Thermosensitivity of medulla oblongata in control of body ... · medulla oblongata is sensitive to heat (3, 12, 28, 33, 42) and cold (3, 13, 33,43) and indicate that the influence

AMERICAN JOURNAL OF PHYSIOLOGY Vol. 224, No. 4, April 1973. Prznted zri U.S.A.

Thermosensitivity of medulla oblongata in

control of body temperature

J. M. LIPTON Psychiatry and Physiology Departments, University of Texas Southwestern Medical School, Dallas, Texas 75235

LIPTON, J. R/I. Thermosensitiuity of medulla oblongata in control of body temperature. Am. J. Physiol. 224(4): 890-897. 1973.-When the temperature of the medulla oblongata (T,) of conscious rats was altered, changes occurred in rectal temperature (T,) and in thermoregulatory behavior that were generally similar to those produced by altering the temperature of the preoptic/anterior hypothalamic (PO/AH) “thermoregulator.” In the majority of rats with thermodes implanted in the lower brainstem, manipu- lating T, for 20-min periods caused changes in T, that were proportional to brain temperature. In other animals AT, was proportional to T, except at high (41-43 C) or low (34-37 C) T, levels. Shivering occurred when T, was lowered to 34-37 C. The T, and shivering responses were unchanged after destruction of the PO/AH region. In behavioral experiments the time spent pressing a pedal to lower ambient temperature was proportional to T,. The influence of T, on this behavior was enhanced by PO/AH destruction. Similarities between effects of altering T, and Tpo/ah together with the lack of dependence of the AT, response on PO/AH mediation, enhancement of T, control over behavioral thermoregulation after PO/AH destruction, and differences in precision of control exerted by the two brain tempera- tures, suggest that medullary thermosensitivity can mediate a separate secondary control of physiological and behavioral thermoregulatory activities.

physiological thermoregulation; behavioral thermoregulation; medulla oblongata; preoptic/anterior hypothalamic region; central thermal sensitivity

PREVIOUS EXPERIMENTS HAVE SHOWN that not all of the central controls of body temperature are confined to the thermosensitive “temperature regulator” in the preoptic/ anterior hypothalamic (PO/AH) region. Additional controls must exist since a considerable capability for both physiological (2, 30,41) and behavioral (11, 32, 39) thermoregulation survives the destruction of the PO/AH region. The failure of thermal clamps of this brain region to com- pletely and continuously determine body temperature (24) and thermoregulatory motivation (1, 20) also indicates the existence of antagonistic thermosensitive controls outside the hypothalamus. These findings raise questions about the locus and the functional characteristics of extrahypothalamic temperature control mechanisms. If it is assumed that the control is brought about primarily by neurons that are especially sensitive to changes in local temperature, then it may be that one or more of several parts of the nervous system (9, 10, 17, 18,28,40, 44) have a role in the regulation of body temperature. One specific thermosensitive brain re-

gion, the medulla oblongata, may be of particular impor- tance since the temperature of this region is known to influence thermoregulatory behavior (33), the most powerful response available to the organism for combatting environmental thermal stress (4).

The aim of the present experiments was to clarify the role of medullary thermosensitivity in thermoregulatory processes by answering two major questions. First, does the local temperature of the medulla influence the physiological control of deep-body temperature? And, after the first ques- tion was answered affirmitively, does the thermosensitivity of the medulla require mediation by the PO/AH region in order to influence physiological and behavioral thermoregulation?

MATERIAL AND METHODS

The general approach was to manipulate the temperature of the medulla (T,) by means of implanted thermodes and to record correlated changes in either the rectal temperature (T,) or the thermoregulatory behavior of unanesthetized rats. Thermodes were placed in the lower brainstem of 72 adult male albino rats (300 g body wt). Thirty-seven of the animals were used in the d which the data described below

.efinitive experimen were obtained, the

pilot experiments to evaluate the techniques.

ts from rest, in

Thermodes and Surgery

The thermodes were constructed of 18- and Z-gauge stainless steel tubing with the outer tube closed in a hemis- phere by cold welding on a lathe. Thermode temperature was sensed by a small thermistor (0.2-0.3 mm diam) ce- mented onto the exposed portion (1 mm) of the thermode tip. The rest of the thermode shaft was insulated with poly- ethylene tubing.

