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Influence of frontal neocortex lesions and body weight manipulation on the severity of lateral hypothalamic aphagia
Physiology& Behavior,Vol. 21, pp. 541-547. Pergamon Press and Brain Research Publ., 1978. Printed in the U.S.A.
Influence of Frontal Neocortex Lesions and Body Weight Manipulation on the Severity of Lateral Hypothalamic Aphagia I B R Y A N K O L B , A R T H U R J. N O N N E M A N
A N D I A N Q. W H I S H A W
Department o f Psychology, University o f Lethbridge, Lethbridge, Alberta, Canada T1K 3M4 and Department o f Psychology, University o f Kentucky, Lexington, Kentucky ( R e c e i v e d 27 F e b r u a r y 1978) KOLB, B., A. J. NONNEMAN AND I. Q. WHISHAW. Influence offrontal neocortex lesions and body weightmanipulation on the severity of lateral hypothalamic aphagia. PHYSIOL. BEHAV. 21(4) 541-547, 1978.--Frontal neocortex lesions produced aphagia, adipsia, and reduced body weight, but also attenuated the duration of aphagia and adipsia which followed lateral hypothalamic lesions given 46-60 days later. These changes were greater after orbital frontal than after medial frontal or frontal polar neocortical lesions. If the rats with orbital frontal lesions were fattened the duration of aphagia and adipsia following lateral hypothalamic lesions increased. When the experimental procedure was reversed so that orbital frontal lesions were given 60 days after lateral hypothalamic lesions the duration of the aphagia and adipsia following the orbital frontal lesions was reduced. If the rats were fattened during the inter-lesion interval the severity of aphagia and adipsia after the second lesion was increased. These results suggest that body weight changes which occur as a consequence of the first lesion may contribute to the duration and severity of aphagia and adipsia following the second lesion. However, components of the orbital frontal cortex and lateral hypothalamus may be part of a common functional system subserving feeding behavior. One stage combined unilateral orbital frontal and contralateral unilateral lateral hypothalamic lesions mimicked the effects of bilateral lesions of either area. Frontal neocortex
LH aphagia
LH adipsia
G L I C K and Greenstein [5] reported the remarkable finding that if rats were given frontal cortex lesions thirty days prior to lateral hypothalamic lesions they did not exhibit the typical aphagia and adipsia of the lateral hypothalamic syndrome [19]. Glick and Greenstein [5] proposed that the prophylactic effect of the frontal lesions was due to the development of denervation supersensitivity in catecholaminergic neural systems which support feeding behavior. Their findings also suggested that there is a relation between frontal neocortical and hypothalamic systems which support feeding behavior. Recent anatomical and electrophysiological work has shown that the region of the frontal cortex which receives terminations from the catecholamine systems is the prefrontal cortex [1, 14, 15]. Further, this cortex is itself comprised of 2 discrete subfields; medial frontal and orbital (ventral or sulcal) cortex [12]. Behavioral studies on the relation of this cortex to feeding behavior have shown that orbital cortex removal produces a more severe disruption of feeding behavior than medial cortex removal [7, 8, 9, 11]. These findings suggested to us that further analysis of the Glick and Greenstein phenomenon might be worthwhile. A first object of the research was to determine if the pro-
tective effect of neocortex removal could be identified with a specific neocortical subfield. Glick and Greenstein's [5] polar frontal lesions appeared to have invaded both medial and orbital cortex in part. Therefore, we compared the protective effects medial, orbital, and polar lesions had on the feeding behavior of rats subjected to lateral hypothalamic lesions. A second object of the experiments was to examine how frontal lesions protected lateral hypothalamic lesioned rats from aphagia. There was at least one possible explanation for the protective effects of frontal lesions. A number of studies have shown that dieting (but not fasting) rats to approximately 80-85% body weight reduced the severity of lateral hypothalamic syndrome aphagia [13,16]. In our research we found that neocortical lesions produced a chronic reduction in body weight comparable to that produced by dieting [ 11]. It seemed worthwhile, therefore, to determine if there was a relation between body weight change in neocortical lesioned rats and their subsequent response to lateral hypothalamic lesions. The converse question was also asked. Do lateral hypothalamic lesions alter the effect of later frontal lesions and, if so, does this interact with preoperative weight? A final object of the research was to
1This research was supported by Canadian National Research Council grants awarded to Bryan Kolb and lan Q. Whishaw and a National Institute of Health grant awarded to A. J. Nonneman. The authors thank Larry Leach and Rajko Dodic for reading and Adria Allen for typing the manuscript. Requests for reprints should be sent Bryan Kolb, Department of Psychology, University of Lethbridge, Lethbridge, Alberta, Canada, TIK 3M4.
C o p y r i g h t © 1978 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/78/100541-07502.00/0
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KOLB, NONNEMAN AND WHISHAW
determine if the orbital frontal cortex and the lateral hypothalamic area shared some common role in the control of feeding behavior. We reasoned that if the 2 structures did share some common control over feeding then unilateral, but contraiaterally placed, lesions in each structure should be equivalent to bilateral destruction of tissue in either structure. METHOD
Animals Feeding behavior was studied in 115 adult male Wistar rats. Mean body weights and standard deviations are reported for each group in the appropriate procedure section. There were no significant differences in initial body weights (analyses of variance, p's>0.05) among groups in any experiment.
Surgery The animals were anesthetized for surgery with 50 mg/kg sodium pentobarbital. Neocortical lesions were performed by the suction technique described previously [11]. The medial frontal lesions were intended to remove the projection field of the lateral portion of the thalamic nucleus medialis dorsalis, while the orbital frontal lesions were intended to remove the projection field of the medial portion of the dorsal medial nucleus [12]. The polar lesions were intended to remove an area of tissue similar in extent to that described by Glick and Greenstein [5]. Lateral hypothalamic lesions were made using the stereotaxic technique [20]. Stereotaxic co-ordinates were 2.5 mm posterior to the bregmoidal intersection, 1.8 mm lateral to the mid-saggital suture, and 8.0 mm ventral to the dura. Anodal electrolytic lesions were made by passing a 15 sec, 1.5 mA direct current through a number 00 insect pin which had been insulated to the cross-section of the tip.
