Physiology and Behavior, Vol. 12, pp. 973-979. Brain Research Publications Inc., 1974. Printed in the U.S.A.

Effects of Dorsomedial Thalamic Lesions on Spontaneous Alternation, Maze, Activity

and Runway Performance in the Rat '

LARRY W. MEANS, THOMAS H. H A R R E L L , ERIC S. M A Y O AND G A Y B. A L E X A N D E R

Department o f Psychology, East Carolina University, Greenville, N. C. 27834

(Received 26 March 1973)

MEANS, L. W., T. H. HARRELL, E. S. MAYO AND G. B. ALEXANDER. Effects ofdorsomedial thalamic lesions on spontaneous alternation, maze activity and runway performance in the rat. PHYSIOL. BEHAV. 12(6) 973 979, 1974. - A group of 15 Long Evans rats with bilateral electrolytic lesions of the dorsomedial area of the thalamus (DMT) and a group consisting of 14 sham-operated and one normal rat were compared on maze activity, spontaneous alternation, runway acquisition and extinction, and response to a novel.alley. The DMT-damaged rats were found to spontaneously "alternate at chance level. Also, relative to controls, the experimental animals were slower to habituate locomotion in the maze and more resistant to extinction in the runway. The two groups did not differ significantly on response to novelty.

Dorsomedial thalamus Activity Spontaneous alternation Acquisition Extinction Novelty

Habituation

IT HAS recen t ly been s h o w n tha t lesions of the media l t ha l amus of rats resul t in defici ts on pos topera t ive acquisi- t i o n and pos topera t ive r e t e n t i o n o f a p reopera t ive ly acqui red visual-tacti le, c o m p o u n d - s t i m u l u s , maze discrimi- na t ion task [ 12] and tha t lesions res t r ic ted to the dorso- medial area of the tha lamus (DMT) p roduce defici ts in post- opera t ive acquis i t ion and pos topera t ive r e t e n t i o n of an operan t , go, no-go, single a l t e rna t ion task [11 ]. These obse rva t ions are cons i s t en t wi th f indings t ha t rats wi th medial tha lamic lesions are def ic ien t on acquis i t ion and r e t e n t i o n of avoidance tasks [ 2 , 2 0 ] , shock -mot iva t ed br ightness d i sc r imina t ion [ 1 7 ] , two-bar a l t e rna t ion [6 ] , and complex mazes [3 ,6 ] . Also, cats wi th media l tha lamic damage are def ic ien t on complex maze p rob l ems [ 2 2 ] , d i sc r imina t ion [ 15] , and avoidance p rob l ems [ 7 ] , and m o n k e y s wi th to ta l de s t r uc t i on of the dorsomedia l nucleus of the t ha l amus (DMN) are def ic ien t on visual d iscr imina- t ion and delayed response tasks [ 1 6 ] . Final ly , Korsakof f pa t i en t s who suffer f rom an te ro- and re t rograde amnesia have cons i s t en t ly been found to have pa tho logy in the DMN [ 2 1 ] .

The purpose of the p resen t s t udy was to examine the effects of DMT lesions cen te red on the DMN in rats on several re la ted behaviors . Thus, in a series of e x p e r i m e n t s tha lamica l ly damaged rats and con t ro l s were c o m p a r e d on

maze act ivi ty , s p o n t a n e o u s a l t e rna t ion , runway acquis i t ion and ex t inc t i on , and response to a novel alley.

GENERAL METHOD

Animals

The same 30 male Long Evans rats were used for all exper iments . They were housed in individual cages and had a 14-hr light, 10-hr dark cycle. The rats were app rox ima te ly 120 days old at the t ime of surgery. All rats were handled 2 at a t ime for 10 min for 3 days pr ior to surgery.

