lower levels
moregulatory integration should, therefore, reflect on the neural axis. This conclusion supports the earlier
changes in peripheral temperature without changes in view of Satinoff (32) who wrote, ‘‘I suggest that the
EEG state. A cell that only changes firing rate with hypothalamus is not the sole integrator of body tempera-
changes in EEG state cannot be responsible for continu- ture. Rather, it is the most important among many in
ous regulatory processes within a state. Because we that it coordinates the activity of other integrating
found no POAH cells that responded to Ts without mechanisms at lower levels of the neuroaxis.’’
corresponding EEG changes, we have to conclude,
contrary to current models of thermointegration, that We are greatly indebted to Dr. Dennis Grahn for his valuable help
the POAH is probably not the site of integration of and advice at all stages of this research.

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Address reprint requests to N. J. Berner.
peripheral temperature information for purposes of
thermoregulation. Received 31 July 1996; accepted in final form 10 September 1997.
Yet, we know that peripheral temperature informa-
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