Each rat was anesthetized with an intraperitoneal injec- tion of sodium pentobarbital (50 mg/kg) and placed in a Kopf stereotaxic instrument. Single thermodes were then implanted in the medullary region according to the coordinates : 0.3-l .7 mm posterior to the transverse sinus; O.O- rt 1.5 mm lateral to the midline; and 6.5-7.6 mm below the brain surface (de Groot planes (14)). Thermodes were implanted in the forebrain, adjacent to the PO/AH region, of other rats.

Dental acrylic was used to attach each thermode and the electrical connectors for the thermode thermistor to three stainless steel screws which had been driven into the cal-

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THERMOSENSITIVITY OF MEDULLA OBLONGATA

varia. Benzathine penicillin G (150,000 units, im) was given to each rat immediately after surgery. Wet Purina labora- tory chow was provided during the 6- to 13-day recovery period to offset postoperative loss of body weight. Almost all animals showed an initial disturbance of motor responses and labyrinthine reflexes after surgery. The most typical postoperative symptoms were a clinging to the floor of the cage and unusual head and body orientations. The severity of the symptoms declined over time so that by the end of the recovery period most of the signs of disturbance had disap- peared.

Later in the experiments the PO/AH region was destroyed in selected animals. The stereotaxic coordinates used were 8.0-8.5 mm anterior to the interaural line; just lateral to the superior sagittal sinus; and 7.1-8.0 mm below the brain surface. Bilateral lesions were made by passing d-c current (2 ma) for 15 set between a stainless steel electrode in the forebrain and a steel rod inserted into the rectum.

Physiological Thermoregulation

Brain temperature was altered while the animal rested in a transparent plastic box located inside an environmental chamber controlled at 23 C. Air velocity within the plastic box was negligible. T, was recorded using a thermistor probe inserted 6 cm into the rectum and taped to the tail.

In the routine procedure brain temperature was not altered until T, had become stable (lo-40 min). There- after, brain temperature was held at randomly selected levels between 34 and 43 C for ZO-min periods by controlling the temperature of the water circulated through the thermode. After each thermal stimulation period, T, was al- lowed to return to base line before the next stimulation was begun. A written record of visible shivering and changes in general activity was made during each manipulation of brain temperature.

Behavioral Thermoregulation

In these experiments animals with medullary thermodes and others with PO/AH thermodes were trained to control the ambient temperature inside a clear plastic chamber by pressing and releasing a pedal (Fig. 1). The temperature of the air flowing through the chamber was 50 C before the pedal was pressed. When the pedal was operated air temperature rapidly dropped to 10 C. The temperature of the thermode, the air temperature inside the animal chamber, and the behavioral responses were recorded on an oscillo- graph. The time spent pressing the pedal for 10 C air was also recorded automatically on an electronic cumulative time meter. The velocity of the air flowing through the chamber, measured at 10 representative points with a heated thermocouple anemometer, averaged 0.52 m/set.

The thermal stimulation experiments were not begun until the proportion of time spent pressing the pedal for 10 C air had become consistent over training sessions for each rat. Thereafter, each thermal stimulation experiment began with an initial 30- to 70-min habituation period, during which the animal responded freely, followed by ZO-min periods in which T, or Tp+h was “clamped” at selected levels between 34 and 43 C.

891

Histblogical Analysis

The anatomical locus of every thermode placement and lesion site was determined by standard histological pro- cedures. An overdose of sodium pentobarbital was adminis- tered, and physiological saline and 10 % Formalin were per- fused through the aorta. The brain was removed and stored in Formalin or Bouin’s fluid. Serial coronal sections 40 p thick were cut from the frozen brain tissue and stained with Luxol fast blue.

