crossed corticothalamic and thalamocortical connections of macaque prefrontal cortex

THE JOURNAL OF COMPARATIVE NEUROLOGY 257~269-281(1987)

Crossed Corticothalamic and Thalamocortical Connections of

Macaque Prefrontal Cortex

TODD M. PREUSS AND PATRICIA S. GOLDMAN-RAKIC Section of Neuroanatomy, Yale University School of Medicine, New Haven,

Connecticut 06510 (T.M.P., P.S.G.-R.); Department of Anthropology, Yale University, New Haven, Connecticut 06520 (T.M.P.)

ABSTRACT We have conducted a systematic comparison of the ipsilateral (un-

crossed) and contralateral (crossed) thalamic connections of prefrontal cortex in macaque monkeys, using cortical implants of horseradish peroxidase pellets and tetramethyl benzidine histochemistry to demonstrate anterograde and retrograde thalamic labeling. Contrary to the prevailing belief that thalamocortical projections are entirely uncrossed, our findings indicate that a modest crossed projection to prefrontal cortex arises from the mesial thalamus, principally the anteromedial and midline nuclei. Also, while confirming that corticothalamic projections are bilateral, we found that the pattern of crossed projections differs from that of uncrossed projections. Projections to mesial thalamic nuclei, specifically to the anteromedial nucleus, the midline nuclei, and the magnocellular part of the mediodorsal nucleus are bilateral, the contralateral projection being nearly as dense as the ipsilateral projection. Projections to the parvicellular part of the mediodorsal and ventral anterior nuclei are also bilateral, but the contralateral projection is much weaker than the ipsilateral projection. Prefrontal projections to the reticular nucleus, medial pulvinar, suprageniculate nucleus, and limitans nucleus appear to be exclusively ipsilateral.

These results indicate that prefrontal cortex has prominent bilateral and reciprocal connections with the nuclei of the mesial thalamic region. As this region of the diencephalon has been implicated by anatomical and behavioral studies in memory functions, our findings suggest that prefrontal cortex, through its connections with this region, may be involved in the bilateral integration of mnemonic systems.

Key words: mediodorsal nucleus, anterior nuclei, midline nuclei, nonspecific thalamus, primate cortex

Functional interpretations of the relationship between the thalamus and cortex in mammals typically emphasize the ipsilateral (uncrossed) and reciprocal organization of thalamocortical and corticothalamic projections (e.g., Ec- cles, '84; Jones, '81; Steriade and Deschenes, '84). A full account of forebrain organization, however, must also con- sider the role of contralateral (crossed) connections between the cortex and thalamus. Anatomical studies have clearly demonstrated crossed corticothalamic projections in primates (Akert and Hartmann-von Monikow, '80; Akert et al., '79; Arikuni et al., '83; Campos-Ortega and Cluver, '69; DeVito, '69; Goldman, '79; Jurgens, '76; Kiinzle, '76, '78; Kuypers and Lawrence, '67; Wiesendanger and Wiesendan-

ger, '85) as well as in carnivores and rodents (literature reviewed by Molinari et al., '85). While commonly reported, crossed corticothalamic projections have nevertheless received little systematic investigation, and their anatomical distribution and contribution t o forebrain function are poorly understood. Current evidence suggests that the ipsilateral and contralateral corticothalamic projections are organized somewhat differently. For exampIe, following injections of tritiated amino acids in macaque prefrontal cortex, Goldman ('79) found label in the contralateral

Accepted August 14, 1986.

0 1987 ALAN R. LISS, INC.

270 T.M. PREUSS AND P.S. GOLDMAN-RAKIC

mediodorsal and central densocellular nuclei, but not in the contralateral reticular, ventral anterior, or pulvinar nuclei, structures that receive dense ipsilateral projections from prefrontal cortex.

Whereas bilateral corticothalamic projections are now well established, modern studies have affirmed with virtual unanimity the strictly ipsilateral organization of thalamic projections to the cortex. Nonetheless, following unilateral injections of horseradish peroxidase (HRP) in macaque prefrontal cortex we have observed labeled thalamic cells that, although lying close to the midline, are clearly located in the contralateral thalamus. Our observations are consistent with recent incidental reports of crossed projections from midline thalamic nuclei to motor cortex (Jurgens, '82) and prefrontal cortex (Asanuma et al., '85) in primates.

The present investigation had two principal goals. The first was to establish with greater certainty the nature of the difference between the crossed and uncrossed projections to the thalamus arising from primate prefrontal cortex. The second was to document the existence of a bilateral thalamocortical projection. In order to label as nearly as possible all the afferent and efferent thalamic connections of prefrontal cortex, we used cortical implants of acrylamide-gel pellets containing HRP and reacted the tissue with the tetramethyl benzidine (TMB) chromagen. Acrylamide- gel pellets produce slow and continual release of HRP and enhanced anterograde and retrograde transport of the enzyme (Griffin et al., '79; Leichnetz, '82), while TMB (Mesu- lam, '78, '82) dramatically improves the resolution of transported HRP compared to the diaminobenzidine (DAB) chromagen used in many of the published studies of thalamocortical projections.

MATERIALS AND METHODS Our conclusions are based on findings obtained in four

macaque monkeys with implants of HRP pellets in the prefrontal cortex. Case 1 was an adult, female, crab-eating (cynomolgus) macaque (Macaca fascicularis). Cases 2 and 3 were adult, male, crab-eating macaques. Case 4 was a 6- month-old infant, male, rhesus macaque (Macaca mulatta). Monkeys received implants of two to eight HRP pellets in the left hemisphere. Pellets, measuring approximately 0.5 mm in diameter and 1-2 mm in length, were prepared according to the method of Griffin et al. ('79) using free HRP (Sigma).

