Lesion studies on the functional significance of the posterior thalamo-mesencephalic tract

Lesion Studies on the Functional Significance of the Posterior Thalamo-mesencephalic Tract

ROBERT THOMPSON, IRENE RICH AND SUSAN K. LANGER Department o f Psychology, Louisiana State Universi ty , Baton Rouge, Louisiana and The Ncuropsychiatric Inst i tute , University o f Cal i fornia Medical Center, Los Angeles , Cal i fornia

There is strong evidence (Ghiselli and Brown, ’38; Lashley, ’35; Layman, ’36; Papez and Freeman, ’30; Thompson and Rich, ’61) that the pretectal area of the rat plays an important role in mediating learned responses based upon vision. Not only do lesions of this region interfere with the retention of brightness and form discrimination habits (Thompson and Rich, ’63), but they seriously impair the postoperative performance of an avoidance conditioned response to photic stimuli (Thompson, ’63a). An intensive investi- gation of this area (Thompson and Rich, ’61) disclosed that the anterior portion of the nucleus posterior thalami may well be the critical subcortical focus for visually guided behavior.z

It has recently been proposed that one route by which visual impulses exert a directive influence on the motor system consists of a caudally oriented pathway extending from the nucleus posterior to the ventral mesencephalon (Thompson, ’63b). According to the work of Papez and Free- man (’30) and Krieg (’47) on the rat, the nucleus posterior projects to the region of the red nucleus and substantia nigra. That this pathway may relate the visual system with the motor syskmi in learned behavior is suggested by several lines of evidence. First of all, transverse knife sections through the pretcctum, presumably cutting this pathway, disrupt the performance of an avoidance conditioned response to light, while longitudinal knife sections through the pretectum are without effect (Thomp- son, Lesse and Rich, ’63). Secondly, lesions of the pretectal area prevent visual impulses from increasing the excitability of the motor cortex (Wall, Remond and Dobson, ’ 5 3 ) . Finally, stimulation of the posterior hypothalamic and ventral mes-

J . COMP. NEUR., 123: 29-44.

encephalic areas produce integrated locomotor responses in anesthetized cats (Waller, ’40), and conversely, destruction of these areas results in either a loss of motor initiative (Collins, ’54; Harrison, ’40; Ranson, ’39; Thompson and Hawkins, ’61) or an obliteration of the locomotor pattern (Hinsey, Ranson and McNattin, ’ 3 0 ) , depending upon the extent of the lesion.

The present study attempted to test three predictions derived from the foregoing conceptualization of the posterior thalamo-mesencephalic tract. These predictions are developed as follows: ( a ) bilateral ventral mesencephalic lesions should abolish previously acquired visual habits, (b ) bilateral pretectal transections should selectively disrupt the performance of visual habits, and finally (c) a unilateral lesion of the nucleus posterior combined with a contralateral lesion of the pentral mesencephalon should impair the retention of visual habits to the same degree as bilateral destruction of the nucleus posterior alone. The experiments described below confirmed each of these predictions.

Adult albino rats of the Harlan strain were used. Forty-two were employed on the brightness discrimination habit, while 64 were involved in the conditioning habit.

MATERIALS AND METHODS

1 This study was supported by grant. 61-2-19 (R-5) from the Department of Mental Hygiene, State of California.

2 The descriptive anatomy dealing with the differ- entiation between posterior thalamic and pretectal structures i s no leqs controversial today than it was at thc time LeGros Clark (’32) wrote his revicw af the mammalian thalamus. No attempt will be made here to resolve this controversy. In the current study, the nucleus posterior thalami will he taken as that part of the thalamus caudal lo the habenulo-peduncu- lar tract whose limits coincide with those described by Gurdjian (’27). The use of the terms “pretectal area” or “pretectum” will denote not only those superficial nuclei classified as pretectal (Kuhlenbeck and Miller, ’421, but the nucleus posterior as well.

29

30 ROBERT THOMPSON, IRENE RICH AND SUSAN K . LANGER

From 4 to 24 hours after learning, the majority of animals were subjected to bilateral subcortical lesions under chloral hydrate anesthesia. Lesions were accomplished by electrocoagulation (constant current of 2 ma passing for 10 to 20 sec through an electrode with 1.0 mm of the tip exposed). In most cases, mesencephalic lesions were made at the level of the third nerve which corresponds to F + 1.5 on the rat atlas of Massopust ('61). A few animals, however, received caudal mesencephalic damage (F + 0.5). Bilateral pretectal transection was accomplished by attaching a small ophthalmic knife to the stereotaxic instrument and inserting it ver- tically through the neocortex to the desired depth (5.5 mm from the cortical surface at F + 3.0). These transections began at approximately 0.5 mm from the midline and extended 2 mm laterally. Following a recovery period of two to three weeks, all subjects were required to relearn the task that was learned preoperatively. If the animal failed to reach the criterion after receiving twice the number of trials that was required in original learning, the postoperative test was terminated. At the conclusion of experimental training, each operated animal was sacrificed with an overdose of Nembutal. The brain was subsequently removed, fixed for 24 hours in 10% formalin. frozen and sectioned either transversely or sagittally at 50 11. Every third unstained section showing the lesion was photographed at 10 X by the method of Guzman-Flores, Alcaraz and Fernandez- Guardiola ('58).

