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Investigation of the role of anterior and lateral connections of the ventromedial hypothalamus in control… Storlien, Leonard Henry 1971

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AN INVESTIGATION OP THE ROLE OF ANTERIOR AND LATERAL CONNECTIONS 0? THE VENTROMEDIAL HYPOTHALAMUS IN CONTROL OF FOOD INTAKE, ACTIVITY, FOOD MOTIVATION AND REACTIVITY TO TASTE by LEONARD HENRY STORLIEN B.Sc, University of Lethbridge, I968  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS  in the Department of Psychology  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA September, 1971  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r  an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e  and  study.  I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may by h i s r e p r e s e n t a t i v e s .  be  granted by  the Head of my  Department or  I t i s understood t h a t copying or p u b l i c a t i o n  of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without written  permission.  Department o f  f The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada  my  i  ABSTRACT The "hyperphagic syndrome" consists of a number of behavioral changes which normally occur along with the increased weight gain following 'VMH lesions in the rat. The present study explored the possibility of separating these behavioral changes from the increased weight gain. The behavioral dimensions sampled were activity, tendency to work for food and reactivity to diet adulteration. Three different methods were employed to produce the increased weight gain: cuts lateral to the VMH,  electrolytic VMH lesions,  and cuts anterior to the VMH.  The results con-  firmed the decreased activity, decreased tendency to work for food, and increased reactivity to taste manipulation previously reported for VMHlesioned animals.  Cuts lateral to the VMH were indistinguishable from  lesions on each of these measures.  Cuts anterior to the VMH resulted  in no change in normal activity level or in the tendency to work for food but did result in increased reactivity to taste manipulation.  The results  are consistent with the notion of a medial-lateral system controlling some facit of energy balance and of an anterior system underlying a sex dependent part of the weight gain in female rats.  ii  TABLE OF CONTENTS Page i  Abstract  ii  Table of Contents  iii  List of Figures and Tables  iv  Acknowledgments Introduction  1  Method  4  Subjects, Surgical Techniques, HistologyTesting Procedure Activity Measurement Bar Pressing for Food Diet Adulteration Statistical Analysis Results  •  8  Y/eight Gain Activity Measurement Bar Pressing for Food Diet Adulteration Summary of Results Discussion References  •  22 25  iii  L I S T OF F I G U R E S AHTJ T A B L E S  Page Figure 1  9  Figure 2  11  Figure 3 Figure 4 • •  •  13 18  Table 1  16  Table 2  20  ACKNOiVLEDGMEl:ITS T  I wish to thank Dr. D.J. Albert and Dr. R.C. Tees f o r their constructive criticism and incredible patience on a l l phases of this thesis. Fred Madryga and John Jamieson were subjected to many helpful discussion sessions. I also thank the people whose close friendships are the most worthwhile result of this thesis.  1. INTRODUCTION The hyperphagic syndrome caused by lesions of the ventromedial hypothalamus (VMH)  i s characterized by increased food intake (Anand, 1961;  Brobeck, Tepperraan & Long,  1943),  viciousness (Wheatley,  spontaneous activity (Hetherington & Ranson,  1942;  1944),  Teitelbaum,  elevated reactivity to taste properties of food ("finickiness";  decreased  1957)» Teitelbaum,  1955)>  a decreased tendency to work for food (Miller, Bailey & Stevenson,  1950;  Teitelbaum,  1957),  altered l i p i d metabolism (Han,  1967),  1967), and a disturbance of 1956). The work of a number of  a decrease  in growth hormone secretion (Han,  sex hormone  secretion (Sawyer & Robinson,  investigators  seems to suggest that the various aspects of the syndrome are due to a collection of independent disturbances which do not invariably occur together.  Ingram  (1952),  Skultety  (1966)  and Anand, & Brobeck  (1951)  each noted a lack of correlation between obesity and viciousness. and Stellar  (19^2)  have  Graff  have found the lesions which produce maximal hyperphagia  to be different from those which produce maximal finickiness. Hetherington and Ranson  (1942) and  Both  Brooks (1946) have shown that the decrease  in spontaneous activity i s not invariably associated with either hyperphagia or obesity.  The altered l i p i d metabolism and disturbance of growth hormone  also do not appear to be invariant features of the syndrome.  