The animals were killed after a 2-day survival period. Under deep anesthesia, the monkeys were perfused through the heart with a phosphate-buffered 0.9% saline solution (pH 7.4, 37°C) until the perfusate ran clear of blood, fol- lowed by 1,200-1,600 ml of a buffered aldehyde fixative solution (pH 7.4,37"C) consisting of 1.0% paraformaldehyde and 1.25-2.5% glutaraldehyde. Following fixation, animals were perfused with a series of buffered sucrose solutions (pH 7.4, 4°C) of increasing concentration in order to flush the fixative and reduce freezing artifact during sectioning. Brains were then removed, blocked, and set in a 20-30% sucrose solution (at 4 "C) overnight prior to sectioning.

Brains were frozen sectioned a t 40-50 pm, and sections were treated with tetramethyl benzidine (TMB) according to a modification of the Mesulam ('78) protocol. At least one section in every twelve through the frontal lGbe and one section in ten through the thalamus was treated. In Cases 1,2, and 3, a series of sections through the injection site was reacted with diaminobenzidine (DAB). Sets of adjacent, un- reacted sections were stained with thionin or cresyl violet

for cytoarchitectonic evaluation of thalamic labeling. Also, selected TMB-reacted sections were counterstained with neutral red for examination of cytoarchitecture.

Sections were examined microscopically under brightfield and darkfield illumination. The frontal areas included in the injection sites were determined by comparison to the macaque cytoarchitectonic map of Walker ('40). Labeled thalamic nuclei were named according to the macaque atlas of Olszewski ('52). For purposes of description, the thalamic reticular nucleus and habenula will be considered together with the dorsal thalamus, although they are de- rived from the subthalamus and epithalamus, respectively. Also, we will use the term "nonspecific" to refer to the midline and intralaminar thalamic nuclei, and "specific" to refer to the sensory, motor, and associational nuclei.

RESULTS Injection sites

The use of slow-release pellets resulted in diffusion of HRP over extensive regions of cortex. We considered the effective injection site to be the area of cortex in which the concentration of TMB reaction product was sufficient to render the cortex opaque or black under brightfield illumination, obscuring labeled axons and perikarya (Mesulam, '82). Estimated injection sites obtained with this criterion were more conservative than those obtained with DAB, the dense TMB zone being considerably larger than the region which contained the core and halo of DAB reaction product. The dense TMB zone was surrounded by a region of lighter, diffuse reaction product.

Injection sites are illustrated in Figure 1. In Case 1, in which two pellets were placed in the ventral rim of the rostral principal sulcus, the injection site included rostral portions of the lateral, medial, and orbital cortex. In Case 2, with two pellets placed near the orbital margin, the injection site covered the lateral part of the orbital surface and much of the cortex ventral to the principal sulcus on the lateral surface. There was no spread of HRP into the medial cortex in this animal. Four pellets were implanted at the dorsomedial margin of the frontal lobe in Case 3, and the injection site included the frontal pole, much of the cortex dorsal to the principal sulcus, and the medial cortex. In Case 4, a total of eight pellets were implanted, five in the dorsal rim of the principal sulcus along its entire length and three in the ventral rim of the sulcus. The injection site included mainly the cortex within and surrounding the principal sulcus, although there was also some involvement of lateral orbital cortex. Only light, diffuse reaction product was found in the medial cortex.

In Cases 1 and 3 the estimated injection sites included the rostral portions of cingulate cortex to varying degrees in addition to prefrontal cortex. In Case 3, in which pellets were placed mesially, the presence of a small amount of diffuse reaction product in the contralateral ventromedial cortex raised the possibility that HRP may have spread to the opposite hemisphere, although this observation is also consistent with anterograde transport from the injection site. In any event, the absence of retrograde label in the mediodorsal nucleus of the contralateral thalamus indi- cates that HRP was not transported from this region.

Thalamic labeling Antemgrade and retmgrade labeling of the ipsilateral

thalamus. In spite of differences in the location of injections, the distribution of labeled cells and fibers in the

CROSSED PREFRONTOTHALAMIC CONNECTIONS 271

Abbreviations

AD AM AS AV Cd Cdc CeM Cif Cim CGS CL Clc CM cs Csl for GM hc HL HM HYP 1c IAM itp LD Li

anterodorsal nucleus anteromedial nucleus arcuate sulcus anteroventral nucleus caudate central densocellular nucleus central medial nucleus central inferior nucleus central intermediate nucleus cingulate sulcus central lateral nucleus central latocellular nucleus centromedian nucleus central superior nucleus central superior lateral nucleus fornix medial geniculate nucleus habenular commissure lateral habenular nucleus medial habenular nucleus hypothalamus internal capsule interanteromedial nucleus inferior thalamic peduncle lateral dorsal nucleus limitans nucleus

LP lateral posterior nucleus LS lateral sulcus MD mediodorsal nucleus MDdc mediodorsal nucleus, densocellular part