Surgical and Histological Procedure

Fi f t een rats received bilateral anoda l DC lesions of the DMT. The lesions were made by passing 2.0 mA for 12 sec t h rough a stainless steel e lec t rode t ha t was insula ted wi th epoxyl i t e excep t for the t ip. The tip of the e lect rodes was cen te red in the DMN at the coord ina tes 1.2 mm beh ind bregma, 1.0 m m lateral to the midl ine and 6.5 mm below the top surface of the skull wi th the rat pos i t ioned in the s te reo tax ic wi th the t o o t h bar 5.0 m m above the ear bars [ 1 4 ] . F o u r t e e n rats received sham ope ra t ions which involved the same surgical p rocedures excep t tha t the elec- t rode was lowered on ly 5.0 m m below the surface of the

~Supported by grants 71A30 and 72A1 from North Carolina Mental Health and by a grant from North Carolina Community Services to Larry W. Means. The authors thank Belinda Broome and James L. Higgins for their helpful comments and Henry Hooks for his assistance.

973

974 MEANS, HARRELL, MAYO AND ALEXANDER

skull and no current was applied. All animals undergoing surgery were anesthetized with sodium pentobarbital (50 mg/kg) and received 0.2 ml of Bicillin. One normal intact animal was also included in the control group.

Upon completion of behavioral testing all animals with DMT lesions and several with sham operations were sacri- ficed with an overdose of sodium pentobarbital, and intra- cardially perfused with saline and then Formalin. The brains were then removed, sectioned at 50 u while frozen, and stained with thionin. The stained slides were projected onto plates of corresponding tissue [14] and a square

counting procedure was used to determine total lesion size and amount of bilateral damage to the various thalamic and extra-thalamic structures.

The lesions were similar but smaller than those reported earlier [121. In general, nuclei of the DMT including the DMN, paraventricularis, habenula, and parafasicularis were damaged bilaterally in most experimental animals. Also, the stria medularis and dorsal hippocampus were bilaterally invaded in many of the experimental animals. Several animals had slight, usually unilateral, damage to the ventral dorsomedial and reuniens nuclei of the thalamus.

t

- L I ~ 0

FIG. 1. Reconstructions of the largest and smallest lesions. Due to poor histological preparation 2 of the 15 DMT-damaged rats were not included in the histological analysis. Behaviorally these animals did not differ from the animals upon which

the histological analysis was based.

DORSOMEDIAL THALAMIC LESIONS AND MAZE BEHAVIOR 975

General Procedure

All behavioral testing was conducted in an evenly illu- minated room. Each animal was tested during the light por- tion of the light-dark cycle by the same experimenter throughout all experiments. All animals were allowed 10 days to recuperate from surgery and then given the follow- ing behavioral tests in the order listed: maze activity, spon- taneous alternation, runway acquisition, response to novel alley, and runway extinction.

EXPERIMENT 1 : MAZE ACTIVITY

Animals with large medial thalamic lesions have been found not to differ from sham-operated rats on total maze activity occurring in two five-minute sessions [12]. How- ever, it has been reported that rats with large medial thalamic lesions explore [ 18] and rear onto their hindlegs [19] more in an unfamiliar box than do control animals. The present experiment was conducted to compare maze exploration and its habituation in DMT-damaged and control animals.

Apparatus

A floorless T-maze which has been described elsewhere [10] was used to measure maze activity. It was painted grey and covered with wire mesh. The maze was placed on a wooden table, the top of which was washed clean each day after the testing of a squad of 10 rats.

Procedure

All rats received a 5 min free exploration session on 2 successive days to adapt to the maze. On the next 2 days each rat was tested once each day for maze activity. Each test consisted of placing a rat in the startbox and allowing him to freely explore the maze for 5 min. The runway and 2 arms of the T-maze constituted 3 sections into which the animal could move. The area at the choice point was not considered when scoring the animal. A rat was considered to have entered a maze section when all 4 paws were in the section. No food was in the maze nor were the rats food- deprived during the maze activity tests. The experimenters recorded the number of maze sections entered each minute.