It has been  reported that only 3C$ of the VMH-lesioned animals accumulate excess fat when pair-fed with non-lesioned controls (Han & Young, 1964) and that the interruption of growth due to the disturbance of the hormone can be alieviated by replacement injections without altering the obesity (Han,  1967).  While this evidence seems to make clear the likelihood of multiple disturbances underlying the hyperphagic syndrome, the evidence i s limited and largely of a correlational nature.  There have been no systematic  2.  i n v e s t i g a t i o n s i n t o which o f t h e s e causes.  T h i s i s not  i t s e l f to the ent  surprising  s i n c e the  to e n t i r e l y  l e s i o n technique  separate  does not  lend  differ-  behaviors. the  complementary t e c h n i q u e  u s e d t o s t u d y the h y p e r p h a g i c A l b e r t & Mali, 1971) Grossman, 1 9 6 9 ;  syndrome.  or l a t e r a l  Gold,  The  o f b r a i n c u t s has  (Albert & Storlien,  only evidence  1969;  Sclafani  They f o u n d no  on b e h a v i o r a l accompaniments  1962)  d i f f e r e n c e between VMH  present experiments are  t h e weight g a i n produced by VMH ioral  changes w h i c h might  with  it.  duced by t h r e e d i f f e r e n t methods: lateral  separated  t o the VMH,  and  decreased  because whereas l e s i o n s d e s t r o y b o t h c e l l  passing i n a p a r t i c u l a r direction. a n t e r i o r cuts to those interest  from t h e  behav-  tendency t o work The  design  e l e c t r o l y t i c l e s i o n s o f t h e VMH,  c u t s a n t e r i o r to the VMH.  passage i n the r e g i o n o f the VMH,  whether  dimensions when t h e weight g a i n i s p r o -  b e h a v i o r a l accompaniments produced by l e s i o n s and interest  Stellar,  behavioral c h a r a c t e r i s t i c s  i n c r e a s e d r e a c t i v i t y to t a s t e m a n i p u l a t i o n .  a l l o w s f o r comparison a l o n g these  VMH  l e s i o n s and c o n t r o l s .  The  i n v e s t i g a t e d a r e lowered spontaneous a c t i v i t y , f o o d , and  (Graff &  concerned s p e c i f i c a l l y w i t h  l e s i o n s can be  interact  and  However, t h e i r r e s u l t s must  c a u t i o n because, u n l i k e o t h e r a u t h o r s  t h e y a l s o f o u n d no The  Grossman  d i f f e r e n c e between c u t s l a t e r a l t o the VMH  l e s i o n s on measures o f r e a c t i v i t y t o t a s t e . be t r e a t e d w i t h  &  have b o t h been f o u n d t o produce  i n c r e a s e d weight g a i n s f o l l o w i n g c u t s i s t h a t o f S c l a f a n i and  (1969).  been  Cuts a n t e r i o r ( A l b e r t , S t o r l i e n ,  1 9 7 0 a , b ) to t h e VMH  i n c r e a s e d weight g a i n s .  for  due  s e p a r a t i o n o f o v e r l a p p i n g n e u r a l systems u n d e r l y i n g  Recently  of  e f f e c t s are  • The  cuts  comparison o f  cuts i s of b o d i e s and  the  particular fibers  of  c u t s p r i m a r i l y i n t e r r u p t o n l y pathways The  comparison o f the e f f e c t s  o f l a t e r a l c u t s and o f l e s i o n s i s a l s o o f  of special  because t h e weight g a i n f o l l o w i n g the a n t e r i o r c u t s a p p e a r s t o  3.  be due to an imbalance of female sex hormones (Albert, Storlien, Albert & Mah, 1971) and might therefore involve quite a different syndrome than that resulting from VMH lesions or lateral cuts.  4.  METHOD The subjects were experimentally naive, female hooded rats (Quebec Breeding Farms) weighing between 160 and 260 grams at the time of surgery. Three types of surgery were performed:  electrolytic lesions of the VMH,  cuts at the lateral or anterior borders of the VMH, and cutter guide stab wounds for the operated controls. Lesions were produced electrolytically using an electrode of twisted (0.25  J&ni dia.) stainless-steel wire, insulated at a l l but the cross-  sectional t i p .  The lesion c i r c u i t was completed through a cathode  connected to the t a i l . at coordinates A 5«8»  The D-G lesioning current was 2 ma for 15 seconds Lr+P«5>  and H  9*0  (deGroot Atlas coordinates;  deGroot,  1959).  Brain cuts were made with a device which has been described previously (Albert, 1969)*  The cutter consists of an outer guide cannula (21  gauge stainless-steel hypodermic tubing) which i s stereotaxically lowered into the brain of an anesthetized animal. With the guide cannula i n place, a 26 gauge insert with a cutting blade of stainless-steel wire (0.15 dia.)  i s lowered into the cannula.  