Procedure The effect of lateral hypothalamic lesions on rats pretreated with frontal neocortex lesions. The rats were divided into 4 groups of 10 rats which received either orbital frontal (mean weight 399 _ 46g), medial frontal (394 -4- 17g), frontal polar (390 ___ 60g) lesions, or anesthesia only (392 _ 29g). After 60 days all animals received bilateral lateral hypothalamic lesions and after a further 10 days they were sacrificed for histological analysis. F o r the first 10 days following each lesion all animals were provided with jars (4 cm high) filled with a diet consisting of lard (30%), corn oil (10%), sucrose (33%), and casein (20%), plus vitamins and salts. On Day 11 after the first lesion the rats were given Purina rat chow. F o o d and water intake and body weight were recorded daily. The effects of interlesion time interval and weight manipulation. Thirty rats were divided into 5 groups of 6 rats each. Four groups received orbital frontal lesions (mean weights 442 -+ 88g, 446 -+ 79g, 416 -- 22g, 439 -- 23g) while the Fifth group received anesthesia only (423 _+ 14g). Ten days later one orbital frontal group received bilateral lateral hypothalamic lesions. Thirty days after first surgery a second orbital frontal group was subjected to a fattening procedure. The animals were fed Purina rat chow supplemented with a mash made from crushed chocolate chip cookies and vitamins [11]. Forty-six days after first surgery this and the
remaining groups were given bilateral lateral hypothalamic lesions. On the day following the lateral hypothalamic lesions, Purina food pellets were scattered on the floor of the living cage. If the rats ate no Purina food, a spatula Fdled with chocolate chip cookie slurry was held near the mouth of the rat for 10 min or until the rat either ate the food or actively rejected it by pushing away the spatula, ventral chin rubbing, or repeated head withdrawal. Rats which failed to eat were retested every few hours until they began to eat. The high fat diet was available to all of the rats on the first 10 days after lateral hypothalamic lesions but after this they were given Purina rat chow and water for the remaining 50 days of the experiment. Those rats which failed to maintain body weight on Purina chow were shifted back and forth from the chow to the high fat diet until they were maintaining body weight on the chow. The effect of orbital frontal lesions on normal, lateral hypothalamic, and fattened lateral hypothalamic lesioned rats. Fifteen rats were divided into 3 groups of five rats each (mean weights, 4 1 4 _ 7g, 415-+ 18g, 4 1 5 - - - l l g ) . Two groups received lateral hypothalamic lesions while the third group received anesthesia only. Thirty days after surgery, one lateral hypothalamic group was fattened by feedings of Purina rat chow supplemented with chocolate chip mash. On the sixteenth day following the fattening procedure all rats received orbital frontal lesions. The rats were tested behaviorally after each lesion by presenting cookie on a spatula as described above. The effect of combined unilateral neocortical and hypothalamic lesions. Twenty-five rats were divided into five groups of five rats each. The groups received either bilateral orbital frontal (mean weight 392 _+ 18g), bilateral lateral hypothalamic (395 -+ 1 lg), unilateral orbital frontal (440 _ 27g), unilateral lateral hypothalamic (437 --- 32g), or unilateral orbital frontal plus contralateral unilateral lateral hypothalamic (390-+ 14g) lesions. Following surgery the animals were tested for aphagia-adipsia as described above. F o r the first 10 post-surgical days they were maintained on the mash diet and thereafter they were given Purina rat chow.
Histological Procedure The animals were sacrificed with intraperitoneal sodium pentobarbital injection. They were perfused intracardially with normal saline followed by 10% formalin. The brains were frozen and 40/z coronal sections were cut for staining with cresyl violet. RESULTS
Anatomical Results Figure 1 shows coronal sections through the region of the lesions for a representative rat from each lesion group in the "effect of lateral hypothalamic lesions on rats with frontal neocortex lesions" study. The neocortical lesions were similar to those we have illustrated elsewhere [10,11]. The orbital frontal lesions removed the sulcal cortex in addition to varying amounts of motor and gustatory cortex while the medial frontal lesions removed the cortex of the medial wall of the anterior 1/3-1/2 of the hemispheres. The polar lesions destroyed an extent of tissue similar to that described by Glick and Greenstein and were restricted to motor cortex. The lateral hypothalamic lesions were similar to those described
NEOCORTEX-HYPOTHALAMUS AND FEEDING
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FIG. 1. Serial sections from the brains of representative rats which received lateral hypothalamic (LH) lesions 60 days after an orbital frontal (OF-LH), frontal polar (FP-LH), medial frontal (MF-LH) lesion or after a sham lesion. Area of stippling includes lesion cavity as well as surrounding neuron-free tissue.
544
KOLB, N O N N E M A N AND W H I S H A W TABLE1 FIRST ~STOPERATIVE DAY TO EXHIBITEATINGAND D~NKING Eat High Fat From Dish Sham-LH OF-LH MF-LH F~LH
1.0 4.0* 1.0 1.0
Stage 1 Drink Water From Richter Tube
Eat High Fat From Dish
1.0 4.4* 1.0 1.0
Stage 2 Drink Water From Richter Tube
8.0* 2.4* 5.9 6.3
10*t 3.4* 6.4 6.0
* Differs significantly from all other groups (p<0.05). t Note that only 1 rat had begun to drink after 10 days. Legend: LH=lat hyp lesion; OF=orbital frontal lesion; MF=medial frontal lesion; FP=frontal polar lesion. iI"
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FIG. 2. (A) Change in body weight as a percent of preoperative weight in rats which received neocortical lesions. In the initial stage bilateral orbital frontal neocortex lesions produced a greater reduction in body weight than medial frontal lesions. Lesion sites are indicated diagrammatically by the parasagittal brain sections adjacent to each curve. (B) Percent change in body weight produced by lateral hypothalamic lesions in rats which received neocortex lesions or no lesion 60 days earlier. Note that orbital frontal lesions appear to give greater protection than medial frontal lesions from profound weight loss produced by lateral hypothalamic lesions. Frontal polar lesions (not illustrated) had effects similar to the medial frontal lesions.
elsewhere as being effective in producing aphagia and adipsia [16,17].