Results and Discussion

The results of the maze activity tests are shown in Fig. 2. As can be discerned from the figure, the sham-operated animals showed normal habituation of the exploratory response across minutes while the experimental animals evidenced no habituation. The results of a 3-way (surgery group x minute x day) analysis of variance confirms this observation. The surgery group x minutes interaction was significant, F(4,112) = 44.21, p<0.001. A posteriori Newman-Keuls test show that the sham group was signifi- cantly more active than the experimental group during the first minute (p<0.01), but that the experimental group was the more active during the remaiTting four minutes (p<0.01 in all cases). The analysis of variance also reveals that the surgery group x days interaction is significant, F(1,28) = 8.89, p<0.01). Newman-Keuls tests reveal that the experimental animals were significantly more active on the second day of testing than either group was on the first day and the sham-operated group was on the second day

[ ] ¢; " / h a ~ LUon

O O Shim O ~ f l ~ n

I I I I I 1 2 3 4 5

MINUTES

FIG. 2. Mean number of maze sections entered each min during the 2 5-min test sessions by the thalamically damaged and sham-

operated groups.

(p<0.01 in all cases). Thus, the experimental animals became significantly more active on the second day of testing while the controls remained about the same. The same analysis also resulted in a significant surgery group effect, F(1,27) = 6.56, p<0.025, reflecting the fact that the experimental animals were slightly more active over the duration of the tests; a minute effect, F(4,112) = 71.79, p<0.001, reflecting the habituation; and a day effect, F(1,28) = 59.04, p<0.001, due to a general increase in activity on the second day.

The total maze activity of the animals with DMT lesions was not found to correlate reliably with total lesion size or the amount of bilateral damage to any of the specific thalamic or extrathalamic structures involved in the lesions. The results of the present study are consistent with the findings of Vanderwolf [18,19] that rats with medial thalamic lesions are more active in nonaversive exploratory situations than are control animals. Further, animals with DMT lesions show greater total activity than sham-operated animals because they do not habituate. The results of the present experiment, while apparently contradictory, are actually consistent with our earlier study [13]. We ob- served greater mean activity by the animals with medial thalamic lesions than by the sham-operated animals, 13.9 and 9.8, respectively, but failed to obtain significant differ- ences, probably due to small group sizes, 10 and 8 respec- tively. All studies considered, lesions of the medial thala- mus or limited to the DMT appear to prolong exploratory activity in non-aversive situations.

EXPERIMENT 2: SPONTANEOUS ALTERNATION

While testing animals with large medial thalamic lesions on maze discrimination [ 12], it was observed that most of the animals failing to obtain criterion became fixated in their response pattern, always responding to either the left or right arm of the maze. The question arose whether re- sponse perseveration results from the thalamic lesions per se or as a frustration reaction to their inability to solve the task [8,9]. To investigate this question the DMT-damaged

976 MEANS, H A R R E L L , MAYO AND A L E X A N D E R

and control rats were tested on spontaneous al ternation. It is well documented that normal rats alternate choices about 80 per cent of the t ime in the T-maze [5 ,13] . Perseveration of choice by the DMT-damaged animal in a si tuation which does not involve contrast ing rewarded and nonrewarded choices would be consistent with the hypothesis that DMT lesions produce response perseveration.

Procedure

Spontaneous al ternat ion testing was initiated on the day following comple t ion of the maze activity tests using the same T-maze. Each rat was given 3 trials per day, an initial reference trial and 2 al ternat ion trials. A trial consisted of placing a rat in the s tar tbox, opening the door , allowing the rat to make a choice, closing the door as soon as the base of his tail was in the arm, and retaining him for approxi- mately 5 to 10 sec. The intertrial interval was approxi- mately 15 sec. If an animal failed to make a choice within 5 min its testing was terminated for that day. All rats were tested daily until they had responded on 20 al ternat ion trials.

Results and Discussion

The results of the spontaneous al ternat ion tests clearly reveal that lesions of the DMT reduce the rate of spontane- ous al ternat ion to approximate ly 50 per cent or chance level. The exper imental and control animals alternated 49.3 and 77.7 per cent of the t ime, respectively. A t-test based on the total number of al ternations by each animal revealed that the exper imental and control groups differ significantly (t = 5.6, d f = 28, p<0 .001) . Observat ion of individual response patterns, however, revealed that the exper imental animals did not fixate on one side or the other. They responded in what appeared to be a nonsystemat ic manner alternating and repeating choices about equally. Thus, it appears that the perseverat ion of choices observed in dis- cr iminat ion training was probably a frustrat ion reaction to the task. However, it is also apparent that DMT lesions alter the normal al ternat ion response pat tern of rats.

