Neurochemical and connectional organization of the dorsal pulvinar complex in monkeys

Neurochemical and ConnectionalOrganization of the Dorsal Pulvinar

Complex in Monkeys

CAROLINA GUTIERREZ,3 MONIQUE G. COLA,1,3 BENJAMIN SELTZER,1,2,3,4AND

CATHERINE CUSICK1,2,3*1Department of Structural and Cellular Biology, Tulane University School of Medicine,

New Orleans, Louisiana 701122Department of Psychiatry and Neurology, Tulane University School of Medicine,

New Orleans, Louisiana 701123Neuroscience Program, Tulane University School of Medicine, New Orleans,

Louisiana 701124V.A. Medical Center, New Orleans, Louisiana 70112

ABSTRACTTo investigate the organization of the dorsal pulvinar complex, patterns of neurochem-

ical staining were correlated with cortico-pulvinar connections in macaques (Macaca mu-latta). Three major neurochemical subdivisions of the dorsal pulvinar were identified byacetylcholinesterase (AChE) histochemistry, as well as immunostaining for calbindin-D28Kand parvalbumin. The dorsal lateral pulvinar nucleus (PLd) was defined on histochemicalcriteria as a distinct AChE- and parvalbumin-dense, calbindin-poor wedge that was found tocontinue caudally along the dorsolateral edge of the pulvinar to within 1 mm of its caudalpole. The ventromedial border of neurochemical PLd with the rest of the dorsal pulvinar,termed the medial pulvinar (PM), was sharply defined. Overall, PM was lighter than PLd forAChE and parvalbumin and displayed lateral (PMl) and medial (PMm) histochemical divi-sions. PMm contained a central “oval” (PMm-c) that stained darker for AChE and parvalbu-min than the surrounding region. The neurochemically defined PLd was labeled by tracerinjections in the inferior parietal lobule (IPL) and dorsolateral prefrontal cortex but not thesuperior temporal gyrus (STG). Label within PMl was found after prefrontal and IPL and, toa lesser extent, after STG injections. The PMm was labeled after injections of the IPL andSTG, but only sparsely following prefrontal injections. The histochemically distinct subregionor module of PMm, PMm-c, was labeled only by STG injections. Overlapping labeling wasfound in dorsal pulvinar divisions PMl and PLd following paired IPL/prefrontal, but notIPL/STG or these particular STG/prefrontal, injections. Thus, PLd may be a visuospatiallyrelated region whereas PM appears to contain several types of territories, some related tovisual or auditory inputs, and others that receive directly converging input from posteriorparietal and prefrontal cortex and may participate in a distributed cortical network con-cerned with visuospatial functions. J. Comp. Neurol. 419:61–86, 2000. © 2000 Wiley-Liss, Inc.

Indexing terms: medial pulvinar; lateral pulvinar; calcium binding proteins; visual cortex; primates

Excluding the anterior nucleus, which might be consid-ered a component of the somatosensory system (Pons andKaas, 1985; Cusick and Gould, 1990; Krubitzer and Kaas,1992; Rausell et al., 1992), the pulvinar of monkeys can bedivided into two broad zones: the inferior pulvinar (PI)complex (Gutierrez et al., 1995; Gray et al., 1999) and the“dorsal pulvinar.” The PI complex contains several chemo-architectonic and retinotopically organized subdivisions

Grant sponsor: NIH; Grant number: EY08906; Grant sponsor: Depart-ment of Veterans Affairs Medical Center, New Orleans, Louisiana; Grantsponsor: Administrators of the Tulane Educational Fund.

*Correspondence to: Catherine G. Cusick, Ph.D., Department of Struc-tural and Cellular Biology SL-49, Tulane University School of Medicine,1430 Tulane Avenue, New Orleans, LA 70112.E-mail: [email protected]

Received 13 July 1999; Revised 24 November 1999; Accepted 29 Novem-ber 1999.

THE JOURNAL OF COMPARATIVE NEUROLOGY 419:61–86 (2000)

© 2000 WILEY-LISS, INC.

(Lin and Kaas, 1979; Bender, 1981; Ungerleider et al.,1983, 1984; Cusick et al., 1993; Gutierrez et al., 1995;Gutierrez and Cusick, 1997; Stepniewska and Kaas, 1997;Gray et al., 1999) and clearly relates to the modality ofvision. The organization of the dorsal pulvinar complex, bycontrast, is less well understood, due in part to a lack ofdemonstrated sensory topography.

Traditionally, the dorsal pulvinar has been divided intolateral (PL) and medial (PM) pulvinar nuclei caudally,with the lateral posterior (LP) nucleus situated rostral tothese zones (Olszewski, 1952; Jones, 1985). Based on itsconnections with the caudal inferior parietal lobule (IPL)and dorsal prelunate cortex (Baleydier and Mauguiere,1977; Divac et al., 1977; Mesulam et al., 1977; Rezak andBenevento, 1979; Weber and Yin, 1984; Asanuma et al.,1985; Schmahmann and Pandya, 1990; Hardy and Lynch,1992; Baleydier and Morel, 1992; Baizer et al., 1993; Ye-terian and Pandya, 1997), the dorsal part of classical PLappears to be predominantly concerned with vision.Whereas the adjacent portions of classical LP also connectwith the caudal inferior parietal lobule (Baleydier andMauguiere, 1977; Mesulam et al., 1977; Asanuma et al.,1985; Baleydier and Morel, 1992), major connections of LPare with somatosensory-related area 5 (Jones et al., 1979;Pons and Kaas, 1985; Yeterian and Pandya, 1985; Acunaet al., 1990). The cortical connections of PM are morewidespread. PM connects not only with certain extrastri-ate visual areas including V4 and inferotemporal andposterior parietal cortex (e.g., Selemon and Goldman-Rakic, 1988; Baleydier and Morel, 1992; Hardy andLynch, 1992; Baizer et al., 1993; Rockland, 1996; Yeterianand Pandya, 1997), but also with auditory and somatosen-sory cortical areas (Burton and Jones, 1976; Friedmanand Murray, 1986; Acuna et al., 1990; Pandya, 1995;Hackett et al., 1998). Moreover, PM interconnects withnon-modality-specific higher order cortex in addition to“paralimbic” association areas, including insular, superiortemporal polysensory (STP), temporopolar, dorsalprearcuate, orbitofrontal, parahippocampal, and cingulatecortex as well as the amygdala (Trojanowski and Jacob-son, 1974, 1976; Bos and Benevento, 1975; Burton andJones, 1976; Jones and Burton, 1976; Baleydier and Mau-guiere, 1977, 1985; Kievit and Kuypers, 1977; Mufson andMesulam, 1984; Markowitsch et al., 1985; Friedman and

Murray, 1986; Huerta et al, 1986; Moran et al., 1987;Stanton et al., 1988; Yeterian and Pandya, 1989, 1991;Barbas et al., 1991; Morecraft et al., 1992; Romanski et al.,1997).

The diversity of its connections suggests that the dorsalpulvinar plays multiple roles in behavior, but its functionsare poorly understood. This may be because the bound-aries and basic units of organization of this heterogeneousregion have not been clearly defined. A case in point is thelarge nucleus PM. A small ventrocaudal portion of thisregion has connections with the middle temporal visualarea (MT; Ungerleider et al., 1984) and striate cortex(Gutierrez and Cusick, 1997) and shares neurochemicalcharacteristics with the medial division of the PI complex,PIM. For these reasons, this part of “PM” has recently beenassigned to the PI complex (Cusick et al., 1993; Gutierrezet al., 1995; Gutierrez and Cusick, 1997; Stepniewska andKaas, 1997; Gray et al., 1999). Other parts of PM may alsohave discrete sets of connections. The more rostral por-tions of the traditional PM, for example, appear to inter-connect with auditory- and somatosensory-related cortexas well as with the higher order areas already enumer-ated. Thus, specific subregions of PM may be predomi-nantly visual, whereas other subregions may be domi-nated by other modalities of sensation or participate indistributed, hemisphere-wide circuits that integrate dif-ferent types of sensory information and are concernedwith directed spatial attention (Selemon and Goldman-Rakic, 1988; Mesulam, 1990; Selter, 1992; Morecraft et al.,1993). Much of the uncertainty concerning the functions ofthe dorsal pulvinar complex, and especially PM, can beattributed to the fact that traditional cytoarchitectonicparcellations of the pulvinar into different nuclei lack aclear relation with the different sets of neural connections.