The two-choice brightness discrimination apparatus and the related experimental procedures have already been described (Thompson and Massopust, '60). Briefly, each rat was trained to respond positively to a white card and negatively to an adjacent dark gray card. Six trials were given daily with an intertrial interval of 45 sec. Eleven correct responses within two successive days constituted the criterion of learning. The measure of performance consisted of the total number of errors (approach responses to the dark gray card) preceding the criterion.

The details necessary for the understanding of the conditioning experiments are presented elsewhere (Thompson, '63a).

In this situation, the rat was required to make a jumping response to the onset of a signal in order to avoid shock to the feet. Most of the animals were trained to a visual stimulus (onset of two 100-watt frosted light bulbs). A few animals, however, were trained to the onset of a tonal stimulus (1000c/sec pure tone having an intensity of 96 decibels). Sixteen to 20 trials were given daily with an intertrial interval ranging from 30 to 90 sec. Nine conditioned responses within a series of ten trials on one day constituted the criterion of learning. Errors (non-appearance of the conditioned response) to criterion comprised the measure of performance.

RESULTS

Mesencephalic lesions Visual habits

Table 1 summarizes the means of the original learning and retention scores for the various operated and control groups. The retention measures are expressed in terms of percentage of error savings which relates the individual relearning score with the corresponding original learning score.3 The Mann-Whitney ('47) nonparametric test was used to determine the significance of the group differences in retention scores. These results will be discussed separately in terms of the site of damage.

As noted in table 1 , lesions in the region of the substantia nigra significantly impaired relearning of both the brightness discrimination and avoidance conditioning habits. Figures 1 and 2A illustrate the extent of the largest nigral lesion examined in this experiment. Of special interest is the finding that these lesions have a more marked effect on the retention of the conditioned response. While all six operated animals trained on the brightness discrimination were able to reacquire the habit, two of the three rats sustaining comparable lesions failed to reach the criterion on the conditioning task even after receiving twice the number of trials that was required in original learning .

Substantia nigra.

Per cent Error Savings = 100 x Errors (learning) - Errurs (relearning)

Errors (learning)

THALAMO-MESENCEPHALIC TRACT 31

TABLE 1

Meun learning and retention scores for all groups

Avoidance conditioning

Retention

Brightness discrimination

Retention Group Learning - Learning

% Savings Range errors Range errors % Savings

Control 5

Rostra1 mesencephalon Substantia

ninra 6 Red

nucleus 5 Lateral

teg- rncnturn 4

Supcrior colliculus arid central gray 4

mesencephalon Central

teg- mcntum 6

Lateral tegmentum 5

Caudal

15.4

11.8

15.2

15.5

14.5

10.3

10.4

95.4 85-100 5 31.0 94.0 85-100

30.8** (-50)-75 3

40.8*” 0-80 3

95.0 89-100 3

95.0 90-100 5

25.0 - 50.3”’ ( - 100)-50

54.0 -40.0”” (-100)-80

35.0 91.0 81-100

34.0 99.0 98-100

47.3” 0-100 4 42.2 43.3 0-100

95.6 78-100 3 37.7 97.3 96-98 -

** Significantly inferior to the control group at the 0.01 level. * Significantly inferior to the control group at the 0 05 level.

Inspection of the placements of the lesions revealed that damage to the medial portion of the nigra tended to produce poorer relearning scores than those confined to the lateral portion. This effect is clearly seen in figure 3A which illustrates the locus of damage in two animals trained on the discrimination habit, one attaining the lowest retention score (medial damage) and the other attaining the highest retention score (lateral damage).

It must be emphasized that the majority of rats receiving bilateral nigral lesions did not exhibit any obvious motor deficits at the time of the postoperative test (see section on unilateral lesions). No tremor was ever observed after a recovery period of two weeks. Only one nigral animal tested on the discrimination task showed a locomotor disturbance which involved the use of the hind legs. Those nigral animals tested on the conditioning habit performed the unconditioned response with approximately the same speed and agility

as the controls. Further proof that a peripheral motor impairment was not responsible for the abolishment of the avoidance habit is revealed by the frequent occur- rence of “spontaneous responses” during the course of the relearning test, a spontaneous response being defined as the appearance of the conditioned response during the intertrial interval. Concerning the two nigral animals which failed to reach the criterion postoperatively, the mean number of conditioned responses and spontaneous responses made over the course of relearning was 16% and 41 % , respectively. Since the number of spontaneous responses greatly exceeded the number of conditioned responses, a peripheral motor impairment could not have been a significant factor in preventing recovery of the avoidance habit. Furthermore, since anticipatory “fear” responses (squeaking, abrupt cessation of breathing, orientation toward the top of the box) to the onset of the visual signal were observable on ap-