The histological analysis suggests that damage to the habenula was most closely associated with the decrease in spontaneous al ternat ion as evidenced by a significant negative correlat ion between per cent al ternat ion and amount of bilateral damage to the habenula (rho = - . 6 5 , d f = 11, p<0.02) . Correlat ions be tween per cent al ternat ion and total lesion size or amount of bilateral damage to o ther structures were not significant.

EXPERIMENT 3: RUNWAY ACQUISITION AND EXTINCTION

It has previously been reported that rats with large medial thalamic lesions will run down a straight alley to obtain food faster than normal animals [20] . The present study was conducted to examine both acquisi t ion and ext inct ion of a runway response in rats with lesions of the DMT.

Apparatus

A wooden straight-alley maze with a goalbox extending at a right angle from the main runway was used to test the animals. A 33-cm long s tar tbox extended on one end of the runway and a 33-cm long concealed chamber extended on the other. The concealed chamber was not used for acquisi-

t ion or ext inct ion, but was used to test for response to novelty (see Exper iment 4). The main runway was t 00 cm long. The goal box which extended to the right of the main runway near the concealed arm was 33 cm long and 15 cm wide. The s tar tbox, runway, and concealed arm were 13 cm wide. The sides of the entire maze were 24 cm high and the maze was covered with wire mesh. The start box and goal- box were separated from the runway by guillotine doors.

Procedure

Four days after comple t ion of the spontaneous alterna- tion testing all rats were placed on a deprivat ion schedule such that they were maintained at 85 per cent of their ad lib weight. All animals were then given maze adaptat ion trials on 2 successive days. An adaptat ion trial consisted of allowing an animal to explore the maze, except for the concealed arm, for either 5 min or until it had consumed 4 Noyes pellets placed in a food cup at the end of the goal- box.

Acquis i t ion trials were initiated the fol lowing day. Each trial consisted of placing a rat in the s tar tbox, opening the door , allowing the animal to run to the goalbox, closing the goalbox door, allowing the rat to consume 4 Noyes pellets, and removing the animals from the goalbox. Each rat received 5 trials per day with an intertrial interval of approximate ly 60 sec. All animals received 5 acquisi t ion sessions for a total of 25 trials. On the third trial of the fifth acquisi t ion session, which served as the response to novelty trial, the removable endplate was removed exposing the previously concealed chamber. Ext inc t ion was begun on the sixth day and was exactly like acquisit ion, except that no Noyes pellets were present in the re inforcement arm. All animals received 7 ext inct ion sessions for a total o f 35 trials. If on any ext inct ion trial an animal failed to respond in 60 sec, the trial was terminated and the latency recorded as 60 sec. Latency, which was defined as the time between the opening of the s tar tbox door and t ime when all 4 feet of the rat were in the goalbox, was recorded with a stop- watch on all trials.

Results

The mean session latency for acquisi t ion and ext inc t ion for both the DMT-damaged and sham-operated groups is shown in Fig. 3. Note that during acquisit ion the 2 groups differed only on the first session. The relatively short latencies during the first session were probably due to the 2 reinforced adapta t ion sessions given on the 2 preceding days. A 2-way analysis of variance, surgery group x sessions, on the mean session latencies during acquisi t ion resulted in bo th a significant session effect , F(4,104) = 16.88, p<0 .001 , and a significant session x surgery group interact ion, F(4,104) = 3.03, p<0.025 . The significant ses- sion effect reflects the decreasing latencies to the sham- operated animals being slower than the DMT-damaged rats during the first session (Newman-Keuls test, p<0 .05) .

