Brain Research, 110 (1976) 57-71

57

~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

C H A N G E S IN T H E D I S T R I B U T I O N OF T H E D E N T A T E G Y R U S ASSOCIATIONAL SYSTEM F O L L O W I N G U N I L A T E R A L OR B I L A T E R A L E N T O R H I N A L LESIONS IN T H E A D U L T RAT

GARY LYNCH, CHRISTINE GALL, GREG ROSE AND CARL COTMAN

Departnwnt o/' Psychobiology, University of Cal(/brnia, lrvine, Cal(f 92 717 (U.S.A.) (Accepted November 17th, 1975)

SUMMARY

The distribution of the dentate gyrus associational system was analyzed in naive adult rats and in those with either unilateral or bilateral lesions of the entorhinal cortex. Horseradish peroxidase histochemistry was used to trace the origin and course of this intrinsic fiber system. The fibers originated in the CA3-4 pyramidal cell field, apparently medial to the origin of the Schaffer collateral system, and followed a trajectory which was essentially identical to that described for this system by Zimmer a6. The associational terminal field occupied the inner 26 ~ of the dentate gyrus molecular layer in normal rats and 35-38 ~ of the normal width of that layer following either ipsilateral or bilateral entorhinal lesion. These measurements are quite similar to those previously obtained on the commissural system terminal field in the normal and partially deafferented dentate gyrus. These results are interpreted to reflect axon sprouting by the associational fibers into the adjacent deafferented dendritic field.

I NTRODUCTION

Collateral sprouting by intact fibers of the peripheral nervous system in regions of partial deafferentation is a well established phenomenon 4,1°,14 and several reports have suggested that an analogous process takes place in the adult brain6,7, 24,27,31. In previous papers we have reported data which indicate that removal of the primary input to the dentate gyrus of the hippocampal formation is followed by extensive growth in the other afferents to that structure, that there are developmental differences in the degree of this growth, and that it results in the formation of functional connections 3,t6,18,19,22,32. In the present paper we report the results of experiments

58 directed at two aspects of "sprouting' m the hippocampus: first, does growth ~akc place in all remaining afferents to the partially deafferented dentate gyrus and sccomt. do the "sprouting" afferenls interact with each other. In many respects the dentate gyrus of the hippocampus is well suited to the study of post-lesion axonal growth. The components of this brain region are remarkably segregated and its anatomy and fiber relationships have been thoroughly described. It is composed of a single layer ofgranule cells whose dendrites ramil} in a uniform relatively cell free molecular layer in which the afferents terminate in discrete lamina. Four sources of afferent input have been identified: (1) the septumea,zs,a°; (2) the regio inferior of the contralateral hippocampus (the commissural system)l,S,ea: (3) the ipsilateral entorhina[ cortex (the temporo-ammonic tract) 1,1~ , and (4) the regio inferior of the ipsilateral hippocampus (the associational system)S,a~L in addition to these extrinsic afferents there are in all probability a number of terminals from local interneurons e. Removal of the entorhinal cortex afferents results in dramatic changes in this orderly arrangement and at least in some cases these changes appear to include axon sprouting. The normally light AChE staining in the deafferented outer molecular layer massively increaseslS,aL an effect that is eliminated by secondary lesions of the medial septal nucleus. A possible explanation for this reaction is a proliferation ol" the cholinergic septal terminals in the deafferented region. The commissural fibers which are normally restricted to the inner molecular layer expand their terminal field and invade the deafferented middle molecular layer. This effect is greater after entorhinal lesions in immature than in mature rats zr 2 rain and rinsed briefly in 30't{, EtOH before being placed in the incubation solution containing 0.1 ';:; benzidine dihydrochloride, 0.031~0 HeOe and 15 °ii EtOH. The incubation solution was prepared fresh and re-used for many sections until signs of precipitation were noted. Sections remained in the benzidine balh for 0.5 1.0 rain, were rinsed briefly in 301:~; EtOH, and were placed into a solution containing 6"~ sodium nitroprusside in 50"/] EtOH for 20 rain. All solutions in this procedure were maintained at 0 :'C except the benzidine which was left at room temperature. From the sodium nitroprusside solution the sections were rinsed briefly in water and mounted onto albumin coated slides from distilled water. The slides were air dried for several hours before being counterstained with safranin-O. RESULTS