MDmc MDmf MDpc mtt Pac PC Pcn Pf PI PL PM PO PS Ret Reu Sf

mediodorsal nucleus, magnocellular part mediodorsal nucleus, multiform part mediodorsal nucleus, parvicellular part mammillothalamic tract caudal paraventricular nucleus posterior commissure paracentral nucleus parafascicular nucleus inferior pulvinar nucleus lateral pulvinar nucleus medial pulvinar nucleus oral pulvinar nucleus principal sulcus reticular nucleus reuniens nucleus subfascicular nucleus

Sg suprageniculate nucleus sm stria medullaris st stria terminalis VA ventral anterior nucleus VAmc VApc VL ventral lateral nucleus VLc VLm VLo VPI ventral posterior intermediate nucleus VPLc VPLo VPM ventral posterior medial nucleus

ventral anterior nucleus, magnocellular part ventral anterior nucleus, parvicellular part

ventral lateral nucleus, caudal part ventral lateral nucleus, medial part ventral lateral nucleus, oral part

ventral posterior lateral nucleus, caudal part ventral posterior lateral nucleus, oral part

CASE 1

Fig. 1. Injection sites in the frontal cortex of four macaque monkeys obtained with slow-release HRP pellets. The region of cortex containing dense tetramethyl benzidine (TMB) reaction product, which we regard as the effective injection site, is indicated by dark hatching. Cortex containing lighter, diffuse reaction product is indicated by light cross-hatching. In all cases, pellets were implanted in the left hemisphere only. In Case 1, the dense TMB zone includes Walker’s area 10 at the frontal pole, rostra1 parts of areas 46 and 9 on the lateral surface, areas 11 and 12 on the orbital

surface, and area 25 on the medial surface. In Case 2, the injection site is centered in area 12 at the orbital marpin, but also involves ventral area 46 in and around the principal sulcus, as well as areas 11 and 13 on the orbital surface. The injection site for Case 3 covers virtually all of Walker’s areas 9 and 10 along with portions of areas 46, 12, 11, 25, and 24. In Case 4, the injection site is centered on the principal sulcus (Walker’s area 46), spread- ing into adjacent parts of areas 9,11, and 12.

272

Antetograde

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T.M. PREUSS AND P.S. GOLDMAN-RAKIC

Retrograde

B

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Fig. 2. Coronal sections depicting labeling at seven levels (A-G) through the rostrocaudal extent of the thalamus in Case 3. Anterograde labeling (left) is represented by stipple, retrogradely labeled cells (right) by large

dots. Each dot represents two t o three cells. In this and all subsequent figures, the left side of the brain is ipsilateral to the cortical injection.

CROSSED PREFRONTOTHALAMIC CONNECTIONS

Anterograde 273

Retrograde

E

F

Figure 2 continued

ipsilateral thalamus was similar in the four cases, the differences between cases being evident mainly in the location of label within particular nuclei. In addition, the pattern of thalamic labeling in the ipsilateral thalamic nuclei was largely consistent with that found in previous studies of primate prefrontothalamic connectivity (see Discussion). Retrograde and anterograde labeling were densest in the mediodorsal nucleus (MD), with dense label also occurring in the ventral anterior nucleus WA), particularly its medial, magnocellular division (VAmc), as well as in the anteromedial (AM) and medial pulvinar (PM) nuclei (Fig. 2). In addition, retrograde and anterograde label were consistently found in other specific nuclei, including the anteroventral (AV) and medial part of the ventral lateral (VLm) nuclei; in the paracentral (Pcn), parafascicular (m, suprageniculate (Sg), and limitans (Li) nuclei of the intralaminar and posterior groups; and in the central densocellular (Cdc),

central superior (Cs), central superior lateral (Csl), central latocellular (Clc), central intermediate (Cim), central inferior (Cif), and reuniens (Reu) nuclei among the midline group. In Case 3, labeling was also observed in the caudal paraventricular nucleus (Pac). The thalamic reticular nucleus (Ret) was always well labeled anterogradely, but contained no labeled cells.

In addition, two structures not generally recognized as having prefrontal connections were lightly labeled in all cases. Retrograde and anterograde label was present in a region immediately subjacent to the reuniens and parafascicular nuclei which evidently corresponds to the subfascicular (Sf) nucleus. Also, anterograde label was found in an epithalamic structure, the lateral habenula (HL).

Antemgrade labeling of the contralateral thalamus. A major result of this study is that in the hemisphere contralateral to the injection, anterograde label was found in

274 T.M. PREUSS AND P.S. GOLDMAN-RAKIC:

eral AM was in all cases very nearly comparable to the density of ipsilateral AM labeling (Fig. 3B). The density of AM labeling (in both hemispheres) varied markedly between cases, being very heavy in Cases 2 and 4, and much lighter in Cases 1 and 3.

Label was consistently observed in the contralateral midline nuclei. The heaviest labeling occurred rostrally, in Cdc, Clc, and Reu. Bilateral anterograde labeling of Cdc and Reu commonly took the form of symmetrical crescents surrounding a lens-like region of sparse labeling centered at the midline (Fig. 5). Anterograde label was also observed in contralateral Cif, Cim, Cs, and (in Case 3 only) Pac.

In addition to the labeled nuclei listed above, modest labeling was observed in VAmc and AV, and in medial parts of Pf, Pcn, and Sf. No anterogradely transported label was found in the contralateral Ret, PM, VLm, Sg, or Li.

