Bram Research, 95 (1975) 39-59
39
© ElsevxerSclent~fic Pubhshmg Company, Amsterdam - Printed m The Netherlands
S O M E C O N N E C T I O N S OF T H E E N T O R H 1 N A L ( A R E A 28) A N D P E R I R H I N A L ( A R E A 35) C O R T I C E S OF T H E R H E S U S M O N K E Y Ill E F F E R E N T C O N N E C T I O N S *
G A R Y W VAN HOESEN** AND D E E P A K N P A N D Y A * * Hat yard Nemologlcal Umt, Boston Ctty Ho~pttal, Boston, Ma~s 02118 and Apha~ta Revearch Center, Department o f Neurology, Boston Umverslt ~, Medteal School, Bo vton, Mas ~ 02130 ( U S A ) (Accepted Aprd 3rd, 1975)
SUMMARY
In this investigation the efferent projections of the entorhlnal and prorhmal cortices relative to their sites of termination in the h~ppocampus and fascm dentata were investigated m the rhesus monkey using exper~menta! silver lmpregnatmn methods Contrary to the often c~ted observations of Lorente de N6, all entorhmal areas, including the laterally lying prorhmal cortex, were found to give rise to the perforant pathway, and furthermore, each cytoarchltectomcally defined subarea was found to contribute a umque component These perforant pathway components terminate m d~stlnct regions of the dendritic zones of the fascia dentata granule cell and the hlppocampal pyramidal cell A previously undescnbed projection to the prosublculum and hlppocampus has been found to originate from the prorhlnal cortex which forms the medial wall of the rhmal sulcus along the lateral-most portion of the entorhlnal cortex m the rhesus monkey These results, m conjunction with our previous observations regarding dlfferentml afferents to the entorhmal cortex, indicate that spectfic afferent and efferent connectmns characterize each cytoarchltectomcally definable subareas of this permllocortlcal regmn Additionally, they indicate that the perforant pathway m~ght be conceptualized as the final hnk in a mult~synaptic series of connections instrumental in p r o w d m g the h~ppocampus with potential modahty specific and multimodal input
I NTRODUCTION
In two previous reports22, 24 some of the afferent connections of the entorhmal * A prehmmary report regarding some of the findings described here has been previously pubhshed23 ** Present address Harvard Neurological Unit, Beth Israel Hospital, Boston, Mass 02215, U S A
40 cortex (area 28) originating in cortical areas were described for the rhesus monkey it was emphasized that the entorhmal subareas 28a and 28b each receive afferent input from contiguous levels of the perlrhlnal cortex (area 35). but, in addmon, recel~e unique and direct projections from specific cortical regions of the ventral frontal and temporal lobes Area 28a, lot example, was found to receive projections from Brt~dmann's 5 areas 49 and 27, as well as Bonm and Bailey's 4 area T F - T H In contrast, area 28b was observed to receive projections from Brodmann's area 51 and Bonln and Bailey's area FF A third entorhmal cortex zone (28~) between areas 28a and 28b was found to receive input from both areas T F - T H and 51 No overlap, however, m the distribution of afferent input was observed between the classical subareas 28a and 28b The prorhlnal cortex located on the medial wall of the rhlnal sulcus between the entorhlnal and perirhmal cortices was observed to receive input from all of the afferent sources that project to areas 28a and 28b, and. m addition, from temporal neocomcal areas T G and TE This specificity of afferent projections gives rise to the question o! whether the various subareas of the entorhmal cortex and prorhmal cortex ha~e specific efferent projections as well The efferent projections of the entorhmal cortex were described by Cajal 7 and dlwded into several pathways The largest and most well-known was named the direct t e m p o r o a m m o m c or perforant pathway This system of individual axons and axon bundles leaves the white matter underlying the entorhmal cortex and ascends (perforates) through the presublcular, sublcular, and prosublcular cortices to the hlppccampal fissure From this position, it dJsmbutes fibers to the molecular layers of the hippccampus and fascia dentata Two smaller pathways emanating from the entorhlnal cortex were also described and labeled the temporoalvear and crossed temporoammonlc pathways These entorhlnal cortex efferents, like those forming the perforant pathway, were thought to be intimately related to the hlppocampus and associated structures, but Cajal was uncertain about their exact distribution A fourth unnamed pathway of entorhmal origin was described by Cajal as leaving the general vicinity of the hlppocampus lateral to the inferior horn of the lateral ventricle He suggested that tt entered the strlate body (lateral genlculate nucleus) and corona radlata but again was uncertain of its exact distribution Since Cajal's 7 description of this area, considerable progress has been made by Blackstad 2,a and his colleagues 9,11.15 m further defining the origin and distribution of entorhmal efferents, and especially, those forming the direct temporoammonlc or perforant pathway [:'or example, it has been shown in the rat that areas 28a it and 28b 9 give rise to specific components of the perforant pathway which terminate m distinct zones along the dendrites of the fascia dentata granule cells and the apical dendrites of the h]ppecampal pyramidal cells Unfortunately, little such precise mformation is available regarding the efferent projections of the entorhlnal cortex in primates Adey and Meyer's ~ observations regarding this subject in a green and a rhesus monkey case are d~vergent from our observatmns in the rhesus monkey 2~ "~ and those reported by Hjorth-Simonsen for the rat 9,H Therefore, m this report experimental silver lmpregnatmn observations regarding the efferent connections of the entorhmal and prorhmal cortices are presented for the rhesus monkey, wlth emphasis
41
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on the origin of these projections relatwe to their sites of termination in the fascm dentata and hlppocampus MATERIALS AND METHODS
Sm gtcal and his tologtcal pt ocedm es The histological material was from the brams of 10 young-adult rhesus monkeys each of whom had recewed a unilateral ablat]on of the entorhmal cortex The surg]cal and hlstologzcal procedures for th~s investigation were identical to those previously described 22 and will not be elaborated again The mare d~fference was that to make entorhmal cortex ablations, some mechanical retraction was necessary to expose the ventromedml portions of the temporal lobe Thus, each ablation was accompanied by a ~mall amount of ancdlary damage to the superficml cortical laminae of areas TE and T F - T H As described m the first report of this series, however, large ablations of these