In the present study, we have investigated the organi-zation of the dorsal pulvinar, encompassing PL and PM aswell as the caudal portion of LP, by combining a chemo-architectonic analysis with the tracing of cortical connec-tions. Neurochemical stains included acetylcholinesterasehistochemistry and immunostaining for the calcium bind-ing proteins calbindin-D28K and parvalbumin. We havepreviously used these methods to reveal divisions of the PIcomplex (Cusick et al., 1993; Gutierrez et al., 1995; Guti-errez and Cusick, 1997; Gray et al., 1999; Cola et al.,

Abbreviations

AChE acetylcholinesteraseARG autoradiographybsc brachium of the superior colliculusCalb. calbindinDLr rostral division of the dorsolateral visual areaDM dorsomedial visual areaFST fundal superior temporal areaIPL inferior parietal lobuleLim nucleus limitansLIP lateral intraparietal visual areaLP lateral posterior nucleusMD mediodorsal nucleusMDdc densocellular division of the mediodorsal nucleusMST medial superior temporal areaMT middle temporal areaMTc crescent of the middle temporal areapaAlt cortical area paAltParv. parvalbuminPdm physiologically defined zone of dorsomedial pulvinarPI complex inferior pulvinar complexPIp posterior division of PI complexPIM medial division of inferior pulvinar complex

PL lateral pulvinar nucleusPLd dorsal PL divisionPM medial pulvinar nucleusPMl lateral division of the PMPMm medial division of the PMPMm-c central division of the PMmPOa parietal visual area POaSg suprageniculate nucleusSTG superior temporal gyrusSTP superior temporal polysensory areaSTS superior temporal sulcusTEO cortical area TEOTPOc, i, r caudal, intermediate, and rostral divisions of cortical area

TPOTpt cortical area TptTs3 cortical area Ts3VLp posterior division of the ventral lateral nucleusVLps posterior superior division of the ventral lateral nucleusWGA-HRP wheat germ agglutinin conjugated to HRPV1 first visual cortical areaV2 second visual cortical area

62 C. GUTIERREZ ET AL.

1999). The cortical sites for injections of anatomical trac-ers were chosen on the basis of previous work as havingthe greatest likelihood of interconnecting with the dorsalpulvinar, particularly PM, but not with the inferior pulv-inar complex. We intentionally paired injections of twodifferent tracers in two different cortical areas of a singlehemisphere in order to compare directly the connections ofmodality-specific and “high order” cortical regions withinsubdivisions of the dorsal pulvinar. The paired sites wereas follows: prearcuate cortex and the caudal inferior pari-etal lobule (IPL), regions thought to be part of a networkof cortical and subcortical areas concerned with visuospa-tial function (Baleydier and Mauguiere, 1987; Selemonand Goldman-Rakic, 1988; Seltzer, 1992; Morecraft et al.,1993); the vision-related caudal IPL and the auditory-

related superior temporal gyrus (STG; Morel et al., 1993;Hackett et al., 1998), i.e., two areas associated with dif-ferent sensory modalities; and, for comparison, dorsalprearcuate cortex and the STG. The label from the indi-vidual tracer injection sites was examined first to seewhether neurochemical divisions of the dorsal pulvinarcorresponded to separate foci of connections. Connectionsfrom two different cortical regions of the same hemispherewere then compared to determine whether or not fibersoverlap in particular subdivisions of the dorsal pulvinar.

MATERIALS AND METHODS

The procedures for these studies were approved by theTulane University Advisory Committee for Animal Re-

Fig. 1. Comparison of traditional parcellation of the dorsal pulvi-nar with chemoarchitectonic subdivisions identified in the presentstudy. A: Line drawing of a Nissl-stained section (A9) showing thetraditional parcellation of the pulvinar into PI, PL, and PM nucleiaccording to Olszewski (1952) at the level of the crossing of thebrachium of the superior colliculus (bsc). The dashed line indicateswhere many investigators have departed from Olszewski’s originalnomenclature and considered PL to continue below the bsc (e.g., Kaasand Huerta, 1988). B: Line drawing of a neighboring section (B9)

stained for AChE. The heavy line indicates the broad division of thepulvinar into the PI complex (described by Gutierrez et al., 1995; Grayet al., 1999) ventrally and the dorsal pulvinar complex dorsally. Themost dorsolateral portion of the pulvinar shows a clearly defined,intensely stained wedge (PLd), a moderately stained intermediatezone (PMl), and a most medial zone (PMm) that contains a moderatelystained oval (PMm-c) surrounded by a more lightly stained rim.Arrows in A9 and B9 indicate the same blood vessel. Case TMJ.

63DORSAL PULVINAR IN MONKEYS

Fig. 2. Low (A–C) and higher (D–L) magnification views of theneurochemical architecture of dorsal pulvinar. The top panels(A,D,G,J) are from a section stained for AChE, the middle panels(B,E,H,K) are from an adjacent section stained for parvalbumin, andthe bottom ones (C,F,I,L) are from an adjacent calbindin-stainedsection. The similarly shaped and oriented arrows point to the sameblood vessels visible at lower (A–C) and higher (D–L) magnification. Aline drawing of the dorsal pulvinar subdivisions for the section shownin A is illustrated in Figure 1B. D–F show the appearance of PLd bythe three different histochemical methods. PLd is AChE and parval-

bumin dense and is displayed equally well as a calbindin-light zone. Asmall outer wedge (pars angularis, abbreviated p.a. on subsequentfigures), above the asterisks in F, shows intense patches of calbindinstain. G–I show the transition from PMl to PMm (large arrow in G–Iindicates middle arrow on A–C). J–L show the PMm zone with theembedded oval, PMm-c (medium arrow in J–L indicates lower arrowon A–C). In H and I, note reciprocal relationship of parvalbumin-lightand -dark zones to calbindin-dark and -light zones. Case TMJ. Scalebar 5 1.25 mm in C (applies to A–C); 0.75 mm in F (applies to D–L).


sources, and the research was conducted in accordancewith NIH guidelines for the care and use of animals. In sixrhesus monkeys (Macaca mulatta) injections of two histo-logically distinguishable tracers, either wheat germ agglu-tinin conjugated to horseradish peroxidase (WGA-HRP) or

radiolabeled amino acids, were placed in two differentcortical locations in a single hemisphere. For each tracer,several closely spaced injections were made that fused toform a single large injection site. Details of these proce-dures for five of these cases (all except TMI) were reported

Figure 2 (Continued)


previously (Seltzer et al., 1996). Four of the cases (TMG,TMH, TMI, and TMJ) had undergone monocular enucle-ation 1–6 months prior to injections (Gutierrez and Cu-sick, 1994). However, no major differences in stainingpattern were detected between these and the intact cases,and the results are based on an analysis of all six.

Following premedication with ketamine (10 mg/kg i.m.),the monkeys were anesthetized with isoflurane and ni-

trous oxide. The heart rate, expired CO2, and body tem-perature were continuously monitored throughout theprocedure. Using aseptic surgical technique, 7–15 injec-tions of 0.3 ml tritiated proline and/or leucine (50–75 mCi/ml) were made into one cortical region, and, 7–8 dayslater, 6–12 injections of approximately 0.25 ml each of1.0% WGA-HRP were placed in the other location. In twocases, WGA-HRP and five or eight injections of 0.2 ml

Fig. 3. Rostral to caudal series of sections (A–D) showing thedivisions of the dorsal pulvinar by parvalbumin (middle column) andAChE (column on right) stains. Sections are spaced at 250-mm inter-vals and are through about the middle two-thirds of dorsal pulvinar.At most levels AChE histochemistry shows the PLd/PMl boundary

especially well, whereas the compartmentation within the divisions ofPM is well displayed by parvalbumin. For further explanation, seetext. Section numbers are consecutive from caudal to rostral. CaseTMI.


[35S]-methionine (200 mCi/ml) were placed in separate lo-cations of the same hemisphere during the same opera-tion. The total injection volumes were intentionally largein order to provide even infiltration by the injectates oflarge regions of cortex.

Forty-eight to 72 hours after the last injection, the an-imals received an intravenous overdose of sodium pento-barbital and were perfused transcardially with saline,followed by 4% paraformaldehyde in 0.1 M phosphatebuffer (pH 7.2–7.4). The brains were sunk in 30% sucrosein the same buffer and cut frozen in the frontal plane atintervals of 25 mm through the thalamus and 50 mmthrough the rest of the brain. Parallel series of closelyspaced sections were processed for emulsion autoradiog-raphy (ARG), WGA-HRP neurohistochemistry (Mesulam,1978), cytoarchitecture (Nissl), and chemoarchitecture asdescribed below. In cases with [35S]-methionine label, filmautoradiography was additionally performed by exposingsections, previously treated for HRP or for parvalbuminimmunohistochemistry, to Kodak X-Omat film for 1–6days.