Fiber pathways to the contralateral thalamus. The massa intermedia is evidently a major decussation of prefrontothalamic fibers. Anterograde labeling traversed the midline in the thalamus, in some regions taking the form of distinct bands. These bands were observed dorsally, at the level of AM and Cdc, particularly in the region where these nuclei appeared fused or cytoarchitectonically continuous at the midline (Figs. 2B,4); at mid-thalamic levels in

many, but not all, of the same nuclei that were labeled in the ipsilateral hemisphere. MD was always labeled contra- laterally, but there were striking differences in the density of labeling of MDmc and MDpc. In all cases, contralateral MDmc was heavily labeled and MDpc lightly labeled even though both subdivisions of MD were very heavily labeled ipsilateral to the injection (Figs. 2, 3A). In addition, there were differences in the density of contralateral MDmc labeling among the four cases. In Case 2, labeling of the medial, magnocellular part of the contralateral MD reached a density comparable to that found in the ipsilateral MDmc (Fig. 3A), although the densely labeled portion of MDmc was more restricted anteroposteriorly in the thalamus contralateral to the injection than ipsilaterally. In the other three cases, MDmc labeling was markedly weaker in the contralateral than in the ipsilateral thalamus, but was still very prominent.

The AM nucleus was also a major target of crossed prefrontothalamic projections. Anterograde label was found thoughout the mediolateral extent of the contralateral AM, including both its ventromedial (densocellular) and dorsolateral (latocellular) subnuclei, but was restricted in anteroposterior extent compared to the ipsilateral nucleus. In contrast to MD, however, the density of label in contralat-

Fig. 3. Low-power darkfield photomicrographs of thalamic labeling in Case 2. In this case, the plane of section was slightly oblique and passed through the left thalamus more rostrally than through the right thalamus. A: In the left thalamus, ipsilateral to the injection, anterograde label is dense in both MDpc and MDmc. In the contralateral MD, however, dense anterograde labeling is restricted largely to MDmc, with the exception of a small focus of dense label in the extreme ventromedial portion of MDpc, which may include labeled fibers traversing MDpc to the overlying part of MDmc. Thus, the prefrontal projection to MDmc consists of strong ipsilat-

eral and contralateral components, while the projection to MDpc consists of a strong ipsilateral and a weak contralateral component. Although labeling of the contralateral MDmc was especially prominent in Case 2, in all cases contralateral MDmc labeling was stronger than MDpc labeling (see, e.g., Fig. 2C-F). B: Bilateral anterograde labeling of AM. This section is just caudal to the level at which the AM nuclei are fused at the midline (compare Fig. 4). Heavy labeling is present in both hemispheres; the appearance of stronger labeling of the dorsolateral part of the right AM compared to the left AM is due to the asymmetry of the plane of section.


Fig. 4. Darkfield (A) and brightfield (B) photomicrographs of a section in Case 4 demonstrating bilateral labeling of AM. At this level the AM nuclei are fused at the midline and anterograde label is continuous across the midline. The location of the midline is indicated by a relatively label-sparse zone a t the level of AM and by a biconcave pattern of anterograde label in

Cdc just ventral to AM. Labeled cells, including some in which the perikarya are completely filled with reaction product, are restricted to the ventromedial part of the right AM but are more widely distributed in the left AM.

Cif and the adjacent, ventral part of Cim; and ventrally, at the level of Reu (Fig. 5B). Label was also continuous across the midline at other levels, particularly the dorsal part of Cim, although it did not take the form of distinct fascicles. By contrast, it appears that few if any crossed prefrontothalamic fibers travel in the large commissures of the forebrain, as we observed no labeled fibers descending from the corpus callosum in the internal capsule contralateral to the injection or in the anterior commissure.

Caudal to the interthalamic adhesion, where the third ventricle broadens, anterograde label in ipsilateral HL, MD, and H appeared to be continuous with label in the dorsal part of the habenulopeduncular tract (Fig. 2F). Thus, it is possible that cortical fibers entered the ipsilateral thalamus and epithalamus through the mesencephalon via the habenulopeduncular tract. Projections to the contralateral thalamus and epithalamus may follow a similar course, as we observed very light labeling of the contralateral habenulopeduncular tract, HL, and posterior MD. However, we were not able to follow labeled fibers from the habenulopeduncular tract to these nuclei. No labeled fibers were observed in the stria medullaris of either hemisphere.

Retmgrade labeling of the contralateral thalamus. Our results clearly indicate the existence of a crossed thalamocortical projection. In contrast to anterograde labeling, cell labeling in the contralateral thalamus was much more restricted: labeled cells were found primarily in the mesial part of AM and in the midline nuclei. Although it was not always possible to determine whether a particular labeled neuron in the medial thalamus was ipsilateral or contralateral, because the location of the midline could not always be accurately determined, labeled cells were commonly found in association with paired foci of anterograde labeling centered on the midline (Figs. 4,5); in such cases it was evident that cell labeling was present on both sides of the midline.

Thus, labeled cells in contralateral AM were always concentrated near the midline in association with a dense focus of anterograde label, facing a similar region of retrograde and anterograde label in the ipsilateral AM across a distinct label-sparse gap (Fig. 4). The region of AM labeled in the contralateral thalamus corresponds, at least in part, to the densocellular AM subnucleus of Olszewski (’52). 01- szewski described this as the “basal, unpaired portion,” of


Fig. 5. Darkfield photomicrographs of retrograde and anterograde labeling of the midline nuclei. A The central densocellular (Cdc) nucleus in Case 2. B: The reuniens (Reu) nucleus in Case 4. Arrows indicate the approxi- mate location of the midline. Anterograde label in Cdc and Reu forms a distinctive biconcave or double-crescent pattern around the midline. Note

also the continuity of anterograde label across the midline as the crescents meet dorsally and ventrally. Labeled cells are present on both sides of the midline, although they are more numerous ipsilateral to the injection. In B a group of labeled cells in the paracentral nucleus (Pcn) appears to be continuous across the midline dorsal to Reu.