mm  When the cutting blade reaches the lower  s l i t , i t extends and cuts through the neural tissue as i t i s lowered further. The cutting blade i s then removed and the guide cannula raised out of the brain. Surgical procedure for the operated controls was similar to that for the cut animals. cut  The cutter guide was lowered into the brain but no  was made. Upon completion of the experiments the subjects were k i l l e d , the  brains fixed in formal-saline, sectioned at 40 microns, and every f i f t h section stained with thionin.  5 .  TESTING PROCEDURE P o s t - o p e r a t i v e l y , s u b j e c t s were m a i n t a i n e d o n f r e e a c c e s s t o P u r i n a Lab Chow p e l l e t s and t a p w a t e r .  The Lab Chow p e l l e t s were p l a c e d  on t h e f l o o r o f t h e cage a s w e l l a s i n t h e f o o d h o p p e r s . was  one t i n ( 4 0 grams d r y w e i g h t ) o f wet mash p e r day.  w e i g h e d d a i l y f o r 5 t o 7 days.  Also available S u b j e c t s were  A t the end o f t h i s p e r i o d animals i n t h e  l e s i o n and two c u t g r o u p s w h i c h were g a i n i n g w e i g h t a t a r a t e above t h e c o n t r o l l e v e l were s e l e c t e d t o c o n t i n u e o n i n t h e s t u d y .  Previous results  o b t a i n e d i n o u r l a b o r a t o r y have shown t h a t a n i m a l s w i t h b a d l y m i s p l a c e d l e s i o n s o r c u t s e x t e n d i n g i n t o t h e a n t e r i o r hypothalamus o r l a t e r a l hypothalamus g a i n w e i g h t a t o r below t h e c o n t r o l l e v e l ( A l b e r t & S t o r l i e n ,  1969). A c t i v i t y Measurement.  A c t i v i t y cages a n d r u n n i n g w h e e l s were  u s e d t o a s s e s s a c t i v i t y i n t h e a n i m a l s which met c r i t e r i o n f o r w e i g h t gain.  The a c t i v i t y cages c o n s i s t e d o f a c r o s s 7 " by 1 0 " by 7 " deep Wahmann  I n d i v i d u a l cages, w i t h a s i n g l e p h o t o c e l l p l a c e d a c r o s s the w i d t h .  The  p h o t o c e l l beam was 1 1 / 4 above t h e f l o o r and e q u i d i s t a n t from e i t h e r end. M  Each beam breakage a c t i v a t e d a R u s t r a c k r e c o r d e r a n d t h e a c t i v i t y r e p r e s e n t s c o u n t s made from t h e R u s t r a c k c h a r t paper. were L a P a y e t t e I n s t r u m e n t  score  The r u n n i n g w h e e l s  Co. M o d e l A34 a c t i v i t y w h e e l s , w i t h a n a t t a c h e d  c o u n t e r , w h i c h i n d i c a t e d t h e number o f w h e e l t u r n s . A c t i v i t y measurement was c a r r i e d o u t o v e r 8 days u n d e r both f o o d d e p r i v e d and non-deprived  c o n d i t i o n s . On t h e f i r s t 2 days t h e a n i m a l s were  r u n i n t h e a c t i v i t y cages f o r 2 h o u r s f o l l o w e d by 2 h o u r s i n t h e r u n n i n g w h e e l s w i t h f r e e a c c e s s t o f o o d and w a t e r . t h e home c a g e s .  On d a y 3 f o o d was removed from  On days 4 a n d 5 t h e a n i m a l s were a g a i n r u n a s on t h e f i r s t  2 days w i t h t h e e x c e p t i o n t h a t t h e y were 19 h o u r s d e p r i v e d a t t h e b e g i n n i n g  6.  of a c t i v i t y measurement.  On day 4, following the test periods, they were  f e d f o r 1 hour i n t h e i r home cages.  Free access to food was reinstated  following the test conditions on day 5> and day 6 was spent free feeding i n the home cages.  The f i n a l two days, days 7 and 8, the animals were  again run i n the a c t i v i t y wheels f o r 2 hours per day and had free access to food.  These f i n a l two days acted as a control f o r learning e f f e c t s i n  the running wheels.  Water was a v a i l a b l e continuously throughout.  Bar Pressing; f o r Food.  Following the f i n a l day i n the a c t i v i t y  wheels subjects were food-deprived f o r 24 hours.  They were then placed i n  S c i e n t i f i c Prototype Model A 106 lever-press boxes.  A r b i t r a r i l y , each  animal was required to press 100 times f o r food before being removed from the lever-press box.  Most animals accomplished t h i s w i t h i n 1 hour and a l l  d i d so within 24 hours.  Ko difference was noted between any o f the groups  i n time taken to l e a r n the required response. A f t e r learning the bar-press response, 4 days were allowed f o r s t a b i l i z a t i o n on a f i x e d r a t i o schedule i n which the animal received one p e l l e t o f food (45 mg Noyes p e l l e t ) f o r each bar-press (FR 1).  On each  p a i r o f days thereafter, the animal was successively required to make more bar-presses f o r each food reward. FR 4, FR 16, FR 64 and FR 128.  The reinforcement schedules used were  Bar pressing f o r food was allowed f o r 1  hour per day throughout the experiment.  In order to maintain the animals  at a f a i r l y stable weight, 1 hour o f free feeding i n the home cage on Purina Lab Chow p e l l e t s was allowed per day.  