The placements were reconstructed on copies of the line drawings in the stereotaxic atlas of Pellegrino and Cushman (34). The thermode tracks and the lesions were traced in by hand in accordance with enlarged images of the brain sections.

RESULTS

Physiological Thermoregulation Experiments

Altering the temperature of the medulla consistently produced changes in T, in 27 of the 34 animals used in these experiments. In the majority of the responsive animals, the AT, over the ZO-min thermal stimulation period was proportional to the T, level (Fig. 2A). The T, response to T, manipulation was, therefore, much like that observed when the temperature of the PO/AH region was altered (Fig. 20). The AT,/T,, relations of the other thermoresponsive rats

FIG. 1. Behavioral thermoregulation chamber. Chamber was located in a large temperature-controlled room (10 & 0.5 C). Ni- chrome heater coils (HC) raised temperature of air, drawn through chamber by exhaust fan (EF), to 50 C. When rat pressed response pedal (RP), heaters were turned off and air temperature at sensor (ATS) dropped to 10 C and remained at this low level as long as pedal was held down. When pedal was released, air temperature returned to 50 C.

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FIG. 2. Changes in rectal temperature produced by altering brain temperature for 20 min in representative animals. A: a proportional relationship between T m and AT, was noted in about 56y0 of the animals with effective thermodes. B: no change in T, with medullary cooling, and a proportional decrease in T, when T, was held at neutral and high levels, was seen in approximately 2670 of the animals. C: in 18y0 of the animals, T, changes that were proportional to T, except at high-T, levels were obtained. D: typical proportional rela-

tion between Tpojah and changes in T,. Lines in A and C fitted by using least-squares method; in B and D, by visual inspection.

fell into two categories: those that showed no increase in T, with medullary cooling and a roughly linear decrease when T, was raised above 37-38 C (B type), and those (C type) that showed a linear relation between AT, and Tm except at high thermal stimulation values (41-43 C) where T, dropped precipitously (Fig. 2). The results confirm that the medulla oblongata is sensitive to heat (3, 12, 28, 33, 42) and cold (3, 13, 33,43) and indicate that the influence of medullary thermosensitivity on body temperature is similar to that of the PO/AH thermosensitivity. That is, altering the temperature of either brain region produces changes in body heat content similar to those which occur or tend to occur when the animal is confronted with environmental thermal stress.

These results clearly relate the thermosensitivity of the medulla to physiological thermoregulatory processes. In

Cooling Heating .

J. M. LIFTON

previous experiments on cardiovascular and respiratory responses to thermal stimulation of the medulla (3, 12, 13, 28, 42, 43), the significance of the thermosensitivity of the lower brainstem to thermoregulation has been unclear. Reasons for this lack of clarity include 1) the animals used were anesthetized or decerebrate and therefore unable to make normal thermoregulatory responses, and/or 2) their deep body tem- peratures were controlled by the experimenters. Discrepan- cies in the results of these experiments also confound possible interpretations in terms of thermoregulation.

Since shivering was observed during medullary cooling in animals that showed no change in T, (B type), T, was altered for longer durations in these animals to see if the failure to obtain a rise in T, was merely the result of short stimulation periods. Increasing the duration of medullary cooling (34 C) to 40-80 min did not produce consistent and lasting elevations in T, (Fig. 3). It is clear that the rate of heat loss must have increased since the rats shivered inter- mittently throughout the cooling period and yet there was no net gain in body-heat content. On the other hand, long- term heating (43 C) of the medulla produced a marked effect, driving T, down as much as 4 C. Similar decreases with medullary heating were also found in rats with A and C type records, although the rats with C type response generally showed a greater rate of fall. The effects of heating and cooling the medulla for longer periods of time confirm the results of the short-term stimulation experiments and provide further evidence for the existence of nonproportional relations between T, and AT,. It is possible that the differences in the types of AT,/T, relations result from differences in the composition of the local thermoreceptor pools stimulated by the thermodes. Guieu and Hardy (22) have listed at least 22 different types of responses of single neurons to changes in local temperature. Slight differences in the thermosensitive characteristics of the population of cells stimulated, or differences in their effector links, thus may account for the different AT,/T, patterns. There was no discernible connec- tion between the type of AT,/T, response and the neuroanatomical loci of the thermodes.