While the 2 groups per formed almost identically during the last four acquisi t ion sessions, as can be seen in Fig. 3, they differed considerably during ext inct ion. By the second ext inct ion session the sham-operated rats were running slower than the DMT-damaged rats. While bo th groups ran slower during the last 6 ex t inc t ion sessions than they did during acquisit ion, the DMT-damaged rats showed much greater resistance to ex t inc t ion than did the sham-operated animals. A 2-way analysis of variance, surgery group x

D O R S O M E D I A L T H A L A M I C LESIONS AND M A Z E B E H A V I O R 977

z o u ,H

Z

>.

z I l l

I - -

. d

z i , i

40

30

20

10

ACQUISITION EXTINCTION

[ ] [] "l'halami¢ Lesion

I I I I I I I I I I I I 1 2 3 4 5 1 2 3 4 5 6 7

S E S S I O N

FIG. 3. Mean session latency on runway acquisition and extinction by the DMT-damaged and sham-operated rats.

session, resulted in a significant surgery group effect , F(1 ,26) = 25.45, p<0 .001 , session effect , F(6 ,156) = 21.00, p<0 .001 , and a surgery group x session inter- action, F(6,156) = 9.35, p<0 .001 . Newman-Keuls tests compar ing the ex t inc t ion session means of the 2 groups revealed that the sham-operated rats ran slower on Sessions 2 through 7 than they did on Session 1 and that they ran slower than the DMT-damaged rats on Sessions 2 through 7 (p<0.01 in all cases). Fur ther , a significant negative corre- lation be tween mean la tency on the last ext inc t ion session and amount of bilateral damage to the stria medularis was observed (rho = - . 6 0 , d.f = 11, p<0 .05) . No o ther signifi- cant brain damage-behavior relat ionship was observed on the runway task.

Thus, while the runway s tudy failed to demons t ra te a significant difference be tween the 2 groups on acquisi t ion, except on the first session, it did result in a large difference be tween the 2 groups on ext inct ion. The DMT-damaged animals, part icularly those with bilateral damage to the stria medularis, were much more resistant to ex t inc t ion than were the sham-operated rats.

EXPERIMENT 4: RESPONSE TO A NOVEL ALLEY

One explanat ion of spontaneous al ternat ion is that when conf ron ted with two stimuli , an animal will approach the one which is the most novel, or the st imulus to which it is least habi tuated. Consistent with this no t ion is the observa- t ion that normal and cort ical ly damaged rats both sponta- neously al ternate in a T-maze and enter a novel alley when given the choice of responding to an alley associated with re inforcement , an alley associated wi th nonre in forcement , and a novel alley, while animals with h ippocampal lesions nei ther spontaneously al ternate nor enter a novel alley [ 13]. It has already been demons t ra ted that rats with DMT

lesions fail to spontaneously al ternate. The present experi- ment was conduc ted to determine whether they respond to a novel alley.

Procedure

The test for response to a novel alley was given on the third acquisi t ion trial for the fifth session ( twenty- third trial) in the runway study. On the novel alley test trial the removable endplate of the runway was removed exposing the formerly concealed arm.

R esults and Discussion

Of the 15 animals With lesions in the DMT 6 entered the novel alley before going to the re inforcement arm, whereas 11 of 15 animals in the control group entered the novel alley first. A Fisher 's Exact test revealed that the two groups did not differ significantly (p>0.05) . Thus, while the results of the novel ty exper iment are in the direction of indicating a lesion-induced decrease in response to novel ty, no such conclusion can be made from the present experi- ment .

GENERAL DISCUSSION

The results of the present series of exper iments reveal that rats with lesions of the DMT are slower to habi tuate explora tory responses in a T-maze, have greater resistance to ex t inc t ion o f a runway response, and are less likely to spontaneously al ternate choices in a T-maze than are sham- operated rats. Also, the data suggest that the DMT-damaged rats are less likely to enter a novel alley than are sham- operated rats. Further , the histological analysis suggests that the various DMT structures are not equally involved in the

978 MEANS, H A R R E L L , MAYO A N D A L E X A N D E R

di f ferent behaviora l deficits. More specifically, h a b e n u l a r damage was found to be negat ively corre la ted wi th per cent spon t aneous a l t e rna t ion and stria medular i s de s t ruc t i on wi th resis tance to e x t i n c t i o n of the runway response.