T h i s period o f free feeding  always began 1 hour a f t e r termination o f the lever-pressing.  Diet Adulteration.  Following the experimental t e s t s o f bar-  pressing f o r food the e f f e c t o f the cuts and lesions on food intake was assessed.  The animals were f i r s t habituated to a l i q u i d diet  (commercially  7.  available Metrecal ) for 4 days.  Following this their intake was measured  when the diet was adulterated with each of the following: 0.5$  1.0/o saccharin,  saccharin; O.O'yo quinine hydrochloride, and 0.0257^ quinine hydro-  chloride.  With 2 days of unadulterated Metrecal between each presentation,  each subject received each level and type of adulteration in a counterbalanced design controlling for order effects.  In a l l cases consumption  was measured over a 24-hour period, with water available at a l l times. It was found that through handling and movement of the cages 3-4 grams of Metrecal was lost per bottle per day.  This amount lost was not  subtracted from any score. It was also found that outside of transient cases of diahorrea, the animals maintained themselves well on the Metrecal and with 2 exceptions (the data of which are discarded) the Metrecal did not coagulate within the 24-hour period. Statistical Analysis. An analysis of variance followed, where appropriate by Neuman-Keuls test for post-hoc comparisons (Winer, 1962) was used throughout for statistical evaluation of the results.  1.  The Metrecal used in the present experiments was generously supplied by Mead-Johnson Canada Limited.  8.  RESULTS Animals were selected for inclusion in the VMH  lesions, Lateral  Cut and Anterior Cut groups on the basis of histological examination. This was done so that the groups included only animals which had cuts and lesions that previous results (Anand & Brobeck, 1 9 5 1 ; 1969;  Albert & Storlien,  Albert et. a l . , 1971) have shown produce maximal weight gains.  The  criterion for inclusion in the VMH-lesion group was that the lesions destroy the entire VMH  bilaterally.  Damage to the dorsomedial nucleus was allowed  but not destruction anterior to the VMH  or lateral to the fornix.  Existing  evidence indicates that anterior or lateral hypothalamic damage may uate the effect of VMH  lesions (Skultety, 1 9 6 6 ;  atten-  Anand & Brobeck, 1 9 5 1 ) .  Animals in the Lateral Cut group had cuts (Fig. 1a,b) which extended the entire length of the VMH. more than 0 . 5 mm  The cuts did not intrude into the VMH  lateral to the fornix.  nor extend  The lateral cuts also extended  dorsally above the most dorsal aspect of the ventromedial nuclei and ventrally to the base of the brain.  Animals in the Anterior Cut group had cuts (Fig.  2a,b) which were in the coronal plane between the anterior tip of the and 0 . 5 mm anterior to this point.  VMH  These cuts extended approximately 2 mm  lateral at the level of the anterior commissure and narrowed to 0 . 5 mm  lateral  at the base of the brain. The magnitude of postoperative  weight gains (Fig. 3) and the group  differences are in good agreement with previous results (Albert & Storlien, 1969;  Albert, Storlien, Albert & Mah,  group (N=6)  The Anterior Cut (N=6)  average of 35 and 36 g respectively.  and Lateral Cut (W=7)  N=9)  (p>.20).  lesioned  groups.  groups gained an"  Both groups gained significantly more  than either the Operated Control (8 g;  (p<.0l)  Animals in the VMH  gained an average of 70 g«, significantly more (p<.Ol) than any  other group.  (lOg;  1971)•  N=8)  or Unoperated Control  The control groups themselves did not differ s t a t i s t i c a l l y  9.  F i g u r e 1.  (a)  A s a g g i t a l s e c t i o n (reporduced from de Groot, 1959) showing the approximate extent o f the l a t e r a l c u t s i n r e l a t i o n to the VMH.  The a c t u a l l o c a t i o n o f the  cut i s l a t e r a l to the VMH. (b)  A coronal s e c t i o n (40 microns t h i c k , t h i o n i n s t a i n ) a t the l e v e l o f the VMH showing the two l a t e r a l cuts i n an animal which gained 34 grams i n 5 days postoperatively.  Arrows i n d i c a t e extent o f c u t s .  •V  10  10b  1 1 .  Figure 2.  (a)  A coronal section (reproduced from de Groot, 1959) showing the approximate extent of the anterior cuts.  The actual cut i s slightly anterior to  this section. (b)  A horizontal section through the VMH  showing the  anterior cuts in an animal which gained 32 grams in the 5 days postoperatively.  The anterior  cuts normally opened slightly along the ventricle. Outer arrows indicate ends of each cut.  12  12b  13.  Figure 3.  Mean weight gain (g) for each of the experimental groups over the f i r s t five days postoperatively.  