42 regions did not lead to degeneration m the hlppocampus and fascia dentata and it IS unlikely that this unavoidable ablation damage affected the results to be described here z2 Also, it is well-known that the retraction of the temporal lobe can restrict or disrupt the blood supply of the hlppocampus Thus, care was taken to restrict the time of retracnon and no ewdence of lschemlc necrosis in the h~ppocampus was detected for any case
The gross morphology of the htppocampus and fascla dentata tn the rhesus monke) Ontogenenc and phylogenetlc considerations regarding the morphology and localization of the hlppocampus and fascm dentata in the adult rhesus monkey are beyond the scope of this report However, much of the existing literature regarding these structures deals w~th rodents, and therefore some comments relating to these issues are necessary for the monkey Unhke lower species, the hlppocampus and fascia dentata of the rhesus monkey he almost totally caudal and ventral to the dlencephalon Rostrally, they protrude beneath the lateral and basal amygdalold regions, but are largely separated from these areas by the rostral tip of the inferior horn of the lateral ventricle As is dlustrated m Fig 1, these structures at rostral levels undergo a pronounced medial flexure of apprommately 90 ° and a dorsal flexure of about 45 ° relative to the longitudinal axis of the hlppocampus This double flexure contributes to a parnal unrolhng and extrusion of the hlppocampus and fascia dentata from their usual position buried m the hlppocampal fissure Therefore, the rostral portions of these structures can be v~ewed on the external surface of the hemisphere The pornons of the hlppocampus and fascia dentata rostral to the medial flexure have been labeled the uncal extremity, and in transverse planes of section (Fig 2A) these structures appear to have a pa~red counterpart medmlly It is essential to keep in mind that the medml segment represents a more rostral pornon of the hlppocampus and fascm dentata than the lateral segment Th~s w~ll have considerable slgmficance when the connections of these areas are discussed Caudal to the uncal extremity, and extending to a level beneath the splenlum of the corpus callosum, the h~ppocampus and fascia dentata assume the characteristic interlocking 'C' arrangement (Fig 2B-C) with the hIppocampal fissure separating the structures The fascia dentata buckles at numerous points m the mare body so that the deeply staining stratum granulosum ~s irregular At these levels, the fascia dentata partmlly protrudes out of the space between the fimbrm-formx and the external medial lip of the cerebral hemisphere (Fig 1) At the caudal levels of the main body proximal to the splemum, the hlppocampus and fascia dentata again undergo conspicuous medlat and dorsal flexures Further discussion of the morphological pecullarlnes of this area, however, wall not be included here since only the connecnons of the uncal extremity and mare body portions of the hlppocampus and fascia dentata will be described in this report The eytoarehttectome orgamzatton of the hippocampus and fascta dentata m the rhesus monkey The cytoarchltectonic features of the h~ppocampus and fascm dentata m the
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Fig 10 A - D this Illustration partially summarizes the results of this ln,cestlgatlon Vclth respect to the termination zones w~thm the fascm dentata and hJppocampus of the ~arlous entorh]nal cortex efferent projections N o t e the manner m which the ~ a n o u s projection zones fit together See the text for further discussion of this illustration
Case 4, hke cases 1, 2 and 3 had a distract pattern of termination m the supelficml prosub~cular pyramids, as well as along the stratum moleculare-stratum radlaturn junctional zone of the hlppocampal C A l a subsector Since all of the cases described to th~s point contained ewdence of termination m these regions, ~t would be expected that the or)gin of this projection would correlate with ablation damage c o m m o n to all cases The most conspicuous region not accounted for would be the caudal portions of area Pr2 Th~s area was damaged m all cases since the surgical
54 approach to the entorhmal cortex was across this area As shown m Fig 8A-C, however, case 5 had an ablation confined to only this region and gave rise to terminal degeneration m the superficmt pyramids of the prosublcular cortex (Fig 9f) and the stratum moleculare-stratum ra&atum zone of the CA1 a subsector No other evidence of terminal degeneration was observed in either the fascia dentata or hippocampus The &stnbutlon of terminal degeneration m these areas for cases 4 and 5 are compared in Fig 8C(2') It is obwous that the termination zone is similar for these cases These observations suggest that the caudal levels of area Pr2 give rise to a &stmct perforant pathway projection to the prosubiculum and hlppocampus that is d~ssocmble from the projection zones of the classical entorhinal cortex subareas 28a and 28b DISCUSSION
The results indicate that in the rhesus monkey each subarea of the entorhlnal cortex, including area Pr2, gives rise to a speofic component of the perforant pathway which terminates In a distinct zone of the fascia dentata and/or hlppocampus These relationships are summarized in Fig IOA-D Area 28a has been found to project to the m~ddle one-third of the molecular layer of the fascia dentata, the proximal or deep portion of the stratum moleculare of the uncal extremity CA3 subfield, and the CA 1CA3 zone of overlap in the main body portions of the hlppocampus The asterisks in Fig 10A call attention to the fact that continuity between the hippocampal and fascia dentata zones of termination ~s not a constant feature of all hippocampal areas m the rhesus monkey, but only those at rostral or uncal extremity levels In main body levels no contmmty has been observed between these zones even when the entire white matter underlying the entorhmal cortex is also ablated Area 28b (Fig 10B) has been found to gwe rise to projections that terminate selectively m the outer one-third of the stratum moleculare of the f a s o a dentata, the superficial portions of the stratum moteculare of the uncal extremity CA3 subfield, and the full width of stratum moleculare m the rostral portions of the hippocampal mare body The caudal levels of the stratum moleculare of the CA3 subfield were never observed to receive substantial input from the entorhmal cortex m our cases Area Pr2 (Fig 10C) has been found to gwe rise to a &stmct component of the perforant pathway which terminates among the superficml prosublcular pyramids and along the stratum moleculare-stratum r a & a t u m junction of the CA Ia subfield The o n g m for these projections appears to be those levels of area Pr2 contiguous with the entorhmal cortex We cannot, however, rule out an additional contribution from the cortex forming the medml wall of the rhmal sulcus rostral to the entorhmal area Area 281 was not selectwely ablated, however, some references about its projecttons seem possible on the basis of its involvement, or lack of involvement, m larger ablations As indicated m Fig 10D, projections arising from this area appear to terminate m the stratum moleculare of the medial-most CA1 subfield We feel that area 28i also projects to a specific zone m the molecular layer of the fascm dentata between those of the areas 28a and 28b This opinion is based on the observation that following a large area 28a ablation the zone of termination in the fascia dentata never
