THEJOURNALOFCOMPARATIVENEUROLOGY442:163–187(2002)

AnalysisofProjectionsFromtheMedial PrefrontalCortextotheThalamusinthe Rat,WithEmphasisonNucleusReuniens

ROBERTP.VERTES* CenterforComplexSystemsandBrainSciences,FloridaAtlanticUniversity, BocaRaton,Florida33431

ABSTRACT Themedialprefrontalcortex(mPFC)isinvolvedinhigh-ordercognitiveprocesses, including,butnotlimitedto,decisionmaking,goaldirectedbehavior,andworkingmemory. AlthoughpreviousreportshaveincludeddescriptionsofmPFCprojectionstothethalamusin overallexaminationsofmPFCprojectionsthroughoutthebrain,nopreviousstudyhas comprehensivelyexaminedmPFCprojectionstothethalamus.Thepresentreportcompares andcontrastsprojectionsfromthefourdivisionsofthemPFC,i.e.,theinfralimbic,prelimbic, anteriorcingulateandmedialagranularcortices,tothethalamusintheratbyusingthe anterogradeanatomictracerPhaseolusvulgaris-leucoagglutinin.Weshowedthat(1)the infralimbic,prelimbic,anteriorcingulatecorticesdistributeheavilyandselectivelyto midline/medialstructuresofthethalamus,includingtheparatenial,paraventricular,inter- anteromedial,anteromedial,intermediodorsal,mediodorsal,reuniens,andthecentralmedial nuclei;(2)themedialagranularcortexdistributesstronglytotherostralintralaminarnuclei (centrallateral,paracentral,centralmedialnuclei)aswellastotheventromedialand ventrolateralnucleiofthalamus;and(3)allfourdivisionsofthemPFCprojectdenselytothe nucleusreuniens(RE)ofthethalamus.Thenucleusreuniensisthemajorsourceofthalamic afferentstothehippocampalformation.Thereareessentiallynodirectprojectionsfromthe mPFCtothehippocampus.ThepresentdemonstrationofpronouncedmPFCprojectionsto REsuggeststhatthenucleusreuniensisacriticalrelayinthetransferofinformationfrom themedialprefrontalcortextothehippocampus.OurfurtherdemonstrationofstrongmPFC projectionstoseveraladditionalthalamicnuclei,particularlytothemediodorsalnucleus, suggeststhatthesethalamicnuclei,likeRE,representimportantoutputstations(orgate- ways)fortheactionsofmPFCondiversesubcorticalandcorticalstructuresofthebrain.J. Comp.Neurol.442:163–187,2002. ©2002Wiley-Liss,Inc.

Indexingterms:infralimbiccortex;prelimbiccortex;mediodorsalnucleus;paraventricular nucleusofthalamus;workingmemory

Anextensivebodyofdataindicatesthatthemedial Price,1995;Swanson,1998;O¨ ngu¨randPrice,2000).The prefrontalcortexisdirectlyinvolvedinhigherordercog- foursubdivisionsofmPFCprojecttoMD,butmPFC-MD nitiveprocesses,includingdecisionmaking,goaldirected projectionsarenotcompletelyreciprocated.Apparently, behavior,andworkingmemory(Goldman-Rakic,1987, MDdoesnotprojecttotheinfralimbiccortex(Krettekand 1994;Fuster,1989;Kolb,1990;Petrides,1995,1998).The medialprefrontalcortex(mPFC)hasextensiveintercon- nectionswiththemediodorsalnucleus(MD)ofthethala- mus.ThePFChas,infact,beendefinedasMD-projection Grantsponsor:NIH;Grantnumber:NS35883;Grantsponsor:NIMH; cortex(Price,1995;O¨ ngu¨randPrice,2000).ThemPFCin Grantnumber:MH01476. theratconsistsoffourmainsubdivisions,whichfrom *Correspondenceto:Dr.RobertP.Vertes,CenterforComplexSystems andBrainSciences,FloridaAtlanticUniversity,BocaRaton,FL33431. dorsaltoventralconsistofthemedialagranular(orme- E-mail:[email protected] dialprecentral),theanteriorcingulate(dorsalandventral Received18May2001;Revised13August2001;Accepted20October divisions),theprelimbic,andtheinfralimbiccortices(Be- 2001 rendseandGroenewegen,1991;RayandPrice,1992; PublishedonlinetheweekofNovember26,2001