14  T  1 DAYS  r  1  i  2  3  FOLLOWING  4  5 OPERATION  15.  Activity Measurement. The results of the measurement in the activity cage and running wheel are shown in Table 1 . With the activity cages, the two scores per group represent the mean number of photocell beam breakages over the 2 days non-deprived and the 2 days deprived respectively.  The f i r s t 1 5 minutes was not included i n an attempt to  minimize any influence on the results due to handling.  Since a comparison  between the operated and unoperated control groups showed that the d i f f erences between these two groups did not approach statistical (p>.20),  significance  the scores for these were combined for the overall between  groups analysis. There were significant (F<=14.2;  p<.00l)  differences between  groups with respect to level of postoperative activity. and Lateral Cut groups were significantly (p<.01;  p<.05)  The VMH Lesion less active  overall than the Control group. No other pair differences were s i g n i f i cant. but  Food deprivation did increase activity overall  (F=20.0;  p<.00l)  since the operative treatment by deprivation interaction did not  approach significance  (F=1.0),  i t would appear that a l l groups reacted  with similar increased activity to deprivation. Table 1 also contains the results of the wheel running measure of activity.  The "non-deprived" scores are the means over 4 days of no  food deprivation and the "deprived" scores are the means over the 2 days deprived.  The total two hour session was used for each score since the  effects of handling were minimized by allowing the animals to quiet in the side cage for approximately 1 0 minutes before opening the sliding door which permitted access to the wheel.  Again, operated and unoperated con-  t r o l groups did not differ significantly  (p>.20)  and were combined for  the between group analysis. As with the activity cage, there were significant (F=3.4,  p<.05)  Table 1 Mean number of activity,responses per test period for each group averaged over the total number of days spent in each condition (standard deviation in brackets).  Non-deprived indicates ad l i b , access to food. Deprived  indicates prior 19 hours spent with no food available. Activity Gage: Mean number of photocell beam breakages i n the last 1 3/4 hours of the 2 hour test period.  Activity Wheel: Mean number of activity wheel  revolutions i n the total 2 hour test period.  Standard deviations for  each mean score appear in brackets following the mean. Group  N  VMH lesion  6  Lateral cut Anterior cut Control  Activity Cage Non-deprived Deorived  142 (64.6)  Activity Wheel Non-deprived Deprived a  7 (7.5)  b  9 (6.2)  b  11 (H.6)  b  54 ( I 9 . 2 )  a  7 6  104 ( 3 3 . 6 )  a  122 (46.8)  162 (27.0)  79 (71.1)  119 (139.4)  17  165 (45.6)  224 (74.1)  67 (59.9)  152 (123.4)  a differ from Control group, p <  125 (38.5)  .05  b differ from Control and Anterior Cut groups, p < .05  a  14 (15-I)  b  differences between groups with respect to level of postoperative activity. Both the VMH Lesion and Lateral Gut groups were significantly active than either the Anterior Cut or Control groups.  (p<.05)  less  The striking  suppression of activity following lesions and lateral cuts i s shown in Table 1 .  No other pair differences were significant.  As with the  activity cage, there was a significant increase in activity with food deprivation (F»8.1, p<.Ol) but the operative treatment by deprivation interaction again did not approach significance Bar-Press for Food.  (F=1.0).  Fig. 4 contains, for each group the mean  bar-press rate over the last 2 days at FR 1 and over the 2 days on each of the other schedules.  The most striking result with the bar-press i s  that while a l l groups pressed at similar rates for FR1, FR4 and FR16, there i s a dramatic drop in rate of pressing on FR 64 and FR 128 schedules for both the VMH Lesion and Lateral Cut groups.  In contrast, the Anterior Cut  and Control groups a l l continued to increase press rate up to and including FR 128.  The VMH Lesion and Lateral Cut groups differed from a l l other  groups (p<.Ol) at FR 128. at FR 64.  These same differences approached significance  No other pair comparisons were significant. Diet Adulteration. The effect of saccharin and quinine hydro-  chloride adulteration on intake of the liquid diet is shov/n in Table 2. The Operated and Unoperated Control groups again did not differ significantly (p>.20) on any measure and were combined for analysis. Three aspects of the results are important.  First, the  VMH  Lesion and Lateral Cut groups stabilized at significantly higher intakes of unadulterated Metrecal than the Control group  (p<.05).  