The effect of lateral hypothalamic lesions on rats pretreated with frontal neocortex lesions. The major finding was that lesions to all 3 frontal cortical regions reduced the effect of the lateral hypothalamic lesion produced 60 days later, but the orbital frontal (OF) lesions had the greatest effect (Fig. 2, Table 1). Analysis of variance showed a significant reduction in both length of aphagia F(3,36)=5.4, p<0.01 and adipsia F(2,27)=15.2, p<0.01 following the cortical lesions. Follow-up tests (Tukey's) showed that the rats with OF lesions had shorter durations of both aphagia and adipsia (p's<0.01) after the lateral hypothalamic (LH) lesions than all other groups. Further, the rats with medial frontal (MF) or frontal polar (FP) lesions had shorter durations of aphagia than the rats in the sham-LH group (p<0.01) while the rats with OF lesions had a shorter duration of adipsia than the rats in the sham-LH group (p<0.01).
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FIG. 3. The effect of lateral hypothalamic lesions on body weight of rats which had received orbital frontal neocortex lesions and a palatable "fattening" diet or standard Purina lab chow "non-fattening" diet. Note that the orbital frontal lesioned rats which had been presurgically fattened showed a greater percentage loss in body weight than the non-fattened group. ~ • Orbital FrontalFattened-Lateral Hypothalamic; • . . . . . . • Orbital Frontal-Sham; A- - -A Orbital Frontal-Lateral Hypothalamic. It is important to note that the mean weight of each group with cortical lesions was less than the mean weight of the sham group at the time of the lateral hypothalamic lesion. The OF group weighed about 85% of the sham control group while the MF and FP groups each weighed about 95% of the sham control group. The overall effect of absolute body weight is significant F(3,36)=5.9, p <0.01 and follow up tests (Tukey's, p's<0.05) showed that all groups differed significantly from the controls and the OF group differed from the MF and FP groups. This result has important implications for the explanation of our results since it is known that dieting rats prior to lesions of the lateral hypothalamus has the effect of reducing the length of aphagia, adipsia and lowering percentage weight lost [ 13,16].
The effect o f interlesion time interval and weight manipulation. The basic finding was that prior fattening of rats with orbital frontal lesions to the weight of the sham control group significantly extended the period of aphagia induced by the lateral hypothalamic lesion to a duration equivalent to that of rats with no prior frontal lesion (Fig. 3, Table 2). A second major finding was that although frontal lesions prevent Stage I of the lateral hypothalamic syndrome [19], the rats still
N E O C O R T E X - H Y P O T H A L A M U S AND F E E D I N G
545
TABLE 2 FIRST POSTOPERATIVEDAY TO EXHIBITVARIOUSBEHAVIORS
Sham-LH Fattened OF-LH OF-LH OF-Sham OF-LH (10 day)
Eat Cookie Mash From Spatula
Gain Weight
Eat Dry food
Drink From Water Spout
3.2* 3.3"t 1.3 1.0 2.2t
7.8 9.5* 4.0 2.8 6.0
9.6 8,0 6.8 1.0t 5.0
9.4 8.0 8.0 1.0I" 9.0
* Differs significantly from OF-LH and OF-sham groups (,0<0.05). t Differs significantly from all groups (p<0.01). Note that all groups had 45 days between lesions except the last group which had only 10 days. TABLE 3 FIRST POSTOPERATIVEDAY TO EXHIBITVARIOUSBEHAVIORS Eats Cookie Mash from Spatula Gain Weight Unil LH Unil OF Bil LH Bil OF OF-LH
1.5 1.2 3.8* 2.4* 3.7*
3.0 2.0 7.2* 4.8* 5.8*
Eat Dry Food
Drink from Water Spout
4.4 1.2 8.0* 6.2* 7.3*
2.6 1.2 7.8* 6.0* 7.3*
*Differs significantly from Unil LH and Unil OF. 11o-
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FIG. 4. The effect of combined neocortical and hypothalamic lesions on body weight of rats. Rats with an orbital frontal lesion contralateral to a lateral hypothalamic lesion showed weight loss comparable to rats which received either bilateral orbital frontal or bilateral lateral hypothalamic lesions. Either unilateral lesion given alone produced only slight body weight loss.
experience Stages II, III and IV. Table 2 shows that the rats with only LH lesions or LH lesions after OF lesions plus fattening were aphagic longer and took longer to gain weight than the rats in the other groups. Analyses of variance showed significant effects on both measures F(4,25)=28.6, p<0.01, F(4,25)=3.9, p<0.05. Significant intergroup comparisons (Tukey's, p's<0.05) are summarized in Table 2. Analyses of variance on time to eat dry food and to drink water were also significant F(4,25)=13.2, p<0.01, F(4,25)=5.6, p<0.05) but the 3
groups with lateral hypothalamic lesions did not differ among themselves. Comparison of Tables 1 and 2 reveals that O F - L H rats are adipsic longer in Table 2. This presumably resulted from the fact that the high fat diet used in the first study had no water whereas the cookie mash diet did have water. Thus drinking from the spout correlates with eating dry food in the second study. When the rats were fed cookie mash from a spatula following the lateral hypothalamic lesion all of the rats in the LH-only group and the fattened OF-LH groups exhibited active rejection of the food including paw patting and ventral rubbing [16]. No rats in the OF-LH group actively rejected food after the LH lesion and all but one ate food on the first presentation of the food. In spite of this, the latter rats did not eat hard food or drink water sooner than the former groups, suggesting that the effect of the prior OF lesion was to abolish Stage I, but not Stages II, III and IV. Finally, rats with only 10 days between the OF and LH lesions were aphagic significantly longer (0<0.05) than normal weight rats with 45 days between the lesions (Table 2). However, they did not differ significantly on any other measure (o<0.05).