©2002WILEY-LISS,INC. DOI10.1002/cne.10083 164 R.P. VERTES

Price, 1977; Groenewegen, 1988; Ray and Price, 1992; tutes of Health Guidelines for the Care and Use of Labo- Price, 1995). ratory Animals. Although medial PFC projections to MD have received Powdered lectin from PHA-L was reconstituted to 2.5% considerable attention, a growing body of evidence indi- in 0.05 M sodium phosphate buffer, pH 7.4. The PHA-L cates that mPFC projects to several other nuclei of the solution was iontophoretically deposited in the brains of and that projections to some of them may be as anesthetized rats (Nembutal: 60 mg/kg, i.p.) by means of a robust as those to MD (Krettek and Price, 1977; Beck- glass micropipette with an outside tip diameter of 40–60 stead, 1979; Room et al., 1985; Sesack et al., 1989; Hurley ␮m. Positive direct current (5–10 ␮A) was applied through et al., 1991; Takagishi and Chiba, 1991; Buchanan et al., a Grass stimulator (model 88) coupled with a high voltage 1994; Reep and Corwin, 1999). To our knowledge, no pre- stimulator (FHC, Bowdoinham, ME) at 2 seconds on/2 vious study has comprehensively examined projections seconds off intervals for 30–40 minutes. After a survival from the mPFC to the thalamus. One aim of this report time of 7–10 days, animals were deeply anesthetized with was to examine, compare, and contrast projections from sodium pentobarbital (120 mg/kg, i.p.) and perfused tran- the medial agranular (AGm), anterior scardially with a buffered saline wash (pH 7.4, 300 ml/ cingulate cortex (AC), prelimbic cortex (PL), and infralim- animal) followed by fixative (2.5% paraformaldehyde, bic cortex (IL) to the thalamus. 0.05–0.1% glutaraldehyde in 0.05 M phosphate buffer, pH In a previous examination of afferent projections to the 7.4) (300–500 ml/animal) and then by 10% sucrose in the nucleus reuniens (RE) of the thalamus by using retro- same phosphate buffer (150 ml/animal). The brains were grade tracers (Vertes and Crane, 1996), we showed that removed and stored overnight at 4°C in 20% sucrose in the RE receives wide ranging projections from diverse sites of same phosphate buffer. On the following day, 40 or 50 ␮m the , , basal forebrain, hippocam- frozen sections were collected in phosphate-buffered sa- pus (mainly the ), and cortex. Particularly strik- line (PBS, 0.9% sodium chloride in 0.01 M sodium phos- ing, we observed pronounced numbers of retrogradely la- phate buffer, pH 7.4) and incubated for 1 hour in diluent beled neurons along the entire wall of mPFC, indicating (10% normal rabbit serum [Colorado Serum, Denver, CO] strong mPFC afferents to RE. A second aim of the present and 1% Triton X-100 [Sigma Chemicals, St. Louis, MO], in report was to examine patterns of mPFC projections to PBS). Sections were then incubated overnight (14–17 nucleus reuniens. hours) at 4°C in primary antiserum directed against PHA-L (biotinylated goat anti-PHA-L, Vector Laborato- ries, Burlingame, CA) at a dilution of 1:500 in diluent. The MATERIALS AND METHODS next day, sections were washed 5 times for 5 minutes each Single injections of Phaseolus vulgaris-leucoagglutinin (5 ϫ 5 minutes) in PBS, and then incubated in the second (PHA-L) were made into the four subdivisions of the antiserum (rabbit anti-sheep IgG, Vector Labs) at a dilu- mPFC in 61 male Sprague-Dawley (Charles River, Wil- tion of 1:500 in diluent for 2 hours. Sections were rinsed mington, MA) rats, each weighing 275–325 g. These ex- again (5 ϫ 5 minutes) and incubated with peroxidase- periments were approved by the Florida Atlantic Univer- antiperoxidase (goat origin, Sternberger Monoclonals, sity Institutional Animal Care and Use Committee and Baltimore, MD) at a dilution of 1:250 for 2 hours. The last conform to all federal regulations and the National Insti- two incubations were repeated (double-bridge procedure),