AM, meaning that the densocellular subnuclei of each thalamus are fused at the midline to create an unpaired structure. (Densocellular AM probably corresponds to part of the “interanteromedial” [IAM] nucleus described by other workers.’) However, labeled cells were sometimes observed in contralateral AM in sections in which the nucleus did not appear to be fused or continuous at the midline (Fig. 3). It is therefore unclear whether retrograde labeling was confined to densocellular AM or extended for some distance into the lateral AM subnucleus.

Although we did not undertake a detailed quantitative evaluation of AM labeling, it was nonetheless clear that many fewer labeled ceIls occurred in the contralateral Ahl than in the ipsilateral nucleus. Further, the distribution of labeled cells in the contralateral AM was restricted in the mediolateral and anteroposterior dimensions compared to ipsilateral labeling: Whereas labeled cells in the contralat- era1 AM were located in the most medial part of the nucleus, they occurred throughout the mediolateral extent of

‘The densocellular subnucleus of AM recognized by Olszewski (’52), and the interanteromedial nucleus (IAM) recognized by oth- ers in primates (Crouch, ’34; Walker, ’38) and nonprimate mammals (Ariens Kappers et al., ’36; Crosby et al., ’62), have each been described as a cell band that is continuous across the midline and interconnects the AM nuclei of the two thalami. Because modern investigators often recognize IAM in primates and nonprimates (e.g., Paxinos and Watson, ’82; Veazey et al., ’82), although 01- szewski’s macaque atlas is still widely used, it is worth pointing out that densocellular AM and IAM are probably not identical structures. They appear to differ in a t least one respect, Olszew- ski’s figures and descriptions indicate that the fused part of AM is less extensive anteroposteriorly than the lateral, unfused part, and that anterior and posterior to the region of fusion, AM is bordered medially by the central densocellular (Cdc) nucleus. Crouch (‘34), on the other hand, states that IAM is more extensive anteroposteriorly than AM, and that a t its poles IAM is completely separate from AM (see his Fig. 2). Scheibel and Scheibel(’67, Fig. 14) illustrate a similar configuration for IAM in rodents. We suggest that IAM corresponds to both the Cdc and densocellular AM of Olszewski.


the ipsilateral AM (Figs. 2B,3B,4). Also, contralateral cell labeling was typically concentrated in one to two sections reacted through AM, with a much smaller number of cells occurring in more rostra1 and caudal sections, while in the ipsilateral AM dense cell labeling typically occurred in three to four sections. Since we observed approximately 15 cells per section in the densely labeled region of contralat- era1 AM, and we saved and reacted every tenth section through the thalamus, we estimate that there were typically several hundred cells in contralateral AM that pro- jected to any given area of prefrontal cortex injected in this study. While it was difficult to compare with precision the amount of reaction product contained in the labeled AM cells of each hemisphere, cells in the contralateral AM appeared to be about as well labeled as those in the corre- sponding part of the ipsilateral nucleus. Some contralateral neurons were very heavily labeled, with reaction product filling the soma and extending into the proximal dendrites (Fig. 4B).

In the contralateral midline nuclei, labeled cells were observed most frequently in Cdc (Fig. 5A), Cif, and Reu (Fig. 5B). In Case 3, many cells were present in Pac. A few labeled cells were found in Clc, Cs, and Cim. As illustrated in Figure 5, labeled neurons in the contralateral and ipsilateral midline nuclei were associated with the double crescents of anterograde label described above. Again, labeled cells were less numerous in the midline nuclei of the contralateral thalamus than in the ipsilateral midline nuclei. Although many cells in the contralateral midline nuclei were lightly labeled, well-filled cells were also present (Fig. 5A,B).

A very few labeled neurons were observed in the contralateral MD in three cases. The largest number was observed in Case 1, but the total observed in all reacted sections of this case did not exceed ten. Virtually all labeled cells in the contralateral MD were found in the magnocellular part of the nucleus and most were located very close to the midline. In addition to MDmc, a few labeled cells in the contralateral hemisphere appeared to lie within the intralaminar nuclei, near the midline. These were found in the most ventromedial parts of Pcn (Cases 3 and 4) and Pf (Case 4). A very few labeled neurons were observed in contralateral Sf.

Possibility of false-positive results. We considered the possibility that the anterograde and retrograde labeling of the contralateral thalamus was artifactual. There are at least two potential sources of false-positive results in this study. First, HRP could have spread from the injection site to the contralateral hemisphere. In three of the four cases, however, HRP was clearly limited to the injected hemisphere; in the one instance (Case 3) in which HRP may have spread to the opposite hemisphere, there was no evidence of subsequent transport to the thalamus. If transport had occurred, we would expect to have observed labeled cells in the contralateral MD and VA nuclei. Such labeling was never observed: in Case 3, as in the other cases, labeled cells in the contralateral thalamus were almost entirely restricted to the AM and midline nuclei. A second possible source of false-positive results is that the contralateral thalamus might have been labeled by transneuronal transport over a number of potential pathways (these pathways are discussed in detail by Goldman, '79, and Molinari et a1.,'85). It is unlikely, however, that transneuronal transport con- tributed to the contralateral labeling we observed. For one thing, we used free HRP rather than wheat germ agglu-

tinin-conjugated HRP (WGA-HRP). Although it it well established that WGA-HRP can be transported transneu- ronally, significant transcellular transport of free HRP evidently does not occur in tracing experiments of the sort reported here (Mesulam, '82, p. 41). Also, the short (2-day) survival periods used in our experiments makes transneuronal transport an unlikely source of error. Finally, the fact that some cells observed in the contralateral thalamus were very well filled with reaction product (Figs. 4, 5) is difficult to reconcile with a hypothesis of transneuronal transport.