The effect of orbital frontal lesions on normal, lateral hypothalamic and fattened lateral hypothalamic lesioned rats. None of the five normal weight lateral hypothalamic lesioned rats which received OF lesions following LH lesions were aphagic whereas all rats which received only OF lesions were aphagic when tested with cookie mash on the spatula (mean 2.8 days, range 2--4). The latter rats all exhibited passive rejection of the food [ 16]. There were no significant differences between these groups (0>0.05) on days to drink water, eat dry food or gain weight. The means for these
546
KOLB, NONNEMAN AND WHISHAW
behaviors were approximately the same for the OF-LH group in the previous study. Thus LH lesions prior to OF lesions abolished aphagia but failed to affect the other behaviors measured, an effect very similar to that observed when LH lesions followed OF lesions. Fattened LH rats which received OF lesions were quite different. All of these rats died from unknown causes in a fiaean of 3.0 days (range 1-5). All rats were aphagic and all were passive rejectors of the cookie presented on a spatula. They were also all akinetic but, paradoxically, all were hyper-responsive when touched anywhere on the body with the spatula as they squealed, jumped in the air and oriented toward the spatula when touched. At the time of surgery these rats weighed about 13% more than the other LH group (p <0.01) but the mean weights of the two groups differed by less than 1% when the fattening procedure began. The effect of combined unilateral neocortical and hypothalamic lesions. Unilateral lesions of either the OF cortex or LH had little effect on food intake whereas unilateral OF and unilateral contralateral LH lesions combined to produce aphagia and adipsia and reduced body weight as much as bilateral OF or LH lesions (Fig. 4, Table 3). Table 3 shows that the various lesions had differential effects on food and water intake. There were significant main effects on all measures: eating mash, F(4,19)=4.6, p<0.01, drinking, F(4,19)=20.3, p<0.01, eating dry food F(4,19)=7.5, p<0.01, and gaining weight, F(4,19)=5.7, p<0.01. Results of follow-up tests (Tukey's, p's<0.05) are summarized on Table 3. Note that the combined orbital frontal-lateral hypothalamic lesion had effects similar to bilateral lesion of either structure. DISCUSSION Glick and Greenstein [5] reported that rats with a frontal polar lesion 30 days prior to a lateral hypothalamic lesion were aphagic and adipsic for 1-5 days, and experienced a 15% reduction in body weight over the first 4 days following the second lesion. Rats with simultaneous frontal and hypothalamic lesions, or hypothalamic lesions alone, were severely aphagic and adipsic, lost about 30% body weight over the same period and all died. Our results confirm that frontal cortex lesions do reduce the effect of lateral hypothalamic lesions and show that if the frontal lesion is in the orbital region there is no aphagia at all and a weight loss of only about 10% following the second lesion. However, the lateral hypothalamic lesions do still have a significant effect on behavior as the rats are adipsic for 3-4 days and do not eat dry food for 6-7 days. In other words, the prior frontal lesions appear to abolish Stage I of the lateral hypothalamic syndrome [19] but Stages II, III and IV still occur and have the usual duration. A similar effect is reported by Schallert and Whishaw [16] who dieted rats prior to lateral hypothalamic lesions in replication of Powley and Keesey [13]. Although they found that lowering body weight abolished the aphagia, as reported by others, the rats still experienced Stages II, III and IV. The similarity between the effect of frontal lesions prior to lateral hypothalamic lesion suggested that the weight of rats with frontal lesions might be very important when they received the lateral hypothalamic lesions. The effect of fattening the rats between the lesions in our current studies confirms this hypothesis. Glick [4] argued that the reason frontal lesions attenuate
the effect of lateral hypothalamic lesions is because the frontal lesions alter the activity of hypothalamic or mesencephalic catecholaminergic neurons. He supported this hypothesis with preliminary data showing changes in hypothalamic noradrenalin and striatal dopamine levels following frontal lesions. Glick suggested that the reduced hypothalamic noradrenalin may result from some partial removal of hypothalamic input and that the increased striatal dopamine resulted from sprouting of dopaminergic neurons. In view of the functional interrelationships between the prefrontal cortex and the hypothalamus [14,15, current study] this hypothesis is reasonable. However, another factor should be carefully considered before accepting this suggestion. It is known that dieting rats produces a large number of metabolic changes [2]. It is plausible to propose that dieting rats could alter brain catecholamine levels. Since we have shown that frontal, especially orbital frontal lesions chronically reduce body weight [11] and produce changes in the effects of lateral hypothalamic lesions [present study] which are similar to those produced by dieting rats prior to lateral hypothalamic lesions [16], the effect of body weight should be considered when proposing that changes in brain catecholamine levels result from lesions. Glick also argued that the reason that frontal lesions just 10 days prior to lateral hypothalamic lesions did not prevent aphagia and adipsia is because the denervation supersensitivity in the catecholaminergic systems had not yet occurred. Since these rats would also weigh less than controls at the time of the lateral hypothalamic lesion, one might have expected an effect similar to the effect of lesions 30 or 60 days later if body weight were an important factor. However, an experiment by Grijalva et al. [6] demonstrated that fasting rats for 6 days prior to a lateral hypothalamic lesion does not produce the Powley and Keesey effect. Rather, the rats must be dieted slowly to lose weight or maintained at the fasted weight for an extended period of time. Thus, Glick's 10 day results could be explained by noting that the animals lost weight too quickly and were essentially similar to Grijalva et al. 's fasted rats. It is interesting to consider our 1 stage combined frontalhypothalamic lesions in light of some other current hypothesis regarding recovery of function following lateral hypothalamic lesions. One view argues that recovery results from changes in the area around the lesion [21] whereas a second view argues for recovery as a result of reencephalization [18]. The fact that combined unilateral contralateral lateral hypothalamic-orbital frontal lesions are additive supports the re-encephalization view and suggests that the reorganization may be occurring in the orbital frontal cortex. It is presumably no coincidence that this cortex is the termination of ascending dopaminergic projections. However, Cytawa and Teitelbaum [13] reported that cortical spreading depression reinstated the lateral hypothalamic syndrome in rats that recovered from previous lateral hypothalamic lesions. They argued that the neocortex had somehow reorganized to facilitate recovery from the lateral hypothalamic lesion. It is peculiar that frontal lesions following lateral hypothalamic lesions do not fully reinstate the lateral hypothalamic syndrome unless the rats are fatened prior to the second lesions. Presumably there is an interaction between central reorganization and factors related to body weight in determining rate of recovery from brain damage.