While the effects of altering T, were, in general, similar to the effects produced by altering Tpo,ah , two major differences were noted between them. First, cooling the medulla to 34-37 C caused shivering in all rats that showed consistent changes in T, (A, B, and C types) when T, was raised and lowered. On the other hand, shivering was seen on only one occasion during PO/AH cooling (34 C) even though T, generally rose when the temperature of this brain region was lowered. The latter result is in agreement with previous

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FIG. 3. Effects of long-term heating (43 C) and cooling (34 C) of medulla on rectal temperature and shivering in an animal which showed a B tyfe (Fig. 2) response to short-term (20 min) manipulations of Tm.

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THERMOSENSITIVITY OF MEDULLA OBLONGATA

research on the rat (15) in which cooling of the anterior hypothalamus produced an increase in oxygen uptake but did not evoke shivering. Brfick and Wiinnenberg (7) have also suggested that shivering in the guinea pig is almost independent of hypothalamic temperature. However, shivering has been observed in rats l-5 min after cooling the PO/AH region to approximately 18 C (38). Taken together, the results suggest that moderate cooling of the PO/AH region in the rat may activate nonshivering thermogenesis, as in the guinea pig, and that shivering is evoked only by a greater degree of cooling. It is not clear whether the dissimilarity in effects is the result of differential thresholds for the activation of shivering and nonshivering thermogenesis or whether slight differences in the location of the thermoreceptors which drive them (e.g., the thermoreceptors which influence shivering may be more laterally placed) are responsible. Since moderate cooling of the medulla caused shivering in the present experiment, it seems likely that the thermoreceptors in this brain region are more closely linked with shivering thermogenesis. The difference in the effects of moderate cooling of the medulla and of the PO/AH region in the rat may thus reflect the activation of two separate types of heat production : nonshivering thermogenesis stimulated by PO/AH cooling and shivering influenced by the temperature of the medulla.

The second difference was in the variability of the response to brain temperature manipulation. While thermal stimulations of the medulla resulted in the same general AT,/T, relation from one test day to the next, the response to a specific level of thermal stimulation was not the same each time. Although this was also true for thermal stimulation of the PO/AH region, the variability in the response over time in the animals with PO/AH thermodes was consider- ably less. This difference in variability may mean that the influence on body temperature exerted by medullary thermosensitivity is less precise or compelling than that exerted by the thermosensitive PO/AH region.

The effects of thermal stimulation of the medulla on general activity were similar to those produced by displacing PO/AH temperatue. Raising the temperature of the medulla above normal caused quieting and relaxation much like that seen with PO/AH warming in the present and in previous (19, 27, 36, 37) experiments. Cooling the medulla produced periods of restlessness which were inter- spersed among bouts of shivering. Lowering Tpoiah produced noticeable increases in locomotor activity.

Effects of PO/AH I esions. Lesions were made in the hypothalamus of 20 of the rats that had shown consistent responses to thermal stimulation of the medulla. The survi- vors that showed minimum postoperative sequelae and the characteristic 0.2-0.5 C rise in resting deep-body temperature that is associated with destruction of the PO/AH region (32) were then retested 7-10 days later according to the procedure used in the preoperative thermal stimulation tests. None of the animals showed a significant change (P > .3 1 or more) in the negative slope of the AT,/T, relation (Fig. 4) whether the lesions destroyed the PO/AH region

( n= 5), the middle hypothalamic (n = Z), or mid- and posterior hypothalamic structures (n = 1). Thus, the influence of T, on deep-body temperature is not mediated through

893

the PO/AH region, nor does it require the integrity of midhypothalamic connections.