Abbreviations

AC anterior cingulate cortex LP lateral posterior nucleus ACC LV lateral ventricle AD anterodorsal nucleus MD,c,l,m mediodorsal nucleus, central, lateral and medial divisions AGm medial agranular (prefrontal) cortex MH medial AId agranular , dorsal division ML AM, AMv anteromedial nucleus; AM, ventral part mPFC medial prefrontal cortex AO anterior olfactory nucleus MT AV anteroventral nucleus OT olfactory tubercle CA1,3 CA1, CA3 fields of Ammon’s horn PC paracentral nucleus CC corpus callosum PF parafascicular nucleus CEM central medial nucleus PH posterior nucleus of CL central lateral nucleus PL prelimbic cortex CLA PO posterior nucleus DG dentate gyrus of hippocampal formation PT paratenial nucleus EC PVa,p paraventricular nucleus; anterior and posterior divisions F fornix RE nucleus reuniens FI fimbria of hippocampal formation FR fasciculus retroflexus RH rhomboid nucleus GU gustatory area of cortex RT reticular nucleus HF hippocampal formation SI primary somatosensory cortex IAD interanterodorsal nucleus SM stria medullaris IAM interanteromedial nucleus SME submedial nucleus IC internal capsule ST IL infralimbic cortex VAL ventral anterior-lateral complex IMD intermediodorsal nucleus VB ventrobasal complex LGNd,v lateral geniculate nucleus, dorsal and ventral divisions VM ventromedial nucleus LH lateral habenula ZI LD lateral dorsal nucleus 3V third ventricle PROJECTIONS FROM THE MPFC TO THE THALAMUS 165 with 5 ϫ 5 minutes rinses after each incubation, for 1 hour the anterior paraventricular nucleus (PVa), interantero- each. After 5 ϫ 5 minutes rinses, the sections were incu- medial nucleus (IAM) and the rostral pole of nucleus re- bated in 0.05% 3,3Ј-diaminobenzidine (DAB) in PBS for 10 uniens (RE) (Fig. 3A,B). Labeling was stronger ipsilater- minutes, followed by a second, 5 minutes, DAB (same ally than contralaterally in each of these sites. concentration) incubation to which 0.018% H2O2 had been Further caudally in the thalamus (Fig. 2C,D), labeled added. Sections were then rinsed again in PBS (3 ϫ 1 fibers progressively coalesced into distinct dorsal and ven- minutes) and mounted onto chrome-alum gelatin-coated tral clusters. Labeled axons of the dorsal cluster termi- slides. An adjacent series of sections was stained with nated massively in the medial and central divisions of MD cresyl violet for anatomic reference. and strongly in the lateral MD (Fig. 4) as well as moder- Sections were examined by using light and darkfield ately in PV and in the intermediodorsal nucleus (IMD). optics. PHA-L–labeled cells (at injection sites) and fibers Those of the ventral cluster primarily distributed to the were plotted onto maps constructed from adjacent Nissl- rhomboid nucleus and RE, terminating heavily in the stained sections. The main criteria used to distinguish ventrolateral RE, ipsilaterally (Fig. 4). IAM, lying be- labeled terminals from fibers of passage were (1) the pres- tween the clusters, was moderately labeled (Fig. 2C). ence or essential absence of axon/terminal specializations, At mid-levels of the thalamus (Fig. 2E,F), labeled fibers and (2) the degree of axonal branching. Terminal sites remained fairly restricted to the dorsal and ventral clus- were typically characterized by a dense array of highly ters, mainly terminating in the MD complex dorsally and branched axons containing numerous specializations (var- RE ventrally. Medial MD (MDm) and IMD were densely icosities, terminal boutons), whereas passing fibers exhib- labeled (Fig. 5); MDc and MDl lightly labeled. As shown in ited minimal branching and contained few specializations. Figure 5, labeled axons blanketed RE (outlining the nu- In schematic representations of patterns of labeling with cleus) and were densely concentrated in ventrolateral as- injections in the infralimbic (Fig. 2), prelimbic (Fig. 7), pects of RE ipsilaterally. PV was moderately labeled. anterior cingulate (Fig. 11), and medial agranular (Fig. The primary targets of labeled fibers at caudal levels of 14) cortices, labeled fibers are depicted as long lines (more the thalamus were the posterior PV (PVp), MDm, and abundant ipsilaterally than contralaterally), whereas ter- IMD dorsally, and the central medial nucleus ventrally minal endings are represented as shorter lines within (Fig. 2G,H). As depicted in Figure 6, the entire extent of boundaries of nuclei. The pronounced ipsilateral (left side) PV was heavily labeled. A few labeled axons were also collection of fibers reflects the fact that labeled axons from present in the dorsal MDl, the central lateral nucleus IL, PL, AC, and AGm predominantly descend ipsilaterally (CL), the lateral dorsal nucleus (LD), and the parafascicu- to the thalamus and innervate the contralateral thalamus lar nucleus (PF) (Fig. 2G,H). from the ipsilateral side. Distinct differences in the ap- There were no differences in patterns of labeling, only pearance of coursing fibers and terminal endings can also differences in density of labeling, with injections along the be seen in the photomicrographs. rostrocaudal continuum of IL. A comparison of rostral, intermediate, and caudal IL injections showed that, rela- RESULTS tive to the other sites, rostral IL injections produced heavier labeling in PT and MDc, intermediate injections The patterns of distribution of labeled fibers to the thal- resulted in stronger labeling in MDm and IMD, and cau- amus after injections in four regions of the medial prefron- dal injections gave rise to denser labeling in IAM and tal cortex (infralimbic, prelimbic, anterior cingulate, and anteromedial nucleus (AM). In addition, the rostral IL medial agranular cortices) are described. Figure 1 sche- projects much more heavily to lateral than to medial re- matically depicts sites of injection in these four regions. gions of RE; the reverse is true for the caudal IL, i.e., The patterns of labeling obtained with these four schemat- stronger projections to the medial than to the lateral RE. ically illustrated cases (see below) are representative of patterns found with nonillustrated cases. Prelimbic cortex: Case 671 Infralimbic cortex: Case 701 Figure 7 schematically depicts the distribution of la- Figure 2 schematically depicts the pattern of distribu- beled fibers within the thalamus after a PHA-L injection tion of labeled fibers to the thalamus after a PHA-L injec- in the PL. As depicted (Fig. 1C,D), PHA-L–filled cells in tion in the IL. As depicted schematically (Fig. 1A,B), PHA- PL were restricted to layers V and VI, predominantly L–filled cells in IL were primarily restricted to layer VI, concentrated in layer VI. with some extension to layer V, mainly ventrally in layer V. Similar to IL, labeled axons from PL descended ipsilat- The main bundle of labeled fibers from IL descended erally to the thalamus and reached the contralateral thal- ipsilaterally on the medial edge of the internal capsule, amus from the ipsilateral side, mainly targeting midline/ turned dorsomedially into the thalamus at the rostral medial groups of the thalamus. At the rostral thalamus thalamus (Fig. 2A,B) and continued caudally through the (Fig. 7A,B), labeled PL fibers distributed densely to PT thalamus giving off terminal axons in route. Labeled fi- (Fig. 8), to ventrolateral aspects of rostral RE (Fig. 8), to bers reached the contralateral thalamus from the ipsilat- IAM, and to the ventral division of AM (AMv) as well as eral side. moderately to the rostral pole of PV (PVa). Further cau- As shown in Figure 2, labeling was virtually confined to dally in the rostral thalamus (Fig. 7C,D), labeling was midline/medial regions of the thalamus. Exceedingly few primarily confined to the MD complex and PV dorsally and labeled fibers were present in lateral parts of the thala- to RE ventrally. As depicted in Figure 9, labeled axons mus. At the rostral thalamus (Fig. 2A,B), labeled axons swept dorsomedially into MD to terminate massively distributed massively to the paratenial nucleus (PT) (Fig. throughout rostral MD bilaterally. RE was also densely 3A) and to medial aspects of the mediodorsal nucleus (MD) labeled, particularly ventrolateral RE, ipsilaterally. IAM (Fig. 3B) as well as strongly, but somewhat less densely, to and RH were moderately labeled. 166 R.P. VERTES

Fig. 1. Schematic representation of sites of injection in the infral- cingulate, and medial agranular cortices were restricted to layers V imbic (A,B), prelimbic (C,D), anterior cingulate (E,F), and medial and VI (see also text). Schematic sections adapted from Swanson agranular (G,H) cortices of the medial prefrontal cortex. Phaseolus (1998). For abbreviations, see list. vulgaris-leucoagglutinin–filled cells in infralimbic, prelimbic, anterior PROJECTIONS FROM THE MPFC TO THE THALAMUS 167

Figure 1 (Continued) Fig. 2. A–H: Schematic representation of selected sections through the diencephalon depicting labeling present in the thalamus produced by a Phaseolus vulgaris-leucoagglutinin injection in the infralimbic cortex (case 701). Sections aligned rostral to caudal. For abbreviations, see list. PROJECTIONS FROM THE MPFC TO THE THALAMUS 169

Fig. 3. Darkfield photomicrographs of transverse sections through the rostral diencephalon showing patterns of labeling at two levels of the rostral thalamus produced by an injection in the infralimbic cortex. Note pronounced labeling in the paratenial nucleus (A), nucleus reuniens (A,B), and the rostral pole of the mediodorsal nucleus (B). For abbreviations, see list. Scale bar ϭ 450 ␮m in B (applies to A,B).