In the region of the pipette tip considerable non-specific tissue destruction was found. The pattern of this damage indicated that it was due to the fluid injected rather than to mechanical disruption by the pipette. Surrounding the site of the tip, cells of' all types were densely labeled with HRP. They appeared shrunken and distorted especially in these cases with longer survival times, suggesting that the relatively high H R P concentrations used in this experiment had some toxic effect. Labeled axons were seen to originate from all injections which included cell populations (Lc., the granule and pyramidal cell layers) but not from the dendritic zones which contain the liber tracts of the hippocampus. These findings suggest that the HRP was taken up in the soma and dendrites and transported (or diffused) into their processes but that axonal uptake was minimal. No effort was made to trace uptake and retrograde transport from axon terminals 1~'. The dentate gyrus associational system appears to originate in the hilus of the dentate gyrus since it could only be detected after injections which densely labeled this region. Injections of the dentate gyrus, which involved granule cell layer but not the hilus, resulted in the appearance of label throughout the mossy fiber system but not in the associational system. Injections which included those portions of the regio inferior outside the hilus commonly produced heavy labeling of the Schaffer collaterals and fimbrial efferents but again never in the associational system. Larger injections which included both the hilus and the adjacent CA3 field labelled both the associational projections and the Schaffer collateral system. Fig. I is a low power photomicrograph of the distribution of the dentate gyrus associational system as revealed by the H R P technique. The fibers originate deep in the hilus and possibly the field CA3c, follow the infragranular zone until they reach the end of the internal (superior) wing of the granule cells, and then swing medially into the inner molecular layer. The fibers run medially parallel to the granule cells around the 'V' of the dentate gyrus until they gain the inner molecular layer of the external (inferior) wing of the granule cells (Figs. 2 and 3). A portion of the external innervation may course directly from the hilus around the lateral edge of the

61

Fig. 1. Light and dark field photomicrographs of the dentate associational system labeled with HRP. Above: low power photomicrograph of a coronal section through the dorsal hippocampus. HRP was injected into the hilar region in a more caudal plane 24 h before the animal was sacrificed. Both the associational and mossy fiber systems are labeled. Abbreviations: assoc., associational terminal field; F, hippocampal fissure; GC, granule cell layer; PC, pyramidal cell layer; mf, mossy fiber terminal field. Below: dark field photomicrographic montage of the same section allowing a more co~v~plete visualization of the associational terminal field.

62

Fig. 2. High power photomicrographs of the associational terminal field illustrating the appearance of the peroxidase-positive deposit. The photomicrographs include light (left) and dark (middle) field views of the entire molecular layer with the granule cell layer near the base of the field and the fissure marked by blood vessels at the top of the field (initial magnification :~ I(X)).A higher magnification photomicrograph ( 4 0 0 ) of the same terminal field can be seen on the right; the granule cell layer can be seen at the base of the micrograph. Safranin-O counterstain.