DISCUSSION The main goals of the present investigation were to deter-

mine the extent to which the pattern of ipsilateral and contralateral prefrontothalamic projections differ, and to determine whether there exists a crossed thalamoprefrontal projection in the macaque. Our results indicate that whereas macaque prefrontal cortex has strong bilateral projections to certain thalamic nuclei, such as AM, MDmc, and the midline nuclei, other nuclei that receive strong uncrossed projections are the targets of rather weak crossed projections (MDpc, VAmc), or, as far as we can determine, receive no crossed projections at all (Ret, PM). An important finding is the crossed thalamoprefrontal projection that arises mainly from the AM and midline nuclei.

Ipsilateral thalamic labeling The observed pattern of retrograde and anterograde la-

beling of the thalamus ipsilateral to the injection is largely consistent with previous investigations of the thalamic connectivity of prefrontal cortex in primates (thalamocortical projections: Asanuma et al., '85; Goldman-Rakic and Por- rino, '86; Jacobson et al., '78; Kievit and Kuypers, '77; corticothalamic projections: Jacobson et al., '78; Kiinzle, '78). There are two exceptions. First, we found anterograde and retrograde label in the subfascicular nucleus, an ob- scure structure not previously reported to have connections with the prefrontal cortex. In addition, we observed weak anterograde labeling of the lateral habenular nucleus, an epithalamic structure. Although the habenula is not generally believed to have direct cortical connections, and autoradiographic studies of primate prefrontal cortex have not revealed such a projection, Leichnetz et al. ('81) have reported anterograde labeling of the lateral habenula following implants of HRP pellets into the dorsolateral prefrontal cortex of New World and Old World monkeys. Further, Beckstead ('79) has reported a projection to HL from anterior cingulate cortex (Brodmann's areas 32 and 24) in the rat.

Crossed corticothalamic projections The projections of prefrontal cortex to the contralateral

thalamus appear to be more widespread than indicated by previous investigations. In addition to confirming projections to contralateral MD, Cdc, Clc, Cif, and Pf described in earlier papers (Akert and Hartmann-von Mmikow, '80; DeVito, '69; Goldman, '79; Kunzle, '781, we also observed anterograde label in AM, AV, VA, Cs, Cim, Reu, Sf, and Pcn. We attribute these differences to the superior sensitivity of the anterograde HRP tracing method used in this investigation compared to the autoradiographic and degeneration methods used in prior studies, and to the large size of our injections. Still, it is difficult to understand the fail-


ure of autoradiography to reveal the massive crossed projection to AM reported here.

The fairly large differences in the strength of projections to AM and MDmc in our four injecions suggests that prefrontal areas differ in their connections with these nuclei. The very dense projection to contralateral MDmc observed in Case 2 may arise from the orbital cortex, as both Gold- man ('79) and Akert and Hartmann-von Monikow ('80) reported dense projections to contralateral MDmc in macaques with injections of radioactive tracer confined to this region. Further, we suggest that the strongest prefrontal projection to contralateral AM may originate from the cortex ventral to the principal sulcus, as this region was involved in both animals (Cases 2 and 4) that exhibited very heavy anterograde labeling of AM

Differences between thalamic nuclei in the laterality of corticothalamic projections

It is significant that in every case examined, we observed marked variation in the laterality of prefrontal projections to different thalamic nuclei, ranging from strong ipsilateral dominance to bilaterality. At one extreme, prefrontal projections to Ret, PM, Sg, and Li are, within the limits of resolution of the technique, exclusively ipsilateral. Projec- tions to MDpc and VA represent an intermediate condition: prefrontal cortex projects bilaterally to these nuclei, but the ipsilateral contingent is much stronger than the contralateral contingent. Finally, in the case of projections to AM, MDmc, and the midline nuclei, the ipsilateral and contralateral contingents are more nearly equal in strength.

Evidence from studies of motor and premotor cortex indicate that the projections of these regions to thalamic nuclei also exhibit differences in laterality. For example, Kun- zle ('76), using the autoradiographic technique in macaques, found that the projections of the precentral motor cortex to Ret and to the thalamic motor nuclei (VL and the oral part of the ventral posterior nucleus) were strictly ipsilateral, while projections to lateral MD and the intralaminar nuclear group were bilateral. Other studies of primates (Akert and Hartmann-von Monikow, '80; Akert et al., '79; Campos-Ortega and Cluver, '69; DeVito, '69; Kun- zle, '78; Kuypers and Lawrence, '67; Wiesendanger and Wiesendanger, '85) and carnivores (Molinari et al., '85; Sakai and Tanaka, '83, '84) have yielded similar results, confirming that projections of the motor and premotor cortex to the intralaminar nuclei, particularly the CM-Pf complex, are bilateral, while projections to the thalamic motor relay nuclei are almost exclusively ipsilateral.

