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Serial lateral hypothalamic destruction: Infancy and adulthood
EXPERIMENTAL
NEUROLOGY
Serial
C.
(1976)
53,646-662
Lateral Hypothalamic Destruction: Infancy and Adulthood ROBERT
Departlrtmt
ALMLI
AND
GREGORY
of Psychology,
Athens, Received
Ohio
Ohio 45701
T.
GOLDEN
1
University,
Jzrne 21,1976
Male and female albino rats sustained unilateral destruction of the lateral hypothalamic area as infants (10 days of age) or as adults (150 days of age). Also, rats receiving unilateral destruction of the lateral hypothalamic area as infants had their contralateral (intact) lateral hypothalamic area destroyed at 150 days of age, i.e., two-stage serial lateral hypothalamic area destruction separated by 140 days, thereby producing bilateral destruction. The animals were tested for homeostatic regulatory capacity. Loss of one lateral hypothalamic area during adulthood produced greater regulatory deficits than were produced by the loss of one during infancy. These results suggest that the intact lateral hypothalamic area of infant rats has greater capacity to maintain function than does the same intact area of adults. The regulatory deficits produced with two-stage lateral hypothalamic area destruction (one lateral hypothalamic area destroyed during infancy followed by destruction of the contralateral area during adulthood) were nearly identical to the deficits produced with one-stage bilateral destruction, i.e., the regulatory deficits were persistent and severe in spite of the fact that 140 days separated the two lesions. Thus, infant rats can maintain approximately normal regulatory capacity with one intact lateral hypothalamic area. This “sparing of function” was due to the intact lateral hypothalamic area, as its subsequent destruction produced more profound regulatory deficits than were produced with unilateral destruction of the lateral hypothalamic area sustained during adulthood. These results suggest that the “plasticity” of the infant lateral hypothalamic area is greater than that of the adult and that infantile ‘plasticity" is manifest by the capacity of the intact lateral hypothalamic area to subsume the function of the damaged contralateral area. 1 This research was supported by NICHHD Grant HD-08504 to C. R. Almli. G. T. Golden is now at the Department of Neurophysiology, University of Wisconsin, Madison, Wisconsin. 646 Copyright All rights
1976 by Academic Press, Inc. o9 reproduction in any form reserved.
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INTRODUCTION Almli and Golden (2, 3) have recently shown that bilateral destruction of the lateral hypothalamic area (LHA) of pre- and postweanling rats yields bodyweight and regulatory deficits which are nearly identical to the deficits produced when the lateral hypothalamic area is bilaterally destroyed in adult rats (4, 10, 23). Thus, infant rats show no more “recovery of function” following bilateral destruction than do adult rats. The present investigation compares the effects of unilateral destruction of the lateral hypothalamic area sustained during infancy versus adulthood and, more importantly, determines if “sparing of function” occurs when the area is destroyed seriatim between infancy and adulthood, i.e., lateral hypothalamic area on one side of the brain destroyed at 10 days of age followed by destruction of the contralateral area when the rats reach 150 days of age. Previous investigations of serial lateral hypothalamic area destruction of adult rats have yielded conflicting results. Gold (13) used a 13-day interlesion interval and reports no sparing of function following the second lesion ; whereas Fass et al. (11) used a 30-day lesion interval and report sparing of function following the second lesion. The present investigation inflicts the first lesion in preweanling rats and uses a 140-day interlesion interval. METHODS An&n& Fifty-four male or female infant albino rat pups (Holtzman strain) were housed as litters with dams in clear plastic group cages (48.4 X 38.1 x 12.3 cm) in a temperature-controlled room (22 to 25°C) under continuous illumination. At 2 to 4 days of age the seven litters were culled to seven or eight pups each, with approximately equal male/female ratios. The dams were removed from the litter cages when the pups reached 25 days of age, and the pups were housed individually in metabolism cages (Acme Metal Products) or wire rack-mounted cages (24.1 X 17.8 x 19.0 cm) from 30 days of age through the completion of the experiment when the rats were 200 to 260 days of age. Apparatus
and Procedures
Phase I. The first phase of the experiment was begun with random assignment of the pups to one of four sex-surgery groups, when the pups reached 10 days of age. The first two groups contained male (N = 16) and female (N = 15) pups which sustained unilateral destruction of the lateral hypothalamic area at 10 days of age (Male Infant Unilateral, MIU, and Female Infant Unilateral, FIU groups, respectively). The second two
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groups contained male (N = 12) and female (N = 11) pups which received sham surgery at 10 days of age (groups MS and FS, respectively). Sztrgery. All operations were done under ethyl ether anesthesia and the lesions were placed stereotaxically (David Kopf Instruments) using the techniques for infant rats described by Almli and Golden (2, 3). The stereotaxic coordinates for the lateral hypothalamic area were 2.6 to 3.7 mm anterior to the lambda suture, 1.2 to 1.5 mm lateral to the midline suture, and 8.0 to 8.5 mm below the surface of the skull. Anodal lesions were made through 0.25mm-diameter stainless-steel electrodes (0.25- to 0.5-mm uninsulated tip) using a Quartet electrolytic lesion maker (1.0 to 2.0 mA for 5 to 20 set). The male and female infant sham-operated (MIS and FIS) control groups received complete surgery, except that no current was passed through the electrode. Daily Measurements. For both the brain-damaged and control groups, body weight (grams) was measured each 24 hr beginning at 9 days of age. Following surgery, a lack of body-weight gain indicated cessation or decrease of suckling, and the maintenance procedures of Almli and Golden (2, 3) were used. Pups showing body-weight loss were maintained on a liquid diet (2, 3) by hand-feeding with a plastic dropper and/or by stomach loading until the pups were maintaining growth through voluntary suckling and/or feeding-drinking. Liquid diet was presented six to eight times daily at a volume of 0.5 to 2.0 ml per feeding. If necessary, tap water was intubated (2 to 5 ml) twice daily. These procedures continued until the rats were maintaining their body weights through voluntary feeding (chocolate chip cookies and Purina rat pellets) and drinking (tap water). When the rats reached 30 days of age they were housed individually and body-weight (grams), food (grams) and water (milliliters) intakes were measured each 24 hr through 200 to 260 days of age. Homeostatic Challenges. All rats were tested for feeding and/or drinking responses following a variety of specific regulatory challenges when the rats were between 40 and 140 days of age. Each challenge was administered twice and challenges were presented as randomly as possible. Water intakes (2, 3) were measured for 3 hr following hypertonic saline injection (subcutaneous, 16% NaCl, 0.1 ml/30 g body weight), polyethylene glycol injection (subcutaneous, 25%, 20,000 molecular weight, 0.5 ml/35 g body weight), and 24-hr water deprivation. Food was not present during these tests. Water intake was also measured during 24-hr food deprivation. Food and water intakes were measured for 2 hr following injections of amphetamine ( 1.5 and 3.0 “g/kg) (2, 6) and 2-deoxy-n-glucose (200 w/kg) (2, 19). Finally, food intake was measured for 2 hr following 24-hr food depri-
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DESTRUCTION
649
vation, and intakes of quinine hydrochloride solutions (0.1, 0.05, and 0.01%) were measured for 24-hr access periods (2, 23). Phase II. The second phase of the experiment was begun when the rats (MIU, FIU, MS, and FS groups) reached 150 days of age. At this time, those which had sustained unilateral lateral hypothalamic area destruction at 10 days of age (MIU and FIU groups) now sustained destruction of the intact contralateral lateral hypothalamic area, thereby producing bilateral destruction of the lateral hypothalamic area in two operations separated by 140 days. These groups are designated MIU-Bi and FIU-Bi, for males and females, respectively. The control groups (MS and FS) were equally divided, and half received unilateral lateral hypothalamic area destruction at 150 days of age (male and female adult unilateral groups, MAU and FAU, respectively), the other half received a second sham surgery (MS and FS groups). The stereotaxic coordinates used for these rats at 150 days of age were : 5.0 to 6.8 mm anterior to the intraaural plane, 1.2 to 1.5 mm lateral to the midline suture, and 8.5 to 9.0 mm below the level of the skull. The lesion parameters were 1.0 to 2.0 mA for 15 to 20 sec. The sham surgeries were identical to those described in Phase I. The homeostatic challenges (described in Phase I) were administered again to the rats in Phase II, and daily measurements were continued through 200 to 260 days of age. Histology. At the completion of the experiment when the rats were 200 to 260 days old, they were killed with ether and were perfused intracardially with physiological saline (0.87% NaCl) solution followed by 10% formalin-saline solution. Frozen frontal sections were cut at 50 pm, and each section through the lesion was stained with cresyl violet. Lesion locus and extent were determined microscopically, and the sections were photographed and redrawn on appropriate figures from the atlas of K&rig and Klippel (15). Undestroyed nuclei and fiber tracts were used as landmarks to determine the locus and extent of neural tissue destruction. RESULTS All results of this experiment were analyzed with Tukey-HSD post-tests, and two-tailed t tests.
analysis
of variance,
Phase I Body Weight (MIU and FIU Groups). On the first day postsurgery, all lo-day-old pups lost body weight; however, by the second day, the control pups (MIS and FIS groups) were suckling and showing body-weight gains. In contrast, the pups sustaining unilateral lateral hypothalamic area destruction (MIU and FIU groups) continued to lose body weight on the
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second and third postoperative days, because they ceased suckling. Nine of the 31 brain-damaged pups died during this period; thus the MIU and FIU groups contained 11 pups each. On the third postoperative day, handfeeding and intubation of liquid diet were begun and the remaining 22 rats survived. These brain-damaged pups required maintenance until 10 to 18 days postlesion (20 to 28 days of age) when the pups maintained body weight through voluntary suckling and/or feeding and drinking. Presented in Fig. 1A are mean body weights of MIU (N = 11)) FIU (N = ll), MIS (N = 12), and FIS (N = 11) groups plotted as a function of days of age. None of the groups differed significantly in body weight at 10 days of age (P’s > 0.05). The control rats (MIS and FIS) showed equal growth until 38 to 40 days of age when the males’ body weights consistently exceeded that of females’ (P < 0.05 or beyond). This sexual dimorphism for body weight of control rats increased through 150 days of age. In contrast, the pups sustaining unilateral lateral hypothalamic area destruction (males and females) showed little or no body-weight increase through the first 10 days postlesion, such that, by 20 days of age, these pups were 27% below control body weights. When the MIU and FIU pups began voluntary feeding and drinking they showed substantial bodyweight gains. These brain-damaged rats displayed a delayed sexual dimorphism for body weight, i.e., the body weights of the MIU rats did not reliably exceed the weights of the FIU rats until 50 to 52 days of age, which is approximately 12 days later than control sexual dimorphism. As seen in Fig. lA, the MIU rats remained 15 to 25% below MIS rats, for body weight, through 150 days of age (P < 0.05 or beyond). On the other hand, the FIU rats achieved control (FIS) body weights by 40 to 44 days of age (P > O.OS), and the two female groups did not significantly differ for body weight through 150 days of age (P > 0.05). Daily food and water intakes of the MIU and FIU rats were highly variable following the resumption of consummatory behaviors at 20 to 28 days of age. By 90 days of age, food and water intakes stabilized at slightly depressed levels, and this mild hypodipsia and hypophagia persisted through 150 days of age (see Table 1). However, these depressed intake levels did not significantly differ from control levels (P’s > 0.05). During that final 60-day period (90 to 150 days of age), the MIU rats’ food intakes were depressed 14% and water intakes lo%,, as compared to male control rats. The food and water intakes of FIU rats were depressed 12 and 17%, respectively, during that same period. Honzeostatic Challenges (MIU and FIU Groz@s). The brain-damaged and control rats were tested for food and/or water intakes following a variety of tests of homeostatic regulatory capacity when the rats were 40 to 140 days of age. The mean intake data are presented in Table 1.