granule cell layer to reach the external associational field 38. Such fibers were seen in some but not all cases in which an external label was present. Occasionally fbers were seen coursing directly through the granule cell layer to gain the inner molecular layer. These fibers could never be followed for more than a few hundred microns (see also refs. 8 and 38). Their occurrence was infrequent enough to discount them as providing a significant contribution to the observed labeled associational field. They were most probably axons of basket interneurons which are known to lie immediately below the granule cell layer within the hilus z. The associational terminal field consistently occupied a discrete narrow zone within the proximal 26 o//o of the molecular layer. The transported label was found over a considerable rostral and caudal distance beyond the plane of the injection (Figs. 2 and 3) covering a much wider range than did the mossy fiberlabel from the same injection. Rostrally, the associational system terminals filled the entire inner molecular layer (Fig. 4) while caudally it was restricted to a narrow band located a short distance above the granule cells. The terminals were found only in the lateral portions of the dorsal leaf in the anterior sections and medially only in the more posterior sections, indicating that the system is organized at an angle to the longitudinal axis of the hippocampal formation. It should be noted that we have made observations following injections at a single level of the rostral hippocampal formation: consequently, the organization of the associational at other septo-temporal levels might be quite different from the description just given. All of these findings are consonant with the very thorough description ol" the associational system given by Zimmera~L The fact that our observations are supportive of Zimmer is of some importance since his use of the Fink-Heimer method necessitated the prior removal of the contralateral hippocampus, so that the denervation produced in the inner molecular layer by the ipsilateral regio inferior lesions would not be contaminated by the cutting of the commissural axons. As Zimmer pointed out, this

63

2

A

C

D

c

F

Fig. 3. Low magnification photomicrographs of a rostrocaudal series of coronal sections through the dorsal hippocampus in which the associational system is labeled with HRP. In 'D' the cell layers and labeled fiber systems are identified with the same abbreviations used in Fig. 1. HRP was injected into the inter-hilar region just below the dorsal leaf of the granule cells approximately at the plane of micrograph 'E'. The labeled terminal field can be seen some distance rostral and caudal to the-zone of incorporation. Note that the associational system can be seen only in the lateral aspect of the dorsal leaf rostrally (A) and fills out medially as one examines progressively more caudal sections. This distribution is more completely illustrated in Fig. 4. In addition, note that the associational field appears thinner and further from the granule cell layer as the sections progress caudally. A faint HRP positive group of fibers extending lateral to the associational label is apparent in F (arrow). This lateral 'wing' was found to contribute to the Schaffer collateral system (refer to Figs. 6 and 7). Initial magnification x 100, safranin-O counterstain. necessary procedure

could alter the distribution

of the associational system via

c o l l a t e r a l s p r o u t i n g . O u r r e s u l t s , h o w e v e r , c o i n c i d e w i t h h i s a n d i n d i c a t e t h a t his d e t a i l e d a n a l y s i s is e s s e n t i a l l y c o r r e c t . Measurements of the percentage of the molecular layer occupied by the associat i o n a l s y s t e m w e r e m a d e a t t h r e e sites o n e a c h o f t h r e e s t a n d a r d a n t e r i o r - p o s t e r i o r

64

Fig. 4. Projection drawings of a series of coronal sections through the hippocarnpus illustrating the distribution of HRP-positive deposit in the associational field following an injection of HRP within the hilus. Small dots indicate the location of transported HRP. Larger dots indicate dense HRP deposit in the area of the injection site. As was seen in Fig. 3 the associational label extends beyond the plane of the injection site. In very rostral sections (upper left) the deposit appears in the dorsal lateral aspect of the dentate and becomes evident in the ventral and medial regions in subsequently more caudal sections, levels (Fig. 5). Only the superior (internal) leaf was analyzed since the width of the inferior (external) leaf molecular layer varied greatly along the mediolateral d i m e n s i o n a n d it was difficult to find c o m p a r a b l e points for each of the rats. Since there was some variance between rats in the a m o u n t of shrinkage caused by fixation a n d individual t r e a t m e n t of tissue sections, we have expressed the m e a s u r e m e n t s in terms of the

Fig. 5. Measurement sites for the data given in Table I. Three standard coronal planes were used spanning a wide rostral (level one) to caudal (level three) extent of the dorsal hippocampus. Measurements were made at three sites on the dorsal (internal) leaf of the dentate gyrus on each plane.