Behavioral Thermoregulation Experiments

Heating and cooling the medulla produced changes in thermoregulatory behavior that were similar to those observed when the temperature of the PO/AH region was altered (Fig. 5). In all rats with effective thermodes the amount of time spent pressing for cold air was proportional to T, . These results confirm previous findings which showed that single warm (42-43 C) and cold (29-30 C) thermal stimulations of the medulla can affect thermoregulatory behavior (33), and extend them by showing that T, and behavioral temperature regulation are related in a more quan- titative manner. A result which was not obvious in the earlier research was that the variability in the behavioral response to repetition of a particular brain temperature manipulation was greater in animals with medullary thermodes than in rats with PO/AH thermodes. This result suggests that the influence on thermoregulatory motivation exerted by Tpoiah may be more precise than that exerted by T, , a conclusion which parallels the one drawn from the physiological thermoregulation experiments.

The neuroanatomical sites where thermal stimulation of the medulla was effective in influencing behavior were within the region where local heating and cooling produced changes in T, (Fig. 6). In the rats that were tested in the physiological and in the behavioral thermoregulation experiments thermal stimulation of the medulla produced changes in both forms of thermoregulation or had no consistent influence on either form.

Efects of PO/AH I esions. Destruction of the PO/AH region by electrolysis produced a significant increase (P < .Ol or better) in the slope of the positive relation between T, and thermoregulatory behavior (Fig. 7) in three out of four rats. On the other hand, destruction posterior to the PO/AH region (n = 3) did not produce changes in the behavior/T, relation (P > .45 or more). The enhancement of the relation between T, and behavioral thermoregulation after PO/AH injury contrasts with the lack of change in the post- surgery A’!lYr/T, relation. This contrast suggests that the effect of the brain injury is not merely to increase the thermosensitivity of the medulla but to alter its significance to behavior.

DISCUSSION

The results show that the influence of the medullary thermosensitivity on body temperature and thermoregulatory behavior is much like the influence exerted by the thermosensitivity of the PO/AH region. Judging from the parallels between these two influences, it may be that the medulla has temperature regulation functions similar to those attributed to the PO/AH thermoregulator. The idea that the medullary region has thermoregulatory capabilities was put forth earlier by researchers who believed that the lower brainstem contained a center for regulation against cold (2 1, 29, 35). It was also suggested that there are centers, located anterior and posterior to the ala cinerea in

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FIG. 4. Effects of forebrain lesions on AT,/T, relation. Injury to PO/AH region (left) produced no significant change in slope of the AT,/T, regression line (prelesion b = 0.08, postlesion b = 0.12). Nor did midhypothalamic damage (right) influence relation (prelesion b = 0.07, postlesion b = 0.09). Brain sections show site of major injury.

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the medulla, wkrose local temperature influences body temperature and sweating (26). Observations of shivering in response to low ambient temperature in rabbits with sections of the brainstem led Dworkin (16) to propose that

the medulla contains a subsidiary center for thermoregulation.

If, as the data indicate, the medullary thermosensitivity has a capability for influencing body temperature and thermoregulatory behavior, then what is the nature of its role in overall thermoregulation? One possibility is that the medullary thermoreceptors normally provide subsidiary information about local temperature to the PO/AH region where it is integrated with thermal signals from other body regions to bring about the regulation of temperature within very narrow limits (24, 25). It has been suggested that the thermoreceptors of two other extrahypothalamic regions, the mesencephalon (8), and spinal cord (23, 3 1, 45) provide such subsidiary temperature information to the PO/AH region. Another possibility, not mutually exclusive with the first but perhaps more explanatory of the present results, is that the capability of the medulla to influence regulatory responses makes up a secondary temperature control. Bligh (5, 6) h as reviewed evidence for a secondary or “broad band” type of thermoregulation in modern homeotherms which is based on central thermosensitive structures inherited from evolutionary ancestors, although it is not necessarily dependent on the thermoreceptive PO/AH region. In this view the thermoresponsiveness of the medulla might play a major role in physiological and behavioral