55 occupies the full width of the middle one-third of the stratum moleculare Similarly, following an ablation of area 28b the zone of termination in the fascia dentata also falls to occupy the full width of the outer one-third of the stratum moleculare Whenever area 281 has also been ablated, however, in combination with either areas 28a or 28b, the pattern of terminal degeneration increases in width Terminal degeneration m only this intermediate zone was observed by Hjorth-Slmonsen 9 m the rat (case S~119, Fig 8b) It is stgnlficant that the ablation causing thls degeneration was locahzed laterally in the ventral portions of area 28a Th~s location in the entorhlnal cortex of the rhesus monkey would correspond to the rostral portions of what we have labeled area 28122 Until th~s area can be selectively studied, this suggested projection m the rhesus monkey should remain in the questionable category as indicated m Fig 10D In F~g 10B, question marks have also been placed in the molecular layers of the sub~culum, prosublculum, and lateral-most subsectors of the hlppocampal CA I subfield The cases prepared for this investigation offer httle defimt~ve mformat~on about the input to the d~stal portions of these zones, although terminal degeneration of apparent ~psdateral origin has been observed In reference to the CA 1a and CA I b zones, heavy terminal degeneration was observed m the stratum moleculare following large ablations m the entorhmal and prorhmal areas which addmonally damaged the paraand presub~cular cortices In these cases the contralateral h~ppocampus contained some evidence of termination in the same zones Th~s projection although small m the primate would appear to be a reflection of Cajal's crossed temporoammonxc pathway which has recently been verified by Steward et al 18 20 in the rat using a variety of experimental techmques Ipsllaterally, the termination is heavy and would appear to reflect the summation of input from the uncal cortex of the contralateral hemisphere as well as input from the parasublcular, presublcular, and rostrally located prorhlnal cortices Ipsllateral input to the CA1 zone in the rhesus monkey does not appear to arise from the preplrlform cortex as has been suggested for the rat 9 This observation is based on two ablations, one of which is described in a previous report z~', where the preplrlform cortex was heavily damaged As recently demonstrated in the rat and cat 21, however, area 51 and/or the amygdalold nuclei m the monkey do appear to contribute some afferents to the molecular layers of the sub~cular and prosublcular cortices Lorente de No 14, on the basis of Golg~ observations, concluded that the laterally lying regions of the entorhmal cortex, including what he erroneously called the area perlrhmalls, give rise to the perforant pathway, and ~t m turn d~str~butes afferents only to the more ventrally located sectors of the h~ppocampus and fascm dentata Our observations m the rhesus monkey do not d~sagree wtth these conclusions, but they strongly indicate that h~s conception of the oNgln of the perforant pathway was far too limited Indeed, the lateral entorhlnal cortex does give r~se to one component of the perforant pathway that, m so far as the hlppocampus is concerned, does project to only the more rostral regions of this structure in the primate homologous with the more ventral components of the structure m carnivores and rodents Additionally this region gives r~se to a previously undescrtbed projection originating m the prorhmal cortex which also forms a component of the perforant pathway
56 The medial entorhmal cortex, according to korente de N614, does not give rl~e to the perforant pathway, but instead, to Cajal's temporoalvear pathway We, hm~ever, have never observed in the rhesus monkey an alvear pathway of entorhmal corte~. o n g m Instead, the authors beheve that both Cajal and Lorente de N6 lnay have m~staken presub~cular efferents, which do join the alveus en route to s~tes of termlnatmn m the hmb~c nucle~ ol the thalamus, for axons hawng entorhmal cortex origin The medial entorhmal cortex m th~s mvest~ganon has been shown to be the source ol one large component of the perforant pathway which terminates selectwely m the hlppocampus and fascia dentata, a finding m total d~sagreement w~th the observatmns of Lorente de N6, as well as with Adey and Meyer's 1 reported confirmation of them using experimental degeneratmn techmques in primate cases Our observations in the rhesus monkey generally support those recently described in the rat o,~x and especially Hjorth-Slmonsen's conclusmn that the e n m e entorhinal cortex gwes r~se to the perforant pathway 9 The specific distribution of the perforant pathway m the rhesus monkey compares most favorably w~th those reported for the rat m the uncaI extremity and rostral mare body levels For example, m these regmns the d l s m b u t m n fields of each subarea neatly fit together to occupy the ennre width of the stratum moleculare for the fascia dentata, as well as for the CA3 subfield of the h~ppocampus As discussed, however, this is not the case at m~ddle and caudal levels of the hippocampus What this ~mphes seems open to speculatmn, but it might suggest that the h~ppocampus m the course of evolution has increased m length, with newer features being added, at least in so far as the h~ppocampus is concerned, behind or caudal to the uncal extremity and rostral mare body p o m o n s When the results regarding d~fferentml efferent projectxons from the entorhlnal cortex to the h~ppocampus and fascia dentata are viewed in the context of earher reports regarding entorhmal cortex afferent connect~ons~,t0,15, iv, ~t ~s obvmus