The calcium binding proteins calbindin-D28K and parv-albumin were localized immunocytochemically by usingmonoclonal antibodies (Sigma, St. Louis, MO) and stan-dard ABC methods (Vector kits, Burlingame, CA; Hsu etal., 1981; see Cusick et al., 1995 for details). The AChEhistochemistry was performed following a modification ofthe Geneser-Jensen and Blackstad (1971) method by us-ing acetylthiocholine iodide (Sigma) as the substrate, fol-lowed by development in 1.25% sodium sulfide, and inten-sification in silver nitrate. Calbindin, parvalbumin, andAChE-stained material from four additional unoperated

hemispheres was included in the chemoarchitectonic anal-ysis of the dorsal pulvinar.

The entire extent of the dorsal pulvinar complex (includ-ing traditional dorsal PL, PM, and adjacent parts of theLP nucleus) was examined microscopically at 250-mm in-tervals for variations in staining features. For each case, aseries processed by one method, usually AChE histochem-istry, was drawn with a camera lucida, and areas of dif-ferent staining density were outlined. Adjacent sectionsprepared for other chemoarchitectonic methods were thenaligned with the first set of drawings and variations instaining by the other marker similarly outlined. Align-ment landmarks included small blood vessels and fiberbundles identified on adjacent sections, and adjustmentsfor differential shrinkage were made by manipulating azoom lens. Candidate chemoarchitectonic borders weredrawn where at least two neurochemical markers showeda distinct change in density.

To examine cortical connections of different neurochem-ical divisions of the pulvinar, sections prepared for HRP orARG were first charted, under darkfield microscopy, forlabeled fiber terminals and cells within the thalamus.Although both anterograde and retrograde WGA-HRP la-bel was found, anterograde label in dorsal pulvinar divi-sions tended to be somewhat broader or better detected.The charts were constructed to depict the total extent ofboth types of label. The drawings of transported label werethen superimposed on those of neurochemically stainedsections, allowing precise analysis of the spatial relation-ships between cortical terminations and thalamic archi-tecture. Next, drawings of adjacent sections prepared for

Fig. 4. Summary drawings of the 12 tracer injection sites from thesix cases. Reconstructions were made by analysis of series of coronalsections treated for HRP histochemistry or autoradiography. Repre-sentative sections through the centers of the injection sites are illus-trated in Cusick et al. (1995) and Seltzer et al. (1996). In cases TMIand TMJ, the arcuate sulcus is partially opened to show the spread of

tracer into the depths of the sulcus. In subsequent figures, digitalphotographs of the patterns of label are overlapped onto photographsof the chemoarchitecture. This approach (Figs. 5–9) allows accuratecomparison of the densest label to the neurochemical divisions,whereas line drawings (Figs. 10–14) display the locations of sparserlabel better.


Fig. 5. A–F: Distribution of dense label transported from IPLcompared with AChE chemoarchitecture. The patches of WGA-HRPlabel were digitally photographed at low magnification in darkfieldwith crossed polarizing filters, and the images were inverted. Thephotographs of label were then overlaid onto brightfield images of theneighboring AChE-stained sections. Patches indicated as focus “1”

occupy the PMl subdivision, whereas focus “2” lies near the dorsaledge of PMm, avoiding the slightly darker AChE oval PMm-c. Sec-tions are spaced at 250-mm intervals and consecutively numberedfrom caudal to rostral. Case TMJ. Scale bar 5 1 mm in A (applies toA–F).


ARG and HRP were aligned and the two labels comparedfor overlap or non-overlap.

For further data analysis and display, images of serialsections were made under brightfield or darkfield illumi-nation by using a Kodak Megaplus II digital camera andNIH Image software. For [35S]-methionine tracing, theX-ray films of these same serial sections were also digi-tally photographed. Using the “layers” function in Photo-shop (Adobe Systems), the separate images of neurochem-ical staining and transported label were aligned. This wasaccomplished by adjusting for differences in shrinkage,temporarily rendering one image semitransparent, andthen overlapping the images by using multiple small bloodvessels and fiber bundles as landmarks. In some in-stances, the transported label was represented as digitallycolored overlays. Illustrations were formatted and printedby using Photoshop 5.0 and Canvas 5.0 (Deneba Systems)software. Connectional data are shown in two formats.Low-magnification photographic overlays of transportedlabel and histochemical stain show the relationship be-tween the densest connections and chemoarchitecture.This procedure masks some of the fine details of the label,which are displayed on line drawings.

RESULTS

Chemoarchitecture of dorsal pulvinarsubdivisions in monkeys

Terminology. On the basis of fiber myelination andcytoarchitecture, the dorsal pulvinar has traditionallybeen divided into medial (PM) and lateral (PL) nuclei(Friedemann, 1911; Crouch, 1934; Walker, 1938; Olsze-wski, 1952; Jones, 1985). In Olszewski’s (1952) parcella-tion, both are separated from the classical inferior pulvi-nar (PI) nucleus by the brachium of the superior colliculus(bsc; Fig. 1A). This schema, which is not tied to the func-tional or connectional organization of the pulvinar (forreview, see Gutierrez et al., 1995), has often been modifiedso that the PL nucleus is defined by the presence of hori-zontally oriented fiber bundles and extends ventrally fromnear the dorsolateral corner of the pulvinar to its inferiormargin (solid and dashed lines, Fig. 1A; Jones, 1985; Kaasand Huerta, 1988; but see Stepniewska and Kaas, 1997).A recent study of the PI complex (Gutierrez et al., 1995)and the present investigation suggest, however, a differ-ent organization (Fig. 1B,B9; see below) in which the tra-ditional PL “nucleus” comprises a heterogeneous regionthat includes portions of two different fundamental unitsof the pulvinar, the PI complex and dorsal pulvinar (Fig.1A; see Kaas and Huerta, 1988 and present Discussion).

For the sake of historical continuity, a nomenclature fordorsal pulvinar is proposed that largely conserves thetraditional one. Thus, the identification of two divisions ofPM and one PLd division follows approximately the tra-ditional interpretation of pulvinar nuclei based on locationof fiber bundles. This parcellation coheres with the extentof the patches of STG connections, which avoid PLd (seebelow), and with evidence for two divisions of PM recentlyshown by Romanski et al. (1997). The term PLd is used foran architectonically distinct, lateral portion of the dorsalpulvinar, to distinguish it from the entire traditional PL.This is not meant, however, to imply that PLd is a com-ponent of a larger, coherent nucleus that includes a “PLv”;more ventral portions of the traditional PL have beenincluded in the PI complex (Gutierrez et al., 1995).

The present study revealed PLd to be a histochemicallydistinct, wedge-shaped zone (Figs. 1B9, 2A,D, 3A–D) at thecoronal level of the bsc, the chemoarchitectonic featuresand connections of which appear continuous with thosefound more rostrally in the traditional LP. This wedge,larger but in a similar location to a cytoarchitectonic zonetermed LP in some previous investigations (Asanuma etal., 1985; Baleydier and Morel, 1992), lies partly withinthe traditional PM and partly in PL. The present parcel-lation uses the term PLd rather than LP to refer to thisdistinct dorsolateral region because major affiliations ofLP appear to be with somatosensory area 5 (Jones et al.,1979; Pons and Kaas, 1985; Yeterian and Pandya, 1985;Acuna et al., 1990). In addition, a previous histochemicalstudy described a similar triangular, AChE-rich zone as adorsolateral component of PL (Lysakowski et al., 1986).The remainder of the dorsal pulvinar, corresponding tothe major part of the traditional PM nucleus, is referred toas “PM” (Fig. 1B). Depending on the section level, a vari-able amount of the present PM reaches the lateral marginof the dorsal pulvinar between PLd and the PI complex(Figs. 1B, 3). On the basis of chemoarchitectonics andconnections detailed below, PM is divided into medial(PMm) and lateral (PMl) subdivisions. Within PMm is anoval region with distinctive connections, termed the cen-tral division of medial PM, PMm-c (Fig. 1B).