At mid-levels of the thalamus (Fig. 7D–F), labeling re- Anterior cingulate cortex: Case 652 mained dense in MDm and IMD (Fig. 10) but subsided in Figure 11 schematically depicts the distribution of la- lateral and central divisions of MD. The PV dorsally and beled fibers within the thalamus after a PHA-L injection RE ventrally continued to be heavily labeled (Fig. 10). A in the AC. As depicted (Fig. 1E,F), PHA-L–filled cells in few labeled fibers extended laterally from MD, termi- AC were restricted to layers V and VI, predominantly nating in the central lateral nucleus and LD (Fig. 7E,F). concentrated in inner layer V and layer VIa (Swanson, At the caudal thalamus (Fig. 7G,H), labeled axons of the 1998). dorsal thalamus distributed densely to medial MDm, Labeled fibers mainly descended ipsilaterally from AC PV, and IMD (Fig. 7G,H); moderately to dorsolateral to the thalamus through dorsomedial aspects of the inter- MD and to the parafascicular nucleus (PF); and lightly nal capsule. At the rostral thalamus (Fig. 11A,B), labeled to CL, LD, and LP; whereas those of the ventral thala- axons distributed over a widespread area of the medial mus terminated strongly in central medial nucleus thalamus, terminating densely in PT, AM (particularly in (CEM; Fig. 7G,H). AMv), IAM, and RE; moderately in PV, RH, and MD; and There were essentially no differences in patterns of lightly in rostral aspects of the anterodorsal (AD), antero- labeling, only differences in density of labeling, with in- ventral (AV), and reticular (RT) nuclei of the thalamus. jections located rostrocaudally within PL. Injections in the Figure 12 shows massive terminal labeling in AM (AMd rostral PL produced stronger labeling in most thalamic and AMv) bilaterally as well as dense labeling in IAM sites, notably including PT, MD, IMD, and posterior as- and RE. pects of PV. Particularly striking was a marked decrease Further caudally in the rostral thalamus (Fig. 11C,D), in the number of labeled fibers in MDc with progressively labeled axons continued to mainly occupy medial regions caudal PL injections. IAM and AM received stronger pro- of the thalamus. The primary targets were PV, AM, IAM, jections from the caudal than rostral PL. MDl, CEM, and LD dorsally, and the rhomboid nucleus 170 R.P. VERTES

Fig. 4. Darkfield photomicrograph of a transverse section through intermediodorsal nuclei dorsally; the nucleus reuniens (RE) ventrally; the rostral diencephalon showing patterns of labeling at the rostral particularly dense terminal fields throughout all divisions of MD thalamus produced by an injection in the infralimbic cortex. Note ipsilaterally (left side); as well as ventrolateral aspects of RE ipsilat- pronounced labeling in the paraventricular, mediodorsal (MD), and erally. For abbreviations, see list. Scale bar ϭ 450 ␮m.

(RH) and RE ventrally (Fig. 11C,D). Ventrolateral aspects Although labeling thinned at mid-levels of the thalamus of RE were densely labeled bilaterally (Fig. 13). Labeled (Fig. 11E,F), it remained dense in dorsal MDl and RE (Fig. axons appeared to course through but not terminate in AV 11E,F) as well as moderate in CL (adjacent to MDl) and in route to MDl. IMD (Fig. 11E,F). Only scattered labeling was observed PROJECTIONS FROM THE MPFC TO THE THALAMUS 171

Fig. 5. Darkfield photomicrograph of a transverse section through and medial mediodorsal (MDm) nuclei dorsally; nucleus reuniens the diencephalon showing patterns of labeling at the mid-thalamus (RE) ventrally; particularly dense terminal fields within MDm bilat- produced by an injection in the infralimbic cortex. Note pronounced erally; and ventrolateral aspects of RE ipsilaterally (left side). For labeling virtually confined to the paraventricular, intermediodorsal, abbreviations, see list. Scale bar ϭ 450 ␮m. outside of these structures. At the caudal thalamus (Fig. stronger projections to PT and RE, whereas those in the 11G,H), labeling continued to be strong in MDl and dorsal caudal AC denser labeling in IAM and AM, particularly CL, but less pronounced elsewhere. PV, IMD, LP, PF, and ventral aspects of AM. By contrast, relatively marked differ- CEM were lightly to moderately labeled. ences were observed with injections along the dorsoventral There were no differences in patterns of labeling, only continuum of AC. For instance, ventral AC injections, com- minor differences in densities, with rostral compared with pared with dorsal ones, produced considerably denser labeling caudal AC injections. Injections in rostral AC gave rise to in PV, MDc, IMD, CEM, and ventrolateral aspects of MDl. 172 R.P. VERTES

Fig. 6. Darkfield photomicrograph of a transverse section through the caudal diencephalon showing patterns of labeling at the caudal thalamus produced by an injection in the infralimbic cortex. Note pronounced labeling throughout the paraventricular nucleus dorsally and within the caudal pole of the central medial nucleus ventrally. For abbreviations, see list. Scale bar ϭ 450 ␮m.

Medial agranular cortex: Case 632 thalamus with AGm injections (Fig. 14A). Further cau- dally within the rostral thalamus (Fig. 14B–D), however, Figure 14 schematically depicts the distribution of la- moderate to dense terminal labeling was observed in (1) beled fibers within the thalamus after a PHA-L injection in the AGm. As depicted (Fig. 1G,H), PHA-L–filled cells in midline structures, including the interanterodorsal nu- AGm were restricted to layers V and VI, predominantly cleus (IAD), IMD, medial AM, IAM, RH, and RE; (2) in- concentrated in layers VIa,b (Swanson, 1998). tralaminar nuclei, including CEM, the paracentral nucleus Labeled fibers mainly descended ipsilaterally from AGm (PC) and central lateral nucleus (Cl); and (3) lateral nuclei, to the thalamus through medial regions of the internal comprising the ventral medial nucleus (VM) and the ventral- capsule. By comparison with the strong labeling in the anterior lateral complex (VAL) (Fig. 15). PV, MD, LD, and rostral thalamus with PL, IL, and AC injections, relatively the submedial nucleus (SME) (Fig. 14B–D) were lightly la- few labeled fibers were seen at the rostral pole of the beled. In contrast to IL, PL, and AC injections, which pro- Fig. 7. A–H: Schematic representation of selected sections through the diencephalon depicting labeling present in the thalamus produced by a Phaseolus vulgaris-leucoagglutinin injection in the prelimbic cortex (case 671). Sections aligned rostral to caudal. For abbreviations, see list. 174 R.P. VERTES