that the dendrmc zones of these structures are potential recipients of input from d~vergent regions of the cerebral mantle including the hlppocampus itself Area 28b, fol example, receives input from the rostral uncal regmn, the caudal orbltofrontal region, and contiguous levels of the penrhmal cortex It m turn projects to the d~stal portmn of the granule cell dendrites of the fascia dentata and the distal portions of the CA3 pyramidal cell dendrites of the hlppocampus Area 28a m the rhesus monkey receives specific afferent input from the neocortex of the caudal parah~ppocampal area, the presublculum, contiguous levels of the perirhmal cortex, and, as shown m the rat, the hlppocampus s It m turn projects selectively to the middle one-third of the dendrmc zone of the fascm dentata granule cell and to the deeper dendrmc zones of the uncal extremity CA3 pyramtds, as well as to the C A I - C A 3 junctional area of the hJppocampal main body Area 281 receives input from sources that project primarily to both areas 28a (area T F - T H ) and 28b (area 51 ), as well as from contiguous levels of the penrhmal cortex It m turn projects selectively to the C A I c subsector of the hippocampus and, possibly, to the dendrmc zone of the fascia dentata granule cell between the area 28a and 28b termination zones Lastly, we would hke to draw special attention to the prorhmal cortex, or that region forming the medial wall of the rhinal sulcus In the rhesus monkey Th~s area
57 receives some input from every afferent source of areas 28a and 28b, as well as from the entire ventral temporal neocortex It projects to the superficial prosublcular pyramids and the C A l a dendritic zone contiguous w~th the point at which their apmal dendrites begin their most prohfic arbor~zatlon Although little Js known of the distribution of the Shaffer collaterals in the primate, if their orgamzatlon is similar to that recently described by Hjorth-Slmonsen 1° in the rat, the prorhlnal projections would partmlly overlap with them We have no m f o r m a t m n regarding the efferents of this area, but the prosublcular cortex m the rat has been said to project directly to the arcuate nucleus of the hypothalamus tv In conclusion, we would hke to re-emphasize that the granule cell of the fascia dentata and the pyramidal cell of the h~ppocampus are potentml recipients of input via multlsynaptm cortlco-cortlcal pathways from a vast expanse of modahty specific and multlmodal association cortex, as discussed in the previous reports in this series Such sources of anatomical input would be predicted by recent physiological findlngs ~ 13 25 These connections m the rhesus monkey would be m harmony with the assertion that one functmn of the h~ppocampus may be to convert momentary sensor~ events into a form of input essential for the effective control of tomc hypothalamlc function 16 Additionally, however, it is well documented that the hzppocampus in higher forms in all hkehhood performs similar functions in respect to numerous types of motivated behavior and some aspects of higher order behavior assocmted with verbal learning and memory The multlsynaptlc pathways that connect the association corttces with the hlppocampus probably underhe these functions Finally, the authors would like to propose that the hlppocampus be viewed m light of this relationship and not simply as a p n m m v e allocomcal region whose functions have been subsumed or overshadowed by the neocortex The former view would emphasize the probable parallel functional evolutmn of this structure with that of neocortex instead of onl) emphasizing the role it may have played originally in the anatomical evolution of neocortex Such a view would also seem necessary to account for the putative hlppocampal complex Involvement in memory processes ACKNOWLEDGEMENTS
We would hke to thank Drs N Geschwlnd and T McLardy for their abiding interest m and encouragement of this research, Dr A Hjorth-Slmonsen for klndl~ providing prepubhcatlon manuscripts of his research findings, Mr V Daforno and Mrs F Small for their histological assistance, and Ms D Hall, K Barry, and Mr L Cherkas for Illustrating and photographic assistance This research was supported by N I H Grants NS 09211 and NS 06209 while G W Van Hoesen was a special postdoctoral fellow (NS 02378) in the Department of Neurology, Harvard Medical School
58 LIST OF ABBREVIA FIONS AB alv fd ff hf hp
= -~ = = =
angular bundle alveus fascm dentata fimbrla-fornlx hlppocampal fissure hippocampus
lpe 1~ pros rs sg sub
~ lamina prmopalls externa -- lateral ventricle -- prosublculum = rhmal sulcus = stratum granulosum =- subiculum
REFERENCES 1 ADEY, W R , AND MEYER, M , Hippocampal and hypothalamJc connextons of the temporal lobe m the monkey, BEam, 75 (1952) 358-384 2 BLACKSTAD,T W , Commlssural connections of the h~ppocampal region m the rat, w~th specml reference to their mode of termination, J comp Neurol, 105 (1956) 417-538 3 BLACKSTAD,T W , On the term¿nation of some afferents to the h~ppocampus and fasoa dentata, Acta anat (Basel), 35 (1958) 202-214 4 BONIN, G VON, AND BAILEY, P , The Neocortex ofMacaca mulatta, Umverslty of Illinois Press, Urbana, Ill, 1947, pp 1-136 5 BRODMANN,K , VerglewhendeLokahsationslehre der Grosshtrnrmde in ~hrenPrmztpten dargestellt aufGrund des Zellenbaues, Barth, Leipzig, 1909, pp 1-324 6 BROWN, K A , AND BUCnWALD, J S , Acoustic responses and plasticity of hmbic units m cats, Exp Neurol, 40 (t973) 608-631 7 CAJAL, S RAMON Y, Studws on the Cerebral Cortex, Yearbook, Chicago, I11,1955, 1-175 8 HJORTH-SIMONSEN,A , Hlppocampal efferents to the ~psdateral entorhmal an experimental study in the rat, J eomp Neural, 142 (1971) 417-438 9 HJORTH-SIMONSEN,A , Pro lections of the lateral part of the entorhlnal area to the h~ppocampus and fasoa dentata, J comp Neurol, 146 (1972) 219-232 10 HJORTH-S1MONSEN, A , Some intrinsic connections of the h~ppocampus m the rat an experimental analysis, J comp Neurol, 147 (1973) 145-162 11 HJORTH-SIMONSEN,A , AND JEUNE, B , Origin and termination of the hlppocampal perforant path in the rat studied by silver impregnation, J eomp Neurol, 144 (1972) 215-232 12 KRETrEK, J E , AND PRICE, J L , ProJections from the amygdala to the penrhmal and entorhmal cortices and the subiculum, Brain Research, 71 (1974) I50-154 13 LIDSKY, T I , LEVINE, M S , AND MACGREGOR, S , JR, Tomc and phasic effects evoked concurrently by sensory stlmuh m hippocampal umts, Exp Neurol, 44 (1974) 130-134 14 LORENTE DE NO, R , Studies on the structure of the cerebral cortex II Continuation of the study of the ammomc system, J Psychot Neurol (Lpz), 46 (1934) 113-177 15 NAESTAO, P H J , An electron microscopic