PLd. All three chemoarchitectonic stains showed adistinct, wedge-shaped area in the dorsolateral pulvinar,corresponding to the present PLd. This region appeareddark with AChE histochemistry (Fig. 2A,D) and moderateto dark with parvalbumin staining (Fig. 2B,E), but palewith calbindin immunocytochemistry (Fig. 2C,F). The PLdwas seen in coronal sections at the crossing of the bsc (Fig.3, levels A, B) and extended caudally (Fig. 3, levels C, D)for up to a millimeter. Both calbindin and AChE stainsdemarcated PLd sharply from medially adjacent zones(Fig. 2D,F). A distinct, outer band of intense calbindinstained fibers and neuropil and clumps of calbindin-positive neurons capped PLd (region above asterisks, Fig.2F). These calbindin-enriched clusters corresponded tosomewhat less obvious triangular areas of diminishedparvalbumin stain (with embedded darker clumps) thatalso capped the pulvinar (Fig. 2E; see also Fig. 3A–C,middle column). In previous reports, this capping zoneappears to have been considered a caudal extension of theposterior superior division of the ventral lateral (VL) nu-cleus (VLps; Olszewski, 1952; Asanuma et al., 1985; Ba-leydier and Morel, 1992) or a posterior portion of the VLnucleus (VLp; Jones, 1985). Walker (1938) termed it thepars angularis of the LP nucleus. Since the IPL and pre-frontal injections that labeled PLd projected to this outerzone as well (see below), and clumps of intense calbindinstain also occurred within PLd proper, we have provision-ally considered it the outer zone of PLd and use the earlierterm pars angularis (p.a.).

PMl. This mediolaterally elongated region adjoinedthe ventral border of the PLd subdivision and the dorsalborder of the PI complex (Figs. 1B, 3A–-D). PMl was not asdarkly and uniformly stained as PLd was by the AChEhistochemical technique (Figs. 1B, 2D,G; 3A–D, right col-umn). In sections prepared by parvalbumin immunohisto-chemistry, PMl had darkly stained cells and moderatelystained neuropil (Figs. 2B,H, 3A–D, middle column). Neu-ropil staining was non-uniform, with patches of lighterand darker stain (Figs. 2B,H, 3A–D). At more caudallevels (e.g., Fig. 3B–D, middle column), the parvalbumin


Figure 6


stain was consistently lighter dorsomedially. Sections ofPMl prepared for calbindin immunocytochemistry re-vealed dark staining of neurons and moderate to darkneuropil. As with the parvalbumin marker, the neuropilstaining was also patchy, but there appeared to be acomplementary pattern of parvalbumin and calbindinstain: locations that were moderate or dark with parval-bumin tended to be lighter with calbindin (compare Fig.2B,C and H,I).

PMm. This most medial and ventral subdivision of thedorsal pulvinar was bordered by PMl, by the medial dorsalnucleus (MD), and by the AChE-rich nucleus limitans(Lim) and suprageniculate (Sg) complex of the thalamus(Figs. 1A,B, 3A–D). The PMm division was easily differ-entiated from PMl due to the much lighter staining of itsneuropil with AChE (Figs. 1B,B9, 2A,G,J, 3A–D, rightcolumn) and generally lighter parvalbumin stain (Figs.2B,K, 3A–D, middle column). Both markers produced non-uniform staining in ventral PMm (see PMm-c, below). Thedorsomedial portion of PMm was pale but showed clustersof intense AChE and moderate parvalbumin staining thatappeared to be continuous with, although less dense than,the densities that typify MD (e.g., Fig. 3A–D, right col-umn). PMm also showed moderate, patchy stain with cal-bindin immunohistochemistry (Fig. 2C,L). As was the casein PMl, patches that stained lightly with parvalbuminappeared to correspond to patches that stained moredarkly for calbindin (Fig. 2B,C).

PMm-c. A distinct oval sector of darker AChE andparvalbumin stain was consistently located within ventralPM, enclosed medially and dorsally by a halo of lighterstain (Figs. 1B, 2J,K, 3B–D, middle column). This zonewas moderately stained with calbindin (Fig. 2C,L). Onindividual coronal sections, this oval was approximately 1mm wide and 2 mm or more long (Fig. 3D). Since this zonealso had distinctive connections (see below), we refer to itas central PMm (PMm-c), but consider it a histochemicalcomponent of PMm rather than a separate nucleus.PMm-c was more distinct with parvalbumin than with theother two stains.

Rostrocaudal extent of neurochemical subdivisions

of dorsal pulvinar. All four histochemical units weremaximally developed near the level of the bsc (Fig. 3B–D),but varied in rostrocaudal extent. Whereas the smallestunit, PMm-c, extended only about 1 mm rostrocaudally,PMm and PMl continued rostrally to adjoin the mediodor-sal and anterior pulvinar nuclei, and PLd merged ros-trally with the traditional LP nucleus. Although PMl andPMm extended to the caudal pole, PLd terminated beforereaching the caudalmost portion of the pulvinar (e.g., Fig.3D was the last level for PLd).

Comparison of cortical connections withchemoarchitecture of the dorsal pulvinar

The thalamic connections of posterior parietal, prefron-tal, and superior temporal cortex were compared with the

neurochemical organization of the dorsal pulvinar pre-sented above (Figs. 4–14). Taken as a whole, these partic-ular cortical injection sites produced label located almostexclusively in the dorsal pulvinar with little to no labelingin the PI complex. Posterior parietal and prefrontal injec-tions consistently produced large amounts of label withinPMl and PMm, whereas superior temporal gyrus connec-tions focused in and around PMm-c. The PLd labelingfrom posterior parietal and prefrontal cortex was moder-ately dense but varied from case to case.

Caudal inferior parietal lobule connections. In fourhemispheres (TMG, TMH, TMJ, and TMQ; Fig. 4), injec-tions were placed in the caudal inferior parietal lobule(area PG; Pandya and Seltzer, 1982). As previously illus-trated on coronal sections and unfolded reconstructions(Seltzer et al., 1996), all four injection sites also involvedthe upper bank of the caudalmost end of the superiortemporal sulcus (STS) to some extent, and cases TMJ andTMQ had large injections of WGA-HRP that may haveincluded part of the MST region. Case TMH, by contrast,had minimal involvement of the STS by the injection oftritiated amino acids. In case TMG, radioisotope was in-jected into the crown of the IPL and extended down thelateral bank of the intraparietal sulcus into area LIP (orPOa; Seltzer and Pandya, 1982).

In all four cases, distinct and dense foci of label werefound in PMm and PMl (Figs. 5, 6). Although label wasfound in PLd, it varied considerably in density from caseto case. Consistent with other reports, dense label in PLdmay have depended on the exact placement of the injec-tions within the IPL or a greater degree of involvement ofarea LIP (Asanuma et al., 1985; Baleydier and Morel,1992; Hardy and Lynch, 1992; Baizer et al., 1993). Exceptfor extremely light label in PIM and PIC (not visible in thephotographs in Figs. 5, 6; see drawings in Figs. 10, 11) inthe two cases whose injection may have involved areaMST (TMJ and TMQ), the neurochemically defined PIcomplex was not labeled.

Superimposition of images of transported label on sec-tions stained for chemoarchitecture revealed that trans-ported label respected the proposed neurochemical subdi-visions (Figs. 5–9). In addition, the different configurationof label in PMl, as opposed to PMm, provided furtherevidence that these are distinct divisions (e.g., Figs. 5B,6G). In case TMJ, the most extensive focus of label formedan ovoid patch, centered and elongated rostrocaudally inPMl (Figs. 5A–F, focus “1,” 10A–F). By contrast, labelwithin PMm occurred in bands oriented more or less par-allel to the outer border of PMm (Figs. 5B–D, focus “2,”10C–F), and in patches more ventrally in PMm (Figs.5B–D, 10C–F). Together, the foci of label clearly avoidedthe location of PMm-c, and thus provided further evidencefor PMm-c as a distinct module within PMm (Fig. 5B,C).Label was also localized to the Lim nucleus in this case(Fig. 10B) and was present, but relatively sparse in PLd(not visible because of the dark AChE stain in Fig. 5; seeFig. 10A–D).