Fig. 8. Darkfield photomicrograph of a transverse section through cleus reuniens (RE) ventrally. Labeling was denser in both PT and RE the rostral diencephalon showing patterns of labeling at the rostral ipsilaterally (left side) than contralaterally. For abbreviations, see thalamus produced by an injection in the prelimbic cortex. Note list. Scale bar ϭ 450 ␮m. pronounced labeling in the paratenial nucleus (PT) dorsally and nu-

duced heaviest labeling in ventrolateral regions of RE, AGm There were no differences in patterns of labeling but injections gave rise to strongest labeling in medial RE (Fig. relatively significant differences in density of labeling 14C–F). with injections along the rostrocaudal continuum of AGm. At mid-levels of the thalamus (Fig. 14E,F), labeling Rostral compared with caudal AGm injections (i.e., caudal remained strong in several of the structures labeled fur- to the rostral pole of the septum) gave rise to considerably ther rostrally. For instance, labeled fibers continued to denser labeling in most thalamic sites, including VM, terminate massively in VAL and VM ipsilaterally, as well VAL, MDl, CL, and PO. There were no thalamic sites at as strongly in RE, IMD, MDl, CEM, PC, CL. The medial which caudal AGm injections produced heavier labeling part of the posterior complex (PO) (Fig. 14F), RH, LD, and than rostral injections. SME were lightly to moderately labeled. The primary targets of labeled fibers at the caudal thalamus (Fig. 14G,H) were CL, LD, CEM, PV, MD, IMD, and PF. Lateral DISCUSSION PVp, MDl, and CL were densely labeled; PF, PO, CEM, We describe projections from the infralimbic, prelimbic, IMD, MDm, and LP were moderately labeled. A few la- anterior cingulate, and medial agranular cortices of the beled axons were observed in LH. mPFC to the thalamus in the rat. The main findings were PROJECTIONS FROM THE MPFC TO THE THALAMUS 175

Fig. 9. Darkfield photomicrograph of a transverse section through ipsilaterally (left side) than contralaterally. Note also pronounced the diencephalon showing patterns of labeling at the rostral thalamus labeling in the paraventricular nucleus (between the two halves of produced by an injection in the prelimbic cortex. Note labeled fibers MD) and the intermediodorsal nucleus dorsally as well as the nucleus coursing dorsomedially into the dorsal thalamus and terminating reuniens ventrally. For abbreviations, see list. Scale bar ϭ 450 ␮m. massively in all divisions of the mediodorsal nucleus (MD), stronger as follows: (1) IL, PL, and AC predominately distribute to four divisions of mPFC distribute densely to nucleus re- midline/medial structures of the thalamus, including the uniens; and (4) IL and PL project massively to MD, AC paratenial, paraventricular, interanteromedial, antero- projects strongly to MD, and AGm distributes moderately medial, intermediodorsal, mediodorsal, reuniens, and cen- to MD, mainly to its caudolateral aspects. tral medial nuclei; (2) the pattern of projections from AGm Projections of the four divisions of mPFC: differs from that of IL, PL, and AC; that is, AGm sends fewer projections to the medial thalamus and considerably Comparisons with previous studies more to the lateral thalamus than do IL, PL, or AC, To our knowledge, no previous report has comprehen- including pronounced projections to the paracentral, cen- sively examined mPFC projections to the thalamus. How- tral lateral, ventromedial, and ventrolateral nuclei; (3) all ever, as part of overall analyses of prefrontal connections, 176 R.P. VERTES

Fig. 10. Darkfield photomicrograph of a transverse section intermediodorsal nucleus, and the medial division of the mediodorsal through the caudal diencephalon showing patterns of labeling at the nucleus dorsally and the nucleus reuniens ventrally. For abbrevia- caudal thalamus produced by an injection in the prelimbic cortex. tions, see list. Scale bar ϭ 450 ␮m. Note labeling essentially confined to the paraventricular nucleus, reports have included descriptions of mPFC projections to anterograde studies as well as those describing mPFC the thalamus (Krettek and Price, 1977; Beckstead, 1979; projections to the thalamus by using retrograde tech- Room et al., 1985; Sesack et al., 1989; Hurley et al., 1991; niques. Takagishi and Chiba, 1991; Buchanan et al., 1994; Reep Infralimbic cortex. As described (Table 1), IL fibers and Corwin, 1999). Comparisons will be made with these virtually exclusively target the midline/medial thalamus. Fig. 11. A–H: Schematic representation of selected sections through the diencephalon depicting labeling present in the thalamus produced by a Phaseolus vulgaris-leucoagglutinin injection in the anterior cingulate cortex (case 652). Sections aligned rostral to caudal. For abbreviations, see list. 178 R.P. VERTES

Fig. 12. Darkfield photomicrograph of a transverse section through the rostral diencephalon showing patterns of labeling at the rostral thalamus produced by an injection in the anterior cingulate cortex. Note pronounced labeling in the dorsal and ventral anteromedial (AM) nucleus bilaterally and particu- larly dense terminal fields in ventral AM ipsilaterally. For abbreviations, see list. Scale bar ϭ 450 ␮m.