The stabilized  intake of the Anterior Cuts group was also greater than that of the Control group but this difference did not reach s t a t i s t i c a l significance (p>.10).  Second, the VMH Lesion  (p<.05;  p<.05),  Lateral Cut  (p<.01;  18.  Figure 4.  Mean number of responses per hour as a function of FR schedule.  The mean for FR 1 was obtained over the  last 2 days of training and the means for the remaining schedules are taken over both days on that particular schedule.  19  2000  CO UJ  cn UJ  or o_  VMH LESION LATERAL CUT ANTERIOR CUT OPERATED CONTROL UNOPERATED CONTROL  I500  or <  or  I000  UJ CD  500 -  I  4 BAR  PRESSES  16  64 PER  I28  PELLET  Table 2 Mean daily intake (g) of the liquid diet.  The stabilization score represent  the mean 24 hour intake averaged over the last 2 days of inadulterated Metrecal prior to the f i r s t presentation of adulterated diet.  A l l other  scores are the mean 24 hour intakes for the single presentation of each type of level of adulterating substance.  Standard deviations for each mean score  appear i n brackets following the mean. Quinine hydrochloride  Saccharin Group  N  VMH Lesion  6  57 ( 9 . l )  a  28 ( 7 . 7 )  Lateral cut  7  63 (9.7)  a  39 ( 1 5 - I )  B  Anterior cut  6  53 (9-6)  39 (I4.5)  b  46 (7.8)  44 (9.5)  Control  17  Stabilize  a differ from Control group, p < .05 b differ from stabilized intake, p < .05  1.0$  0.5$ a , b  0.025$  35 ( I 2 . 2 )  B  38 ( I 2 . 0 )  B  11 ( 5 . D  0.05$ a , b  9 (3.5)  55 (11.6)  8 (5-2)  50 (12.5)  30 ( H . 4 )  a , b  A , B  b  7 (5-7) ' a  b  9 (3.0) '  B  8 (l.9) '  b  A  a  1 8 (7-9)  b  21.  p<.05),  (p<.01;  and A n t e r i o r Cut  on b o t h the 0.025fo and important  aspect  0.05^  o f the  p < . 0 5 ) groups a l l a t e  quinine  r e s u l t s was  conditions respectively.  (p<.0l)  L a t e r a l Cut  groups and  both c u t groups.  This  f o r both l e v e l s o f a d u l t e r a t i o n f o r the VMH significant  The  t h e tendency to r e d u c e d i n t a k e  s a c c h a r i n a d u l t e r a t i o n f o r the L e s i o n and significant  less than c o n t r o l s  ( p < . 0 5 ) f o r the A n t e r i o r Cut  third with  proved Lesion  and  group a t  t h e 1 »Qffo s a c c h a r i n l e v e l o f a d u l t e r a t i o n . Summary o f R e s u l t s .  B o t h the VMH  L e s i o n and L a t e r a l Cut  groups  were s i g n i f i c a n t l y d i f f e r e n t from t h e c o n t r o l s on each b e h a v i o r a l measure. B o t h groups g a i n e d more weight p o s t o p e r a t i v e l y t h a n c o n t r o l s , were active,  slowed b a r - p r e s s  schedules, The  and  r a t e d r a m a t i c a l l y on  r e a c t e d more t o both sweet and  L a t e r a l Cut  group was  not  i n c r e a s i n g FR  less  reinforcement  bitter adulteration of  significantly different  from the  diet.  Lesion  group on any measure e x c e p t f o r a s l o w e r r a t e o f p o s t o p e r a t i v e w e i g h t The  A n t e r i o r Cut  higher taste.  group d i f f e r e d from the  c o n t r o l s only with respect  p o s t o p e r a t i v e r a t e o f w e i g h t g a i n and  i t s greater r e a c t i v i t y  gain.  to i t s to  21.  p<.05),  and Anterior Cut  on both the  0.025$  and  (p<.01;  0.05$  p «05) <  groups a l l ate less than controls  quinine conditions respectively.  The third  important aspect of the results was the tendency to reduced intake with saccharin adulteration for the Lesion and both cut groups. This proved significant  (p<.0l)  for both levels of adulteration for the VMH Lesion and  Lateral Cut groups and significant  (p<.05)  for the Anterior Cut group at  the 1 . 0 $ saccharin level of adulteration. Summary of Results.  Both the VMH Lesion and Lateral Cut groups  were significantly different from the controls on each behavioral measure. Both groups gained more weight postoperatively than controls, were less active, slowed bar-press rate dramatically on increasing FR reinforcement schedules, and reacted more to both sweet and bitter adulteration of diet. The Lateral Cut group was not significantly different from the Lesion group on any measure except for a slower rate of postoperative weight gain. The Anterior Cut group differed from the controls only with respect to i t s higher postoperative rate of weight gain and i t s greater reactivity to taste.  22.  DISCUSSION The most surprising aspect of the present experiments i s the lack of difference i n behavioral characteristics between animals with cuts lateral to the VMH and those with VMH lesions.  Animals with each  of these disturbances showed decreased activity, increased reactivity to taste, and decreased willingness to work for food.  