study on the termination of perforant path fibres m the hlppocampus and fascia dentata, Z Zellforsch, 76 (1967) 532-542 16 RAISMAN, G , Some aspects of the neural connectmns of the hypothalamus In L MARTINI, M MOTTA AND E FRASCmNI (Eds), The Hypothalamus, Academic Press, New York, 1970, pp 1-15 17 RAISMAN, G , COWAN, W M , AND POWELL, T P S , The extrinsic afferent, comm~ssural and assooatmn fibres of the hlppocampus, BEam, 88 (1965) 963-996 18 STEWARD, O , COTMAN, C W , AND LYNCH, G S , Growth of new fiber projections in the brain of adult rats re-mnervataon of the dendate gyrus by the contralateral entorhmal cortex following lpsdateral entorhmal leslons, Exp BEam Res, 20 (1974) 45-66 19 STEWARD, O , COTMAN, C W , AND LYNCH, G , Re-estabhshment of electrophysmlog~calty functmnal entorhmal cortex input to the dentate gyrus deafferented by ~psflateral entorhmal lesions innervatlon by the contralateral entorhmal cortex, Exp BEam Re~, 18 (1973) 396-4t4 20 STEWARD, O , COTMAN, C , AND LYNCH, G , The nature of increased hlstochemlcal deposmon of INT formazan m fields of degenerating synaptic terminals, Brain Research, 63 (1973) 183-193 21 VAN HOESEN, G W , AND PANDYA,D N , Projections from the parahlppocampal area to the hippocampus in the rhesus monkey, Anat Rec, 169 (1971) 445 22 VAN HOESEN, G W , AND PANDYA,D N , Some connections of the entorhmal (area 28) and
59 perlrhmal (area 35) cortices of the rhesus monkey I Temporal lobe afferents, Bram Research, 95 (1975) 1-24 23 VAN HOESEN, G W , PANDYA,D N , AND BUTTFRS, N , Cortical afferents to the entorhmal cortex of the rhesus monkey, Science, 175 (1972) 1471-1473 24 VAN HOESEN, G W , PAND'tA, D N , AND BUTTERS, N , Some connections of the entorhmal (area 28) and penrhmal (area 35) cortices of the rhesus monkey II Frontal lobe afferents, Brain Research, 95 (1975) 25-38 25 VINOGRADOVA, O S , Registration of reformation and the hmblc system In G HORN AND R A HINDE (Eds), Short-term Changes in Neural Aettvlt) and Behavior, Cambridge Umverslty Press, Cambridge, 1970, pp 95-140
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S O M E C O N N E C T I O N S OF T H E E N T O R H 1 N A L ( A R E A 28) A N D P E R I R H I N A L ( A R E A 35) C O R T I C E S OF T H E R H E S U S M O N K E Y Ill E F F E R E N T C O N N E C T I O N S *
G A R Y W VAN HOESEN** AND D E E P A K N P A N D Y A * * Hat yard Nemologlcal Umt, Boston Ctty Ho~pttal, Boston, Ma~s 02118 and Apha~ta Revearch Center, Department o f Neurology, Boston Umverslt ~, Medteal School, Bo vton, Mas ~ 02130 ( U S A ) (Accepted Aprd 3rd, 1975)
SUMMARY
In this investigation the efferent projections of the entorhlnal and prorhmal cortices relative to their sites of termination in the h~ppocampus and fascm dentata were investigated m the rhesus monkey using exper~menta! silver lmpregnatmn methods Contrary to the often c~ted observations of Lorente de N6, all entorhmal areas, including the laterally lying prorhmal cortex, were found to give rise to the perforant pathway, and furthermore, each cytoarchltectomcally defined subarea was found to contribute a umque component These perforant pathway components terminate m d~stlnct regions of the dendritic zones of the fascia dentata granule cell and the hlppocampal pyramidal cell A previously undescnbed projection to the prosublculum and hlppocampus has been found to originate from the prorhlnal cortex which forms the medial wall of the rhmal sulcus along the lateral-most portion of the entorhlnal cortex m the rhesus monkey These results, m conjunction with our previous observations regarding dlfferentml afferents to the entorhmal cortex, indicate that spectfic afferent and efferent connectmns characterize each cytoarchltectomcally definable subareas of this permllocortlcal regmn Additionally, they indicate that the perforant pathway m~ght be conceptualized as the final hnk in a mult~synaptic series of connections instrumental in p r o w d m g the h~ppocampus with potential modahty specific and multimodal input
I NTRODUCTION
In two previous reports22, 24 some of the afferent connections of the entorhmal * A prehmmary report regarding some of the findings described here has been previously pubhshed23 ** Present address Harvard Neurological Unit, Beth Israel Hospital, Boston, Mass 02215, U S A
40 cortex (area 28) originating in cortical areas were described for the rhesus monkey it was emphasized that the entorhmal subareas 28a and 28b each receive afferent input from contiguous levels of the perlrhlnal cortex (area 35). but, in addmon, recel~e unique and direct projections from specific cortical regions of the ventral frontal and temporal lobes Area 28a, lot example, was found to receive projections from Brt~dmann's 5 areas 49 and 27, as well as Bonm and Bailey's 4 area T F - T H In contrast, area 28b was observed to receive projections from Brodmann's area 51 and Bonln and Bailey's area FF A third entorhmal cortex zone (28~) between areas 28a and 28b was found to receive input from both areas T F - T H and 51 No overlap, however, m the distribution of afferent input was observed between the classical subareas 28a and 28b The prorhlnal cortex located on the medial wall of the rhlnal sulcus between the entorhlnal and perirhmal cortices was observed to receive input from all of the afferent sources that project to areas 28a and 28b, and. m addition, from temporal neocomcal areas T G and TE This specificity of afferent projections gives rise to the question o! whether the various subareas of the entorhmal cortex and prorhmal cortex ha~e specific efferent projections as well The efferent projections of the entorhmal cortex were described by Cajal 7 and dlwded into several pathways The largest and most well-known was named the direct t e m p o r o a m m o m c or perforant pathway This system of individual axons and axon bundles leaves the white matter underlying the entorhmal cortex and ascends (perforates) through the presublcular, sublcular, and prosublcular cortices to the hlppccampal fissure From this position, it dJsmbutes fibers to the molecular layers of the hippccampus and fascia dentata Two smaller pathways emanating from the entorhlnal cortex were also described and labeled the temporoalvear and crossed temporoammonlc pathways These entorhlnal cortex efferents, like those forming the perforant pathway, were thought to be intimately related to the hlppocampus and associated structures, but Cajal was uncertain about their exact distribution A fourth unnamed pathway of entorhmal origin was described by Cajal as leaving the general vicinity of the hlppocampus lateral to the inferior horn of the lateral ventricle He suggested that tt entered