65 per cent of the distance f r o m the granule cells to the hippocampal fissure occupied by the labeled terminals. That is, the distance from the granule cells to the most distal terminals of the associational system was divided by the distance from the granule cells to the hippocampal fissure for each of the standard measurement sites. Using these procedures we arrived at the values presented for the control rats reported in Table I. It can be seen from this table that the associational system occupies 25 27 ~o of the entire molecular layer and that the a m o u n t o f variance between rats was relatively small. Entorhinal lesions produced an outward expansion of the dentate gyrus associational system. When the percentage of the molecular layer occupied by the associational system ipsilateral to the entorhinal lesion was calculated an average value of 42 to was obtained (see the uncorrected values on Table I). However, this last value may be somewhat exaggerated since a bilateral comparison of the measurement sites revealed that the molecular layer was shrunken between 12 and 17°o on the side ipsilateral to the lesion. To correct for this shrinkage in rats with unilateral lesions, we calculated the percentage occupancy of the associational system on the lesioned side by dividing its width by the width of the molecular layer at the h o m o t o p i c point of the contralateral side. Using this correction procedure we found that the associational system had expanded to include 35-38 ~ of the molecular layer (Table I). Note that the degree of outward m o v e m e n t by associational system was relatively constant along both the mediolateral and anterior-posterior extent o f its terminal field. In one rat with a unilateral entorhinal lesion and comparable bilateral labeling o f the associational system it was possible to make direct measurements o f the degree o f expansion. The values obtained at several measurement points were exactly the TABLE 1 T H E PER C E N T O F T H E D E N T A T E G Y R U S M O L E C U L A R CONTROL

RATS AND THOSE WITH

Unlesioned ( N -- 15)

LAYER OCCUPIED

BY T H E A S S O C I A T I O N A L S Y S T E M IN

UNILATERAL AND BILATERAL ENTORHINAL

LESIONS

Unilateral entorhflml lesion ( N - 8)

Bilateral entorhinal lesion (N 6)

Uncorrected

Corrected

Uncorrected

Corrected* *

Level 1

S1 $2 $3

26.1 ( 6)* 27.4 (10) 25.5 (10)

38.0 (6) 38.7 (3) 39.7 (5)

34.3 (5) 38.1 (3) 35.7 (4)

41.1 (4) 38.7 (5) 35.4 (3)

37.6 35.2 31.9

Level 2

SI $2 S3

28.5 (5) 26.7 (9) 25.8 ( 8 )

42.3 (5) 41.6 (4) 39.3 (7)

36.6 (6) 37.3 (7) 35.2 (7)

40.0 (2) 39.0 (6) 38.2 (5)

36.5 35.5 34.7

Level 3

SI $2 $3

26.6 (8) 27.6 (9) 26.3 (10)

41.1 (4) 39.4 (2) 41.7 (5)

34.8 (5) 36.2 (5) 34.3 (4)

38.6 (1) 4O.2 (2) 39.6 (4)

35.1 36.7 36.1

* The numbers in parentheses indicate the number of animals from which measurements were pooled to give these average values. ** Correction factor - --3.5

66 same as those recorded for the group data reported in Table 1. Thus we conclude that entorhinal lesion causes the associational system to expand to 140",i o f its normal width. Since both dentate gyri were deafferented in the experiments with bilateral lesions we could not use the same controls for lesion-induced shrinkage that we had used in the animals with unilateral lesions. Therefore, we first measured the width of the zones o f associational innervation and calculated the percentage occupancy but corrected for the mean a m o u n t o f shrinkage as detected in our unilateral lesion animals. Using these procedures, we found that the a m o u n t o f expansion o f the field corrected and uncorrected t\)r shrinkage was similar to that obtained alter unilateral lesions (Table I). Therefore, we conclude that the extent o f sprouting of the associational system is not influenced by the presence o f the crossed entorhinal projections. DISCUSSION