Like TMJ, case TMQ had a large focus of label in PMlthat occupied nearly the entire rostral-to-caudal extent ofthe dorsal pulvinar (Figs. 6, “focus 1,” 11A–I). Althoughthe densest label was less extensive than in case TMJ,label was also found in PMm (Fig. 6, “focus 2,” 11A–F)where it avoided PMm-c (Figs. 6F–H, 11C,D). Of the fourcases, TMQ had the largest amount of label in the PLddivision (Figs. 6, “focus 3,” 11A–G). This focus extendedrostrally from near the caudal end of PLd (Fig. 6I) for more

Fig. 6. A–J: Distribution of WGA-HRP label transported from IPLcompared with parvalbumin chemoarchitecture. The overlays of HRPlabel onto directly adjacent sections treated for parvalbumin immu-nocytochemistry were composed as in Figure 5. Focus 1 occupies PMl,focus 2 occupies the outer edge of PMm, and focus 3 is a dense patchin the PLd subdivision. Anteriorly, focuses 1 and 3 fuse and continuerostrally into the lateral posterior nucleus (LP) of Olszewski (1952).Case TMQ. Scale bar 5 1 mm in A (applies to A–J).


than 1 mm, fused with the label in PMl (Fig. 6D,E), andcontinued rostrally in the location of the traditional LPnucleus (Olszewski, 1952; ig. 6A,B). Although not an em-phasis of the present study, patches of label were found incase TMQ that precisely overlapped parvalbumin-enriched patches within Olszewski’s (1952) densocellulardivision of MD (Fig. 7B, inset). This case also had sparselabel in the SG-Lim complex (Fig. 11A–C) and in PIM andPIC (Fig. 11A, B), the latter of which may have been due toinvolvement of the MST region by the tracer injection(Boussaoud et al., 1992).

The two remaining posterior parietal injections (casesTMG and TMH) revealed essentially the same pattern ofprojections to the dorsal pulvinar (Figs. 8, 12, 13). Al-though a small focus was found in PLd (Figs. 8A, purplelabel, 13A–E) in case TMH, the densest label occupiedPMl (Figs. 8A–F, 13A–I). A separate, more rostrocaudally

restricted focus of dense label occurred in PMm (Figs.8B–E, 13C–F) that avoided PMm-c (Figs. 8C–F, 13C–F).In both cases, the PMl and PMm foci partially fused (e.g.,Figs. 8, levels B,E, 12G–I), and additional label was foundin MDdc (Figs. 12A, 13A).

Dorsolateral prefrontal connections. Prefrontal in-jections of radiolabeled amino acids in cases TMJ, TMI,TMP, and TMQ were located in the cortex between theupper bank of the principal sulcus and the rostral bank ofthe upper spur of the arcuate sulcus, corresponding toarea 46 and, except for case TMJ, extended caudally toencompass portions of the frontal eye fields (area 8,Walker, 1940) (Fig. 4; see Cusick et al., 1995). In additionto the expected label in the mediodorsal and more rostralthalamic nuclei (see Huerta et al., 1986; Stanton et al.,1988), connections were found in separate locations in PLdand PMl (Figs. 7A–D, 10A–F, 11A–D, 14A–F).

Fig. 7. Overlapping and non-overlapping projections from dorso-lateral prefrontal and IPL cortex into subdivisions of dorsal pulvinar.A–D: Enlargements of C–F of Figure 6 with the IPL label coloredpurple. Most of this WGA-HRP label appears to be anterograde trans-port, and the images captured at low magnification do not allowretrogradely labeled neurons to be distinguished. The [35S] label,transported from prefrontal cortex and visualized on films of theidentical parvalbumin immunoreacted sections, is colored red. Areas

of overlapping ARG and HRP label (see insets) appear pink (or fuch-sia). Overlays were composed as for Figure 5, with the addition ofcolor in semitransparent layers so that regions of overlap would behighlighted. Insets (enlarged to 250%): Zones of overlap and non-overlap in PMl (A, D), PLd (B, top, and C) and the densocellulardivision of MD (i.e., the lateral part of MD containing denser clustersof parvalbumin stain; see B, bottom). Case TMQ. Scale bar 5 1 mm inB (applies to A–D).


In case TMQ, radiolabeled terminals were generallyrestricted to the more rostral sector of the dorsal pulvinar(Figs. 7A–D, reddish label, 11, black label), tending toform multiple small patches, between 250 and 500 mm indiameter, in PLd and PMl. This contrasted with thebroader pattern of label from the IPL at the same levels(Figs. 7A–D, 11A–D). Frontally derived label in PMm wasextremely sparse and generally restricted to its ventrome-dial edge (Fig. 11A), although dense label was foundwithin the caudal pole of MD (Figs. 7A–C, 11A–C) inaddition to a distinct, narrow focus of label in Lim (Figs.7A,B, 11A,B).

The pattern of labeling within the dorsal pulvinar inthe other three cases with prefrontal injections was

generally similar to that of TMQ. Cases TMI (not illus-trated), TMJ (Fig. 10A–F), and TMP (Fig. 14A–F) eachshowed distinct foci of label in PMl. Significant labelwas also found in PLd, except in case TMJ, whose pre-frontal injection did not reach the “bend” of the arcuatesulcus. Two cases, TMJ (Fig. 10A–D) and TMP (Fig.14D–F), showed notable, albeit light, label in PMm. Innone of the four cases was prefrontal label found inPMm-c.

Superior temporal gyrus connections. Large injec-tions of WGA-HRP (Fig. 4) were placed in either the mid-dle (cases TMG and TMH) or caudal third (cases TMI andTMP) of the STG. Cases TMG and TMH had injectionsthat involved areas Ts3 and paAlt, whereas TMI and TMP

Fig. 8. A–F: Non-overlapping projections from cortical injectionsites in the IPL and STG. Transported ARG label from the IPL isshown in purple, and WGA-HRP label is shown in green on an adja-cent series of sections stained for AChE. The HRP label appears to bemainly anterograde. Insets: The predominant pattern for PMl, which

is of closely apposed but non-overlapping label. Overlays were com-posed as for previous figures. Sections are arranged from rostral tocaudal and spaced about 250 mm apart. Insets are enlarged 300%.Case TMH. Scale bar 5 1 mm in C (applies to A–F).


Figure 9


involved paAlt and Tpt (Pandya and Sanides, 1973). Theseare predominantly auditory areas (Morel et al., 1993;Hackett et al., 1998), and, as might be predicted, theinjections produced label within the medial geniculatecomplex and thalamic cell groups dorsal to it, i.e., in Sg-Lim (Figs. 8A , 9A, 12A–D, 13A–D).

Projections from the STG to the dorsal pulvinar werepredominantly to the PMm subdivision (Figs. 8, 13, caseTMH; Fig. 9, TMI; Fig. 12, TMG; Fig. 14, TMP). Labeledterminals were focused over PMm-c in all four cases,densely filling it on individual coronal sections in caseTMI (Fig. 9B9,C9). In three cases, lighter label also ex-tended beyond PMm-c into PMm proper (e.g., Fig. 8B–E).By contrast to the pattern of label in PMm, the PMldivision contained widely dispersed, small (less than 500mm) foci of HRP label that varied in location (Figs. 8A–D,9B9, 12D, 13B–E,G,H, 14B,C,F). PMl label was slightlymore prominent in the case with the rostralmost injection(TMH; Figs. 8A–D, 13B–E,G,H) compared with the others(Figs. 9B9, 12, 14). A few small PMl foci occurred within anarrow AChE- and parvalbumin-poor zone at the PMl/PLd border, but no foci were detected within PLd itself(e.g., Figs. 8A–C and insets A,B, 9D9).

Double labeling: parietal vs. prefrontal connections.

The two hemispheres with paired injection sites in the IPLand dorsolateral prefrontal cortex (cases TMJ and TMQ)showed both overlapping and non-overlapping patterns ofconnections within the dorsal pulvinar. Although the totalarea of actual overlap was comparatively small, this mightbe due to the cortical injections not being completelymatched, or, more likely, the relatively restricted patternof prefrontal projections to the dorsal pulvinar. When theamount of overlap is compared with the total amount ofprefrontal label seen in the dorsal pulvinar, it is clear thatabout half of the patches of prefrontal connections areoverlapped by IPL connections (e.g., 7 of 15 patches indorsal pulvinar shown in Fig. 7A–D, 10A,C–F). Overlap-ping and non-overlapping connections were also observedat the edge of the MD nucleus and in its densocellulardivision in case TMQ (Fig. 7A,B, lower inset in B).

Parietal vs. superior temporal connections. The twohemispheres with matched injections in the caudal IPLand STG showed closely apposed but only non-overlappinglabel in PMm and PMl (Figs. 8A–F, 12, 13). In PMl, theSTG label generally presented as smaller, isolated patchesat the edge of the IPL label. Indeed, on pairs of adjacentsections of PMl, the STG projections appeared to interlockthe IPL projections by invaginating into the larger block ofIPL label (Fig. 8, insets A–F). The reverse pattern, i.e.,parietal connections inserted into a larger region of supe-rior temporal connections, was not found.