IL projects: (1) densely to the paratenial, paraventricular, (Buchanan et al., 1994), and to RE in the cat (Room et al. mediodorsal, intermediodorsal, reuniens, and central me- 1985). dial nuclei; (2) moderately to interanteromedial and rhom- In accord with the foregoing, injections of retrograde boid nuclei; and (3) at best sparingly to remaining regions tracers in several medial thalamic sites, including PT-PV of thalamus. (Chen and Su, 1990; Hurley et al. 1991; Risold et al., The results of previous studies largely support the 1997), MDm (Groenewegen, 1988; Cornwall and Phillip- present findings showing that IL distributes heavily to the son, 1988; Hurley et al., 1991), and RE (Herkenham, 1978; medial thalamus but minimally to other parts of the thal- Hurley et al., 1991; Risold et al., 1997) have been shown to amus (Room et al., 1985; Hurley et al, 1991; Takagishi and produce strong retrograde cell labeling in IL. For instance, Chiba, 1991; Buchanan et al., 1994). By using PHA-L in Groenewegen (1988) described pronounced numbers of la- rats, Hurley et al. (1991) showed that IL distributes vir- beled cells in IL with injections in MDm but exceedingly tually exclusively to PT, PV, MD, and nucleus reuniens of few with injections in MDc or MDl. the medial thalamus. For example, they reported that IL Interestingly, despite strong IL to MD (MDm) projec- fibers (1) project densely to the lateral part of PV and tions, there appear to be no return projections from MD to medial aspects of MD (their PV-MD border zone), and (2) IL (Krettek and Price, 1977; Groenewegen, 1988; Ray and essentially blanket RE. They remarked, in fact, that la- Price, 1992). By contrast, both PV (Berendse and Groe- beling was so dense in RE that it precluded a determina- newegen, 1990; Moga et al., 1995; Otake and Nakamura, tion of the orientation of labeled fibers. 1998) and RE (Herkenham, 1978; Ohtake and Yamada, Other reports in various species have similarly shown 1989; Risold et al., 1997) send pronounced projections to IL. that IL distributes strongly to nuclei of the medial thala- Although previous findings generally support present mus, that is, to PT, PV, MD, CEM, and RE in the rat results, there are some notable differences. For instance, (Takagishi and Chiba, 1991), to PT and PV in the rabbit in accord with previous studies (Groenewegen, 1988; PROJECTIONS FROM THE MPFC TO THE THALAMUS 179

Fig. 13. Darkfield photomicrograph of a transverse section nucleus and the dorsolateral part of the mediodorsal nucleus dorsally through the diencephalon showing patterns of labeling at the mid- and along the midline from dorsal to ventral in the central medial thalamus produced by an injection in the anterior cingulate cortex. nucleus, rhomboid nucleus, and throughout nucleus reuniens ven- Note pronounced labeling ipsilaterally (left side) in the central lateral trally. For abbreviations, see list. Scale bar ϭ 450 ␮m.

Cornwall and Phillipson 1988; Hurley et al, 1991; Tak- thalamus. Differences could involve variations in place- agishi and Chiba, 1991), we found that IL distributes ments of IL injections across studies. Alternatively, massively to MDm, but unlike these reports, we also dem- most of the above structures lie lateral to, and in the onstrated moderately dense IL projections to MDc and path of, fibers coursing from the internal capsule to the MDl. In addition, we did not observe IL projections to medial thalamus, suggesting that the labeling seen pre- several sites described previously, including the reticular viously may have largely represented passing fibers (Takagishi and Chiba, 1991), anteromedial (Takagishi rather than terminal endings. In this regard, labeled and Chiba, 1991; Room et al., 1985), anteroventral (Tak- cells have not been observed in IL after injections of agishi and Chiba, 1991), ventral medial (Takagishi and retrograde tracers in VM or VL (Herkenham, 1979; Chiba, 1991; Hurley et al., 1991; Buchanan et al., 1994), Jimenez-Castellanos and Reinoso-Suarez, 1985; Na- and the ventral basal complex (Buchanan et al., 1994) of kano et al., 1985). Fig. 14. A–H: Schematic representation of selected sections through the diencephalon depicting labeling present in the thalamus produced by a Phaseolus vulgaris-leucoagglutinin injection in the medial agranular cortex (case 632). Sections aligned rostral to caudal. For abbreviations, see list. PROJECTIONS FROM THE MPFC TO THE THALAMUS 181

Fig. 15. Darkfield photomicrograph of a transverse section through the rostral diencephalon showing patterns of labeling at the rostral thalamus produced by an injection in the medial agranular cortex. Note dense labeling in the ventral anterior lateral complex and in the nucleus reuniens, which is stronger ipsilaterally (left side) than contralaterally. For abbreviations, see list. Scale bar ϭ 450 ␮m.

Prelimbic cortex. As described (Table 1), PL fibers, distributes strongly to PT, PV, IAM, IMD, RH, RE, and like those of IL, predominantly target the medial thala- CEM, and very densely to RE, rostral MDm, and MDl. mus. PL fibers terminate densely in PT, PV, rostromedial Sesack et al. (1989) further described PL projections to part of AM, IAM, IMD, MD, RH, RE, and caudal CEM, and RT, AV, VM, paracentral, and the central lateral nuclei. moderately in the parafascicular and lateral posterior nu- We found that PL fibers traverse, but essentially do not clei. There was a significant overlap in PL and IL projec- terminate in, each of these cell groups. tions to the thalamus raising the possibly that injections In accord with the foregoing, injections of retrograde in the two sites at least partially overlapped. We discount tracers in several medial thalamic sites, including PT-PV this possibility, however, based on our findings that IL (Chen and Su, 1990; Hurley et al., 1991; Risold et al., and PL essentially only project to common sites in the 1997), IMD-MD (Groenewegen, 1988; Cornwall and Phill- thalamus, that is, aside from the thalamus, they distrib- ipson, 1988), RE (Herkenham, 1978; Risold et al., 1997), ute to very different structures throughout the brain and AM (Seki and Zyo, 1984), have been shown to give rise (Vertes and Todorova, 1999). to pronounced numbers of labeled neurons in PL. Further- In accord with present findings, early autoradiographic more, it was generally reported that retrograde injections examinations of PL projections in rats (Beckstead, 1979) in most of these structures produced roughly equivalent and cats (Room et al., 1985) demonstrated significant PL numbers of labeled cells in IL and PL, supporting our projections to dorsal regions of the medial thalamus (PV, findings of overlapping IL and PL projections to nuclei of PT, MD) but, unlike present results, only described minor the medial thalamus. The single exception appears to be projections to other (ventral) parts of the medial thala- AM, which receives projections from PL but not from IL mus. By contrast, recent studies using PHA-L (Buchanan (Seki and Zyo, 1984 and present results). et al., 1994; Sesack et al., 1989) confirm our demonstration There are pronounced return projections to the prelim- of widespread PL projections throughout the medial thal- bic cortex from PT-PV (Conde et al., 1990, 1995; Berendse amus. For instance, Sesack et al. (1989) reported that PL and Groenewegen, 1991; Moga et al., 1995; Otake and 182 R.P. VERTES