This study illustrates some advantages and drawbacks to the use o f anterograde transport o f H R P for tracing fiber systems. The major problem o f the procedure is that in some cases it fails to label the terminals o f the system being traced; in the present study for example, we could follow axons f r o m injections in CA3 and the hilus into the fimbria but we were unable to follow them to their termination sites in the contralateral hippocampus (see Lynch et al. 17, for further examples). The possibility that some uptake and transport into axons o f passage occurred has not been conclusively ruled out, but we did not detect any evidence for this in the present study. Again, we made no effort to follow retrograde transport in these studies. On the positive side,

Fig. 6. Schematic drawing of the coronal hippocampal section pictured in Fig. 7. The HRP was injected into the lateral hilus region labeling both CA4 and CA3c. The associational and mossy fiber systems were extensively labeled. The Schaffer collateral system was only partially labeled with HRPpositive deposits evident only in the more distal aspect of the normal Schaffer terminal field on the CA1 pyramidal cell dendrites. The arrow with asterisk serves as a reference point marker for the homotopic point of Fig. 7. Abbreviations as in Fig. 1.

67 the technique is relatively easy to use and allows for very localized injections. More importantly, with some modification 9 it opens the way for correlative light and electron microscopic studies of populations of axons and terminals. As expected, the dentate gyrus associational system proved a difficult subject for experimental neuroanatomy. The proximity of the cells and terminals of this intrinsic projection insured that even the most localized injection would produce damage and background in some portions of its area of innervation. Nonetheless, by using a localized injection in a variety of hippocampal areas we were able to establish that the associational system originated in the hilus and verified the description of its normal trajectory and distribution provided by Zimmer 36. One case which involved a partial Schaffer collateral label deserves particular mention (Figs. 6 and 7). The Schaffer collateral system arises from the hippocampal pyramids of field CA3 immediately lateral to the apparent origin of the associational system. Both lesion and transport studies have shown that the Schaffer system projects to a wide expanse of the ipsilateral CA1 apical dendritic field 12,av. In this particular case a relatively large injection of H R P was made into the hilus, successfully labeling that region and marginal zone just lateral to it. The injection produced transport throughout the associational system but only the most distal portion of the

Fig. 7. Dark field photomicrographic montage of a portion of the hippocampal section drawn in Fig. 6. The labeled mossy fibers (mf) and pyramidal cell layer (Pyr) form an arc near the top of the montage. The Schaffer collateral label (Sch) appears to branch off the associational (assoc) projection, curve around the lateral edge of the hippocampal fissure (F) and transverse a narrow zone within the CAI pyramidal cell dendritic field.

68 normal Schaffer terminal lield showed evidence of transported HRP. t-he pattcH~ ,,H this partiat label suggests a topography of the Schaffer projection in ~which the nio~t medial cells of origin, CA3c, give rise to the most distal CAI innervation. %¥ith at more lateral injection of H R P a fuller terminal field, including the more proxilnal region of the CA I dendrites, shows transport. This observation may indicate that the CA3 cell field innervates the dendrites of the CA I pyramidal cells topographically with the most lateral CA3 cells (CA3a) projecting to the portions of the dendrites closest to the somata and the more medial CA3 (CA3c) cells, projecting to the more distal dendritic field. Following entorhinal lesions, the terminal field of the associational system expands to about 140{',, of its normal size. Zimmer a8 has studied the distribution of the associational system alter entorhinal lesions in neonatal rats and has found a greater degree of expansion on these animals than we have recorded here lk~r adults. Comparable effects have been recorded for the commissural projections to the dentate gyrus following entorhinal lesions in immature and mature rats l'q,ee,:~s. The most economical explanation of these results is that the observed expansion of the associational system is due to some form of collateral sprouting. That is, following entorhinal lesions the axons of the commissural and associational systems send branches which invade the deafferented middle molecular layer and establish terminal fields there: in young rats these collaterals grow further than they do in the adults. A less likely possibility is that dendritic growth plays a role in the expansion of the commissural and associational fields. I f the inner portion of the dendritic tree were to begin growing, or shifting, outwards following entorhinal lesions, it could carry the commissural and associational fibers with it. This seems unlikely since it would require that the outer lengths of the granule cell dendrites be removed since otherwise the molecular layer would expand when in fact it shrinks. Furthermore, the process would still require a proliferation of the commissural and associational projections, since electron microscopic studies of terminal density in the molecular layer after entorhinal lesions show that normal density is maintained throughout the expanded commissural/associational zones (unpublished data). It seems more reasonable to conclude that a sprouting process, analogous to that seen at the neuromuscular junction (see Edds 4 for a review) or superior cervical ganglion l° following partial deafferentation, is responsible for the expansion of commissural and associational systems after entorhinal lesions. In conjunction with our earlier reports these results indicate that every afferent system which borders on or terminates within the outer molecular layer shows marked changes following entorhinal lesions. Histochemical changes are evident in the septal fibers while biochemical studies reveal a probable reaction by the interneuron system. The changes in these systems are consonant with proliferation of their terminal populations but it is also possible that the effects are due to increased enzyme activity rather than sprouting. A crossed entorhinal-dentate gyrus projection becomes evident after ipsilateral entorhinal lesions but interpretation of this result is confused by our recent finding that a very slight previously undetected connection exists in the normal rat a. The fact that this system is readily detected by autoradiographic methods