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AND FEEDING
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REFERENCES
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Influence of Frontal Neocortex Lesions and Body Weight Manipulation on the Severity of Lateral Hypothalamic Aphagia I B R Y A N K O L B , A R T H U R J. N O N N E M A N
A N D I A N Q. W H I S H A W
Department o f Psychology, University o f Lethbridge, Lethbridge, Alberta, Canada T1K 3M4 and Department o f Psychology, University o f Kentucky, Lexington, Kentucky ( R e c e i v e d 27 F e b r u a r y 1978) KOLB, B., A. J. NONNEMAN AND I. Q. WHISHAW. Influence offrontal neocortex lesions and body weightmanipulation on the severity of lateral hypothalamic aphagia. PHYSIOL. BEHAV. 21(4) 541-547, 1978.--Frontal neocortex lesions produced aphagia, adipsia, and reduced body weight, but also attenuated the duration of aphagia and adipsia which followed lateral hypothalamic lesions given 46-60 days later. These changes were greater after orbital frontal than after medial frontal or frontal polar neocortical lesions. If the rats with orbital frontal lesions were fattened the duration of aphagia and adipsia following lateral hypothalamic lesions increased. When the experimental procedure was reversed so that orbital frontal lesions were given 60 days after lateral hypothalamic lesions the duration of the aphagia and adipsia following the orbital frontal lesions was reduced. If the rats were fattened during the inter-lesion interval the severity of aphagia and adipsia after the second lesion was increased. These results suggest that body weight changes which occur as a consequence of the first lesion may contribute to the duration and severity of aphagia and adipsia following the second lesion. However, components of the orbital frontal cortex and lateral hypothalamus may be part of a common functional system subserving feeding behavior. One stage combined unilateral orbital frontal and contralateral unilateral lateral hypothalamic lesions mimicked the effects of bilateral lesions of either area. Frontal neocortex
LH aphagia
LH adipsia
G L I C K and Greenstein [5] reported the remarkable finding that if rats were given frontal cortex lesions thirty days prior to lateral hypothalamic lesions they did not exhibit the typical aphagia and adipsia of the lateral hypothalamic syndrome [19]. Glick and Greenstein [5] proposed that the prophylactic effect of the frontal lesions was due to the development of denervation supersensitivity in catecholaminergic neural systems which support feeding behavior. Their findings also suggested that there is a relation between frontal neocortical and hypothalamic systems which support feeding behavior. Recent anatomical and electrophysiological work has shown that the region of the frontal cortex which receives terminations from the catecholamine systems is the prefrontal cortex [1, 14, 15]. Further, this cortex is itself comprised of 2 discrete subfields; medial frontal and orbital (ventral or sulcal) cortex [12]. Behavioral studies on the relation of this cortex to feeding behavior have shown that orbital cortex removal produces a more severe disruption of feeding behavior than medial cortex removal [7, 8, 9, 11]. These findings suggested to us that further analysis of the Glick and Greenstein phenomenon might be worthwhile. A first object of the research was to determine if the pro-
tective effect of neocortex removal could be identified with a specific neocortical subfield. Glick and Greenstein's [5] polar frontal lesions appeared to have invaded both medial and orbital cortex in part. Therefore, we compared the protective effects medial, orbital, and polar lesions had on the feeding behavior of rats subjected to lateral hypothalamic lesions. A second object of the experiments was to examine how frontal lesions protected lateral hypothalamic lesioned rats from aphagia. There was at least one possible explanation for the protective effects of frontal lesions. A number of studies have shown that dieting (but not fasting) rats to approximately 80-85% body weight reduced the severity of lateral hypothalamic syndrome aphagia [13,16]. In our research we found that neocortical lesions produced a chronic reduction in body weight comparable to that produced by dieting [ 11]. It seemed worthwhile, therefore, to determine if there was a relation between body weight change in neocortical lesioned rats and their subsequent response to lateral hypothalamic lesions. The converse question was also asked. Do lateral hypothalamic lesions alter the effect of later frontal lesions and, if so, does this interact with preoperative weight? A final object of the research was to
1This research was supported by Canadian National Research Council grants awarded to Bryan Kolb and lan Q. Whishaw and a National Institute of Health grant awarded to A. J. Nonneman. The authors thank Larry Leach and Rajko Dodic for reading and Adria Allen for typing the manuscript. Requests for reprints should be sent Bryan Kolb, Department of Psychology, University of Lethbridge, Lethbridge, Alberta, Canada, TIK 3M4.
C o p y r i g h t © 1978 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/78/100541-07502.00/0
542
KOLB, NONNEMAN AND WHISHAW
determine if the orbital frontal cortex and the lateral hypothalamic area shared some common role in the control of feeding behavior. We reasoned that if the 2 structures did share some common control over feeding then unilateral, but contraiaterally placed, lesions in each structure should be equivalent to bilateral destruction of tissue in either structure. METHOD
Animals Feeding behavior was studied in 115 adult male Wistar rats. Mean body weights and standard deviations are reported for each group in the appropriate procedure section. There were no significant differences in initial body weights (analyses of variance, p's>0.05) among groups in any experiment.
Surgery The animals were anesthetized for surgery with 50 mg/kg sodium pentobarbital. Neocortical lesions were performed by the suction technique described previously [11]. The medial frontal lesions were intended to remove the projection field of the lateral portion of the thalamic nucleus medialis dorsalis, while the orbital frontal lesions were intended to remove the projection field of the medial portion of the dorsal medial nucleus [12]. The polar lesions were intended to remove an area of tissue similar in extent to that described by Glick and Greenstein [5]. Lateral hypothalamic lesions were made using the stereotaxic technique [20]. Stereotaxic co-ordinates were 2.5 mm posterior to the bregmoidal intersection, 1.8 mm lateral to the mid-saggital suture, and 8.0 mm ventral to the dura. Anodal electrolytic lesions were made by passing a 15 sec, 1.5 mA direct current through a number 00 insect pin which had been insulated to the cross-section of the tip.