SERIAL
LATERAL
HYPOTHALAMIC
TABLE
651
DESTRUCTION
1
Responses to Homeostatic Challenges of Control Rats and Rats Sustaining Unilateral Destruction of the Lateral Hypothalamic Area at 10 Days of Age Controls
Daily intake (24 hr) Food
deprivation
Amphetamine
(24 hr) 1.5 mg/kg 3.0 mg/kg
ZbDeoxy-D-glucose Hypertonic saline Polyethylene glycol Water deprivation (24 hr) Quinine hydrochloride
Food* Waterb Food Water Fo& Water Food Water Foodd Water Water Water Water O.Olyp 0.05% 0.10%
Operated
Male 12 rats
Female 11 rats
Male (MIU) 11 rats
Female (FW 11 rats
6.6 10.2 1.2 4.5 -24%~ -36%0 - 90%9 -91%9
8.6 13.9 1.0 6.5 -32%~ -42%~ - 86%70r -91%9 +75%9 +9% 3.8 4.1 7.6 10.39 5.99 2.19
5.7 9.1 1.1 2.1’ -42%Q -39%* -8l%Q -91%0 40%9
7.6 11.5 1.2 3.8’ -69%~ -46%* -97%’ -92%~ +34%# +13% 3.5 3.2 6.8 9.29 4.89 1.79
+63%* +6% 3.1 2.2 6.9 8.40 .5.3g
1.29
-50%‘~’
3.0 1.8 5.5
8.00 5.29 0.S
a Grams per 100 g body weight. b Milliliters per 100 g body weight. c Basal treatment is 24-hr food and water deprivation with physiological saline injection, intake measured for 2 hr. d Basal treatment is ad lib&m food and water with physiological saline injection, intake measured for 2 hr. BBasal treatment is 24-hr water intake on preceding day. f P’s < 0.05 or beyond, compared to control. # P’s < 0.05 or beyond, compared to basal treatment.
The brain-damaged rats’ water intakes following injections of hypertonic saline or polyethylene glycol and after 24-hr water deprivation were smaller than control for both sexes; however, the differences were unreliable (P’s > 0.05). In addition, intakes of quinine hydrochloride solutions decreased with increasing concentration for both the brain-damaged and control groups (P’s < 0.05 or beyond), but again, the brain-damaged and control rats did not reliably differ for any concentration tested (P’s > 0.05). The MIU and FIU rats also showed a normal anorexic effect of amphetamine injection (P’s < 0.05) and a normal stimulation of feeding after injection of 2-deoxy-n-glucose (P's < O.OS), and the intakes did not differ significantly from control levels (P's > 0.05).
6.52
ALMLI
AND
GOLDEN
Whereas the MIU and FIU rats responded to most homeostatic challenges in a “normal” fashion, the brain-damaged rats reliably differed from controls for the prandial test. During 24-hr food deprivation, the MIU and FIU rats showed reliably attenuated water intakes (P’s < O.Ol), suggesting they were “prandial” drinkers ( 14). In summary unilateral destruction of the lateral hypothalamic area in lo-day-old rats yields a transient cessation of suckling and body-weight loss for both male and female rats. Such lesions also result in a delayed sexual dimorphism for body weight for male and female rats. Although depression of growth is temporary for female brain-damaged rats, the males had not achieved control body weights even by 1.50 days of age. Daily food and water intakes of the brain-damaged rats did not reliably differ from control levels; however, the rats tended toward hypodipsia and hypophagia through 150 days of age. The MIU and FIU rats responded to most homeostatic challenges in a normal fashion. Food and/or water intakes following hypertonic saline, polyethylene glycol, amphetamine, 2-deoxy-n-glucose, water deprivation, and quinine hydrochloride treatments did not significantly differ from control levels. However, these brain-damaged rats reliably decreasedwater intakes during food deprivation. Phase II Body Weights. Male and female adult rats sustaining unilateral destruction of the lateral hypothalamic area at 1.50days of age (MAU and FAU groups, respectively) showed short periods of aphagia-adipsia, and all were voluntarily feeding and drinking by 2 or 3 days postlesion. These rats did not require intubation of liquid diet or water for survival. As shown in Fig. lB, the MAU rats (N = 5) were 9% below control body weights by 10 days postlesion. The unilateral lesion essentially stopped normal growth as their body weights at 260. days of age did not differ from their body weights at 150 days (P > 0.05). In contrast, FAU rats (N = 5) quickly regained their postlesion body weight Ioss (6 to 9%), and from 160 to 260 days of age the FAU and female sham-operated groups did not differ significantly in body weights (P > 0.05). The MAU and FAU rats were reliably hypophagic and hypodipsic from 20 to 110 days postlesion (P’s < 0.05 or beyond). The male brain-damaged rats consumed 72% of the food and 78% of the water of control males during that go-day period, and females ingested 47 and 77% (for food and water, respectively) of control levels (see Table 2). Homeostatic Challenges (MA U a.nd FA U Groups). Presented in Table 2 are the intake data in response to homeostatic challenges of the MAU and FAU rats. Each treatment was administered once between 20 and 110
SERIAL
LATERAL
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570 530
90 50 10 10 20
30
40
50
60
70
90
90
110
t LEJlON
lml
I30
I90
IW
200
z?o
240
250
t LESION
DAYS
OF
AGE
FIG. 1. Mean body weight (grams) of brain-damaged and control rats (males and females) plotted as a function of days of age. Lesions were made at 10 and/or 1.50 days of age. Control rats are represented by dashed line-open squares (males) and dashed line-open circles (females) in A and B. Rats sustaining unilateral hypothalamic lesions at 10 days of age (MIU and FIU groups) are represented by solid line-filled squares (males) and solid line-filled circles (females) in A. Rats sustaining unilateral lesions at 150 days of age are represented by solid line-open triangles for both males (MAU, upper curve) and females (FAU, lower curve) in B. The MIU and FIU groups which become the MIU-Bi and FIU-Bi groups at 150 days of age, are represented in B by solid line-filled squares (MIU-Bi) and solid line-filled circles (FIU-Bi) .
days postlesion. In addition to the statistically reliable daily hypodipsia and hypophagia of the MAU and FAU rats, they reliably attenuated water intakes during 24-hr food deprivation (P’s < O.Ol), displayed no potentiation of feeding following 2-deoxy-o-glucose injection (P’s > O.OS), and reliably attenuated intakes of 0.1 and 0.050/oquinine hydrochloride solutions (P’s < 0.05 or beyond). Also, MAU rats (P < O.OS), but not FAU rats (P > O.OS), showed reliably attenuated water intakes following hypertonic saline injection. While the other tests yielded results which tended toward hypodipsia and/or hypophagia, only the challenges presented above produced reliable differences between MAU or FAU rats and their respective controls. When the MIU and FIU rats (of Phase I) reached 150 days of age, the intact contralateral lateral hypothalamic area was destroyed, thereby pro-
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TABLE Responses Destruction Destruction lateral Area
GOLDEN
2
to Homeostatic Challenges of Control Rats, Rats Sustaining Unilateral of the Lateral Hypothalamic Area at 1.50 Days of Age, and Rats Sustaining of One Area at 10 Days of Age Followed by Destruction of the Contraat 150 Days of Age Operated
Controls
Daily Food
intake deprivation
Amphetamine
1.5 mg/kg 3.0 mg/kg
Z-Decay-o-glucose Hypertonic saline Polyethylene glycol Water deprivation Quinine hydrochloride
Food’ Watera Food water Food< Water Food Water Foodd Water Water water Water o.ol%e 0.05 70 0.10%
as adults
Operated as infants and adults ~ Male Female (MN-Bi) (FIU-Bi) 4 rats 4 rats
MC& 7 rats
Female 6 rats
Male (MAU) 5 rats
Female (FAU) 5 rats
6.8 9.4 1.8 5.4 -29%0 -34To”oo -90%9 -89%~ --55qp -5% 3.8 2.7 4.7 8.3R 5.40 1.60
9.3 11.7 1.6 7.0 -22Y@ -4O%S --87qo~ -91%9 +sl%s -11% 4.1 3.9 5.2 10.29 5.6~ 1.70
4.91 7.3) 1.0 2.21 -29%~ -69%~ --8l%S -5l%S --6O%f.~
4.4f 9.11 1.1 1.7f -SO%@ -83%f.V -lOO%S -91%0 -4O%f*O
-92q~f.o
-w%
1.9f 2.0 3.3 3.4f,o 0.3f.u 1.os
a Grams per 100 g body weight. * Milliliters per 100 g body weight. c Basal treatment is 24-hr food and water deprivation with physiological for 2 hr. d Basal treatment is ad Zibilunt food and water with physiological for 2 hr. 6 Basal treatment is 24-hr water intake on preceding day. f P’s < 0.05 or beyond compared to control. s P’s < 0.05 or beyond compared to basal treatment.