Superior temporal vs. prefrontal connections. In

two hemispheres (TMI, not illustrated and TMP, Fig. 14),injections in the superior temporal gyrus were combinedwith prefrontal ones. Few STG connections were foundoutside of PMm-c and PMm, and few prefrontal connec-tions were found in PMm. Consequently, the differenttypes of label tended to be widely separated from eachother (Fig. 14A–D) or were extremely sparse (Fig. 14E,F)and were neither interlocking nor overlapping.

DISCUSSION

Neurochemical organization of thedorsal pulvinar

Converging neurohistochemical and connectional evi-dence supports the parcellation of the dorsal pulvinar inmacaques into three broad zones, termed PLd, PMl, andPMm. A further connectional/architectonic subregion ormodule of PMm is identified as PMm-c. Table 1 summa-rizes the neurochemical characteristics of these divisions,and Figure 15 summarizes their projection patterns fromthe regions of posterior parietal, dorsolateral prefrontal,and superior temporal cortex that were injected with neu-roanatomical tracers. In considering an overall term forthe general region of pulvinar that excludes the inferiorpulvinar complex (Gutierrez et al., 1995) and the anteriorpulvinar nucleus, we chose “dorsal pulvinar” rather than“superior pulvinar” because the latter term might imply acoherent unit at the same level of organization as theinferior pulvinar complex. Although the IPL connectionstargeted all three divisions in some of our cases, the PLd,PMl, and PMm divisions seem less unified by a commonset of connections and sensory topography than the PIcomplex is by striate connections and topography.

Of the three divisions, PLd stains darkest and mostuniformly for AChE and parvalbumin, but appears palewith calbindin immunostaining. It receives dense connec-tions from dorsolateral prefrontal cortex and the IPL.Compared with PLd, PMl has less intense AChE andparvalbumin stain, but also connects with prefrontal cor-tex and the IPL. PMm has the lightest AChE and parval-bumin stain. In addition to projections from the IPL andminor connections from the prefrontal cortex, PMm is themain dorsal pulvinar target of the superior temporal gy-rus. This latter projection focuses on the subdivisionPMm-c. The specific location of PMm-c is avoided by IPLand prefrontal connections. Both PMl and PMm show apatchy pattern of light and dark AChE and parvalbuminstain that is generally complementary to dark and lightpatches of calbindin immunoreactivity. The existence ofthese irregularly shaped regions of lighter and darkerhistochemical stain (e.g., Fig. 2A–C), together with thepatchy patterns of connections within PMl and PMm,suggests that PM as a whole may have a modular orcompartmental organization. Indeed, the unit termedPMm-c might best be interpreted as a module withinPMm that may be auditory-related.

Traditional cytoarchitectonic parcellations (e.g., Friede-mann, 1911; Crouch, 1934; Walker, 1938; Olszewski,1952; Jones, 1985) differ considerably with regard to theextent of the PM and PL nuclei. Indeed, up to now, themain distinguishing architectonic criterion has been thepresence of mediolaterally directed fiber bundles in PLand their absence in PM (Kaas and Huerta, 1988). Modernneuroanatomical tracing studies (e.g., Benevento andRezak, 1976; Rezak and Benevento, 1979; Benevento and

Fig. 9. Distribution of WGA-HRP traced from the superior tempo-ral gyrus to divisions of dorsal pulvinar. A–D: Locations of chemoar-chitectonic divisions on parvalbumin stained sections. A*–D*: Thesame sections with transported WGA-HRP label (black regions) over-laid. The densest label is focused in the ventral portion of PMm, andoverlies the parvalbumin-dense PMm-c (ovals on sections B–D). Labelin A appears within the Sg-Lim complex, from which point it extendsposteriorly into PMm-c. B also shows a much lighter focus of label inPMl. The arrow in D9 points to a small but dense focus of label over theintralaminar zone between PMl and PLd. The sections are labeledA–-D from rostral to caudal and are spaced at 250-mm intervals. CaseTMI. Scale bar 5 2 mm in D9 (applies to all panels).


Figure 10


Standage, 1983; Ungerleider et al., 1983; Baleydier andMorel, 1992) and several architectonic studies (Crouch,1934; Rezak and Benevento, 1979; Gutierrez et al., 1995)show that the traditional PL has in fact distinct dorsal andventral sectors. The ventral part of classical PL overlapsthe retinotopically mapped zone of the pulvinar (Gattasset al., 1978; Bender, 1981) in monkeys and is a striaterecipient region that has connections with many, if notmost, retinotopically organized cortical areas (Ogren andHendrickson, 1976; Benevento and Davis, 1977; Ogrenand Hendrickson, 1979; Graham, 1982; Ungerleider et al.,1983, 1984; Lysakowski et al., 1988; Gutierrez and Cusick,1997; Beck and Kaas, 1998; Stepniewska et al., 1999).Based on this pattern of connections and its distinctivechemoarchitectonic features, we have proposed that theventral part of classical PL more appropriately be consid-ered part of the retinotopically organized PI complex (Gu-tierrez et al., 1995; Gray et al., 1999).

By contrast, the dorsal sector of classical PL does notinterconnect with visuotopically organized cortical areas(for reviews, see Kaas and Huerta, 1988; Gutierrez et al.,1995; Robinson and Cowie, 1997) but rather has well-established connections with “high order” areas of theparietal and frontal lobes (reviewed in the Introduction).This pattern of connections allies the dorsal part of clas-sical PL with adjacent portions of the PM nucleus. In thepresent parcellation, therefore, the designation PLd isused to denote a distinct triangular region of AChE stainin the nonretinotopically organized dorsal sector of classi-cal PL. It appears to correspond to what has alternativelybeen regarded as “dorsolateral PL” (Lysakowski et al.,1986) or a caudal extension of the LP nucleus (Tro-janowski and Jacobson, 1974; Asanuma et al., 1985; Ba-leydier and Mauguiere, 1987; Baleydier and Morel, 1992).Because major connections of the LP nucleus are withsomatosensory area 5 (Jones et al., 1979; Pons and Kaas,1985; Yeterian and Pandya, 1985; Acuna et al., 1990), thepresent parcellation follows the more traditional designa-tion of this region as PL rather than LP.

Previous studies show that lateral and medial sectors ofthe classical PM nucleus have different patterns of corticalconnections (Romanski et al., 1997). Indeed, distinctAChE staining patterns within PM distinguish sectorsthat project to orbitofrontal cortex from others with pari-etal and temporal association cortex connections (Cavadaet al., 1995). These findings are compatible with thepresent observations, based on three different architec-tonic stains, indicating a division of the medial pulvinarinto two broad neurochemical zones, PMl and PMm, eachwith distinctive patterns of cortical connections. Furtherstudies are needed to determine how cortical and subcor-tical connections other than those with the regions in-jected in this study relate to these neurochemical subdi-visions, but some suggestions can be made from previousstudies. For example, PMm, rather than PMl, appears to

be a specific medial sector within the dorsal pulvinar thathas significant connections with auditory “belt” and “para-belt” cortex (Morel et al., 1993; Pandya et al., 1994; Hack-ett et al., 1998). Previous studies also suggest thatconnections with superior temporal polysensory, parahip-pocampal and orbitofrontal cortices may concentratewithin PMm while connections of insular cortex may focuswithin PMl (Bos and Benevento, 1975; Mufson and Mesu-lam, 1984; Baleydier and Mauguiere, 1985; Friedman andMurray, 1986; Yeterian and Pandya, 1989, 1991; Barbaset al., 1991; Romanski et al., 1997). In addition, someinferotemporal-to-dorsal pulvinar connections appear totarget a zone at the traditional PL/PM border, correspond-ing in location to the present PMl (Baleydier and Morel,1992; Baizer et al., 1993; Rockland, 1996; Yeterian andPandya, 1997). PMl, rather than PMm, may receive aseparate focus of projections from the superior colliculus(Harting et al., 1980; Benevento and Standage, 1983).