32 ROBERT THOMPSON, IRENE RICH AND SUSAN K. LANGER

R- 6C

Fig. 1 Camera-lucida drawings of interrupted serial sections (50 ,u) showing extent of bilateral lesions in the ventral mesencephalon. Lesioned areas are enclosed by cross-hatch- ing.

Left Column Right Column Abbreviations:

Rat R-6C. Lesion in the region of the substantia nigra. Rat R-l9C. Lesion in the region of the red nucleus. cg, central gray; DBC, decussation of the brachia conjunctiva; DM, dor-

soinedial thalamic nucleus; fm, fasciculus retroflexus; gm, medial geniculate nucleus; IC, inferior colliculus; in, interpeduncular nucleus; lm, medial lemniscus; mb, mamillary bodies; NP, nucleus pontis; OC, oculomotor nucleus; P. cerebral peduncle; RF, reticular formation; rn, red nucleus; SC, superior colliculus; sn, substantia nigra; 111, third nerve.

Fig. 2

A Rat R-6C. Lesion in the substantia nigra. B Rat R-19C. Lesion in the red nucleus.

Photographs of unstained sections (50 ,u) showing bilateral lesions in the ventral mesencephalon. Lesioned areas are enclosed by interrupted lines.


Fig. 3 Schematic drawings at the level of the third nerve illustrating the placeineiits of lateral (areas enclosed by horizontal lines) and medial (areas enclosed by vertical lines) lesions of the ventral mesencephalon. Medial damage produced a greater retention loss than lateral damage.

A

B C See figure 1 for key to abbreviations.

Medial and lateral lesions of the substantia nigra superimposed on the same section. Medial and lateral lesions of the red nuclcus superimposed on the same section. Stippled region on the right side of the section illustrates the critical area.

proximately half of the relearning trials, a primary sensory deficit is also unlikely.

It is noteworthy to mention that five out of the nine animals suffering damage to the substantia nigra failed to eat (or drink) during the first postoperative week. (Start- ing on the fourth postoperative day, we sustained these animals with daily injec- tions of 20 cm” of 10% dextrose in saline). This aphagia is reminiscent of rats with lateral hypothalamic (Anand and Brobeck, ’51; Teitelbaum and Epstein, ’62; and many others) and pallidal (Morgane, ’61) damage.

Red nucleus. Figures 1 and 2B illustrate the extent of the largest lesion of the rubral area examined in this experiment. As noted in table 1, rubral lesions resulted in retention deficits similar to those produced by nigral lesions. Not only did these lesions cause more marked effects on the conditioning task, but medially placed lesions tended to have more serious conse-

quences than laterally placed lesions (see fig. 3B) .

None of the eight rats sustaining rubral damage manifested any obvious motor defects at the time of the postoperative test. It is interesting to note that the one rat which failed to relearn the avoidance task exhibited considerably more spontaneous responses (36% ) than conditioned responses (15% ), a result which further demonstrates that a peripheral motor disturbance is not critically involved. This animal likewise displayed anticipatory fear responses on about half of the relearning trials. A n additional correspondence between rubral and nigral lesions concerns the incidence of aphagia - three of the eight rubral rats failed to eat for the first postoperative week.

Other mesencephalic lesions. Table 1 shows that rats sustaining dorsal mesencephalic lesions destroying the central gray, lateral tegmentum and superior col-

34 ROBERT THOMPSON, IRENE RICH A N D S U S A N K. LANGER

Fig. 4

See figure 1 for key to abbreviations.

Camera-lucida drawings of interrupted serial sections (50 p ) showing the extent of bilateral damage to the dorsal mesencephalon in Rat R-68C.

liculus were indistinguishable from the controls in retention performance. Figures 4 and 5 illustrate the largest lesion of the dorsal mesencephalon explored in this experiment. This rat earned a retention score of 98% which is well within the range earned by the controls.

In general, damage to the caudal mesencephalon did not appreciably disturb postoperative retention provided that the lesion did not invade the central tegmentum. Figure 6 illustrates the lesions in four animals, three of whom earned excellent retention scores (fig. 6B, C, D) . Rats with central tegmental damage (see fig. 6A) , on the other hand, were significantly inferior to the controls in relearning the brightness discrimination. Two rats with similarly placed lesions were retarded in reacquiring the conditioning habit. Unlike the various operated groups discussed up to this point, all ten rats with central tegmental damage manifested obvious motor disturbances at the time of the postoperative test. Both postural (marked flexion

Fig. 5 Photograph of unstained section (50 p ) showing bilateral damage to the dorsal mesence- Fhalon in Rat R-68C.

of the head to one side) and ataxic (diffi- culties in running and jumping) disturbances were detectable. The interruption of the decussation fibers of the brachium conjunctivum very probably is responsible


Fig. 6 Photographs of unstained sections (50 /A) showing bilateral lesions of the caudal mesencephalon in four rats.