3.1 2.8 3.7 5.6J.9 2.01.0 1.01
saline saline
4.0f
5.7f
3.21 1.0 0.6, -71%9 -lOO%f.’ -lOO%r -810/@ -lOO%f.s -loo~o~.u
1.3 1.71 -27%~ +14%f.g --6O%g -42yol.r -36%f,g --58%f.P 1.1) 0.41 1.61
injection, injection,
3.61
2.4f.s
0.0f.r 0.2f .I
2.6f
2.4f 2.41 1.7JJ 0.4f.P 1.20
intake
measured
intake
measured
ducing bilateral destruction of the lateral hypothalamic area (MIU-Bi and FIU-Bi groups). In spite of the fact that 140 days separated the production of the two lesions, the immediate consequences of the second lesion were adipsia and aphagia, and two males and four females died within 3 days. In addition, five males and three females died during (or following) tubing accidents (liquid diet entering the lungs) at between 6 and 26 days postlesion. These eight rats were still adipsic and aphagic at the time of death. The surviving eight rats, four males and four females, lived more than 260 days (110 days postlesion). These rats began to feed (hydrated cookies, wet mash) and maintain body weight by 6 to 29 days postlesion, and they began drinking water at 7 to 66 days postlesion, when they were able to maintain their body weights through voluntary feeding (hydrated cookies, wet mash, and pellets) and drinking (tap water). As shown in Fig. lB, both the MIU-Bi and FIU-Bi groups showed permanent slowing of growth following the second lesion (P’s < 0.05 or
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beyond). The males lost 23% of their prelesion body weight within 10 days postlesion, and remained relatively stable at that reduced level through 260 days of age, when they weighed only 50% as much as the control. Likewise, the FIU-Bi rats lost 21% of their body weight within 10 days postlesion ; thereafter, they paralleled control female growth and by 260 days of age these female rats were 23% below the body weights of the controls (P < 0.01). As indicated by the permanent body-weight depression, both the MIUBi and FIU-Bi rats were reliably hypophagic and hypodipsic between 210 and 260 days of age (60 to 110 days postlesion) (P’s < 0.01 or beyond). During the final SO-day interval, the MIU-Bi rats were consuming only 52% (food) and 61% ( wa t er ) o f control amounts, and FIU-Bi rats were eating 57% and drinking 73% compared to controls (Table 2). Homeostatk Challenges (MIU-Bi and FIU-Bi Groups). The homeostatic challenges were administered once each at between 50 and 110 days postlesion, and the results are presented in Table 2. The MIU-Bi and FIUBi rats showed reliably attenuated water intakes after injections of hypertonic saline and polyethylene glycol, following 24-hr water deprivation and during 24-hr food deprivation (P’s < 0.05 or beyond). These braindamaged rats also showed decreased intakes of 0.01 and 0.05% quinine hydrochloride solutions (P’s < 0.05 or beyond) and did not show a stimulation of feeding after 2-deoxy-n-glucose injection (P’s > 0.05). The only test yielding a “normal” response for the MIU-Bi and FIU-Bi rats was the amphetamine treatment where these rats showed a dose-dependent anorexia effect which did not differ significantly from control (P’s > 0.05). Histological
and Postmortem
Analysis
Presented in Fig. 2 are photomicrographs through the centers of the lesions of representative rats of the MIU-Bi (Fig 2a) and MAU (Fig. 2b) groups. In the MIU-Bi rat, the lesion on the left was made at 10 days of age, and the lesion on the right at 150 days of age. The lesion in the MAU rat was made at 150 days of age. For each group, the lateral hypothalmic area, at the level of the ventromedial nucleus, was destroyed between the fornix and the internal capsule. For some rats, the neural damage invaded the fornix medially, the fields of fore1 and zona incerta .dorsally, and the internal capsule laterally. However, the common damage for all brain-damaged rats was confined to the lateral hypothalamic area and the medial extent of the internal capsule, and the lesions included important fiber systems, i.e., medial forebrain bundle, nigrostriatal bundle, trigeminal lemniscus, and hypothalamic gustatory projections (20, 24, 28). It is interesting to note that, for each rat sustaining unilateral lateral hypothalamic area destruction at 10 days of age, the third ventricle dilated
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FIG. 2. Photomicrographs of frontal sections through the centers of the lesions of representative rats of the MIU: MILT-Bi group (a) and MAU group (b). In the top section (a), the lesion on the left was made at 10 days of age (MIU group) and on the right at 150 days of age (MIU-Bi group). The lesion in (b) (MAU group) was made at 150 days of age. Brain sections were stained with cresyl violet and magnified X10. Both rats were killed at 260 days of age.
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toward the lesion side (see Fig. 2a). This dilation or “filling-in” may account for the tendency for early lesions to decrease in size with time (250 days for the present study). bolf and DiCara (26) have shown that neural lesions of adult rats decrease in size with time, and Bernardis (5) has reported similar ventricular dilation with early lesions. Immediately prior to perfusion and brain extraction the nose-anus lengths were measured for each rat. In addition, the carcasses were visually inspected for fat deposits and the stomachs for ulcers. At 260 days of age, the body weights of MIU-Bi and FIU-Bi rats were significantly depressed (see Fig. l), and body length was significantly reduced 11% for males and 10% for females (P’s < 0.05). The MAU and FAU rats were intermediate for body length between the bilateral and control groups and did not statistically differ from either group (P’s > 0.05). Inspection of the rat carcasses revealed complete absence of fat deposits for the MIU-Bi and FIU-Bi groups. The MAU rats showed reduced fat deposits; however, the FAU rats could not be distinguished from control females. In addition, the rats of the MIU-Bi and FIU-Bi groups all showed ulceration of both the rumenal and glandular portions of the stomach. These stomachs tended to be transparent with decreased rugae as compared to control rats. The rats of the MAU and FAU groups also showed stomach ulceration, as did some control rats. This stomach pathology replicates our previous work (3) and that reported for lateral hypothalamic area destruction sustained during adulthood ( 16). TABLE
3
Summary of Results for Infant and Adult Rats Sustaining Unilateral Destruction of the Lateral Hypothalamic Area and for Rats Sustaining Destruction of One Area at 10 Days of Age Followed by Destruction of the Contralateral Area at 150 Days of Age Infant
Body Daily Daily
weight water food
Intracellular Extracellular
dehydration dehydration
Water deprivation Finickyb Prandiale P-Deoxy-wglucose Amphetamine s UNI-LHA, unilateral b Quinine hydrochloride c Water intake during
UNI-LHA”
-
Adult
UNI-LHA=’
Infant-Adult
Male
Female
Male
Female
Male
4 Normal Normal Normal Normal Normal Normal 4 Normal Normal
Normal Normal Normal Normal Normal Normal Normal & Normal Normal
k + a $ Normal Normal i 4 4 Normal
Normal 4 & Normal Normal Normal 4 4 + NOrlIla
4 J 4 4 4 & 4 c 4 Normal
destruction solutions. 24-hr food
of lateral deprivation.
hypothalamic
area;
Bi-LHA.
bilateral
destruction.
Bi-LHAa Female h 4 4 4 4 4 4 4 4
Normal
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AND
GOLDEN
DISCUSSION The results of the present experiment are summarized and presented in Table 3, where each response measure is classified as “normal” (i.e., not statistically different from control) or “below normal” (i.e., statistically different from control P’s < 0.05 or beyond). In terms of variety of regulatory deficits, the two-stage (infancy-adult) lateral hypothalamic area lesions produced the greatest deficits, the adult unilateral-lesion rats were intermediate, and the infant unilateral lesions produced the fewest deficits. Unilateral destruction of the lateral hypothalamic area sustained at 10 days of age produced a cessation of suckling and these pups required “emergency maintenance” procedures to keep them alive. However, once these pups began voluntary consummatory behaviors they developed quite “normally” and showed few regulatory deficits. Both males and females persisted in a prandial style of drinking (14), and males showed permanent body-weight deficits of approximately 20%. Thus, one intact lateral hypothalamic area was sufficient to maintain nearly normal homeostatic regulatory capacity. The results reported here for unilateral destruction of the lateral hypothalamic area of adult (150 days of age) rats are in agreement with previous reports (11, 13, 25). Comparison of the regulatory deficits of our adult and infant unilateral-lesion rats reveals that the rats sustaining the lesion as adults were more diversely affected than were infants. Although the adults did not require emergency maintenance procedures as did the infants, the adults showed a wider variety of specific regulatory deficits (Table 3). The infant-adult comparison suggests that “sparing of function” occurred to a greater degree following the infant lesion, or that, when one lateral hypothalamic area is destroyed during infancy, the intact area is “plastic” enough to subsume and maintain function. Further comparison of the infant- and adult-unilateral groups yields some interesting sexual differences and age-group similarities. Male rats (of the adult group) showed attenuated drinking following intracellular dehydration, whereas females drank normally. Wampler (25) has also reported normal drinking for females under these conditions. Also, it is interesting that males of both age groups showed permanent body-weight deficits (approximately 20% ) , while females attained control body-weight levels. Further discussion of the body-weight deficits is presented later. The regulatory deficits displayed by the present serial (two-stage) -lateral hypothalamic area rats (Table 3) are nearly identical to the regulatory deficits reported by others for simultaneous bilateral destruction of the lateral hypothalamic area sustained by infant (2, 3, 17) or by adult rats (4, 10, 23). These results demonstrate that serial destruction of the lateral hypothalamic area (lesions sustained between infancy and adulthood) does
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LATERAL
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DESTRUCTION
659
not yield “sparing of function” as has been reported for serial destruction of the lateral hypothalamic area of adult rats (11) or other neuralbehavioral investigations (1, 12, 22). However, it is well recognized that serial destruction of the lateral hypothalamic area (13) or other brain areas does not lead to a universal “sparing of function” (8, 12). Although our serial-lateral hypothalamic area results closely approximate the effects of simultaneous bilateral destruction of the lateral hypothalamic area sustained during infancy or adulthood, the effects are not identical. First, adult rats with bilateral destruction of the lateral hypothalamic area do not reduce feeding in response to amphetamine treatment (6)) whereas bilateral lateral hypothalamic area lesions sustained during infancy (2) and the present serial-lateral hypothalamic area lesions yield rats which show a normal amphetamine anorexia. Second, although male rats show permanent body-weight deficits following destruction of the lateral hypothalamic area sustained during infancy (2, 3) or adulthood (4, 10, 21), female rats of either age group show only a transitory body-weight loss with recovery of control levels (2, 7). The permanent body-weight deficits of female rats sustaining serial destruction of the lateral hypothalamic area represent the first demonstration of permanent body-weight deficits for females with lateral hypothalamic area destruction. This result is the opposite of “sparing of function“’ notions for serial LHA destruction, i.e., the two lateral hypothalamic area lesions separated by 140 days yield more severe bodyweight deficits than simultaneous bilateral destruction of the lateral hypothalamic area. Reports concerning the effects of serial destruction of the lateral hypothalamic area of adult rats have yielded conflicting results. Dubuc (9) and Fass et al. (11) report that multiple-stage bilateral or two-stage serial lesions of the lateral hypothalamic area spare body-weight deficits and the severe aphagia-adipsia which are associated with simultaneous bilateral destruction of the lateral hypothalamic area. In contrast, Gold (13) reports severe and persistent adipsia-aphagia and body-weight deficits following two-stage bilateral destruction of the lateral hypothalamic area of adult rats. The present serial-lateral hypothalamic area results agree with those reported by Gold (13), in spite of the fact that 10 to 13 days separated the two lesions in Gold’s study, whereas 140 days separated the two lesions in the present study. In addition to the initial adipsia-aphagia and bodyweight deficits, we also show that these serial lesions of the lateral hypothalamic area yield permanent disruption of regulatory capacity in response to specific homeostatic challenges (Table 3). Thus, the present two-stage lesions produce feeding-drinking and body-weight deficits which are typically associated with one-stage bilateral destruction of the lateral hypothalamic area of infant (2, 3) or adult rats (4, 10, 21, 23).