Correlation of neurochemical organizationwith cortical-pulvinar connection patterns

Because the dorsal pulvinar connects to cortical areasthat are without clear retinotopic or other sensory orga-nization, it is difficult to use topographical connections asa guide for determining its organization. The present ex-periments utilizing large injections of tracer revealed,however, other attributes of the pattern of labeling sup-porting the hypothesis that PLd, PMl, and PMm are sep-arate structural/functional entities. Similar to the presentfindings, posterior parietal projections have previouslybeen described as forming multiple patches in a disk-likeor lamellar configuration within the dorsal pulvinar (We-ber and Yin, 1984; Asanuma et al., 1985; Baleydier andMauguiere, 1987; Baleydier and Morel, 1992; Hardy andLynch, 1992). Although the existence of multiple patchesof connections does not in itself indicate separate pulvinarzones, the correlation with architectonic features and thedifferences in configuration (caliber, periodicity, or orien-tation) of projections can help define valid subdivisions.[Such an approach has been useful for defining corticalsubdivisions. For example, certain cortical areas such asthe MT crescent (MTc) and the caudal, intermediate, androstral divisions of area TPO (TPOc, -i, and -r) were ini-tially distinguished by their unique geometry of connec-tions from better known areas (Kaas and Morel, 1993;Cusick et al., 1995)].

Thus, foci of label originating in the IPL differ in num-ber, size, shape, and orientation in PLd, PMl, and PMm.The IPL projections to PLd form a rostrocaudal cylinder oflabel (Figs. 5–8), whereas the projections to PMl typicallyform a single but broader, rostrocaudally elongated zone,and those to PMm span a short rostrocaudal distance andappear as flattened disks on individual sections (e.g., Figs.5B,D, 6G) that cap and do not enter the PMm-c. Theconfiguration of STG projections, which also differ withregard to the target within the dorsal pulvinar, adds fur-ther support to the present parcellation. Elongated foci ofSTG-derived label are consistently found within PMm,focused on the AChE- and parvalbumin-dark PMm-c. Bycontrast, smaller, widely scattered foci of STG connectionscharacterize PMl. These latter foci tend to overlap AChE-and parvalbumin-light patches. The prefrontal-to-dorsalpulvinar connections, in themselves, give less informationon potential divisions of the dorsal pulvinar due to thesparser amount of label and smaller foci of projectionscompared with those derived from the IPL. By adding to,

Fig. 10. A–F: Charts of label in the dorsal pulvinar in case TMJwith prefrontal and IPL injection sites. The ARG label from theprefrontal cortex is shown in black, and the HRP label from the IPL isindicated by gray dots. The borders of dorsal pulvinar subdivisions arefrom sections stained for parvalbumin and for AChE. Both antero-grade and retrograde label is found with the WGA-HRP method, andthe charts depict the distribution of label without distinguishing thetype. Camera lucida drawings of rostral to caudal series of sectionsspaced at 250-mm intervals.


and intermingling with, zones of IPL label (e.g., Figs. 7,10, 11), however, prefrontal label gives emphasis to thepattern and overall orientation of the IPL connections and

supports the proposed divisions. Thus, frontally derivedlabel is considerably denser in PMl compared with PLd.Frontal label within PMm is often most conspicuous dor-

Fig. 11. A–I: Transported label in the dorsal pulvinar from pre-frontal and IPL injection sites in case TMQ. The ARG label from theprefrontal cortex is shown in black, and the HRP label from the IPL is

indicated by gray dots. Regions with overlapping projections are il-lustrated on Figure 7. The subdivisions PIM and PIC extend caudal tolevel C but are not shown. Conventions as in Figure 10.


Fig. 12. A–I: Transported label in the dorsal pulvinar from IPL and STG injection sites in case TMG. TheSTG label is shown in black, and the IPL label is indicated by gray dots. Conventions as in Figure 10.


Fig. 13. A–I: Transported label in the dorsal pulvinar from IPL and STG injection sites in case TMH.Conventions as in Figure 12.


Fig. 14. A–F: Transported label in the dorsal pulvinar from dorsolateral prefrontal and STG injectionsites in case TMP. Autoradiographic label from the prefrontal cortex is shown in black, and HRP label isshown in gray. Other conventions as in Figure 10.

somedially, typically in small foci located near the caudalpole of MD. This topographic distribution of prefronto-pulvinar connections is in general agreement with previ-

ous studies (Asanuma et al., 1985; Huerta et al., 1986;Stanton et al., 1988; Barbas et al., 1991).

How do distributed networks connect to thedifferent subdivisions of dorsal pulvinar?

Implications of overlapping and non-overlapping connections

In a previous study (Seltzer et al., 1996), comparingterminal label within superior temporal polysensory cor-tex following two intentionally large cortical injections ofdifferent tracers in the same hemisphere, we found thatareas of cortex that interconnect with each other, such asdorsal prearcuate cortex and the caudal IPL (Barbas andMesulam, 1981; Andersen et al., 1985, 1990a; Selemonand Goldman-Rakic, 1988; Cavada and Goldman-Rakic,1989), exhibited overlapping connections within the com-mon target, STP, whereas non-interconnected areas, suchas the vision-related IPL and presumed auditory regionsof the STG (Seltzer and Pandya, 1984; Anderson et al.,1990a; Morel et al., 1993; Pandya, 1995) showed non-overlapping projections to adjacent cortical columns in theSTP. An intermediate pattern, viz., overlap within layerVI, and mainly non-overlap in layers III and IV, was notedfollowing paired injections of non-interconnected regionsof prefrontal and STG cortex (Seltzer et al., 1996).

The present analysis of pulvinar connections from thesame matched cortical injections shows striking parallelsto the STP projections. Only paired prefrontal and IPLinjection sites produce overlapping connections in the dor-sal pulvinar; these are found mainly in PLd and PMl, butalso in the adjacent densocellular division of MD. Thenon-convergence of prefrontal and STG projections to thedorsal pulvinar might be predicted from the fact that theinjected portions of these cortical regions did not signifi-cantly interconnect with each other. However, several pre-vious connectional studies (Barbas et al., 1999; Hackett etal., 1999; Romanski et al., 1999) suggest the existence ofdistributed networks with a prefrontal-STG component.Perhaps injections in other, more anterior or ventral, pre-frontal locations would have resulted in prefrontal/STGoverlap in dorsal pulvinar.

The present results of non-overlapping STG and IPLconnections in dorsal pulvinar are predicted by the gen-eral principle that cortical regions relating to different, inthis case auditory and visual, sensory modalities haveseparate corticothalamic pathways. In fact, the projectionzones frequently lie in direct apposition to each other, withthe STG label filling a notch in the IPL label (e.g., Fig. 8).These findings, combined with the patches of light anddark histochemical stain in PMl and PMm, and especiallythe existence of the consistently identifiable unit PMm-c,suggest that the widespread connections of PM with nu-

TABLE 1. Neurochemical Characteristics of Dorsal Pulvinar Subdivisions

Histochemicalmarker PLd PMl PMm PMm-c

AChE Dense, uniform; dorsolateraledge somewhat lighter,patchy

Moderate, uniform topatchy

Moderate to light,patchy

Moderate, darker thansurrounding zone

Parvalbumin Dense, uniform; dorsolateraledge somewhat lighter,patchy

Moderate, patchy Moderate to light,patchy

Moderate, darker thansurround

Calbindin Light; dorsolateral edgedark with intenselystained cells

Moderate, patchy Moderate, patchy Moderate

Fig. 15. Schematic diagram of the projections of prefrontal, poste-rior parietal, and superior temporal cortex onto neurochemical divi-sions of the dorsal pulvinar. The thick, intermediate, and thin arrowsindicate dense, moderate, and sparse connections, respectively. Al-though only corticopulvinar projections are represented, the densestprojection zones are likely to have reciprocal connections. The branch-ing of the arrows is not intended to suggest that single corticalneurons send axons that branch to all the targeted divisions, althoughthis is a possibility. The prefrontal cortex and the inferior parietallobule project to similar locations in the dorsal pulvinar, and some,but not all, of these projections overlap. The projections of the superiortemporal gyrus, by contrast, do not overlap the prefrontal or posteriorparietal projections.


merous functionally different cortices may be sortedwithin the nucleus by a “modular” type of organization.Such a compartmentation might be considered a basicfeature of thalamic organization, analogous to that shownby sensory thalamic relay nuclei. For example, differentsensory channels segregate into separate modules (e.g.,lemniscal vs. spinothalamic) within the ventroposteriorcomplex (Rausell et al., 1992) and into separate layers(i.e., magno-, parvi-, and koniocellular) within the lateralgeniculate nucleus (Casagrande, 1994).

Functional implications of separate dorsalpulvinar subdivisions

Dorsal prearcuate and posterior parietal cortex havebeen hypothesized to be part of a hemisphere-wide, dis-tributed system of cortical areas concerned with complexbut related visuospatial functions, such as directed atten-tion and control of visually guided actions (Mesulam,1990; Seltzer, 1992; Morecraft et al., 1993; Selemon andGoldman-Rakic, 1988). That these areas project in anoverlapping fashion to multiple foci in dorsal pulvinarsuggests that at least portions of the PMl, PMm, and PLdsubdivisions also belong to the same distributed network,which may include portions of posterior cingulate andparahippocampal cortex as well (Baleydier and Maugui-ere, 1987).