These effects are  similar to those obtained previously with VMH lesions (Miller et. a l . , 1950;  Teitelbaum, 1955 and 1957) except for the results with saccharin  adulteration.  The animals i n the present experiments tended to decrease  food intake when the liquid diet was sweetened above i t s baseline level, instead of increasing food intake i n response to the increased sweetness. The reason for this may be that the normal Metrecal diet was already quite sweet and that further saccharin tended to decrease i t s palatability by making i t too sweet. The only difference found between the VMH lesioned animals and those with lateral cuts was that the lesioned animals showed a significantly greater postoperative weight gain. The failure to find behavioral differences between VMH lesioned animals and those with lateral cuts does not exclude the possibility of a series of independent effects caused by the interruption of several distinct pathways by the same lesion or cut. The results do, however, offer substantial support for those theories which account for both the increased weight gain and some behavioral changes i n terms of damage to one fiber system.  One such explanation i s i n terms of a medial-lateral  system controlling energy intake.  I f the medial hypothalamic area i s  conceived of as an area monitoring energy balance, cuts lateral to i t or lesions of i t could result, v i a the mechanism of a lateral hypothalamic system, i n the organism constantly behaving as though i t were experiencing  23.  an energy d e f i c i t .  From this point of view, the increased weight gain  can be looked upon as a result of excess food intake i n response to a neural system that i s constantly signalling an energy deficit and the decreased tendency to work for food could occur as a result of an attempt to conserve energy.  The apparent increased sensitivity to taste  in spite of increased hunger might be explained i n terms of Jacobs' (1966) findings of increased finickiness with increased deprivation. Alternatively, the increased sensitivity to taste may represent a rather nonspecific disturbance of the feeding system;  disturbances of many parts  of the brain associated with food intake have been observed to result in changes in sensitivity to taste [amygdala (Kemble and Schwartzbaum, 1969), septum (Beatty and Schwartzbaum, 1967), lateral hypothalamus (Booth and Quartermain, 1 9 ^ 5 ) ] .  A closely related possibility i s that the increased  weight gain following VMH  lesions i s due to an increased tendency to  store fat (see Teitelbaum, 1 9 6 1 ) .  Assuming this tendency i s very severe,  the result would be a deficit in energy expendible for other purposes and the behavioral effects would be in terms of an actual energy d e f i c i t . There i s at least one other interpretation of the increased weight gain following VMH Lesion which tends to be supported by the present findings. This i s the suggestion of Grossman (1966) that a l l of the effects including the increased weight gain are due to an increase i n affective responsivity. Thus, reduced activity and decreased willingness to work for food are interpreted in terms of the negative aspects of these behaviors while increased food intake and consequent increased weight are attributed to the positive response to the taste properties of palatable food. The findings with anterior cuts while less surprising are also important.  The present experiments find an increased weight gain as has  24.  been reported previously (Albert et. a l . , 1971)«  However, i n contrast to  the effect with lateral cuts, there are no significant differences from controls i n activity level or tendency to work for food. increased sensitivity to diet adulteration.  There i s an  These findings are an  interesting contrast to those with lateral cuts and VMH lesions because they show that an increased rate of weight i t s e l f does not necessarily cause the various behavioral changes and i n fact could account for the fact that lesions i n the region of the VMH sometimes seem to cause an increased weight gain but l i t t l e behavioral change (see introduction). It has been suggested that the increased weight gain with anterior cuts i s due to a disturbance of female sex hormones (Albert et. a l . , 1970• The present findings are generally consistent with that point of view i n that both anterior cuts and ovariectomy (Wade & Zucker, 1970) seem to cause an increased sensitivity to diet adulteration.  Albert, D. J.  A simple method of making cuts i n brain tissue.  Physiology and Behavior. 1969, 4, 863 - 864. Albert, D. J., and Storlien, L. H.  Hyperphagia i n rats with cuts  between the ventromedial and lateral hypothalamus.  