In general, therefore, it appears that the so-called nonspecific thalamic nuclei-that is, the intralaminar and midline nuclei-are prominent targets of bilateral projections from frontal cortex. Further, there are evidently regional differences in the crossed projections to the nonspecific thalamus: motor and premotor cortex project primarily to the intralaminar nuclei while prefrontal cortex projects mainly to the midline nuclei. On the other hand, projections to the "specific" thalamic nuclei, with the exceptions of AM and MDmc, exhibit a very strong ipsilateral dominance.

Variation in the laterality of corticothalamic projections may be related to the different morphological types of corticothalamic fibers described by Scheibel and Scheibel('66, '67, '70). Using the Golgi method, they observed that cortical fibers which terminate in the nonspecific thalamic nuclei are of small caliber and have sparse terminal fields which extend over several nuclei; significantly, axon collat-

erals cross the massa intermedia into contralateral nonspecific nuclei. On the other hand, the somatosensory relay nuclei (ventrobasal complex) contain large-caliber fibers with dense, spatially restricted endings, in addition to a population of thin fibers. Accordingly, we suggest that the asymmetry of corticothalamic projections observed in anterograde tracing studies may reflect the differential distribution of two types of corticothalamic fibers, large-caliber fibers with dense, restricted terminations being distributed primarily to the specific nuclei of the ipsilateral thalamus, while small-caliber fibers with sparse but widespread terminations are distributed predominantly to the nonspecific nuclei of both thalami.

Crossed thalamocortical projections The present study provides evidence for a modest crossed

projection to the prefrontal cortex from the mesial portion of AM and from the midline nuclei and is the first study to present detailed documentation of crossed thalamocortical projections. Previous investigations of the thalamic projections to primate prefrontal cortex with HRP did not demonstrate a crossed projection (Jacobson et al., '78; Kievit and Kuypers, '77; Goldman-Rakic and Porrino, '86). Indeed the overwhelming majority of investigations of thalamocortical projections conducted with modern axon transport techniques, beginning with the HRP study of Jones and Leavitt ('74), have indicated that the mammalian thalamocortical projection is exclusively ipsilateral. To our knowl- edge, there are only three other explicit claims of crossed thalamocortical projections in the recent literature. Moli- nari et al. ('85) injected WGA-HRP into rat motor cortex and noted that "one or two labeled cells were occasionally observed in some sections in the contralateral thalamus." These results would indicate that the crossed thalamocortical projection is essentially trivial. However, Jurgens ('82) noted bilateral retrograde labeling of Cif, Reu, and MD following injections of free HRP into squirrel monkey motor cortex, and Asanuma et al. ('85) observed bilateral retrograde labeling of Cdc and the central medial nucleus (CeM) with fluorescent dye injections in macaque prefrontal cortex (CeM probably corresponds to Cif in Olszewski's nomen- clature). While neither paper treated contralateral labeling in detail, these observations of labeling in the midline region are similar to our findings. It is interesting, further- more, that Scheibel and Scheibel ('671, with the Golgi method, found that the richly branched axons of cells in AM and the nonspecific nuclei send collaterals across the massa intermedia, although they did not indicate that crossed collaterals might reach all the way to the cortex.

We can offer several reasons that significant retrograde labeling of the contralateral thalamus was found in this study, and almost without exception, not observed or reported in many other reports of thalamocortical connectivity. First, we used the TMB chromagen (as did Jurgens, '823, which greatly enhances sensitivity of retrograde (as well as anterograde) HRP tracing (Mesulam, '78, '82) compared to DAB, the chromagen used in most earlier studies of thalamocortical connectivity. Second, the prevailing con- viction that thalamocortical projections are strictly ipsilateral, combined with the difficulty of determining precisely the location of the thalamic midline, might make workers reluctant to regard labeled cells that occur close to the midline as cells of the contralateral thalamus. For instance, Jones ('851, while noting that labeled cells are sometimes observed near the midline in the thalamus contralateral to


a cortical tracer injection, concludes: "Though not completely ruling out a bilateral projection from these midline regions of the thalamus, it seems to me that the most parsimonious explanation of such results is simply an irreg- ularity in the position of the midline." In this study, however, the occurrence of labeled cells embedded in paired foci of anterograde label centered on the midline (Figs. 4, 5) allowed u s to conclude confidently that labeled cells were present in both thalami.

Finally, it may be the case that crossed thalamocortical projections have not been more commonly reported because they arise exclusively, or very nearly so, from only a few nuclei, particularly the AM and midline nuclei. Studies of cortical areas that do not have strong connections with these nuclei, such as the sensory areas, would then be expected to demonstrate only ipsilateral thalamocortical projections. However, the crossed projections originating from these nuclei may not terminate exclusively in the prefrontal region, as Cavada and Goldman-Rakic (unpub- lished observation) have observed labeled cells in the contralateral AM following injections of WGA-HRP in macaque posterior parietal cortex. (These observations, made with much smaller injections of tracer than those of the present study, also indicate that large injections are not required to demonstrate crossed thalamocortical projections.) Never- theless, we believe that projections from the thalamus to the contralateral cortex are not common features of thalamic organization, but arise only from nuclei that lie close to the midline (i.e., the mesial thalamic region). We suggest that the development of crossed thalamocortical fibers may depend on the fusion of the thalami during gestation, the mama intermedia providing a substrate for the decussation of outgrowing axon collaterals.