Procedure The effect of lateral hypothalamic lesions on rats pretreated with frontal neocortex lesions. The rats were divided into 4 groups of 10 rats which received either orbital frontal (mean weight 399 _ 46g), medial frontal (394 -4- 17g), frontal polar (390 ___ 60g) lesions, or anesthesia only (392 _ 29g). After 60 days all animals received bilateral lateral hypothalamic lesions and after a further 10 days they were sacrificed for histological analysis. F o r the first 10 days following each lesion all animals were provided with jars (4 cm high) filled with a diet consisting of lard (30%), corn oil (10%), sucrose (33%), and casein (20%), plus vitamins and salts. On Day 11 after the first lesion the rats were given Purina rat chow. F o o d and water intake and body weight were recorded daily. The effects of interlesion time interval and weight manipulation. Thirty rats were divided into 5 groups of 6 rats each. Four groups received orbital frontal lesions (mean weights 442 -+ 88g, 446 -+ 79g, 416 -- 22g, 439 -- 23g) while the Fifth group received anesthesia only (423 _+ 14g). Ten days later one orbital frontal group received bilateral lateral hypothalamic lesions. Thirty days after first surgery a second orbital frontal group was subjected to a fattening procedure. The animals were fed Purina rat chow supplemented with a mash made from crushed chocolate chip cookies and vitamins [11]. Forty-six days after first surgery this and the
remaining groups were given bilateral lateral hypothalamic lesions. On the day following the lateral hypothalamic lesions, Purina food pellets were scattered on the floor of the living cage. If the rats ate no Purina food, a spatula Fdled with chocolate chip cookie slurry was held near the mouth of the rat for 10 min or until the rat either ate the food or actively rejected it by pushing away the spatula, ventral chin rubbing, or repeated head withdrawal. Rats which failed to eat were retested every few hours until they began to eat. The high fat diet was available to all of the rats on the first 10 days after lateral hypothalamic lesions but after this they were given Purina rat chow and water for the remaining 50 days of the experiment. Those rats which failed to maintain body weight on Purina chow were shifted back and forth from the chow to the high fat diet until they were maintaining body weight on the chow. The effect of orbital frontal lesions on normal, lateral hypothalamic, and fattened lateral hypothalamic lesioned rats. Fifteen rats were divided into 3 groups of five rats each (mean weights, 4 1 4 _ 7g, 415-+ 18g, 4 1 5 - - - l l g ) . Two groups received lateral hypothalamic lesions while the third group received anesthesia only. Thirty days after surgery, one lateral hypothalamic group was fattened by feedings of Purina rat chow supplemented with chocolate chip mash. On the sixteenth day following the fattening procedure all rats received orbital frontal lesions. The rats were tested behaviorally after each lesion by presenting cookie on a spatula as described above. The effect of combined unilateral neocortical and hypothalamic lesions. Twenty-five rats were divided into five groups of five rats each. The groups received either bilateral orbital frontal (mean weight 392 _+ 18g), bilateral lateral hypothalamic (395 -+ 1 lg), unilateral orbital frontal (440 _ 27g), unilateral lateral hypothalamic (437 --- 32g), or unilateral orbital frontal plus contralateral unilateral lateral hypothalamic (390-+ 14g) lesions. Following surgery the animals were tested for aphagia-adipsia as described above. F o r the first 10 post-surgical days they were maintained on the mash diet and thereafter they were given Purina rat chow.
Histological Procedure The animals were sacrificed with intraperitoneal sodium pentobarbital injection. They were perfused intracardially with normal saline followed by 10% formalin. The brains were frozen and 40/z coronal sections were cut for staining with cresyl violet. RESULTS
Anatomical Results Figure 1 shows coronal sections through the region of the lesions for a representative rat from each lesion group in the "effect of lateral hypothalamic lesions on rats with frontal neocortex lesions" study. The neocortical lesions were similar to those we have illustrated elsewhere [10,11]. The orbital frontal lesions removed the sulcal cortex in addition to varying amounts of motor and gustatory cortex while the medial frontal lesions removed the cortex of the medial wall of the anterior 1/3-1/2 of the hemispheres. The polar lesions destroyed an extent of tissue similar to that described by Glick and Greenstein and were restricted to motor cortex. The lateral hypothalamic lesions were similar to those described
NEOCORTEX-HYPOTHALAMUS AND FEEDING
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FIG. 1. Serial sections from the brains of representative rats which received lateral hypothalamic (LH) lesions 60 days after an orbital frontal (OF-LH), frontal polar (FP-LH), medial frontal (MF-LH) lesion or after a sham lesion. Area of stippling includes lesion cavity as well as surrounding neuron-free tissue.
544
KOLB, N O N N E M A N AND W H I S H A W TABLE1 FIRST ~STOPERATIVE DAY TO EXHIBITEATINGAND D~NKING Eat High Fat From Dish Sham-LH OF-LH MF-LH F~LH
1.0 4.0* 1.0 1.0
Stage 1 Drink Water From Richter Tube
Eat High Fat From Dish
1.0 4.4* 1.0 1.0
Stage 2 Drink Water From Richter Tube
8.0* 2.4* 5.9 6.3
10*t 3.4* 6.4 6.0
* Differs significantly from all other groups (p<0.05). t Note that only 1 rat had begun to drink after 10 days. Legend: LH=lat hyp lesion; OF=orbital frontal lesion; MF=medial frontal lesion; FP=frontal polar lesion. iI"
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DAYS
FIG. 2. (A) Change in body weight as a percent of preoperative weight in rats which received neocortical lesions. In the initial stage bilateral orbital frontal neocortex lesions produced a greater reduction in body weight than medial frontal lesions. Lesion sites are indicated diagrammatically by the parasagittal brain sections adjacent to each curve. (B) Percent change in body weight produced by lateral hypothalamic lesions in rats which received neocortex lesions or no lesion 60 days earlier. Note that orbital frontal lesions appear to give greater protection than medial frontal lesions from profound weight loss produced by lateral hypothalamic lesions. Frontal polar lesions (not illustrated) had effects similar to the medial frontal lesions.
elsewhere as being effective in producing aphagia and adipsia [16,17].