660
ALMLI
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The results for the infant unilateral-lateral hypothalamic area lesions suggest that one lateral hypothalamic area is sufficient to maintain approxiwhen the intact lateral mately normal homeostatic function. However, hypothalamic area is destroyed 140 days later, profound deficits in regulatory capacity are produced. The fact that adult rats sustaining unilateral destruction of the lateral hypothalamic area are less severely affected suggests that the infant lesions produced residual effects which were not manifest until the second lesion was inflicted. With respect to body-weight regulation of male rats, it is interesting that the infant and adult unilateral-lateral hypothalamic area males showed approximately 20% body-weight deficits, whereas the serial bilateral-lateral hypothalamic area rats showed deficits of approximately 50% for body weight. These. results seem to suggest that destruction of one lateral hypothalamic area during infancy produces a lowering of the set-point for bodyweight regulation (21), with a further reduction following destruction of the intact lateral hypothalamic area during adulthood. In adult rats, onestage bilateral destruction of the lateral hypothalamic area lowers the bodyweight set-point by 20% (21)) which is also true for bilateral destruction of the lateral hypothalamic area of preweanling rats (2). In other words, bilateral destruction in infant or adult rats each results in a reduction of normal growth, and the effects on growth are additive when the lateral hypothalamic area is destroyed in two stages, one in infancy and one during adulthood. In the case of females, the effects on body weight parallel males, except females do not show permanent body-weight deficits following unilateral or one-stage bilateral destruction of the lateral hypothalamic area sustained during infancy (2) or adulthood (7). However, although females attain normal growth following one-stage unilateral or bilateral destruction, they are unable to compensate for a second lesion, when the lateral hypothalamic area is destroyed in two stages, i.e., infancy and adulthood. These body-weight effects cannot be completely explained by gastric pathology (16) ; however, gastric pathology and the subsequent effects on feeding behavior may be contributing to the body-weight reductions. We have found that females and males sustaining bilateral destruction of the lateral hypothalamic area at 10 days of age both show considerable gastric pathology, in spite of the fact that females attain control body weights and males are permanently depressed by 20% (unpublished observations). Also, in the present study males and females sustaining unilateral destruction of the lateral hypothalamic area as adults both show gastric pathology ; however, females attain control body weights whereas males do not. These results suggest that the effects on feeding and body-weight regulation following lateral hypothalamic area destruction cannot be solely char-
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acterized by gastric pathology. The differential effects on body-weight regulation shown between males and females are more likely due to sexual dimorphism in hypothalamic control of endocrine function (18, 27). Although the lateral hypothalamic area lesions of the present study include important fiber systems coursing through or near the lateral hypothalamic area, e.g., nigrostriatal bundle (24) and gustatory (20) and trigeminal projections (28), the results show that one lateral hypothalamic area is sufficient to maintain approximately normal regulatory function when one area is destroyed during the preweanling period. However, destruction of the intact lateral hypothalamic area during adulthood leads to severe and persistent regulatory deficits. These results demonstrate quite conclusively that “sparing of function” following the infantile lesion was due to compensation by the intact lateral hypothalamic area, rather than any change in neural tissue on the side of the initial lesion. REFERENCES 1. ADAMETZ, J. H. 1959. Rate of recovery of functioning in cats with rostra1 reticular lesions. J. Neurosurg. 16: 85-98. 2. ALMLI, C. R., and G. T. GOLDEN. 1976. Pre-weanling rats: Recovery from lateral hypothalamic damage. J. Cow@. Physiol. Physchol., in press. 3. ALMLI, C. R., and G. T. GOLDEN. 1974. Infant rats: Effects of lateral hypothalamic destruction. Physiol. Behav. 13 : 81-90. 4. ALMLI, C. R., and C. S. WEISS. 1974. Drinking behaviors: Effects of lateral preoptic and lateral hypothalamic destruction. Physiol. Behav. 13 : 528-538. 5. BERNARDIS, L. L. 1972. Delayed ventricular changes in the hypothalamus of the weanling rat following electrolytic lesions of the ventromedial nucleus. J. Neurovisc.
Relat.
32 : 347-354.
6. CARLISLE, H. J. 1964. Differential effects of amphetamine on food and water intake in rats with lateral hypothalamic lesions. J. Camp. Physiol. Psychol. 58: 47-54. 7. Cox, V. C., and J. W. KA~OLEWSKI. 1970. Sex differences in body weight regulation in rats following lateral hypothalamic lesions. Con~mzkn. Behav. Biol. 5 : 195-197. 8. DAWSON, R. G., L. CONRAD, and G. LYNCH. 1973. Single and two-stage hippocampal lesions : A similar syndrome. Exp. Neural. 40: 263-277. 9. DUBUC, P. U. 1974. Body weight regulation following multistage hypothalamic lesions. Amer. J. Physiol. 227 : 697-702. 10. EPSTEIN, A. N. 1971. The lateral hypothalamic syndrome: Its implications for the physiological psychology of hunger and thirst, pp. 263-317. In “Progress in Physiological Psychology,” Vol. 4. E. Stellar and J. M. Sprague [Eds.]. Academic Press, New York. 11. FASS, B., H. JORDAN, A. RUBMAN, S. SEIBEL, and D. STEIN. 1975. Recovery of function after serial or one-stage lesions of the lateral hypothalamic area in rats. Behav. Biol. 14 : 283-294. 12. FINGER, S., B. WALBRAN, and D. G. STEIN. 1973. Brain damage and behavioral recovery: Serial lesion phenomena. Brain Res. 63 : I-18. 13. GoLD, R. M. 1966. Aphagia and adipsia produced by unilateral hypothalamic lesions in rats. Amer. J. Physiol. 211 : 1274-1276.
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H. R. 1971. Acquisition of prandial drinking in weanling rats and in rats recovering from lateral hypothalamic lesions. J. C~mfi. Ph~siol. PsYChd 77 : 97-109. K~NIG, J. F. R., and R. KLIPPEL. 1963. “The Rat Brain: A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem.” Williams and Wilkins, Baltimore. LINDHOLM, E., G. SCHUMWAY, C. GRIJALVA, T. SCHALLERT, and M. RUPPEL. 1975. Gastric pathology produced by hypothalamic lesions in rats. Physiol. Behav. 14: 165-170. LYTLE, L. D., and B. A. CAMPBELL. 1975. Effects of lateral hypothalamic lesions on consummatory behavior in developing rats. Physiol. Behav. 15: 323-331. NANCE, D. M., and R. A. GORSKI. 1975. Neurohormonal determinants of sex differences in the hypothalamic regulation of feeding behavior and body weight in the rat. Pharmacol. Biochem. Behav. 3: 1.55-162. NANCE, D. M., and R. A. GORSKI. 1973. Effects of chronic diabetes on 2-deoxy-nglucose induced feeding and drinking. Pharmacol. Biochem. 1: 483-485. NORGREN, R. 1976. Taste pathways to hypothalamus and amygdala. J. Co@. Neural. 166 : 17-30. POWLEY, T. L., and R. E. KEESEY. 1970. Relationship of body weight to the lateral hypothalamic feeding syndrome. J. Conzfi. Physiol. Psychol. 70 : 2536. SCHULTZE, M. J., and D. G. STEIN. 1975. Recovery of function in the albino rat following either simultaneous or seriation lesions of the caudate nucleus. Exp. Neurol. 46 : 291-301. TEITELBAUM, P., and A. N. EPSTEIN. 1962. The lateral hypothalamic syndrome: Recovery of feeding and drinking after lateral hypothalamic lesions. Psychol.
14. KISSILEFF,
15. 16. 17. 18. 19. 20. 21. 22. 23.
Rev.
69 : 74-90.
24. UNGERSTEDT, U. 1971. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol. Stand. 367: 95-122. 25. WAMPLER, R. S. 1971. Regulatory deficits in rats following unilateral lesions of the lateral hypothalamus. I. COT@. Physiol. Psychol. 75 : 190-199. 26. WOLF, G., and L. V. DICARA. 1969. Progressive morphologic changes in electrolytic brain lesions. Exp. Neural. 23: 529-536. 27. WEEDS, S. C., E. DECKE, and J. R. VASSELLI. 1974. Metabolic hormones and regulation of body weight. Psychol. Rev. 81: 26-43. 28. ZEIGLER, H. P., and H. S. KARTEN. 1974. Central trigeminal structures and the lateral hypothalamic syndrome in the rat. Scietzce 186: 636-637.
NEUROLOGY
Serial
C.