A

B

C Rat R-8C. Lesion immediately caudal to the red nucleus.

D Rat R-6C. Lesion of the dorsolateral tegmentum.

Rat R-28D. Lesion of the central tegmentum.

Rat R-51D. Lesion of the caudal portion of the ventrolateral tegmentum.

for the motor deficit (Carrea and Mettler, '55) and consequent retention loss.

Auditory habit A total of seven rats were trained pre-

operatively to make a jumping response to the onset of a tonal stimulus. Subse- quently, three sustained damage to the substantia nigra, two received rubral lesions and the remaining two suffered damage to the central gray and lateral tegmentum. The latter two animals attained retention scores of 82% and 9076, respectively. In contrast, the five animals sub-

jected to ventral mesencephalic lesions were severely retarded in relearning. No animal earned a retention score in excess of 10%. Thus, it would appear that ventral mesencephalic damage disturbs postoperative performance of non-visual habits as well as visual habits.

Trunsection of the pretectum It was previously reported that trans-

verse knife sections through the pretectum interfered with the performance of an avoidance conditioned response to light (Thompson, Lesse and Rich, '63). This

36 ROBERT THOMPSON, IRENE RICH AND SUSAN K . LANGER

finding was interpreted in terms of the interruption of the posterior thalamo-mesencephalic tract. The current series of experiments attempted to explore the effects of this type of lesion on retention of a brightness discrimination and an avoidance conditioned response to sound.

After acquiring the brightness discrimination habit, seven rats were subjected to bilateral pretectal transection and tested for retention two weeks later. Examina- tion of the lesion placements warranted a separation of the seven animals into two groups. One group ( n = 3 ) sustained transection of the middle portion of the pretectum - the lesion was in the frontal plane immediately abutting the rostra1 bor- der of the superior colliculus (see fig. 7A) . These animals earned retention scores of 60%, 65% and 96%, respectively.

The second group ( n = 4 ) received a lesion lying approximately 0.50 to 0.75 mm anterior to that of the first group. That is, the very anterior portion of the pretectum was transected (fig. 7B) . In contrast to the first group, all four animals attained savings scores in excess of 85%. While the difference in retention scores between the two groups falls slightly short of statis- tical significance ( p = .l 1 for a one-tailed test), i t is in the expected direction when we consider the orientation of the knife sections in relation to the probable trajectory of the posterior thalamo-mesencephalic tract (see fig. 7C). It will be observed that those animals with anterior pretectal incisions (Group 2 ) sustained considerably less damage to this descending projection than those with middle pretectal incisions (Group 1 ) . Furthermore, it will be noted that a middle pretectal transection does not completely sever the entire tract. This would explain why pretectal transection fails to produce as profund a retention deficit as does pretectal electrocoagulation (see Thompson and Rich. '63).

This finding on the possible differential effect of anterior and middle pretectal transections prompted us to reexamine our previous data on these lesions (Thompson, Lesse and Rich, '63) in connection with the retention of an avoidance conditioned response to light. In the study by Thompson, Lesse and Rich, no distinction was made with respect to the level of the pretectal

incision. Of the six animals involved, however, three had sustained an anterior trans- section, while the remaining three had received a middle transection. A comparison of the retention scores earned by these animals definitely disclosed a differential effect, but it was in the direction opposite to that described for the discrimination habit. None of the three rats with an anterior pretectal transection was able to regain the avoidance response to light - all achieved savings scores of - 100%. On the other hand, the three animals with middle pretectal transection, although exhibiting a loss in retention, were able to relearn. Their savings scores ranged from - 20% to 30%. This difference between the two groups is significant at the 0.05 level (one- tailed test). Again, it will be noted that pretectal electrocoagulation leads to more marked effects on the avoidance habit than middle pretectal transection (see Thompson, '63a).

The foregoing results suggest the possibility that two distinct thalamo- mesence- phalic projections may be critical for the maintenance of an avoidance conditioned response, one originating in the nucleus posterior which subserves visual habits only and the other having its origin some- what more rostrad which functions in both visual and non-visual habits. To test this possibility, we compared the effects of anterior and middle pretectal transections on the retention of an avoidance conditioned response to tonal stimuli. Five rats previously trained on the auditory task were found to be seriously impaired in relearning following an anterior pretectal transection. Their savings scores ranged from - 100% to - 20%. Four additional rats with middle pretectal transection, in contrast, earned retention scores in cx- cess of 80%.