The effect of lateral hypothalamic lesions on rats pretreated with frontal neocortex lesions. The major finding was that lesions to all 3 frontal cortical regions reduced the effect of the lateral hypothalamic lesion produced 60 days later, but the orbital frontal (OF) lesions had the greatest effect (Fig. 2, Table 1). Analysis of variance showed a significant reduction in both length of aphagia F(3,36)=5.4, p<0.01 and adipsia F(2,27)=15.2, p<0.01 following the cortical lesions. Follow-up tests (Tukey's) showed that the rats with OF lesions had shorter durations of both aphagia and adipsia (p's<0.01) after the lateral hypothalamic (LH) lesions than all other groups. Further, the rats with medial frontal (MF) or frontal polar (FP) lesions had shorter durations of aphagia than the rats in the sham-LH group (p<0.01) while the rats with OF lesions had a shorter duration of adipsia than the rats in the sham-LH group (p<0.01).
I 0
10
i
I 20
i
i 30
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I 40
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I 50
DAYS
FIG. 3. The effect of lateral hypothalamic lesions on body weight of rats which had received orbital frontal neocortex lesions and a palatable "fattening" diet or standard Purina lab chow "non-fattening" diet. Note that the orbital frontal lesioned rats which had been presurgically fattened showed a greater percentage loss in body weight than the non-fattened group. ~ • Orbital FrontalFattened-Lateral Hypothalamic; • . . . . . . • Orbital Frontal-Sham; A- - -A Orbital Frontal-Lateral Hypothalamic. It is important to note that the mean weight of each group with cortical lesions was less than the mean weight of the sham group at the time of the lateral hypothalamic lesion. The OF group weighed about 85% of the sham control group while the MF and FP groups each weighed about 95% of the sham control group. The overall effect of absolute body weight is significant F(3,36)=5.9, p <0.01 and follow up tests (Tukey's, p's<0.05) showed that all groups differed significantly from the controls and the OF group differed from the MF and FP groups. This result has important implications for the explanation of our results since it is known that dieting rats prior to lesions of the lateral hypothalamus has the effect of reducing the length of aphagia, adipsia and lowering percentage weight lost [ 13,16].
The effect o f interlesion time interval and weight manipulation. The basic finding was that prior fattening of rats with orbital frontal lesions to the weight of the sham control group significantly extended the period of aphagia induced by the lateral hypothalamic lesion to a duration equivalent to that of rats with no prior frontal lesion (Fig. 3, Table 2). A second major finding was that although frontal lesions prevent Stage I of the lateral hypothalamic syndrome [19], the rats still
N E O C O R T E X - H Y P O T H A L A M U S AND F E E D I N G
545
TABLE 2 FIRST POSTOPERATIVEDAY TO EXHIBITVARIOUSBEHAVIORS
Sham-LH Fattened OF-LH OF-LH OF-Sham OF-LH (10 day)
Eat Cookie Mash From Spatula
Gain Weight
Eat Dry food
Drink From Water Spout
3.2* 3.3"t 1.3 1.0 2.2t
7.8 9.5* 4.0 2.8 6.0
9.6 8,0 6.8 1.0t 5.0
9.4 8.0 8.0 1.0I" 9.0
* Differs significantly from OF-LH and OF-sham groups (,0<0.05). t Differs significantly from all groups (p<0.01). Note that all groups had 45 days between lesions except the last group which had only 10 days. TABLE 3 FIRST POSTOPERATIVEDAY TO EXHIBITVARIOUSBEHAVIORS Eats Cookie Mash from Spatula Gain Weight Unil LH Unil OF Bil LH Bil OF OF-LH
1.5 1.2 3.8* 2.4* 3.7*
3.0 2.0 7.2* 4.8* 5.8*
Eat Dry Food
Drink from Water Spout
4.4 1.2 8.0* 6.2* 7.3*
2.6 1.2 7.8* 6.0* 7.3*
*Differs significantly from Unil LH and Unil OF. 11o-
l.-r ILl
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11
DAYS
FIG. 4. The effect of combined neocortical and hypothalamic lesions on body weight of rats. Rats with an orbital frontal lesion contralateral to a lateral hypothalamic lesion showed weight loss comparable to rats which received either bilateral orbital frontal or bilateral lateral hypothalamic lesions. Either unilateral lesion given alone produced only slight body weight loss.
experience Stages II, III and IV. Table 2 shows that the rats with only LH lesions or LH lesions after OF lesions plus fattening were aphagic longer and took longer to gain weight than the rats in the other groups. Analyses of variance showed significant effects on both measures F(4,25)=28.6, p<0.01, F(4,25)=3.9, p<0.05. Significant intergroup comparisons (Tukey's, p's<0.05) are summarized in Table 2. Analyses of variance on time to eat dry food and to drink water were also significant F(4,25)=13.2, p<0.01, F(4,25)=5.6, p<0.05) but the 3
groups with lateral hypothalamic lesions did not differ among themselves. Comparison of Tables 1 and 2 reveals that O F - L H rats are adipsic longer in Table 2. This presumably resulted from the fact that the high fat diet used in the first study had no water whereas the cookie mash diet did have water. Thus drinking from the spout correlates with eating dry food in the second study. When the rats were fed cookie mash from a spatula following the lateral hypothalamic lesion all of the rats in the LH-only group and the fattened OF-LH groups exhibited active rejection of the food including paw patting and ventral rubbing [16]. No rats in the OF-LH group actively rejected food after the LH lesion and all but one ate food on the first presentation of the food. In spite of this, the latter rats did not eat hard food or drink water sooner than the former groups, suggesting that the effect of the prior OF lesion was to abolish Stage I, but not Stages II, III and IV. Finally, rats with only 10 days between the OF and LH lesions were aphagic significantly longer (0<0.05) than normal weight rats with 45 days between the lesions (Table 2). However, they did not differ significantly on any other measure (o<0.05).