(1976)
53,646-662
Lateral Hypothalamic Destruction: Infancy and Adulthood ROBERT
Departlrtmt
ALMLI
AND
GREGORY
of Psychology,
Athens, Received
Ohio
Ohio 45701
T.
GOLDEN
1
University,
Jzrne 21,1976
Male and female albino rats sustained unilateral destruction of the lateral hypothalamic area as infants (10 days of age) or as adults (150 days of age). Also, rats receiving unilateral destruction of the lateral hypothalamic area as infants had their contralateral (intact) lateral hypothalamic area destroyed at 150 days of age, i.e., two-stage serial lateral hypothalamic area destruction separated by 140 days, thereby producing bilateral destruction. The animals were tested for homeostatic regulatory capacity. Loss of one lateral hypothalamic area during adulthood produced greater regulatory deficits than were produced by the loss of one during infancy. These results suggest that the intact lateral hypothalamic area of infant rats has greater capacity to maintain function than does the same intact area of adults. The regulatory deficits produced with two-stage lateral hypothalamic area destruction (one lateral hypothalamic area destroyed during infancy followed by destruction of the contralateral area during adulthood) were nearly identical to the deficits produced with one-stage bilateral destruction, i.e., the regulatory deficits were persistent and severe in spite of the fact that 140 days separated the two lesions. Thus, infant rats can maintain approximately normal regulatory capacity with one intact lateral hypothalamic area. This “sparing of function” was due to the intact lateral hypothalamic area, as its subsequent destruction produced more profound regulatory deficits than were produced with unilateral destruction of the lateral hypothalamic area sustained during adulthood. These results suggest that the “plasticity” of the infant lateral hypothalamic area is greater than that of the adult and that infantile ‘plasticity" is manifest by the capacity of the intact lateral hypothalamic area to subsume the function of the damaged contralateral area. 1 This research was supported by NICHHD Grant HD-08504 to C. R. Almli. G. T. Golden is now at the Department of Neurophysiology, University of Wisconsin, Madison, Wisconsin. 646 Copyright All rights
1976 by Academic Press, Inc. o9 reproduction in any form reserved.
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INTRODUCTION Almli and Golden (2, 3) have recently shown that bilateral destruction of the lateral hypothalamic area (LHA) of pre- and postweanling rats yields bodyweight and regulatory deficits which are nearly identical to the deficits produced when the lateral hypothalamic area is bilaterally destroyed in adult rats (4, 10, 23). Thus, infant rats show no more “recovery of function” following bilateral destruction than do adult rats. The present investigation compares the effects of unilateral destruction of the lateral hypothalamic area sustained during infancy versus adulthood and, more importantly, determines if “sparing of function” occurs when the area is destroyed seriatim between infancy and adulthood, i.e., lateral hypothalamic area on one side of the brain destroyed at 10 days of age followed by destruction of the contralateral area when the rats reach 150 days of age. Previous investigations of serial lateral hypothalamic area destruction of adult rats have yielded conflicting results. Gold (13) used a 13-day interlesion interval and reports no sparing of function following the second lesion ; whereas Fass et al. (11) used a 30-day lesion interval and report sparing of function following the second lesion. The present investigation inflicts the first lesion in preweanling rats and uses a 140-day interlesion interval. METHODS An&n& Fifty-four male or female infant albino rat pups (Holtzman strain) were housed as litters with dams in clear plastic group cages (48.4 X 38.1 x 12.3 cm) in a temperature-controlled room (22 to 25°C) under continuous illumination. At 2 to 4 days of age the seven litters were culled to seven or eight pups each, with approximately equal male/female ratios. The dams were removed from the litter cages when the pups reached 25 days of age, and the pups were housed individually in metabolism cages (Acme Metal Products) or wire rack-mounted cages (24.1 X 17.8 x 19.0 cm) from 30 days of age through the completion of the experiment when the rats were 200 to 260 days of age. Apparatus
and Procedures
Phase I. The first phase of the experiment was begun with random assignment of the pups to one of four sex-surgery groups, when the pups reached 10 days of age. The first two groups contained male (N = 16) and female (N = 15) pups which sustained unilateral destruction of the lateral hypothalamic area at 10 days of age (Male Infant Unilateral, MIU, and Female Infant Unilateral, FIU groups, respectively). The second two
648
ALMLI
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groups contained male (N = 12) and female (N = 11) pups which received sham surgery at 10 days of age (groups MS and FS, respectively). Sztrgery. All operations were done under ethyl ether anesthesia and the lesions were placed stereotaxically (David Kopf Instruments) using the techniques for infant rats described by Almli and Golden (2, 3). The stereotaxic coordinates for the lateral hypothalamic area were 2.6 to 3.7 mm anterior to the lambda suture, 1.2 to 1.5 mm lateral to the midline suture, and 8.0 to 8.5 mm below the surface of the skull. Anodal lesions were made through 0.25mm-diameter stainless-steel electrodes (0.25- to 0.5-mm uninsulated tip) using a Quartet electrolytic lesion maker (1.0 to 2.0 mA for 5 to 20 set). The male and female infant sham-operated (MIS and FIS) control groups received complete surgery, except that no current was passed through the electrode. Daily Measurements. For both the brain-damaged and control groups, body weight (grams) was measured each 24 hr beginning at 9 days of age. Following surgery, a lack of body-weight gain indicated cessation or decrease of suckling, and the maintenance procedures of Almli and Golden (2, 3) were used. Pups showing body-weight loss were maintained on a liquid diet (2, 3) by hand-feeding with a plastic dropper and/or by stomach loading until the pups were maintaining growth through voluntary suckling and/or feeding-drinking. Liquid diet was presented six to eight times daily at a volume of 0.5 to 2.0 ml per feeding. If necessary, tap water was intubated (2 to 5 ml) twice daily. These procedures continued until the rats were maintaining their body weights through voluntary feeding (chocolate chip cookies and Purina rat pellets) and drinking (tap water). When the rats reached 30 days of age they were housed individually and body-weight (grams), food (grams) and water (milliliters) intakes were measured each 24 hr through 200 to 260 days of age. Homeostatic Challenges. All rats were tested for feeding and/or drinking responses following a variety of specific regulatory challenges when the rats were between 40 and 140 days of age. Each challenge was administered twice and challenges were presented as randomly as possible. Water intakes (2, 3) were measured for 3 hr following hypertonic saline injection (subcutaneous, 16% NaCl, 0.1 ml/30 g body weight), polyethylene glycol injection (subcutaneous, 25%, 20,000 molecular weight, 0.5 ml/35 g body weight), and 24-hr water deprivation. Food was not present during these tests. Water intake was also measured during 24-hr food deprivation. Food and water intakes were measured for 2 hr following injections of amphetamine ( 1.5 and 3.0 “g/kg) (2, 6) and 2-deoxy-n-glucose (200 w/kg) (2, 19). Finally, food intake was measured for 2 hr following 24-hr food depri-
SERIAL
LATERAL
HYPOTHALAMIC
DESTRUCTION
649
vation, and intakes of quinine hydrochloride solutions (0.1, 0.05, and 0.01%) were measured for 24-hr access periods (2, 23). Phase II. The second phase of the experiment was begun when the rats (MIU, FIU, MS, and FS groups) reached 150 days of age. At this time, those which had sustained unilateral lateral hypothalamic area destruction at 10 days of age (MIU and FIU groups) now sustained destruction of the intact contralateral lateral hypothalamic area, thereby producing bilateral destruction of the lateral hypothalamic area in two operations separated by 140 days. These groups are designated MIU-Bi and FIU-Bi, for males and females, respectively. The control groups (MS and FS) were equally divided, and half received unilateral lateral hypothalamic area destruction at 150 days of age (male and female adult unilateral groups, MAU and FAU, respectively), the other half received a second sham surgery (MS and FS groups). The stereotaxic coordinates used for these rats at 150 days of age were : 5.0 to 6.8 mm anterior to the intraaural plane, 1.2 to 1.5 mm lateral to the midline suture, and 8.5 to 9.0 mm below the level of the skull. The lesion parameters were 1.0 to 2.0 mA for 15 to 20 sec. The sham surgeries were identical to those described in Phase I. The homeostatic challenges (described in Phase I) were administered again to the rats in Phase II, and daily measurements were continued through 200 to 260 days of age. Histology. At the completion of the experiment when the rats were 200 to 260 days old, they were killed with ether and were perfused intracardially with physiological saline (0.87% NaCl) solution followed by 10% formalin-saline solution. Frozen frontal sections were cut at 50 pm, and each section through the lesion was stained with cresyl violet. Lesion locus and extent were determined microscopically, and the sections were photographed and redrawn on appropriate figures from the atlas of K&rig and Klippel (15). Undestroyed nuclei and fiber tracts were used as landmarks to determine the locus and extent of neural tissue destruction. RESULTS All results of this experiment were analyzed with Tukey-HSD post-tests, and two-tailed t tests.
analysis
of variance,
Phase I Body Weight (MIU and FIU Groups). On the first day postsurgery, all lo-day-old pups lost body weight; however, by the second day, the control pups (MIS and FIS groups) were suckling and showing body-weight gains. In contrast, the pups sustaining unilateral lateral hypothalamic area destruction (MIU and FIU groups) continued to lose body weight on the
650
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second and third postoperative days, because they ceased suckling. Nine of the 31 brain-damaged pups died during this period; thus the MIU and FIU groups contained 11 pups each. On the third postoperative day, handfeeding and intubation of liquid diet were begun and the remaining 22 rats survived. These brain-damaged pups required maintenance until 10 to 18 days postlesion (20 to 28 days of age) when the pups maintained body weight through voluntary suckling and/or feeding and drinking. Presented in Fig. 1A are mean body weights of MIU (N = 11)) FIU (N = ll), MIS (N = 12), and FIS (N = 11) groups plotted as a function of days of age. None of the groups differed significantly in body weight at 10 days of age (P’s > 0.05). The control rats (MIS and FIS) showed equal growth until 38 to 40 days of age when the males’ body weights consistently exceeded that of females’ (P < 0.05 or beyond). This sexual dimorphism for body weight of control rats increased through 150 days of age. In contrast, the pups sustaining unilateral lateral hypothalamic area destruction (males and females) showed little or no body-weight increase through the first 10 days postlesion, such that, by 20 days of age, these pups were 27% below control body weights. When the MIU and FIU pups began voluntary feeding and drinking they showed substantial bodyweight gains. These brain-damaged rats displayed a delayed sexual dimorphism for body weight, i.e., the body weights of the MIU rats did not reliably exceed the weights of the FIU rats until 50 to 52 days of age, which is approximately 12 days later than control sexual dimorphism. As seen in Fig. lA, the MIU rats remained 15 to 25% below MIS rats, for body weight, through 150 days of age (P < 0.05 or beyond). On the other hand, the FIU rats achieved control (FIS) body weights by 40 to 44 days of age (P > O.OS), and the two female groups did not significantly differ for body weight through 150 days of age (P > 0.05). Daily food and water intakes of the MIU and FIU rats were highly variable following the resumption of consummatory behaviors at 20 to 28 days of age. By 90 days of age, food and water intakes stabilized at slightly depressed levels, and this mild hypodipsia and hypophagia persisted through 150 days of age (see Table 1). However, these depressed intake levels did not significantly differ from control levels (P’s > 0.05). During that final 60-day period (90 to 150 days of age), the MIU rats’ food intakes were depressed 14% and water intakes lo%,, as compared to male control rats. The food and water intakes of FIU rats were depressed 12 and 17%, respectively, during that same period. Honzeostatic Challenges (MIU and FIU Groz@s). The brain-damaged and control rats were tested for food and/or water intakes following a variety of tests of homeostatic regulatory capacity when the rats were 40 to 140 days of age. The mean intake data are presented in Table 1.