These results thus confirm the existence of a second fiber system coursing through the anterior extension of the pretectum which participates in the performance of avoidance conditioned responses based upon visual or tonal stimuli. Quite con- ceivably, this second fiber system repre- sents the thalamo-tegmental projection identified electrophysiologically by Schlag and Chaillet ('63). According to these in- vestigators, this descending system which


$$.. . ...-

Fig. 7 Photographs and schematic drawings of sagittal sections showing placements of bilateral transecting incisions through the pretectum.

A Photograph of unstained section (50 p ) showing a middle pretectal transection. Arrow indicates the direction and depth of the incision.

B Photograph of unstained section (50 p ) showing an anterior pretectal transection. Arrow indicates the direction and depth of the incision.

C Schematic drawing illustrating the proposed trajectory of the posterior thalamo-mesencephalic tract in relation to anterior (Group 11) and middle (Group I ) pretectal incisions. Pretectal incisions are indicated in heavy solid lines.

D Schematic drawing illustrating the proposed trajectory of the medial thalamo-mesencephalic tract in relation to anterior (Group 11) and middle(Group I ) pretectal incisions. Pretectal incisions are indicated in heavy solid lines.

See figure 1 for key to abbreviations.

38 ROBERT THOMPSON, IRENE RICH A N D S U S A N K . LANGER

projects through the anterior pretectum originates either in the medial dorsal thalamic nucleus or in the habenula. We favor the former origin for two reasons. First, bilateral damage to the medial thalamus profoundly upsets postoperative performance of avoidance conditioned responses to either visual or auditory stimuli (Thomp- son, Lesse, and Rich, '63). Secondly, one unique characteristic of rats haviing dorsomedial thalamic lesions is that they exhibit virtually no spontaneous responses during the postoperative test (Thompson, '63a). Of the five rats trained on the auditory task which subsequently underwent anterior pretec tal transection, three exhibited no spontaneous responses throughout the entire relearning session. Figure 7D illustrates the proposed trajectory of this second tract in relation to the incisions performed at the anterior and middle portions of the pretec tum .

Combined unilateral destruction of the posterior thalamic and ventral

mesencephalic areas In the foregoing experiments, two fiber

systems relating the thalamus with the ventral mesencephalon have been reason- ably demonstrated, one possibly taking its origin in the medial dorsal thalamic nucleus and the other originating in the nucleus posterior. Bilateral interruption of these fiber systems either by electrocagula- tion or by incisions has been shown to produce a loss in retention of an avoid-

ance conditioned response to visual stimuli. Further evidence for the involvement of these descending projections would be obtained if a unilateral thalamic lesion COU- pled with a contralateral mesencephalic lesion ( Contralateral Combination Group) would produce a retention deficit comparable to that produced by bilateral thalamic destruction alone, As a control for this surgical design, two additional operated groups have been included. One of these groups sustained unilateral damage to thalamic and mesencephalic structures on the same side (Ipsilateral Combination Group). The second group consisted of those animals receiving a single lesion of either the thalamus or the mesencephalon (Single Lesion Group). In all of these groups, the behavioral test involved the retention of an avoidance conditioned response to photic stimuli.

Table 2 summarizes the original learning and retention scores for all groups. It will be noted that the three main groups are further divided into various subgroups, dif- ferentiated on the basis of the locus of the thalamic lesion. The locus of ventral mesencephalic damage was relatively constant and included destruction of the critical area illustrated in figure 3C.

Contralateral combination. Inspection of table 2 shows that those rats receiving a thalamic lesion on one side and a mesencephalic lesion on the contralateral side were impaired in relearning. The severity of the impairment, however, tended to be re-

TABLE 2

M e a n learning and retent ion scores f o r those groups sustaining various combinat ions of diencephalic and mesencephal ic lesions

Group Learning Retention

% Savings Ranae errors N

Contralateral combination MDN + MES (MDNCNP) CMES NP+MES

Ispislateral combination

2 22.5 - 100 - 4 38.0 ~ 100 - 4 28.8 - 19.0 (-100)-60

(MDN+NP)+MES 3 40.0 19.7 ( - 58)-77 NP + MES 2 33.3 45.0 40-50

Single lesion (MDN+ NP ) 2 28.5 ~~

NP 2 55.0 MES 3 36.7

1 Abbreviations: MDN, medial dorsal nucleus; MES, ventral

80.0 70-90 88.0 83-93 54.3 0-83

mesencephalon; NP, nucleus posterior. ~. ~

-


lated to the locus of the thalamic lesion. Thus, the six animals having lesions destroying either the dorsomedial nucleus to- gether with the nucleus posterior or the dorsomedial nucleus alone were unable to reach the criterion on the postoperative test. This is to be contrasted with the performance of the four animals sustaining thalamic lesions largely confined to the nucleus posterior - three out of the four succeeded in reaching the criterion.