TABLE 1. Density of Labeling in Nuclei of the Thalamus Produced by that is, relatively light projections to the medial thalamus PHA-L Injections in the Infralimbic, Prelimbic, Anterior Cingulate and 1 and strong ones to the lateral thalamus (see below). This Medial Agranular Cortices finding suggests that this injection was mainly localized to Injection sites AGm and not AC. Structures of thalamus IL PL AC AGm In accord with present results (and Buchanan et al., 1994), injections of retrograde tracers in PT-PV (Chen and Anterodorsal n. ϪϪ ϪϪ ϩ ϪϪ Anteromedial n. ϩϩ ϩϩϩ ϩϩϩϩ ϩϩϩ Su, 1990; Hurley et al., 1991; Risold et al., 1997), MD Anteroventral n. ϪϪ ϪϪ ϩϩ ϪϪ (Groenewegen, 1988; Cornwall and Phillipson, 1988), RE Central lateral n. ϪϪ ϩ ϩ ϩϩϩϩ Central medial n. ϩϩϩ ϩϩϩ ϩϩ ϩϩϩ (Herkenham, 1978; Risold et al., 1997) or AM (Seki and Interanterodorsal n. ϩϩϩϩϩϩZyo, 1984) have been shown to produce significant num- Interanteromedial n. ϩϩϩ ϩϩϩϩ ϩϩϩ ϩϩϩ bers of labeled cells in AC. Consistent with the demon- Intermediodorsal n. ϩϩϩ ϩϩϩ ϩϩ ϩϩ Lateral geniculate n. ϪϪ ϪϪ ϪϪ ϪϪ stration that AC fairly selectively distributes to MDl of the Lateral habenula ϩϩϩϪϪMD complex (Beckstead, 1979; Buchanan et al., 1994; and Lateral dorsal n. ϩ ϩ ϩϩ ϩϩϩ Lateral posterior n. ϪϪ ϪϪ ϩ ϩ present results), retrograde injections in MDl, but not in Medial geniculate n. ϪϪ ϪϪ ϪϪ ϪϪ MDc or MDm, resulted in labeled neurons in AC (Groe- Medial habenula ϪϪ ϪϪ ϪϪ ϪϪ Mediodorsal n. ϩϩϩϩ ϩϩϩϩ ϩϩϩ ϩϩ newegen, 1988; Cornwall and Phillipson, 1988). Medial division ϩϩϩϩ ϩϩϩϩ ϩϩ ϩ There are pronounced return projections to AC from Central division ϩϩ ϩϩ ϩ ϩ PT-PV (Conde et al., 1990; Berendse and Groenewegen, Lateral division ϩϩ ϩϩϩ ϩϩϩϩ ϩϩϩ Paracentral n. ϪϪ ϪϪ ϩ ϩϩϩ 1991; Moga et al., 1995), MD/IMD (Krettek and Price, Parafascicular n. ϩ ϩϩ ϩ ϩϩϩ 1977; Groenewegen, 1988; Conde et al., 1990, 1995; Ray Paratenial n. ϩϩϩϩ ϩϩϩϩ ϩϩϩ ϩ Paraventricular n. ϩϩϩϩ ϩϩϩϩ ϩϩϩ ϩϩ and Price, 1992), RE (Ohtake and Yamada, 1989; Conde et Rostral part ϩϩϩϩ ϩϩϩϩ ϩϩ ϩ al., 1990, 1995; Risold et al., 1997), and AM (Beckstead, Caudal part ϩϩϩ ϩϩϩ ϩϩ ϩϩϩ Posterior n. ϪϪ ϪϪ ϪϪ ϩϩ 1976; Shibata, 1993; van Groen et al., 1999). Reticular n. ϪϪ ϪϪ ϩϩ ϪϪ Medial agranular cortex. As shown (Table 1), the Reuniens n. ϩϩϩϩ ϩϩϩϩ ϩϩϩϩ ϩϩϩϩ pattern of AGm projections to thalamus significantly dif- Rhomboid n. ϩϩ ϩϩ ϩϩ ϩϩϩ Ventral anterior-lateral n. ϪϪ ϪϪ ϩ ϩϩϩϩ fers from that of other divisions of mPFC; that is, AGm Ventromedial n. ϪϪ ϪϪ ϩ ϩϩϩϩ fibers predominately target the lateral rather than the Ventroposteromedial n. ϪϪ ϪϪ ϪϪ ϪϪ Ventroposterolateral n. ϪϪ ϪϪ ϪϪ ϪϪ medial thalamus. AGm distributes densely to (1) the in- tralaminar nuclei of thalamus (PC, CL, and CEM); (2) 1ϩ, light labeling; ϩϩ, moderate labeling; ϩϩϩ, strong labeling; ϩϩϩϩ, dense label- ing; ϪϪ, absence of labeling; n, nucleus; PHA-L, Phaseolus vulgaris-leucoagglutinin; anterior nuclei (IAM and medial aspects of AM); and (3) for other abbreviations, see list. the ventral thalamus (VM and VAL) and RE. AGm projects moderately to MD, LD, LP, PO, RH, PF, and PV. An early report by Leonard (1969), by using silver de- generation techniques in rats, demonstrated projections Nakamura, 1998), MD/IMD (Krettek and Price, 1977; from an anterodorsal region of mPFC (her shoulder area) Groenewegen, 1988; Berendse and Groenewegen, 1991; to RT and VM and dense ones to dorsolateral MD. A recent Ray and Price, 1992; Otake and Nakamura, 1998), RE examination of AGm projections in rats, by using (Ohtake and Yamada, 1989; Conde et al., 1990, 1995; [3H]leucine/proline and Fluoro-Ruby (Reep and Corwin, Risold et al., 1997; Otake and Nakamura, 1998), and AM 1999) showed a pattern of projections to the thalamus (Beckstead, 1976; Shibata, 1993; Conde et al., 1995; van strikingly similar to that reported here. Injections were Groen et al., 1999). made at three rostrocaudal levels of AGm. The primary Anterior cingulate cortex. As described (Table 1), AC destinations of fibers from the rostral AGm were PC, CL, fibers predominantly target the medial thalamus, project- CEM, MDl, VM, VL, RH, and LP. Injections at progres- ing to PT, PV, MDl, RH, RE, CEM, and massively to IAM sively caudal levels of AGm produced a shift in labeling to and AM. Unlike IL/PL, however, AC also distributes sig- more lateral and caudal regions of the thalamus. Accord- nificantly to some structures of the lateral thalamus, in- ingly, caudal AGm injections produced strong labeling in cluding CL, LD, and LP. VL, LP, LD, and PO. In partial conflict with present re- In general accord with present findings, Beckstead sults, Reep and Corwin (1999) made no mention of AGm (1979) demonstrated pronounced AC projections to AM, projections to IAM, medial AM or RE. The latter differ- less dense ones to MD and LD, and minor projections to ences probably involve the fact that our injections extend PT. Unlike our results, however, no mention was made of rostral to theirs in AGm. AC projections to PV, IAM, RH, or CEM, and only light Finally, as discussed above, Sesack et al. (1989) de- projections were described to RE. Differences could in- scribed a case with an injection that partially encom- volve the fact that the injections of Beckstead (1979) ap- passed AGm and showed projections from this site to peared caudal to ours in AC. By contrast, Buchanan et al. nuclei of the lateral thalamus, including CL, MDl, VL, PO, (1994), by using PHA-L in rabbits, demonstrated a very LD, and LP. similar pattern of AC projections to thalamus as shown Consistent with the foregoing, injections of retrograde here. They showed that AC fibers (1) distribute widely tracers in MDl (Groenewegen, 1988; Cornwall and Phill- throughout the medial thalamus to PT, CEM, RE, RH, ipson, 1988), RE (Herkenham, 1979), AM (Seki and Zyo, MD; (2) terminate densely in MDl and AM; and (3) avoid 1984), rostral intralaminar complex (PC, CL, and CEM) AD and AV. In a study primarily devoted to PL (see (Kaufman and Rosenquist, 1985), VM and VAL (Herken- above), Sesack et al. (1989) described projections from an ham, 1978; Jimenez-Castellanos and Reinoso-Suarez, injection site spanning dorsal AC and AGm. This injection 1985; Nakano et al., 1985), and LP (Sukekawa, 1988) have produced patterns of labeling similar to those we observed been shown to produce significant numbers of labeled cells with our AGm injections, but not with our AC injections; in AGm. PROJECTIONS FROM THE MPFC TO THE THALAMUS 183