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THERMOSEl’$3ITIVITY OF MEDULLA OBLONGATA

FIG. 6. Cross-sectional drawings of lower brainstem of rat showing points where thermal stimulation produced consistent changes in T, and behavioral thermoregulation. Sites where thermal stimulation

temperature regulation when deep-body temperature de- viates beyond usual levels (in fever, heat and cold stress, and in exercise). Two findings of the present experiments, the appropriateness of medullary thermoresponsiveness to temperature homeostasis (e.g., raising T, produced decreases in T,) and the relatively less precise influence on thermoregulatory processes exerted by T, as compared with that exerted by the Tpo,&h, might be expected if the medulla contains a secondary thermosensitive mechanism for the control of body temperature.

The persistence of the influence of medullary temperature on T, after PO/AH injury suggests that the thermoresponsiveness of the medulla has considerable survival value. It is possible that the physiological capacity to prevent deviations in body temperature which remains after PO/AH injury is mediated by the medullary temperature receptors and their extrahypothalamic links with effecters. Since the temperature of the medulla oblongata has been shown to influence cardiovascular and respiratory responses in anesthetized and decerebrate animals (3, 12, 13, 28, 42, 43), it may be established in future experiments that the changes in body temperature produced by altering T, in conscious

was effective were found to lie below floor of fourth ventricle between level of caudal edge of inferior colliculus and a point slightly posterior to radix nervi abducentis.

animals result from more direct links betwen the thermosensitive cells and the cardiovascular and respiratory centers located within this brain region. The shivering response to local cooling of the medulla was also observed after the PO/AH region was destroyed and may, therefore, depend on connections with the spinal cord rather than with dien- cephalic structures. In behavioral thermoregulation, the influence of T, does not require mediation by the PO/AH region but appears to be normally inhibited by it. It is inter- esting to note, in light of the proposal of a primitive temperature regulation based on inherited central thermosensitivity (5, 6), that injury to the forebrain did not change the significance of T, to physiological thermoregulation but did enhance its significance to behavioral thermoregulation, the form of temperature control that was the most important to the precursors of the modern homeotherms.

In summary, the results indicate that the medullary thermosensitivity is capable of exerting a secondary control of body temperature that is independent of the hypothalamic thermoregulator. It is now appropriate to ask how the thermosensitive cells in other parts of the nervous system (8,40,44) relate to the thermoresponsiveness of the medulla.

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896 J. M. LIPTON

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relation between medullary temperature and amount of time spent pressing a pedal for cold air. Destruction of PO/AH region (left) produced an enhancement of slope of behavior/T, regression line (prelesion b = 30.0; postlesion b = 66.0; P < .OOl). Injury posterior to PO/AH region (right) did not cause a change in behavioral response to medullary thermal stimulation (prelesion b = 27.0; postlesion b = 23.2). Brain sections show sites of major injury.

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ADDENDUM to W. G. Clark and S. M. McCann for their comments on the manu-

While this paper was in press, Chai and Lin (J. Physiol. London 225 : 297-308, 1972) independently reported that thermal stimulation of the medulla oblongata can influence physiological thermoregulation in unanesthetized macaques. Their data and inferences are in agreement with several of the major ideas of the present report.

script, to W. E. Romans for bioengineering services, and to P. D. Ward of Grant Instruments Development Ltd., Cambridge, U. K., for fitting the thermistors.

This research was supported by Public Health Service Research Grant I-ROl-NS-10046-01 from the National Institute of Neuro- logical Diseases and Stroke.

The author is indebted to Patrick Dwyer for his expert assistance, Received for publication 5 September 1972.

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Thermosensitivity of medulla oblongata in control of body ... · medulla oblongata is sensitive to heat (3, 12, 28, 33, 42) and cold (3, 13, 33,43) and indicate that the influence