Science.  1969, I65,, 599 - 600. Albert, D. J., Storlien, L. H., Albert, J. G., and Mah, C. J . Obesity following disturbance of the ventromedial hypothalamus: a comparison of lesions, lateral cuts, and anterior cuts. Anand, B. K.  Physiology and Behavior. 197^t in press.  Nervous regulation of food intake. Physiological Review.  1961, 41,  677 - 708.  Anand, B. K., and Brobeck, J . R.  Hypothalamic control of food intake  in rats and cats. Yale Journal of Biology and Medicine. 1951. 24, 123 - 140. Beatty, V/. W.,  and Schwantzbaum, J . S.  Enhanced reactivity to quinine  and saccharin solutions following septal lesions in the rat. Psychonomic Science. 1967, 8, 483 - 484. Booth, D. A., and Quartermain, D.  Taste sensitivity of eating e l i c i t e d  by chemical stimulation of the rat hypothalamus. Psychonomic Science. 1965, 3_, 525 - 526. Brobeck, J . R., Tepperman, J., and Long, C. N. H.  Experimental hypo-  thalamic hyperphagia i n the albino rat. Yale Journal of Biology and Medicine. 1943, 1£, 831 - 853. Brooks, C. McC.  The relative importance of changes i n activity i n the  development of experimentally produced obesity i n the rat. American Journal of Physiology. 1946, 147. 708 - 716. De Groot, J .  The rat brain in stereotaxic coordinates. N. V. Noord-  Hollandsche Uitgevers Maatschappij, Amsterdam, 1959.  26.  Gold, R. M.  Hypothalamic hyperphagia produced by parasaggital knife  cuts. Gold, R. M.  Physiology and Behavior, 197°a,  23 - 25*  Hypothalamic hyperphagics: males get just as fat as  females.  Journal of Comparative and Physiological Psychology,  1970b, 11,  347 - 356.  Graff, H., and Stellar, E.  Hyperphagia, obesity, and.finickiness.  Journal of Comparative and Physiological Psychology, 1962,  55, 418 - 424. Grossman, S. P.  The VMHs  or both? Han, P. W.  a center for affective reactions, satiety,  Physiology and Behavior, 1966, 1, 1 - 10.  Hypothalamic obesity i n rats without hyperphagia. Transactions of the New York Academy of Science, 1967,  12,  229 - 243. Han, P. W., and Young, T. K.  Obesity i n rats without hyperphagia  following hypothalamic operations. Physiology. 1964, 12,  Chinese Journal of  143 - 156.  Hetherington, A. W., and Ranson, S. W.  The spontaneous activity and  food intake of rats with hypothalamic lesions.  American  Journal of Physiology. 1942, 136. 609 - 617. Ingram, W. R.  Brainstem mechanisms of behavior. Electroencephalography  and C l i n i c a l Neurophysiology. 1952, 4, 397 - 406. Jacobs, H. L.  i n Proceedings of the 7th Internation Congress on Nutrition  1966, Vol. 2.  Regulation of Hunger and Satiety, pages 17 - 29.  Kemble, E. D., and Schwartzbaum, J. S.  Reactivity to taste properties  of solutions following amygdaloid lesions.  Physiology and  Behavior. 1969, 4, 981 - 985. Miller, N. E., Bailey, C. J., and Stevenson, J . A. P.  "Decreased hunger"  but increased food intake resulting from hypothalamic lesions. Science. 1950, H 2 ,  256 - 259.  27.  Sawyer, C. N., and Robinson, B.  Separate hypothalamic areas c o n t r o l l i n g  p i t u i t a r y gonadotropic function and mating behavior i n female cats and r a b b i t s .  Journal o f C l i n i c a l Endocrinology. 1956,  16,,  914 - 915. S c l a f a n i , A., and Grossman, S. P.  Hyperphagia produced by k n i f e cuts  between the medial and l a t e r a l hypothalamus i n t h e r a t . Physiology and Behavior. 1969, Skultety, P. M.  4, 505 -  507.  Changes i n c a l o r i e intake following brainstem l e s i o n s  i n cats.  I l l E f f e c t s of lesions of the periaqueductal gray  matter and r o s t r a l hypothalamus.  Archives of Neurology.  1966,  14, 670 - 680. Teitelbaum, P.  Sensory control o f hypothalamic hyperphagia.  of Comparative and P h y s i o l o g i c a l Psychology. 1955, Teitelbaum, P.  Journal 48, 158 ~  Random and food-directed a c t i v i t y i n hyperphagic  normal r a t s .  Journal o f Comparative  163.  and  and P h y s i o l o g i c a l Psychology, 1957»  50, 486 - 490. Teitelbaum, P.  Disturbances i n feeding and drinking behavior a f t e r hypo-  thalamic l e s i o n s . Jones, Ed.  In Nebraska Symposium on Motivation;  Lincoln:  Wade, G. N., and Zucker, I .  M.  University o f Nebraska Press, 1961,  R.  39 - 69.  Hormonal modulation of responsiveness to an  aversive t a s t e stimulus i n r a t s .  Physiology and Behavior. 1970,  Jj>,  269 - 273. Wheatley, M. 0.  The hypothalamus and a f f e c t i v e behavior i n cats.  o f Neurology and Psychiatry (Chicago). 1944, Winer, B. J .  £2, 296 -  S t a t i s t i c a l P r i n c i p l e s i n Experimental Design.  McGraw-Hill,  1962.  New  Archives  316. York:  

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