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LATERAL
HYPOTHALAMIC
TABLE
651
DESTRUCTION
1
Responses to Homeostatic Challenges of Control Rats and Rats Sustaining Unilateral Destruction of the Lateral Hypothalamic Area at 10 Days of Age Controls
Daily intake (24 hr) Food
deprivation
Amphetamine
(24 hr) 1.5 mg/kg 3.0 mg/kg
ZbDeoxy-D-glucose Hypertonic saline Polyethylene glycol Water deprivation (24 hr) Quinine hydrochloride
Food* Waterb Food Water Fo& Water Food Water Foodd Water Water Water Water O.Olyp 0.05% 0.10%
Operated
Male 12 rats
Female 11 rats
Male (MIU) 11 rats
Female (FW 11 rats
6.6 10.2 1.2 4.5 -24%~ -36%0 - 90%9 -91%9
8.6 13.9 1.0 6.5 -32%~ -42%~ - 86%70r -91%9 +75%9 +9% 3.8 4.1 7.6 10.39 5.99 2.19
5.7 9.1 1.1 2.1’ -42%Q -39%* -8l%Q -91%0 40%9
7.6 11.5 1.2 3.8’ -69%~ -46%* -97%’ -92%~ +34%# +13% 3.5 3.2 6.8 9.29 4.89 1.79
+63%* +6% 3.1 2.2 6.9 8.40 .5.3g
1.29
-50%‘~’
3.0 1.8 5.5
8.00 5.29 0.S
a Grams per 100 g body weight. b Milliliters per 100 g body weight. c Basal treatment is 24-hr food and water deprivation with physiological saline injection, intake measured for 2 hr. d Basal treatment is ad lib&m food and water with physiological saline injection, intake measured for 2 hr. BBasal treatment is 24-hr water intake on preceding day. f P’s < 0.05 or beyond, compared to control. # P’s < 0.05 or beyond, compared to basal treatment.
The brain-damaged rats’ water intakes following injections of hypertonic saline or polyethylene glycol and after 24-hr water deprivation were smaller than control for both sexes; however, the differences were unreliable (P’s > 0.05). In addition, intakes of quinine hydrochloride solutions decreased with increasing concentration for both the brain-damaged and control groups (P’s < 0.05 or beyond), but again, the brain-damaged and control rats did not reliably differ for any concentration tested (P’s > 0.05). The MIU and FIU rats also showed a normal anorexic effect of amphetamine injection (P’s < 0.05) and a normal stimulation of feeding after injection of 2-deoxy-n-glucose (P's < O.OS), and the intakes did not differ significantly from control levels (P's > 0.05).
6.52
ALMLI
AND
GOLDEN
Whereas the MIU and FIU rats responded to most homeostatic challenges in a “normal” fashion, the brain-damaged rats reliably differed from controls for the prandial test. During 24-hr food deprivation, the MIU and FIU rats showed reliably attenuated water intakes (P’s < O.Ol), suggesting they were “prandial” drinkers ( 14). In summary unilateral destruction of the lateral hypothalamic area in lo-day-old rats yields a transient cessation of suckling and body-weight loss for both male and female rats. Such lesions also result in a delayed sexual dimorphism for body weight for male and female rats. Although depression of growth is temporary for female brain-damaged rats, the males had not achieved control body weights even by 1.50 days of age. Daily food and water intakes of the brain-damaged rats did not reliably differ from control levels; however, the rats tended toward hypodipsia and hypophagia through 150 days of age. The MIU and FIU rats responded to most homeostatic challenges in a normal fashion. Food and/or water intakes following hypertonic saline, polyethylene glycol, amphetamine, 2-deoxy-n-glucose, water deprivation, and quinine hydrochloride treatments did not significantly differ from control levels. However, these brain-damaged rats reliably decreasedwater intakes during food deprivation. Phase II Body Weights. Male and female adult rats sustaining unilateral destruction of the lateral hypothalamic area at 1.50days of age (MAU and FAU groups, respectively) showed short periods of aphagia-adipsia, and all were voluntarily feeding and drinking by 2 or 3 days postlesion. These rats did not require intubation of liquid diet or water for survival. As shown in Fig. lB, the MAU rats (N = 5) were 9% below control body weights by 10 days postlesion. The unilateral lesion essentially stopped normal growth as their body weights at 260. days of age did not differ from their body weights at 150 days (P > 0.05). In contrast, FAU rats (N = 5) quickly regained their postlesion body weight Ioss (6 to 9%), and from 160 to 260 days of age the FAU and female sham-operated groups did not differ significantly in body weights (P > 0.05). The MAU and FAU rats were reliably hypophagic and hypodipsic from 20 to 110 days postlesion (P’s < 0.05 or beyond). The male brain-damaged rats consumed 72% of the food and 78% of the water of control males during that go-day period, and females ingested 47 and 77% (for food and water, respectively) of control levels (see Table 2). Homeostatic Challenges (MA U a.nd FA U Groups). Presented in Table 2 are the intake data in response to homeostatic challenges of the MAU and FAU rats. Each treatment was administered once between 20 and 110
SERIAL
LATERAL
HYPOTHALAMIC
653
DESTRUCTION
570 530
90 50 10 10 20
30
40
50
60
70
90
90
110
t LEJlON
lml
I30
I90
IW
200
z?o
240
250
t LESION
DAYS
OF
AGE
FIG. 1. Mean body weight (grams) of brain-damaged and control rats (males and females) plotted as a function of days of age. Lesions were made at 10 and/or 1.50 days of age. Control rats are represented by dashed line-open squares (males) and dashed line-open circles (females) in A and B. Rats sustaining unilateral hypothalamic lesions at 10 days of age (MIU and FIU groups) are represented by solid line-filled squares (males) and solid line-filled circles (females) in A. Rats sustaining unilateral lesions at 150 days of age are represented by solid line-open triangles for both males (MAU, upper curve) and females (FAU, lower curve) in B. The MIU and FIU groups which become the MIU-Bi and FIU-Bi groups at 150 days of age, are represented in B by solid line-filled squares (MIU-Bi) and solid line-filled circles (FIU-Bi) .
days postlesion. In addition to the statistically reliable daily hypodipsia and hypophagia of the MAU and FAU rats, they reliably attenuated water intakes during 24-hr food deprivation (P’s < O.Ol), displayed no potentiation of feeding following 2-deoxy-o-glucose injection (P’s > O.OS), and reliably attenuated intakes of 0.1 and 0.050/oquinine hydrochloride solutions (P’s < 0.05 or beyond). Also, MAU rats (P < O.OS), but not FAU rats (P > O.OS), showed reliably attenuated water intakes following hypertonic saline injection. While the other tests yielded results which tended toward hypodipsia and/or hypophagia, only the challenges presented above produced reliable differences between MAU or FAU rats and their respective controls. When the MIU and FIU rats (of Phase I) reached 150 days of age, the intact contralateral lateral hypothalamic area was destroyed, thereby pro-
654
ALMLI
AND
TABLE Responses Destruction Destruction lateral Area
GOLDEN
2
to Homeostatic Challenges of Control Rats, Rats Sustaining Unilateral of the Lateral Hypothalamic Area at 1.50 Days of Age, and Rats Sustaining of One Area at 10 Days of Age Followed by Destruction of the Contraat 150 Days of Age Operated
Controls
Daily Food
intake deprivation
Amphetamine
1.5 mg/kg 3.0 mg/kg
Z-Decay-o-glucose Hypertonic saline Polyethylene glycol Water deprivation Quinine hydrochloride
Food’ Watera Food water Food< Water Food Water Foodd Water Water water Water o.ol%e 0.05 70 0.10%
as adults
Operated as infants and adults ~ Male Female (MN-Bi) (FIU-Bi) 4 rats 4 rats
MC& 7 rats
Female 6 rats
Male (MAU) 5 rats
Female (FAU) 5 rats
6.8 9.4 1.8 5.4 -29%0 -34To”oo -90%9 -89%~ --55qp -5% 3.8 2.7 4.7 8.3R 5.40 1.60
9.3 11.7 1.6 7.0 -22Y@ -4O%S --87qo~ -91%9 +sl%s -11% 4.1 3.9 5.2 10.29 5.6~ 1.70
4.91 7.3) 1.0 2.21 -29%~ -69%~ --8l%S -5l%S --6O%f.~
4.4f 9.11 1.1 1.7f -SO%@ -83%f.V -lOO%S -91%0 -4O%f*O
-92q~f.o
-w%
1.9f 2.0 3.3 3.4f,o 0.3f.u 1.os
a Grams per 100 g body weight. * Milliliters per 100 g body weight. c Basal treatment is 24-hr food and water deprivation with physiological for 2 hr. d Basal treatment is ad Zibilunt food and water with physiological for 2 hr. 6 Basal treatment is 24-hr water intake on preceding day. f P’s < 0.05 or beyond compared to control. s P’s < 0.05 or beyond compared to basal treatment.