As expected, several rats displayed some motor disturbance as a result of unilateral mesencephalic damage. Flexion of the head, circling and some ataxia were observed in the majority of cases. These disturbances were invariably localized on the side contralateral to the mesencephalic lesion. These motor defects, however, did not seriously interfere with the ability of the animals to perform the unconditioned response. Of the seven rats which failed to relearn postoperatively, all made at least twice as many spontaneous responses (mean of 30.3% ) as conditioned responses (12.7%) during the course of the retention test.

Ipsilateral combination. Reference to table 2 shows that a unilateral thalamic lesion coupled with an ipsilateral mesencephalic lesion was also associated with an impairment in postoperative performance, but the magnitude of the impairment was considerably reduced in comparison to that of the contralateral group described above. It will be noted that the retention deficit was greatest in those animals enduring lesions of the dorsomedial thalamic nucleus.

SingEe lesion. Unilateral destruction of the nucleus posterior did not appreciably affect the retention of the avoidance habit. This finding agrees with that reported ear- lier in connection with visual discrimination performance (Thompson and Masso- pust, '60). Similarly, posterior thalamic lesions which extended rostrally to destroy portions of the medial dorsal nucleus also failed to interfere with the avoidance habit. On the other hand, one of the three rats subjected to unilateral destruction of the ventral mesencephalon had some difficulty in relearning. This animal, however, received the largest midbrain lesion of this particular subgroup.

DISCUSSION

The finding that lesions of the nucleus posterior thalami interfere with visually guided behavior has been difficult to inter- pret on anatomical grounds. According to the available neuroanatomical data, the nucleus posterior receives only a sparse contribution from the optic tract (Hayhow, Sefton and Webb, '62; Lashley, '34; Nauta and van Straaten, '54). Several investiga- tors disclaim the existence of thalamopetal fibers (Combs, '49, '51; Waller, '34), although Krieg ('47) and Papez and Freeman ('30) have observed fibers entering the posterior thalamic radiation from the nucleus posterior. dHollander ('22) showed that an extensive corticofugal fiber system terminates in the nucleus posterior in rabbits and offered what now appears to be an exceptionally acute suggestion that this thalamic nucleus functions as a motor organ and correlative center for the visual system. Clark ( '32) and Combs ('49, '51) have confirmed this cortico-thalamic projection in the rat, but Krieg ('47) main- tains that this projection terminates in the tectum rather than the pretectum. Recipro- cal connections with the nucleus medialis dorsalis, pretectalis, lateralis posterior, parafascicularis, geniculatus lateralis as well as the superior colliculus are evident in normal material (Gurdjian, '27; Kuhlen- beck and Miller, '42; and many others).

Despite the lack of agreement, the nucleus posterior must be strongly linked with both neocortical and subcortical visual structures. This conclusion is based on the repeated observation (Thompson, '63a; Thompson and Massopust, '60; Thompson and Rich, '61) that posterior thalamic lesions produce losses in visual performance which are similar, although not identical, to those following visual cortical ablation. The anatomical relationship existing between the nucleus posterior and the superior colliculus, however, must be of second- ary importance in view of the negative effects ensuing from extensive tectal lesions (Thompson, '63a, '63b).

There is substantially more concordance in the existence of a posterior thalamo-tegmental tract. This tract has been identified in a variety of animals ranging from sub- mammalian species to the primates (see Clark, ' 3 2 ) and even man (Kuhlenbeck

40 ROBERT THOMPSON, IRENE RICII AND SUSAN K. LANGER

and Miller. ’49). In the rat, Krieg (’47) states that the fibers of this tract “con- tinue in the diffuse tegmental nuclei dorsomedial to the nigra as far as the pons” (p. 304). Papez and Freeman (’30) de- scribe this tract as originating in the nucleus posterior and terminating in “the red nucleus or its neighborhood” (p. 427). It must be more than coincidence that the sites to which this tract distributes are enclosed by the critical area shown in figure 3C which summarizes our lesion experiments on the ventral mesencephalon.

Several lines of evidence suggest that this posterior thalamo-mesencephalic tract functions specifically in visually guided behavior. In the first place, electrocoagulation of the nucleus posterior disrupts visual habits but spares auditory habits (Thompson. Lesse and Rich, ’63). Sec- ondly, the present study has shown that transections of the middle portion of the pretectum, presumably cutting this tract, selectively impairs visual performance. Thirdly. bilateral damage to the region of the midbrain to which this tract terminates (red nucleus and substantia nigra) abolishes previously acquired visual habits. In the fourth place, the effects of ventral mesencephalic damage parallel, to some degree, those stemming from posterior thalamic damage. For example. posterior thalamic lesions have a greater deleterious effect on the avoidance habit as contrasted with the discrimination habit (Thompson, ’63a). As shown in the current study. this differential effect was also obtained following mesencephalic lesions. Finally, the effects of combined damage to the right nucleus posterior and the left ventral mesencephalon are similar to those ensuing from bilateral destruction of the nucleus posterior alone.