The results of the present series of expe r imen t s , a long wi th earlier observa t ions f rom our l abora to ry [ l 1,12] form a fairly cons i s ten t pa t t e rn . Rats wi th DMT lesions are def ic ient on tasks tha t require t hem to form new associa- t ions or to util ize previously es tabl ished associations. Animals failing to establ ish or to util ize associat ions to novel s t imuli would be expec ted to show slower hab i tua- t ion. In order to a l te rna te choices in a T-maze, an animal , among o the r things, mus t hab i t ua t e to or r e m e m b e r which arm was en tered on the previous trial. Also, if ex t i nc t i on is viewed as learning to wi thho ld a m o t o r response, the observed increased resis tance to e x t i n c t i o n could be viewed as an acquis i t ion deficit .

The of ten observed defici ts in rats wi th DMT damage on the acquis i t ion of avoidance responses [2 ,20] as well as the repor ted deficits on acquis i t ion of d i sc r imina t ion [17] and complex maze p rob lems [3,6] are cons i s ten t wi th the no t ion tha t DMT-damaged animals are def ic ien t in the pe r fo rmance of tasks tha t require e i ther the f o r m a t i o n of new associat ions or the u t i l iza t ion of previous associations. Also, the acquis i t ion deficits observed in cats and m o n k e y s wi th DMT damage (see i n t roduc t i on ) , and the amnes t ic s y m p t o m s observed in Korsakof f pa t i en t s [211 are consis- t en t wi th the defici t pa t t e rn observed in rats.

The only observa t ion in the present series of experi- ments tha t would appear to be incons i s ten t wi th the general pa t t e rn is the normal acquis i t ion of the runway response. It may be tha t DMT damage only affects acquis i t ion on complex tasks, or tasks where s t imulus cond i t ions are changed f rom trial to trial. However, it may also be the case tha t the normal acquis i t ion by the DMT-damaged rats on the runway task was due to the fact tha t DMT-damaged rats are s lower to hab i t ua t e l o c o m o t o r responses in a maze. If

hab i t ua t i on , a decrease in response speed over trials, and acquis i t ion, an increase in response speed over trials, are forms of i ncompa t ib l e learning, a defici t in h a b i t u a t i o n by the DMT-damaged animals could c o m p e n s a t e for a defici t in acquis i t ion, resul t ing in appa ren t no rma l acquis i t ion of the runn ing response. Admi t t ed ly , the la t te r exp lana t ion is speculat ive.

O the r invest igators have found rats wi th DMT damage to be faci l i ta ted on the pe r fo rmance of s imple bar-press responses [1] and normal on the acquis i t ion of fear responses [4 ,13 ] . Faci l i ta ted pe r fo rmance of bar-press responses may be related to an h a b i t u a t i o n defici t . Of course, it may also be the case tha t DMT damage does not affect acquis i t ion of s imple CRF or VI-l rain bar-press tasks [1 ] . Normal a u t o n o m i c fear cond i t ion ing in animals wi th medial tha lamic damage may indicate tha t a u t o n o m i c responses or classical cond i t ion ing is not d is rupted by DMT damage.

The defici t p a t t e rn observed in animals wi th lesions or pa tho logy of the DMT does no t d e m o n s t r a t e tha t the DMT is the unique locus of engrams or of some specific consoli- da t ion or retrieval mechanism. The acquis i t ion and re- t en t i on of a response involves n u m e r o u s in te r re la ted processes including s t imulus regis t ra t ion, a t t e n t i o n to relevant cues, m o t o r selection, conso l ida t ion , and m a n y others . Dis rup t ion of any one or more of these processes could result in a defici t in the f o r m a t i o n or u t i l i za t ion of associat ions. The fact tha t DMT lesions d is rupt perfor- mance of modera t e ly complex choice tasks more than simple bar-press and runway tasks does suggest tha t the DMT-damaged animals may have an a t t e n t i o n defici t . How- ever, wi th the behaviora l and physiological da ta cur ren t ly available, it wou ld seem p rema tu re to suggest a more specific hypo thes i s concern ing the effects of DMT damage. An apparen t ly safe conc lus ion is tha t DMT des t ruc t i on results in defici ts on mode ra t e ly complex tasks requir ing the f o r m a t i o n and u t i l iza t ion of new associat ions.

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DORSOMED1AL THALAMIC LESIONS AND MAZE BEHAVIOR 979

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