the strlate body (lateral genlculate nucleus) and corona radlata but again was uncertain of its exact distribution Since Cajal's 7 description of this area, considerable progress has been made by Blackstad 2,a and his colleagues 9,11.15 m further defining the origin and distribution of entorhmal efferents, and especially, those forming the direct temporoammonlc or perforant pathway [:'or example, it has been shown in the rat that areas 28a it and 28b 9 give rise to specific components of the perforant pathway which terminate m distinct zones along the dendrites of the fascia dentata granule cells and the apical dendrites of the h]ppecampal pyramidal cells Unfortunately, little such precise mformation is available regarding the efferent projections of the entorhlnal cortex in primates Adey and Meyer's ~ observations regarding this subject in a green and a rhesus monkey case are d~vergent from our observatmns in the rhesus monkey 2~ "~ and those reported by Hjorth-Simonsen for the rat 9,H Therefore, m this report experimental silver lmpregnatmn observations regarding the efferent connections of the entorhmal and prorhmal cortices are presented for the rhesus monkey, wlth emphasis
41
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on the origin of these projections relatwe to their sites of termination in the fascm dentata and hlppocampus MATERIALS AND METHODS
Sm gtcal and his tologtcal pt ocedm es The histological material was from the brams of 10 young-adult rhesus monkeys each of whom had recewed a unilateral ablat]on of the entorhmal cortex The surg]cal and hlstologzcal procedures for th~s investigation were identical to those previously described 22 and will not be elaborated again The mare d~fference was that to make entorhmal cortex ablations, some mechanical retraction was necessary to expose the ventromedml portions of the temporal lobe Thus, each ablation was accompanied by a ~mall amount of ancdlary damage to the superficml cortical laminae of areas TE and T F - T H As described m the first report of this series, however, large ablations of these
42 regions did not lead to degeneration m the hlppocampus and fascia dentata and it IS unlikely that this unavoidable ablation damage affected the results to be described here z2 Also, it is well-known that the retraction of the temporal lobe can restrict or disrupt the blood supply of the hlppocampus Thus, care was taken to restrict the time of retracnon and no ewdence of lschemlc necrosis in the h~ppocampus was detected for any case
The gross morphology of the htppocampus and fascla dentata tn the rhesus monke) Ontogenenc and phylogenetlc considerations regarding the morphology and localization of the hlppocampus and fascm dentata in the adult rhesus monkey are beyond the scope of this report However, much of the existing literature regarding these structures deals w~th rodents, and therefore some comments relating to these issues are necessary for the monkey Unhke lower species, the hlppocampus and fascia dentata of the rhesus monkey he almost totally caudal and ventral to the dlencephalon Rostrally, they protrude beneath the lateral and basal amygdalold regions, but are largely separated from these areas by the rostral tip of the inferior horn of the lateral ventricle As is dlustrated m Fig 1, these structures at rostral levels undergo a pronounced medial flexure of apprommately 90 ° and a dorsal flexure of about 45 ° relative to the longitudinal axis of the hlppocampus This double flexure contributes to a parnal unrolhng and extrusion of the hlppocampus and fascia dentata from their usual position buried m the hlppocampal fissure Therefore, the rostral portions of these structures can be v~ewed on the external surface of the hemisphere The pornons of the hlppocampus and fascia dentata rostral to the medial flexure have been labeled the uncal extremity, and in transverse planes of section (Fig 2A) these structures appear to have a pa~red counterpart medmlly It is essential to keep in mind that the medml segment represents a more rostral pornon of the hlppocampus and fascm dentata than the lateral segment Th~s w~ll have considerable slgmficance when the connections of these areas are discussed Caudal to the uncal extremity, and extending to a level beneath the splenlum of the corpus callosum, the h~ppocampus and fascia dentata assume the characteristic interlocking 'C' arrangement (Fig 2B-C) with the hIppocampal fissure separating the structures The fascia dentata buckles at numerous points m the mare body so that the deeply staining stratum granulosum ~s irregular At these levels, the fascia dentata partmlly protrudes out of the space between the fimbrm-formx and the external medial lip of the cerebral hemisphere (Fig 1) At the caudal levels of the main body proximal to the splemum, the hlppocampus and fascia dentata again undergo conspicuous medlat and dorsal flexures Further discussion of the morphological pecullarlnes of this area, however, wall not be included here since only the connecnons of the uncal extremity and mare body portions of the hlppocampus and fascia dentata will be described in this report The eytoarehttectome orgamzatton of the hippocampus and fascta dentata m the rhesus monkey The cytoarchltectonic features of the h~ppocampus and fascm dentata m the
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Fig 10 A - D this Illustration partially summarizes the results of this ln,cestlgatlon Vclth respect to the termination zones w~thm the fascm dentata and hJppocampus of the ~arlous entorh]nal cortex efferent projections N o t e the manner m which the ~ a n o u s projection zones fit together See the text for further discussion of this illustration
Case 4, hke cases 1, 2 and 3 had a distract pattern of termination m the supelficml prosub~cular pyramids, as well as along the stratum moleculare-stratum radlaturn junctional zone of the hlppocampal C A l a subsector Since all of the cases described to th~s point contained ewdence of termination m these regions, ~t would be expected that the or)gin of this projection would correlate with ablation damage c o m m o n to all cases The most conspicuous region not accounted for would be the caudal portions of area Pr2 Th~s area was damaged m all cases since the surgical