After reviewing his research on visual discrimination learning in brain-dam- aged rats, Lashley (’50) summarized, “The conduction of impulses is from the retina to the lateral geniculate nuclei; thence to the striate areas, and from them down to some subcortical mechanism (p. 467) .” This subcortical mechanism that Lashley referred to very probably includes the nucleus posterior along with its projection fibers to the ventral mesencephalon. It must be emphasized, however, that this is only

one of several possible routes by which visual impulses can exert a directive influence on the motor system. That at least one additional pathway is involved is indicated by a comparison of the effects of visual cortical and posterior thalamic damage. Complete extirpation of the striate cortex prevents rats from relearning either a visual pattern (Lashley and Frank, ’34) or a successive brightness (Thompson and Malin, ’61) discrimination habit. In contrast, extensive injury to the nucleus posterior allows the rat to regain either habit (Thompson and Rich, ’63). A second difference is found in connection with the retention of an avoidance conditioned response. This habit is grossly impaired by posterior thalamic lesions (Thompson, ’63a j, but only moderately affected by ablation of the striate cortex (Thompson, ’60). On the basis of these and other differences (‘Thompson, ’63a ) , an inverse relationship between these two visual “centers” is evident. It appears that as the visual habit be- comes more perceptually complex - from the onset of a photic stimulus to a pattern discrimination - the nucleus posterior de- creases in importance, and conversely, the visual cortex increases in importance. Thus, the proposed pathway extending from the visual cortex to the nucleus posterior, and thence to the ventral mesencephalon is essential in those situations involving a primitive type of visual percep- tion. More complexly organized visual tasks, on the other hand, may be mediated by a direct cortico-mesencephalic pathway. Anatomical (Valverde, ’62) as well as elec- trophysiological (Jasper, Ajmone-Marsan and Stoll, ’52) studies support the existence of such a connection.

The significance of the ventral mesencephalon in learned behavior can only be speculative at this time. The present study has shown that lesions of the ventral mesencephalon produce behavioral defects which are similar to those following posterior lateral hypothalamic lesions, particu- larly with reference to feeding disturbances and retention deficits (Thompson and Hawkins, ’61). In all likelihood, these two adjacent regions of the brain stem are anatomically continuous (Crosby and Woodburne, ’51; Krieg, ’32; Nauta, ’58) and functionally interrelated (Abrahams,


Hilton and Malcolm, '62; Gellhorn, '61; Magoun, '40; Moruzzi and Magoun, '49). In understanding the role played by the ventral mesencephalon in learning, special cognizance must be given to those studies which have shown that autonomic (Bard, ' 28 ) , defensive (Abrahams, Hilton and Zbrozyna, '60) locomotor (Waller, '40) and eating (Baillie and Morrison, '63) behavior patterns are probably integrated by the posterior hypothalamic and near-by midbrain structures. It is only a short ex- trapolation to the assumption that these areas likewise are essential for the integra- tion of approach and avoidance behavioral complexes involved in simple learning situations, such as the discrimination and conditioning habits studied in this experiment. The elicitation of appropriate response patterns to visual stimuli by the impingement of impulses upon the hypothalamo-mesencephalic area (via the visual cortical-posterior thalamic route) was the thesis of a previous paper (Thompson, '63b).

In the light of our results on knife incisions through the pretectum, the evocation of an avoidance conditioned response must require the function of an additional subcortical mechanism. One of the chief differences between the discrimination habit and the avoidance conditioning habit lies in the fact that the latter is abolished following damage to either the frontal cortex (Pinto-Hamuy, '61 ; Thompson, '63a), midline thalamic nuclei (Cardo, '61 ; Thompson, '63a), medial dorsal thalamic nucleus (Pechtel, Masserman and Schre- iner, '55; Thompson, '63a) or the limbic system (Horvath, '63; Kimura, '58; Peretz, '60; and many others). The discrimination habit remains intact following similar Ie- sions (Thompson, '63b). This differential effect of certain brain lesions on these two habits was further emphasized in the present study in connection with anterior pretectal transection - this lesion failed to alter discrimination performance, but seriously impaired avoidance conditioning performance. According to the recent work of Schlag and Chaillet ('63), an anterior pretectal transection in cats grossly interferes with the production of enduring cortical arousal by stimulation of the midline and intralaminar thalamic nuclei. Since their lesions resided outside of the known ascend-