Pathways of crossed projections There are several possible pathways for decussating cor-

ticothalamic fibers. We found that labeled fibers were continuous across the midline in the mama intermedia (interthalamic adhesion) in agreement with several other studies of crossed corticothalamic connectivity (Campos-Or- tega and Cluver, '69; Kiinzle, '76, '78; Molinari et al., '85; Sakai and Tanaka, '84; Scheibel and Scheibel, '66, '67, '70). It has long been appreciated that the massa intermedia of most mammalian species is composed of cell and fiber bands which traverse the midline (Ariens Kappers et al., '36; Bodian, '40; Crosby et al., '62; Glees and Wall, '48; Gurd- jian, '27; Scheibel and Scheibel, '67). These earlier workers evidently believed that the massa intermedia consists largely of crossed thalamothalamic fibers. It is now clear, however, that corticothalamic fibers are an important component of the massa intermedia.

The possibility that there exist additional pathways for crossing fibers deserves consideration because the massa intermedia, which is well developed in many mammalian orders, is reduced in most primates and is nearly vestigial in apes and humans (Ariens Kappers et al., '36; Crosby et al., '62; Rosales et al., '68; Scheibel and Scheibel, '67; Walker, '38). Uncrossed and crossed corticofugal fibers may enter the thalamus ventrally, through the hypothalamus, subthalamus, and mesencephalon, as described in primates by workers using silver-degeneration techniques (Campos- Ortega and Cluver, '69; DeVito, '69; Kuypers and Law- rence, '67). Fibers may cross the midline just ventral to the third ventricle at caudal thalamic levels (Campos-Ortega and Cluver, '69; Kuypers and Lawrence, '67), or possibly in

the posterior commissure, which contained labeled fibers in our cases. Our observation of anterograde label in the habenulopeduncular tract bilaterally (Fig. 2F) is consistent with a transmesencephalic pathway.

The corpus callosum and anterior commisure have also been suggested as pathways for crossing corticothalamic fibers (Rinvik, '68, '72). However, Molinari et at. ('85) have reported that sectioning the corpus callosum in rats results in no apparent diminution of anterograde labeling of the contralateral thalamus following cortical HRP injections. They argue that most, if not all, crossed corticothalamic fibers decussate in the mass intermedia. Their study does not address the possibility that fibers cross in the anterior commissure.

Possible functional significance of bilateral thalamic connectivity

The functions of the crossed connections between the cortex and thalamus, consisting mostly of corticothalamic projections, are unknown. One possibility is that these connections serve as substrates for the interhemispheric transfer of specific cortical information, analogous to the corpus callosum. This is unlikely, however, since destruc- tion of the callosum by itself effectively eliminates the exchange of specific information between hemispheres in humans. However, as Sargent ('86) points out, "split-brain" patients behave as unified individuals, arguing that subcortical centers must be involved in integrating the activity of the cerebral hemispheres. We suggest that the crossed connections between the cortex and thalamus described here may constitute part of this integrative system. An integrative role is consistent with the observation that the nonspecific (intralaminar and midline) thalamic nuclei, which we have shown are prominent targets of bilateral projections from frontal cortex, are involved in mechanisms of cortical activation and arousal (Brodal, '81; Steriade and Deschenes, '84). These projections may complement func- tionally the bilateral frontal projections to brainstem mon- oaminergic cell groups reported by Arnsten and Goldman- Rakic ('84).

The crossed thalamic connections of the prefrontal cortex may have an additional, mnemonic, function. The MDmc, AM, and midline nuclei, which have prominent crossed connections with prefrontal cortex, are also connected with three structures that have been strongly implicated in memory: the amygdala, mammillary bodies, and hippocampal formation (Squire, '82; Van Hoesen, '85). In primates, the amygdala (Aggleton and Mishkin, '84; Porrino et al., '81) and hippocampal formation (Aggleton et al., '86) have been shown to project to MDmc, while AM and the midline nuclei receive projections from the mammillary bodies (Ve- azey et al., '82) and are reciprocally connected with the hippocampal formation (Aggleton et al., '86; Amaral and Cowan, '80). It may be particularly significant, in view of our results, that the hippocampal formation projects bilaterally to the AM and rostra1 midline nuclei, while its projections to other thalamic nuclei are almost exclusively ipsilateral (Aggleton et al., '86). There is also behavioral evidence indicating a mnemonic role for the mesial thalamus, as pathology of this region is characteristic of individuals with Korsakoffs amnesic syndrome (Victor et al., '71) and experimental lesions of the mesial thalamus in macaques yield memory deficits (Aggleton and Mishkin, '83; Isseroff et al., '82). The potential importance of AM in human memory is underscored by recent evidence that

T.M. PREUSS AND P.S. GOLDMAN-RAKIC 280

amnesia can result from interruption of the mammillothalamic tract, thereby disconnecting the anterior thalamic nuclei from the mammillary bodies (Cramon et al., '85). We suggest that by means of bilateral projections to MDmc, AM, and the midline nuclei, which are reciprocated by AM and the midline group, the prefrontal cortex of one hemisphere could influence, and be influenced by, the mnemonic systems of both hemispheres.

ACKNOWLEDGMENTS This study was supported by NIMH grants 00298 and

38546 and NIHM Fellowship 09146. We wish to recognize the able technical assistance of Susan Maturo, Susan Mor- genstern, Joseph Musco, Mariamma Pappy, and JoAnn Treffeisen.

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crossed corticothalamic and thalamocortical connections of macaque prefrontal cortex

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