3.1 2.8 3.7 5.6J.9 2.01.0 1.01
saline saline
4.0f
5.7f
3.21 1.0 0.6, -71%9 -lOO%f.’ -lOO%r -810/@ -lOO%f.s -loo~o~.u
1.3 1.71 -27%~ +14%f.g --6O%g -42yol.r -36%f,g --58%f.P 1.1) 0.41 1.61
injection, injection,
3.61
2.4f.s
0.0f.r 0.2f .I
2.6f
2.4f 2.41 1.7JJ 0.4f.P 1.20
intake
measured
intake
measured
ducing bilateral destruction of the lateral hypothalamic area (MIU-Bi and FIU-Bi groups). In spite of the fact that 140 days separated the production of the two lesions, the immediate consequences of the second lesion were adipsia and aphagia, and two males and four females died within 3 days. In addition, five males and three females died during (or following) tubing accidents (liquid diet entering the lungs) at between 6 and 26 days postlesion. These eight rats were still adipsic and aphagic at the time of death. The surviving eight rats, four males and four females, lived more than 260 days (110 days postlesion). These rats began to feed (hydrated cookies, wet mash) and maintain body weight by 6 to 29 days postlesion, and they began drinking water at 7 to 66 days postlesion, when they were able to maintain their body weights through voluntary feeding (hydrated cookies, wet mash, and pellets) and drinking (tap water). As shown in Fig. lB, both the MIU-Bi and FIU-Bi groups showed permanent slowing of growth following the second lesion (P’s < 0.05 or
SERIAL
LATERAL
HYPOTHALAMIC
DESTRUCTION
655
beyond). The males lost 23% of their prelesion body weight within 10 days postlesion, and remained relatively stable at that reduced level through 260 days of age, when they weighed only 50% as much as the control. Likewise, the FIU-Bi rats lost 21% of their body weight within 10 days postlesion ; thereafter, they paralleled control female growth and by 260 days of age these female rats were 23% below the body weights of the controls (P < 0.01). As indicated by the permanent body-weight depression, both the MIUBi and FIU-Bi rats were reliably hypophagic and hypodipsic between 210 and 260 days of age (60 to 110 days postlesion) (P’s < 0.01 or beyond). During the final SO-day interval, the MIU-Bi rats were consuming only 52% (food) and 61% ( wa t er ) o f control amounts, and FIU-Bi rats were eating 57% and drinking 73% compared to controls (Table 2). Homeostatk Challenges (MIU-Bi and FIU-Bi Groups). The homeostatic challenges were administered once each at between 50 and 110 days postlesion, and the results are presented in Table 2. The MIU-Bi and FIUBi rats showed reliably attenuated water intakes after injections of hypertonic saline and polyethylene glycol, following 24-hr water deprivation and during 24-hr food deprivation (P’s < 0.05 or beyond). These braindamaged rats also showed decreased intakes of 0.01 and 0.05% quinine hydrochloride solutions (P’s < 0.05 or beyond) and did not show a stimulation of feeding after 2-deoxy-n-glucose injection (P’s > 0.05). The only test yielding a “normal” response for the MIU-Bi and FIU-Bi rats was the amphetamine treatment where these rats showed a dose-dependent anorexia effect which did not differ significantly from control (P’s > 0.05). Histological
and Postmortem
Analysis
Presented in Fig. 2 are photomicrographs through the centers of the lesions of representative rats of the MIU-Bi (Fig 2a) and MAU (Fig. 2b) groups. In the MIU-Bi rat, the lesion on the left was made at 10 days of age, and the lesion on the right at 150 days of age. The lesion in the MAU rat was made at 150 days of age. For each group, the lateral hypothalmic area, at the level of the ventromedial nucleus, was destroyed between the fornix and the internal capsule. For some rats, the neural damage invaded the fornix medially, the fields of fore1 and zona incerta .dorsally, and the internal capsule laterally. However, the common damage for all brain-damaged rats was confined to the lateral hypothalamic area and the medial extent of the internal capsule, and the lesions included important fiber systems, i.e., medial forebrain bundle, nigrostriatal bundle, trigeminal lemniscus, and hypothalamic gustatory projections (20, 24, 28). It is interesting to note that, for each rat sustaining unilateral lateral hypothalamic area destruction at 10 days of age, the third ventricle dilated
656
ALMLI
AND
GOLDEN
FIG. 2. Photomicrographs of frontal sections through the centers of the lesions of representative rats of the MIU: MILT-Bi group (a) and MAU group (b). In the top section (a), the lesion on the left was made at 10 days of age (MIU group) and on the right at 150 days of age (MIU-Bi group). The lesion in (b) (MAU group) was made at 150 days of age. Brain sections were stained with cresyl violet and magnified X10. Both rats were killed at 260 days of age.
SERIAL
LATERAL
HYPOTHALAMIC
657
DESTRUCTION
toward the lesion side (see Fig. 2a). This dilation or “filling-in” may account for the tendency for early lesions to decrease in size with time (250 days for the present study). bolf and DiCara (26) have shown that neural lesions of adult rats decrease in size with time, and Bernardis (5) has reported similar ventricular dilation with early lesions. Immediately prior to perfusion and brain extraction the nose-anus lengths were measured for each rat. In addition, the carcasses were visually inspected for fat deposits and the stomachs for ulcers. At 260 days of age, the body weights of MIU-Bi and FIU-Bi rats were significantly depressed (see Fig. l), and body length was significantly reduced 11% for males and 10% for females (P’s < 0.05). The MAU and FAU rats were intermediate for body length between the bilateral and control groups and did not statistically differ from either group (P’s > 0.05). Inspection of the rat carcasses revealed complete absence of fat deposits for the MIU-Bi and FIU-Bi groups. The MAU rats showed reduced fat deposits; however, the FAU rats could not be distinguished from control females. In addition, the rats of the MIU-Bi and FIU-Bi groups all showed ulceration of both the rumenal and glandular portions of the stomach. These stomachs tended to be transparent with decreased rugae as compared to control rats. The rats of the MAU and FAU groups also showed stomach ulceration, as did some control rats. This stomach pathology replicates our previous work (3) and that reported for lateral hypothalamic area destruction sustained during adulthood ( 16). TABLE
3
Summary of Results for Infant and Adult Rats Sustaining Unilateral Destruction of the Lateral Hypothalamic Area and for Rats Sustaining Destruction of One Area at 10 Days of Age Followed by Destruction of the Contralateral Area at 150 Days of Age Infant
Body Daily Daily
weight water food
Intracellular Extracellular
dehydration dehydration
Water deprivation Finickyb Prandiale P-Deoxy-wglucose Amphetamine s UNI-LHA, unilateral b Quinine hydrochloride c Water intake during
UNI-LHA”
-
Adult
UNI-LHA=’
Infant-Adult
Male
Female
Male
Female
Male
4 Normal Normal Normal Normal Normal Normal 4 Normal Normal
Normal Normal Normal Normal Normal Normal Normal & Normal Normal
k + a $ Normal Normal i 4 4 Normal
Normal 4 & Normal Normal Normal 4 4 + NOrlIla
4 J 4 4 4 & 4 c 4 Normal
destruction solutions. 24-hr food
of lateral deprivation.
hypothalamic
area;
Bi-LHA.
bilateral
destruction.
Bi-LHAa Female h 4 4 4 4 4 4 4 4
Normal
658
ALMLI
AND
GOLDEN
DISCUSSION The results of the present experiment are summarized and presented in Table 3, where each response measure is classified as “normal” (i.e., not statistically different from control) or “below normal” (i.e., statistically different from control P’s < 0.05 or beyond). In terms of variety of regulatory deficits, the two-stage (infancy-adult) lateral hypothalamic area lesions produced the greatest deficits, the adult unilateral-lesion rats were intermediate, and the infant unilateral lesions produced the fewest deficits. Unilateral destruction of the lateral hypothalamic area sustained at 10 days of age produced a cessation of suckling and these pups required “emergency maintenance” procedures to keep them alive. However, once these pups began voluntary consummatory behaviors they developed quite “normally” and showed few regulatory deficits. Both males and females persisted in a prandial style of drinking (14), and males showed permanent body-weight deficits of approximately 20%. Thus, one intact lateral hypothalamic area was sufficient to maintain nearly normal homeostatic regulatory capacity. The results reported here for unilateral destruction of the lateral hypothalamic area of adult (150 days of age) rats are in agreement with previous reports (11, 13, 25). Comparison of the regulatory deficits of our adult and infant unilateral-lesion rats reveals that the rats sustaining the lesion as adults were more diversely affected than were infants. Although the adults did not require emergency maintenance procedures as did the infants, the adults showed a wider variety of specific regulatory deficits (Table 3). The infant-adult comparison suggests that “sparing of function” occurred to a greater degree following the infant lesion, or that, when one lateral hypothalamic area is destroyed during infancy, the intact area is “plastic” enough to subsume and maintain function. Further comparison of the infant- and adult-unilateral groups yields some interesting sexual differences and age-group similarities. Male rats (of the adult group) showed attenuated drinking following intracellular dehydration, whereas females drank normally. Wampler (25) has also reported normal drinking for females under these conditions. Also, it is interesting that males of both age groups showed permanent body-weight deficits (approximately 20% ) , while females attained control body-weight levels. Further discussion of the body-weight deficits is presented later. The regulatory deficits displayed by the present serial (two-stage) -lateral hypothalamic area rats (Table 3) are nearly identical to the regulatory deficits reported by others for simultaneous bilateral destruction of the lateral hypothalamic area sustained by infant (2, 3, 17) or by adult rats (4, 10, 23). These results demonstrate that serial destruction of the lateral hypothalamic area (lesions sustained between infancy and adulthood) does
SERIAL
LATERAL
HYPOTHALAMIC
DESTRUCTION
659
not yield “sparing of function” as has been reported for serial destruction of the lateral hypothalamic area of adult rats (11) or other neuralbehavioral investigations (1, 12, 22). However, it is well recognized that serial destruction of the lateral hypothalamic area (13) or other brain areas does not lead to a universal “sparing of function” (8, 12). Although our serial-lateral hypothalamic area results closely approximate the effects of simultaneous bilateral destruction of the lateral hypothalamic area sustained during infancy or adulthood, the effects are not identical. First, adult rats with bilateral destruction of the lateral hypothalamic area do not reduce feeding in response to amphetamine treatment (6)) whereas bilateral lateral hypothalamic area lesions sustained during infancy (2) and the present serial-lateral hypothalamic area lesions yield rats which show a normal amphetamine anorexia. Second, although male rats show permanent body-weight deficits following destruction of the lateral hypothalamic area sustained during infancy (2, 3) or adulthood (4, 10, 21), female rats of either age group show only a transitory body-weight loss with recovery of control levels (2, 7). The permanent body-weight deficits of female rats sustaining serial destruction of the lateral hypothalamic area represent the first demonstration of permanent body-weight deficits for females with lateral hypothalamic area destruction. This result is the opposite of “sparing of function“’ notions for serial LHA destruction, i.e., the two lateral hypothalamic area lesions separated by 140 days yield more severe bodyweight deficits than simultaneous bilateral destruction of the lateral hypothalamic area. Reports concerning the effects of serial destruction of the lateral hypothalamic area of adult rats have yielded conflicting results. Dubuc (9) and Fass et al. (11) report that multiple-stage bilateral or two-stage serial lesions of the lateral hypothalamic area spare body-weight deficits and the severe aphagia-adipsia which are associated with simultaneous bilateral destruction of the lateral hypothalamic area. In contrast, Gold (13) reports severe and persistent adipsia-aphagia and body-weight deficits following two-stage bilateral destruction of the lateral hypothalamic area of adult rats. The present serial-lateral hypothalamic area results agree with those reported by Gold (13), in spite of the fact that 10 to 13 days separated the two lesions in Gold’s study, whereas 140 days separated the two lesions in the present study. In addition to the initial adipsia-aphagia and bodyweight deficits, we also show that these serial lesions of the lateral hypothalamic area yield permanent disruption of regulatory capacity in response to specific homeostatic challenges (Table 3). Thus, the present two-stage lesions produce feeding-drinking and body-weight deficits which are typically associated with one-stage bilateral destruction of the lateral hypothalamic area of infant (2, 3) or adult rats (4, 10, 21, 23).