ing reticular pathways to the diencephalon, Schlag and Chaillet concluded that a descending projection to the tegmentum must exist, originating either in the medial dorsal thalamic nucleus or in the habenula. It is interesting to note that a connection of this sort to the posterior hypothalamus was intimated by a number of investi- gators (Grossman, '58; Peacock and Hodes, '51; Rhines and Magoun, '46) who found that stimulation of the nonspecific thalamic nuclei altered somato-motor activity. It is not improbable, therefore, that the abolishment of avoidance conditioned responses by electrocoagulation of the mesial thalamus or by anterior pretectal transection results from the disruption of a pathway relating nonspecific thalamic activity to the hypothalamo-mesencephalic area.4 Furthermore, the limbic system which is also critical for the performance of avoidance conditioned responses has strong projections to the midline and medial dorsal thalamic nuclei (Guillery, '59; Nauta, '53, '56, '58, '61). In the light of these anatomical and behavioral considerations, it is conceivable that the avoidance conditioned response is elicited and maintained by the convergence of two descending pathways upon the hypothalamo-mesencephalic area, one involving a specific input related to changes in the external environment (sensory system) and the second involving a nonspecific input related to changes in the internal environment (motivational system). The former, in the case of visual conditioned stimuli, includes a pathway from the visual cortex to the hypothalamo- mesencephalic area via the nucleus posterior. The latter may consist of a pathway extending from the limbic structures and orbitofrontal cortex to the mesial thalamus, and thence to the hypothalamo-mesencephalic area. This conceptual model is illustrated in figure 8.

One cannot fail to recognize that this scheme bears a close resemblance to the centrencephalic system of Penfield ('54) and to the cortico-hypothalamic relation- ships stressed by Gellhorn (Gellhorn and

4Since our paper was completed, an excellent demonstration of this descending projection emerged from the recent study of Wells and Sutin ('63) These mvestlgators report that anterior pretectai lesions in cats abolish slow-wave activie in the ventral tegmental area.


Fig. 8 A semidiagrammatic representation of the brain of the rat showing the specific (stippled areas) and nonspecific (horizontally lined areas) systems mediating an avoidance conditioned response to visual stimuli. Evocation and maintenance of the avoidance response occur as a result of the convergence of impulses upon the hypothalamo-mesencephalic area (HMA) from the nucleus posterior thalami and the nucleus medialis dorsalis. The enlarged arrows indicate ascending and descending motor pathways acti- vated by the hypothalamo-mesencephalic area. See text for a further description.

Abbreviations: F. CORT, orbitofrontal cortex; HMA, hypothalamo-mesencephalic area; LS, limbic structures (amygdala, anterior cingulate, hippocampus, septum) ; M.TH, mesial thalamus (midline, inhalaminar and dorsomedial nuclei) ; n, nucleus posterior; V.CORT, striate and peri- striate areas.

Loofbourrow, ’63; Murphy and Gellhorn, ’45) to be implicated in emotional, per- ceptual and learning phenomena. In con- tradistinction to this model is the theory of conditioning advanced by Gastaut (’58) who emphasizes the functional significance of ascending reticular activating systems. Undoubtedly, the cephalically directed reticular formation functions in an important way in the acquisition of conditioned responses (Cardo, ’61). The specific role that it plays, however, may be more related to maintaining the excitability of those structures composing the descending sys-

tems rather than participating in “closure” and “irradiation” phenomena.

SUMMARY

On the basis of previous reports, it was hypothesized that the posterior thalamo- mesencephalic tract which originates in the nucleus posterior and projects to the region of the red nucleus and substantia nigra subserves learned responses governed by visual stimuli. Three lesion experiments using adult albino rats are described which were designed to test the plausibility of this hypothesis. The following results were obtained :

1. Bilateral destruction of the substantia nigra or red nucleus significantly interfered with the relearning of both a brightness discrimination and an avoidance conditioned response to visual stimuli. Medially placed lesions tended to produce greater deficits in relearning than laterally placed lesions. Nigral and rubral damage also impaired the postoperative performance of an auditory habit.

2. Transection of the middle pretectal area, presumably cutting the posterior thalamo-mesencephalic tract, caused disturbances in retention of the brightness discrimination as well as the avoidance response to a visual signal. This lesion, however, failed to affect the retention of the conditioning habit elicited by an auditory signal. Transection of the anterior pretectal area, while leaving the discrimination habit intact, abolished the avoidance response to either visual or auditory cues.

3. A unilateral thalamic lesion coupled with a contralateral mesencephalic lesion produced retention deficits comparable to those produced by bilateral thalamic damage alone. Combined ipsilateral lesions yielded less severe effects and single lesions had virtually no effect.

4. A conceptual model explaining the effects of these lesions on discrimination and conditioning performance is summarized in figure 8.

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Lesion studies on the functional significance of the posterior thalamo-mesencephalic tract