54 approach to the entorhmal cortex was across this area As shown m Fig 8A-C, however, case 5 had an ablation confined to only this region and gave rise to terminal degeneration m the superficmt pyramids of the prosublcular cortex (Fig 9f) and the stratum moleculare-stratum ra&atum zone of the CA1 a subsector No other evidence of terminal degeneration was observed in either the fascia dentata or hippocampus The &stnbutlon of terminal degeneration m these areas for cases 4 and 5 are compared in Fig 8C(2') It is obwous that the termination zone is similar for these cases These observations suggest that the caudal levels of area Pr2 give rise to a &stmct perforant pathway projection to the prosubiculum and hlppocampus that is d~ssocmble from the projection zones of the classical entorhinal cortex subareas 28a and 28b DISCUSSION
The results indicate that in the rhesus monkey each subarea of the entorhlnal cortex, including area Pr2, gives rise to a speofic component of the perforant pathway which terminates In a distinct zone of the fascia dentata and/or hlppocampus These relationships are summarized in Fig IOA-D Area 28a has been found to project to the m~ddle one-third of the molecular layer of the fascia dentata, the proximal or deep portion of the stratum moleculare of the uncal extremity CA3 subfield, and the CA 1CA3 zone of overlap in the main body portions of the hlppocampus The asterisks in Fig 10A call attention to the fact that continuity between the hippocampal and fascia dentata zones of termination ~s not a constant feature of all hippocampal areas m the rhesus monkey, but only those at rostral or uncal extremity levels In main body levels no contmmty has been observed between these zones even when the entire white matter underlying the entorhmal cortex is also ablated Area 28b (Fig 10B) has been found to gwe rise to projections that terminate selectively m the outer one-third of the stratum moleculare of the f a s o a dentata, the superficial portions of the stratum moteculare of the uncal extremity CA3 subfield, and the full width of stratum moleculare m the rostral portions of the hippocampal mare body The caudal levels of the stratum moleculare of the CA3 subfield were never observed to receive substantial input from the entorhmal cortex m our cases Area Pr2 (Fig 10C) has been found to gwe rise to a &stmct component of the perforant pathway which terminates among the superficml prosublcular pyramids and along the stratum moleculare-stratum r a & a t u m junction of the CA Ia subfield The o n g m for these projections appears to be those levels of area Pr2 contiguous with the entorhmal cortex We cannot, however, rule out an additional contribution from the cortex forming the medml wall of the rhmal sulcus rostral to the entorhmal area Area 281 was not selectwely ablated, however, some references about its projecttons seem possible on the basis of its involvement, or lack of involvement, m larger ablations As indicated m Fig 10D, projections arising from this area appear to terminate m the stratum moleculare of the medial-most CA1 subfield We feel that area 28i also projects to a specific zone m the molecular layer of the fascm dentata between those of the areas 28a and 28b This opinion is based on the observation that following a large area 28a ablation the zone of termination in the fascia dentata never
55 occupies the full width of the middle one-third of the stratum moleculare Similarly, following an ablation of area 28b the zone of termination in the fascia dentata also falls to occupy the full width of the outer one-third of the stratum moleculare Whenever area 281 has also been ablated, however, in combination with either areas 28a or 28b, the pattern of terminal degeneration increases in width Terminal degeneration m only this intermediate zone was observed by Hjorth-Slmonsen 9 m the rat (case S~119, Fig 8b) It is stgnlficant that the ablation causing thls degeneration was locahzed laterally in the ventral portions of area 28a Th~s location in the entorhlnal cortex of the rhesus monkey would correspond to the rostral portions of what we have labeled area 28122 Until th~s area can be selectively studied, this suggested projection m the rhesus monkey should remain in the questionable category as indicated m Fig 10D In F~g 10B, question marks have also been placed in the molecular layers of the sub~culum, prosublculum, and lateral-most subsectors of the hlppocampal CA I subfield The cases prepared for this investigation offer httle defimt~ve mformat~on about the input to the d~stal portions of these zones, although terminal degeneration of apparent ~psdateral origin has been observed In reference to the CA 1a and CA I b zones, heavy terminal degeneration was observed m the stratum moleculare following large ablations m the entorhmal and prorhmal areas which addmonally damaged the paraand presub~cular cortices In these cases the contralateral h~ppocampus contained some evidence of termination in the same zones Th~s projection although small m the primate would appear to be a reflection of Cajal's crossed temporoammonxc pathway which has recently been verified by Steward et al 18 20 in the rat using a variety of experimental techmques Ipsllaterally, the termination is heavy and would appear to reflect the summation of input from the uncal cortex of the contralateral hemisphere as well as input from the parasublcular, presublcular, and rostrally located prorhlnal cortices Ipsllateral input to the CA1 zone in the rhesus monkey does not appear to arise from the preplrlform cortex as has been suggested for the rat 9 This observation is based on two ablations, one of which is described in a previous report z~', where the preplrlform cortex was heavily damaged As recently demonstrated in the rat and cat 21, however, area 51 and/or the amygdalold nuclei m the monkey do appear to contribute some afferents to the molecular layers of the sub~cular and prosublcular cortices Lorente de No 14, on the basis of Golg~ observations, concluded that the laterally lying regions of the entorhmal cortex, including what he erroneously called the area perlrhmalls, give rise to the perforant pathway, and ~t m turn d~str~butes afferents only to the more ventrally located sectors of the h~ppocampus and fascm dentata Our observations m the rhesus monkey do not d~sagree wtth these conclusions, but they strongly indicate that h~s conception of the oNgln of the perforant pathway was far too limited Indeed, the lateral entorhlnal cortex does give r~se to one component of the perforant pathway that, m so far as the hlppocampus is concerned, does project to only the more rostral regions of this structure in the primate homologous with the more ventral components of the structure m carnivores and rodents Additionally this region gives r~se to a previously undescrtbed projection originating m the prorhmal cortex which also forms a component of the perforant pathway