660
ALMLI
AND
GOLDEN
The results for the infant unilateral-lateral hypothalamic area lesions suggest that one lateral hypothalamic area is sufficient to maintain approxiwhen the intact lateral mately normal homeostatic function. However, hypothalamic area is destroyed 140 days later, profound deficits in regulatory capacity are produced. The fact that adult rats sustaining unilateral destruction of the lateral hypothalamic area are less severely affected suggests that the infant lesions produced residual effects which were not manifest until the second lesion was inflicted. With respect to body-weight regulation of male rats, it is interesting that the infant and adult unilateral-lateral hypothalamic area males showed approximately 20% body-weight deficits, whereas the serial bilateral-lateral hypothalamic area rats showed deficits of approximately 50% for body weight. These. results seem to suggest that destruction of one lateral hypothalamic area during infancy produces a lowering of the set-point for bodyweight regulation (21), with a further reduction following destruction of the intact lateral hypothalamic area during adulthood. In adult rats, onestage bilateral destruction of the lateral hypothalamic area lowers the bodyweight set-point by 20% (21)) which is also true for bilateral destruction of the lateral hypothalamic area of preweanling rats (2). In other words, bilateral destruction in infant or adult rats each results in a reduction of normal growth, and the effects on growth are additive when the lateral hypothalamic area is destroyed in two stages, one in infancy and one during adulthood. In the case of females, the effects on body weight parallel males, except females do not show permanent body-weight deficits following unilateral or one-stage bilateral destruction of the lateral hypothalamic area sustained during infancy (2) or adulthood (7). However, although females attain normal growth following one-stage unilateral or bilateral destruction, they are unable to compensate for a second lesion, when the lateral hypothalamic area is destroyed in two stages, i.e., infancy and adulthood. These body-weight effects cannot be completely explained by gastric pathology (16) ; however, gastric pathology and the subsequent effects on feeding behavior may be contributing to the body-weight reductions. We have found that females and males sustaining bilateral destruction of the lateral hypothalamic area at 10 days of age both show considerable gastric pathology, in spite of the fact that females attain control body weights and males are permanently depressed by 20% (unpublished observations). Also, in the present study males and females sustaining unilateral destruction of the lateral hypothalamic area as adults both show gastric pathology ; however, females attain control body weights whereas males do not. These results suggest that the effects on feeding and body-weight regulation following lateral hypothalamic area destruction cannot be solely char-
SERIAL
LATERAL
HYPOTHALAMIC
DESTRUCTION
661
acterized by gastric pathology. The differential effects on body-weight regulation shown between males and females are more likely due to sexual dimorphism in hypothalamic control of endocrine function (18, 27). Although the lateral hypothalamic area lesions of the present study include important fiber systems coursing through or near the lateral hypothalamic area, e.g., nigrostriatal bundle (24) and gustatory (20) and trigeminal projections (28), the results show that one lateral hypothalamic area is sufficient to maintain approximately normal regulatory function when one area is destroyed during the preweanling period. However, destruction of the intact lateral hypothalamic area during adulthood leads to severe and persistent regulatory deficits. These results demonstrate quite conclusively that “sparing of function” following the infantile lesion was due to compensation by the intact lateral hypothalamic area, rather than any change in neural tissue on the side of the initial lesion. REFERENCES 1. ADAMETZ, J. H. 1959. Rate of recovery of functioning in cats with rostra1 reticular lesions. J. Neurosurg. 16: 85-98. 2. ALMLI, C. R., and G. T. GOLDEN. 1976. Pre-weanling rats: Recovery from lateral hypothalamic damage. J. Cow@. Physiol. Physchol., in press. 3. ALMLI, C. R., and G. T. GOLDEN. 1974. Infant rats: Effects of lateral hypothalamic destruction. Physiol. Behav. 13 : 81-90. 4. ALMLI, C. R., and C. S. WEISS. 1974. Drinking behaviors: Effects of lateral preoptic and lateral hypothalamic destruction. Physiol. Behav. 13 : 528-538. 5. BERNARDIS, L. L. 1972. Delayed ventricular changes in the hypothalamus of the weanling rat following electrolytic lesions of the ventromedial nucleus. J. Neurovisc.
Relat.
32 : 347-354.
6. CARLISLE, H. J. 1964. Differential effects of amphetamine on food and water intake in rats with lateral hypothalamic lesions. J. Camp. Physiol. Psychol. 58: 47-54. 7. Cox, V. C., and J. W. KA~OLEWSKI. 1970. Sex differences in body weight regulation in rats following lateral hypothalamic lesions. Con~mzkn. Behav. Biol. 5 : 195-197. 8. DAWSON, R. G., L. CONRAD, and G. LYNCH. 1973. Single and two-stage hippocampal lesions : A similar syndrome. Exp. Neural. 40: 263-277. 9. DUBUC, P. U. 1974. Body weight regulation following multistage hypothalamic lesions. Amer. J. Physiol. 227 : 697-702. 10. EPSTEIN, A. N. 1971. The lateral hypothalamic syndrome: Its implications for the physiological psychology of hunger and thirst, pp. 263-317. In “Progress in Physiological Psychology,” Vol. 4. E. Stellar and J. M. Sprague [Eds.]. Academic Press, New York. 11. FASS, B., H. JORDAN, A. RUBMAN, S. SEIBEL, and D. STEIN. 1975. Recovery of function after serial or one-stage lesions of the lateral hypothalamic area in rats. Behav. Biol. 14 : 283-294. 12. FINGER, S., B. WALBRAN, and D. G. STEIN. 1973. Brain damage and behavioral recovery: Serial lesion phenomena. Brain Res. 63 : I-18. 13. GoLD, R. M. 1966. Aphagia and adipsia produced by unilateral hypothalamic lesions in rats. Amer. J. Physiol. 211 : 1274-1276.
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AND
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H. R. 1971. Acquisition of prandial drinking in weanling rats and in rats recovering from lateral hypothalamic lesions. J. C~mfi. Ph~siol. PsYChd 77 : 97-109. K~NIG, J. F. R., and R. KLIPPEL. 1963. “The Rat Brain: A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem.” Williams and Wilkins, Baltimore. LINDHOLM, E., G. SCHUMWAY, C. GRIJALVA, T. SCHALLERT, and M. RUPPEL. 1975. Gastric pathology produced by hypothalamic lesions in rats. Physiol. Behav. 14: 165-170. LYTLE, L. D., and B. A. CAMPBELL. 1975. Effects of lateral hypothalamic lesions on consummatory behavior in developing rats. Physiol. Behav. 15: 323-331. NANCE, D. M., and R. A. GORSKI. 1975. Neurohormonal determinants of sex differences in the hypothalamic regulation of feeding behavior and body weight in the rat. Pharmacol. Biochem. Behav. 3: 1.55-162. NANCE, D. M., and R. A. GORSKI. 1973. Effects of chronic diabetes on 2-deoxy-nglucose induced feeding and drinking. Pharmacol. Biochem. 1: 483-485. NORGREN, R. 1976. Taste pathways to hypothalamus and amygdala. J. Co@. Neural. 166 : 17-30. POWLEY, T. L., and R. E. KEESEY. 1970. Relationship of body weight to the lateral hypothalamic feeding syndrome. J. Conzfi. Physiol. Psychol. 70 : 2536. SCHULTZE, M. J., and D. G. STEIN. 1975. Recovery of function in the albino rat following either simultaneous or seriation lesions of the caudate nucleus. Exp. Neurol. 46 : 291-301. TEITELBAUM, P., and A. N. EPSTEIN. 1962. The lateral hypothalamic syndrome: Recovery of feeding and drinking after lateral hypothalamic lesions. Psychol.
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24. UNGERSTEDT, U. 1971. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol. Stand. 367: 95-122. 25. WAMPLER, R. S. 1971. Regulatory deficits in rats following unilateral lesions of the lateral hypothalamus. I. COT@. Physiol. Psychol. 75 : 190-199. 26. WOLF, G., and L. V. DICARA. 1969. Progressive morphologic changes in electrolytic brain lesions. Exp. Neural. 23: 529-536. 27. WEEDS, S. C., E. DECKE, and J. R. VASSELLI. 1974. Metabolic hormones and regulation of body weight. Psychol. Rev. 81: 26-43. 28. ZEIGLER, H. P., and H. S. KARTEN. 1974. Central trigeminal structures and the lateral hypothalamic syndrome in the rat. Scietzce 186: 636-637.