The effect of orbital frontal lesions on normal, lateral hypothalamic and fattened lateral hypothalamic lesioned rats. None of the five normal weight lateral hypothalamic lesioned rats which received OF lesions following LH lesions were aphagic whereas all rats which received only OF lesions were aphagic when tested with cookie mash on the spatula (mean 2.8 days, range 2--4). The latter rats all exhibited passive rejection of the food [ 16]. There were no significant differences between these groups (0>0.05) on days to drink water, eat dry food or gain weight. The means for these
546
KOLB, NONNEMAN AND WHISHAW
behaviors were approximately the same for the OF-LH group in the previous study. Thus LH lesions prior to OF lesions abolished aphagia but failed to affect the other behaviors measured, an effect very similar to that observed when LH lesions followed OF lesions. Fattened LH rats which received OF lesions were quite different. All of these rats died from unknown causes in a fiaean of 3.0 days (range 1-5). All rats were aphagic and all were passive rejectors of the cookie presented on a spatula. They were also all akinetic but, paradoxically, all were hyper-responsive when touched anywhere on the body with the spatula as they squealed, jumped in the air and oriented toward the spatula when touched. At the time of surgery these rats weighed about 13% more than the other LH group (p <0.01) but the mean weights of the two groups differed by less than 1% when the fattening procedure began. The effect of combined unilateral neocortical and hypothalamic lesions. Unilateral lesions of either the OF cortex or LH had little effect on food intake whereas unilateral OF and unilateral contralateral LH lesions combined to produce aphagia and adipsia and reduced body weight as much as bilateral OF or LH lesions (Fig. 4, Table 3). Table 3 shows that the various lesions had differential effects on food and water intake. There were significant main effects on all measures: eating mash, F(4,19)=4.6, p<0.01, drinking, F(4,19)=20.3, p<0.01, eating dry food F(4,19)=7.5, p<0.01, and gaining weight, F(4,19)=5.7, p<0.01. Results of follow-up tests (Tukey's, p's<0.05) are summarized on Table 3. Note that the combined orbital frontal-lateral hypothalamic lesion had effects similar to bilateral lesion of either structure. DISCUSSION Glick and Greenstein [5] reported that rats with a frontal polar lesion 30 days prior to a lateral hypothalamic lesion were aphagic and adipsic for 1-5 days, and experienced a 15% reduction in body weight over the first 4 days following the second lesion. Rats with simultaneous frontal and hypothalamic lesions, or hypothalamic lesions alone, were severely aphagic and adipsic, lost about 30% body weight over the same period and all died. Our results confirm that frontal cortex lesions do reduce the effect of lateral hypothalamic lesions and show that if the frontal lesion is in the orbital region there is no aphagia at all and a weight loss of only about 10% following the second lesion. However, the lateral hypothalamic lesions do still have a significant effect on behavior as the rats are adipsic for 3-4 days and do not eat dry food for 6-7 days. In other words, the prior frontal lesions appear to abolish Stage I of the lateral hypothalamic syndrome [19] but Stages II, III and IV still occur and have the usual duration. A similar effect is reported by Schallert and Whishaw [16] who dieted rats prior to lateral hypothalamic lesions in replication of Powley and Keesey [13]. Although they found that lowering body weight abolished the aphagia, as reported by others, the rats still experienced Stages II, III and IV. The similarity between the effect of frontal lesions prior to lateral hypothalamic lesion suggested that the weight of rats with frontal lesions might be very important when they received the lateral hypothalamic lesions. The effect of fattening the rats between the lesions in our current studies confirms this hypothesis. Glick [4] argued that the reason frontal lesions attenuate
the effect of lateral hypothalamic lesions is because the frontal lesions alter the activity of hypothalamic or mesencephalic catecholaminergic neurons. He supported this hypothesis with preliminary data showing changes in hypothalamic noradrenalin and striatal dopamine levels following frontal lesions. Glick suggested that the reduced hypothalamic noradrenalin may result from some partial removal of hypothalamic input and that the increased striatal dopamine resulted from sprouting of dopaminergic neurons. In view of the functional interrelationships between the prefrontal cortex and the hypothalamus [14,15, current study] this hypothesis is reasonable. However, another factor should be carefully considered before accepting this suggestion. It is known that dieting rats produces a large number of metabolic changes [2]. It is plausible to propose that dieting rats could alter brain catecholamine levels. Since we have shown that frontal, especially orbital frontal lesions chronically reduce body weight [11] and produce changes in the effects of lateral hypothalamic lesions [present study] which are similar to those produced by dieting rats prior to lateral hypothalamic lesions [16], the effect of body weight should be considered when proposing that changes in brain catecholamine levels result from lesions. Glick also argued that the reason that frontal lesions just 10 days prior to lateral hypothalamic lesions did not prevent aphagia and adipsia is because the denervation supersensitivity in the catecholaminergic systems had not yet occurred. Since these rats would also weigh less than controls at the time of the lateral hypothalamic lesion, one might have expected an effect similar to the effect of lesions 30 or 60 days later if body weight were an important factor. However, an experiment by Grijalva et al. [6] demonstrated that fasting rats for 6 days prior to a lateral hypothalamic lesion does not produce the Powley and Keesey effect. Rather, the rats must be dieted slowly to lose weight or maintained at the fasted weight for an extended period of time. Thus, Glick's 10 day results could be explained by noting that the animals lost weight too quickly and were essentially similar to Grijalva et al. 's fasted rats. It is interesting to consider our 1 stage combined frontalhypothalamic lesions in light of some other current hypothesis regarding recovery of function following lateral hypothalamic lesions. One view argues that recovery results from changes in the area around the lesion [21] whereas a second view argues for recovery as a result of reencephalization [18]. The fact that combined unilateral contralateral lateral hypothalamic-orbital frontal lesions are additive supports the re-encephalization view and suggests that the reorganization may be occurring in the orbital frontal cortex. It is presumably no coincidence that this cortex is the termination of ascending dopaminergic projections. However, Cytawa and Teitelbaum [13] reported that cortical spreading depression reinstated the lateral hypothalamic syndrome in rats that recovered from previous lateral hypothalamic lesions. They argued that the neocortex had somehow reorganized to facilitate recovery from the lateral hypothalamic lesion. It is peculiar that frontal lesions following lateral hypothalamic lesions do not fully reinstate the lateral hypothalamic syndrome unless the rats are fatened prior to the second lesions. Presumably there is an interaction between central reorganization and factors related to body weight in determining rate of recovery from brain damage.
NEOCORTEX-HYPOTHALAMUS
AND FEEDING
547
REFERENCES
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