69 in the deafferented outer molecular layer might indicate that it is increasing its terminal density or that more labeled protein is being transported to the normal population of endings thereby rendering them more evident to the technique. It can be seen that the three systems which normally share the outer molecular layer with the ipsilateral entorhinal projections undergo changes following removal of these last-named afferents, but it is not certain if these changes are reflective of axon sprouting. Recent electron microscopic studies from our laboratory (unpublished data) reveal that the outer molecular layer beyond the zone of the expanded commissural/associational systems is partially repopulated between 10 and 60 days after the entorhinal lesion. This provides further support for the hypothesis that like the commissural and associational systems, the septal, crossed entorhinal and interneuron systems undergo sprouting in response to the entorhinal lesion. However, while some type of response is evident in every afferent remaining to the dentate gyrus, the resultant reorganization of its inputs is ceitainly not random. Comparison of the results of this study with those of our earlier experiments on the commissural system 22 indicate that the commissural and associational systems expand to almost exactly the same degree, that is, to about 140 o/ o/ o f their normal values. We interpret this to indicate that both systems grow outwards until they encounter some 'barrier' located at about 37~o of the distance from the granule cells to the hippocampal fisst:re. The nature of this block remains unknown. Removal of the crossed entorhinal projection in the present study had no effect on the expansions of the associational projections indiating that a 'competition' between these systems cannot be the causal agent. It is still possible that interneuron or septal sprouting might inhibit the growth of associational/commissural inputs; however, it is then difficult to understand why septal and interneuron terminals do not block the expansion of the inner plexus axons into the middle molecular layer. Alternatively, it is conceivable that axonal degeneration or the neuroglial response to it plays a critical role in directing the response of intact fibers and terminals to deafferentation. This is suggested by our observation that persistent degeneration products from the entorhinal lesion occupy the outer molecular layer from a point 40 ~o of the distance from the granule cells to the hippocampal fissure; below this level the degeneration products appear to be rapidly removed 20. In addition, the endogenous population of neuroglia undergoes extensive alteration as the sprouting process proceeds 2°. Regulation of the fiber growth as a consequence of this phenomenon is currently being examined. ACKNOWLEDGEMENTS

Supported by Grants BMS 7202237-2 from NSF and Grants MH 19793-04 from N I M H and NS 11589-01 from N I H to G.S.L. and M H 19691-04 from NIMH to C.W.C.

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Changes in the distribution of the dentate gyrus associational system following unilateral or bilateral entorhinal lesions in the adult rat.

The distribution of the dentate gyrus associational system was analyzed in naive adult rats and in those with either unilateral or bilateral lesions o...
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