The specific role of the dorsal pulvinar in such networks isnot completely understood, and the network concept does notimply that all components of a given system have the samefunctional contributions. Anatomical data have promptedthe suggestion that cortico-pulvinar-cortical loops may pro-vide an alternative to the corticocortical route by which in-formation can reach higher cortical areas (Sherman andGuillery, 1996, 1998). Although both pathways terminate inlayers III and IV of the cortex (Levitt et al., 1995; Rocklandet al., 1999), physiological studies suggest that thalamiccontributions to cortical activity patterns differ markedlyfrom those of corticocortical circuits. Thus, thalamocorticalconnections have stronger effects than the corticocortical ineliciting self-sustained activity and postinhibitory reboundexcitation in the cortex (Steriade et al., 1998; Grenier et al.,1998), and, for primary somatosensory cortex at least,thalamocortical synapses appear to be more effective thancorticocortical (Gil et al., 1999).

Although these recent lines of evidence suggest differ-ent functional consequences of pulvinocortical and corti-cocortical connections for the activity of high-order corticalnetworks, the existence of multiple subdivisions connectedto the same or to different networks suggests furtherfunctional specialization within dorsal pulvinar. This issupported by the previous suggestion that the PLd regioncorresponds specifically to a zone of pretectal inputs (Ly-sakowski et al., 1986). Furthermore, based on its location,PMl may partly correspond to the physiologically defineddorsomedial pulvinar, Pdm (Petersen et al., 1985; Robin-son et al., 1986), in which a substantial proportion ofneurons showed spatially selective attentional enhance-ment of visual responses. In agreement with this possiblePdm/PMl correlation, PMl has dense interconnectionswith area 7a, and Pdm has physiological properties closelyresembling the visuospatial processing that occurs withinarea 7a (Mountcastle et al., 1975; Robinson et al., 1978;Petersen et al., 1987; Andersen, 1987; Siegel and Read,1997).

The nature of functional specialization among subdivi-sions of the dorsal pulvinar is difficult to predict, espe-

cially in light of the multiple roles that have been pro-posed for the posterior parietal areas with which all threedivisions connect (Mountcastle et al., 1975; Lynch et al.,1977; Robinson et al., 1978; Andersen, 1987; Andersen etal., 1990b; Siegel and Read, 1997). In addition to visualresponse properties, dorsal pulvinar neurons are stronglymodulated by attention or movement intention (Petersenet al., 1987; Acuna et al., 1990; Robinson and Petersen,1992; Salzmann, 1995). For example, neurons in LP andadjacent portions of the dorsal pulvinar have been foundto be activated by reaching movements of the limbs andsome show goal direction selectivity (Acuna et al., 1990).Furthermore, because of its widespread connections withsensory cortex of different modalities, the dorsal pulvinarhas been suggested as a site of sensorimotor integration,and single pulvinar neurons have been found to exhibitboth movement-related and auditory responses (Yirmiyaand Hocherman, 1987). As a starting point for examiningfunctional specialization of dorsal pulvinar subdivisions,the present study suggests that auditory and visual func-tions may be partly segregated and provides a histochem-ical map that will allow testing of this hypothesis.

How do the dorsal pulvinar and the inferiorpulvinar complex relate to functional

streams of primate visual cortex?

Both the dorsal pulvinar, encompassing PLd, PMl andPMm, and the inferior pulvinar complex have been longbeen implicated as playing roles in spatial or visual atten-tion (LaBerge and Buchsbaum, 1990; reviewed by Cha-lupa, 1991; Robinson and Cowie, 1997). Each connectswith multiple, but different, sets of visual cortical areas.Unlike the PI complex, the dorsal pulvinar has no connec-tions with striate cortex or area V2 (Rezak and Benevento,1976; Ungerleider et al., 1983; Kennedy and Bullier, 1985)and lacks retinotopic organization (Bender, 1981; see Rob-inson and Cowie, 1997 for review). Since posterior parietalcortex connects densely with the dorsal pulvinar and lacksconnections with the PI complex, the dorsal pulvinar maytherefore relate to the dorsal cortical visual stream deal-ing with localization of visual stimuli and other “visuospa-tial” functions. PM of the dorsal pulvinar also has well-established connections with inferotemporal cortex, partof the ventral visual stream dealing with form and colorrecognition (e.g., Baleydier and Morel, 1992; Baizer et al.,1993; Steele and Weller, 1993; Rockland, 1996; Yeterianand Pandya, 1997). Thus, the dorsal pulvinar relates toboth dorsal and ventral streams of visual processing. Pos-terior parietal and inferotemporal connections, however,occupy segregated territories of PM (Baleydier and Morel,1992; Baizer et al., 1993).

By contrast, the inferior pulvinar complex of New Worldand Old World monkeys relates to retinotopically orga-nized visual areas, such as V1, V2, DLr, DM, MT, MST,and FST (Wong-Riley, 1977; Ungerleider et al., 1983,1984; Kennedy and Bullier, 1985; Lysakowski et al., 1988;Boussaoud et al., 1992; Cusick et al., 1993; Gutierrez andCusick, 1997; Beck and Kaas, 1998; Gray et al., 1999;Stepniewska et al., 1999), as well as area TEO and lateralportions of the inferior temporal cortex (Benevento andRezak, 1976; Baleydier and Morel, 1992; Baizer et al.,1993; Steele and Weller 1993; Rockland, 1996). This pat-tern of connections would appear at first to associate theinferior pulvinar complex with the ventral cortical visualstream dealing with color and form perception (Ungerlei-


der and Mishkin, 1982; Van Essen and Gallant, 1994;Casagrande, 1994). Because of its connections with themotion-related areas MT, MST, and FST (Standage andBenevento, 1983; Ungerleider et al., 1984; Boussaoud etal., 1992), however, the PI complex cannot be simply con-sidered the ventral stream component of the pulvinar,rather, a more accurate generalization might be to con-sider the PI complex as the retinotopic or striate-recipientzone of the pulvinar, as opposed to the dorsal pulvinar,which is dominantly parietal-recipient.

Although the dorsal pulvinar and inferior pulvinar com-plex show different cortical connections, many visual ar-eas appear to connect with both of these units. For exam-ple, in New World monkeys and in macaques, areas MT,the adjacent rostral dorsolateral area (DLr), and area DMconnect not only with the PI complex but also with aspecific zone of dorsal pulvinar in the location of PMl(Cusick et al., 1993; Beck and Kaas, 1998; Gray et al.,1999). Ventral stream areas V4, TEO, and lateral TEconnect mainly with the PI complex, but also with foci indorsal pulvinar at the classical PM/PL border, correspond-ing in location to the present PMl (Baleydier and Morel,1992; Baizer et al., 1993; Steele and Weller, 1993; Websteret al., 1993; Rockland, 1996; Yeterian and Pandya, 1997).

This lack of an absolute partitioning of visual corticalconnections between dorsal pulvinar and inferior pulvinarcomplex may reflect the significant degree of integrationbetween the two visual streams that occurs at every level ofthe cortex (Merigan and Maunsell, 1993; Webster et al.,1994; Schall et al., 1995). An alternative, albeit closely re-lated view, would hold that the major divisions of the pulv-inar reflect dichotomous contributions for actions in space vs.visual perception (Milner and Goodale, 1993) for the dorsalpulvinar and inferior pulvinar complex, respectively. A neu-robiological model of cortical information processing hasbeen proposed in which the pulvinar was assigned a key rolein the integration of dorsal and ventral stream activities(Olshausen et al., 1993). Indeed, a vision-related zone in thedorsal pulvinar such as PMl, which, based on its location,appears to connect to areas belonging to both streams (Ba-leydier and Morel, 1992; Baizer et al., 1993), and to corre-spond to a location in which neurons are sensitive to bothcolor/pattern and spatial stimulus properties (Beneventoand Port, 1995), might be a candidate site for dorsal/ventralstream integration.

ACKNOWLEDGMENTS

We thank C’Lita Henry for technical assistance,Amanda Yaun, MD, for help with the AChE preparations,and Todd M. Preuss, PhD, and Jeff Padberg for commentson an earlier version of the manuscript.

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Neurochemical and connectional organization of the dorsal pulvinar complex in monkeys