56 The medial entorhmal cortex, according to korente de N614, does not give rl~e to the perforant pathway, but instead, to Cajal's temporoalvear pathway We, hm~ever, have never observed in the rhesus monkey an alvear pathway of entorhmal corte~. o n g m Instead, the authors beheve that both Cajal and Lorente de N6 lnay have m~staken presub~cular efferents, which do join the alveus en route to s~tes of termlnatmn m the hmb~c nucle~ ol the thalamus, for axons hawng entorhmal cortex origin The medial entorhmal cortex m th~s mvest~ganon has been shown to be the source ol one large component of the perforant pathway which terminates selectwely m the hlppocampus and fascia dentata, a finding m total d~sagreement w~th the observatmns of Lorente de N6, as well as with Adey and Meyer's 1 reported confirmation of them using experimental degeneratmn techmques in primate cases Our observations in the rhesus monkey generally support those recently described in the rat o,~x and especially Hjorth-Slmonsen's conclusmn that the e n m e entorhinal cortex gwes r~se to the perforant pathway 9 The specific distribution of the perforant pathway m the rhesus monkey compares most favorably w~th those reported for the rat m the uncaI extremity and rostral mare body levels For example, m these regmns the d l s m b u t m n fields of each subarea neatly fit together to occupy the ennre width of the stratum moleculare for the fascia dentata, as well as for the CA3 subfield of the h~ppocampus As discussed, however, this is not the case at m~ddle and caudal levels of the hippocampus What this ~mphes seems open to speculatmn, but it might suggest that the h~ppocampus m the course of evolution has increased m length, with newer features being added, at least in so far as the h~ppocampus is concerned, behind or caudal to the uncal extremity and rostral mare body p o m o n s When the results regarding d~fferentml efferent projectxons from the entorhlnal cortex to the h~ppocampus and fascia dentata are viewed in the context of earher reports regarding entorhmal cortex afferent connect~ons~,t0,15, iv, ~t ~s obvmus that the dendrmc zones of these structures are potential recipients of input from d~vergent regions of the cerebral mantle including the hlppocampus itself Area 28b, fol example, receives input from the rostral uncal regmn, the caudal orbltofrontal region, and contiguous levels of the penrhmal cortex It m turn projects to the d~stal portmn of the granule cell dendrites of the fascia dentata and the distal portions of the CA3 pyramidal cell dendrites of the hlppocampus Area 28a m the rhesus monkey receives specific afferent input from the neocortex of the caudal parah~ppocampal area, the presublculum, contiguous levels of the perirhmal cortex, and, as shown m the rat, the hlppocampus s It m turn projects selectively to the middle one-third of the dendrmc zone of the fascm dentata granule cell and to the deeper dendrmc zones of the uncal extremity CA3 pyramtds, as well as to the C A I - C A 3 junctional area of the hJppocampal main body Area 281 receives input from sources that project primarily to both areas 28a (area T F - T H ) and 28b (area 51 ), as well as from contiguous levels of the penrhmal cortex It m turn projects selectively to the C A I c subsector of the hippocampus and, possibly, to the dendrmc zone of the fascia dentata granule cell between the area 28a and 28b termination zones Lastly, we would hke to draw special attention to the prorhmal cortex, or that region forming the medial wall of the rhinal sulcus In the rhesus monkey Th~s area
57 receives some input from every afferent source of areas 28a and 28b, as well as from the entire ventral temporal neocortex It projects to the superficial prosublcular pyramids and the C A l a dendritic zone contiguous w~th the point at which their apmal dendrites begin their most prohfic arbor~zatlon Although little Js known of the distribution of the Shaffer collaterals in the primate, if their orgamzatlon is similar to that recently described by Hjorth-Slmonsen 1° in the rat, the prorhlnal projections would partmlly overlap with them We have no m f o r m a t m n regarding the efferents of this area, but the prosublcular cortex m the rat has been said to project directly to the arcuate nucleus of the hypothalamus tv In conclusion, we would hke to re-emphasize that the granule cell of the fascia dentata and the pyramidal cell of the h~ppocampus are potentml recipients of input via multlsynaptm cortlco-cortlcal pathways from a vast expanse of modahty specific and multlmodal association cortex, as discussed in the previous reports in this series Such sources of anatomical input would be predicted by recent physiological findlngs ~ 13 25 These connections m the rhesus monkey would be m harmony with the assertion that one functmn of the h~ppocampus may be to convert momentary sensor~ events into a form of input essential for the effective control of tomc hypothalamlc function 16 Additionally, however, it is well documented that the hzppocampus in higher forms in all hkehhood performs similar functions in respect to numerous types of motivated behavior and some aspects of higher order behavior assocmted with verbal learning and memory The multlsynaptlc pathways that connect the association corttces with the hlppocampus probably underhe these functions Finally, the authors would like to propose that the hlppocampus be viewed m light of this relationship and not simply as a p n m m v e allocomcal region whose functions have been subsumed or overshadowed by the neocortex The former view would emphasize the probable parallel functional evolutmn of this structure with that of neocortex instead of onl) emphasizing the role it may have played originally in the anatomical evolution of neocortex Such a view would also seem necessary to account for the putative hlppocampal complex Involvement in memory processes ACKNOWLEDGEMENTS
We would hke to thank Drs N Geschwlnd and T McLardy for their abiding interest m and encouragement of this research, Dr A Hjorth-Slmonsen for klndl~ providing prepubhcatlon manuscripts of his research findings, Mr V Daforno and Mrs F Small for their histological assistance, and Ms D Hall, K Barry, and Mr L Cherkas for Illustrating and photographic assistance This research was supported by N I H Grants NS 09211 and NS 06209 while G W Van Hoesen was a special postdoctoral fellow (NS 02378) in the Department of Neurology, Harvard Medical School
58 LIST OF ABBREVIA FIONS AB alv fd ff hf hp
= -~ = = =
angular bundle alveus fascm dentata fimbrla-fornlx hlppocampal fissure hippocampus
lpe 1~ pros rs sg sub
~ lamina prmopalls externa -- lateral ventricle -- prosublculum = rhmal sulcus = stratum granulosum =- subiculum
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