There are significant return projections to the medial that mPFC distributes massively to RE, coupled with the agranular cortex from MD (Krettek and Price, 1977; Reep demonstration that RE is a major source of afferents to the et al., 1984; Groenewegen, 1988; Conde et al., 1990, 1995; , suggests that RE represents an important Hicks and Huerta, 1991; Ray and Price, 1992; Reep and relay in the transfer of information from mPFC to the Kirkpatrick, 1999), RE (Herkenham, 1978; Ohtake and hippocampus. This system of connections (mPFC-RE-HF) Yamada, 1989; Conde et al., 1990; Hicks and Huerta, appears to be the major route from the prefrontal cortex to 1991), AM (Robertson and Kaitz, 1981; Shibata, 1993; van the hippocampus and, accordingly, would complete an im- Groen et al., 1999), the rostral intralaminar complex portant functional loop between HF and mPFC. (Reep et al., 1984; Conde et al. 1990, 1995; Berendse and Groenewegen, 1991; Hicks and Huerta, 1991; Reep and The “nonspecific” thalamus: An important Kirkpatrick, 1999), VM-VAL (Herkenham, 1979; Reep et relay in the transfer of information from al., 1984; Conde et al. 1990, 1995; Hicks and Huerta, 1991; mPFC to subcortical/cortical sites. Reep and Kirkpatrick, 1999), and LP and LD (Sukekawa, All cortical areas receive and send projections to the 1988; Conde et al., 1990; Hicks and Huerta, 1991; van thalamus (Jones, 1985). The conventional view is that Groen and Wyss, 1992; Reep and Kirkpatrick, 1999). cortical projections to the thalamus primarily serve to Massive projections from all divisions of modulate return thalamocortical projections. Although, in part, this is undoubtedly the case, the paradoxical findings mPFC to nucleus reuniens: A critical role that there are 10-fold greater numbers of corticothalamic for RE in cortical-thalamo-hippocampal than thalamocortical fibers suggests that cortical projec- circuitry tions to thalamus do not merely modulate return projec- We showed that all four divisions of mPFC (IL, PL, AC, tions to cortex. AGm) project strongly throughout the rostrocaudal extent Deschenes et al. (1998) recently addressed this issue of RE. IL, PL, and AC fibers terminate heavily in lateral arguing for a revision to the principle of reciprocity, regions of RE; AGm fibers terminate strongly in the whereby cortical output to thalamus merely reciprocates medial RE. its thalamic input. They instead proposed an organization RE is the largest of the midline nuclei of thalamus and based on the rule of parity rather than on reciprocity; that is the principal source of thalamic projections to the hip- is, a match between inputs to thalamus from cortex and pocampus and parahippocampal structures (Herkenham inputs to thalamus from all sources (parity), rather than a 1978; Wyss et al., 1979; Riley and Moore, 1981; Room and match between cortical input to thalamus and thalamic Groenewegen, 1986; Yanagihara et al., 1987; Su and Ben- output to the cortex (reciprocity). tivoglio, 1990; Wouterlood et al., 1990; Wouterlood, 1991; Alternatively, Llinas and coworkers (1998) recently pro- Dolleman-Van der Weel and Witter, 1996). RE distributes posed that the thalamus (or nonspecific thalamus) may densely to CA1 of Ammon’s horn, the ventral subiculum, serve as a way station in the transfer of signals from the and the medial entorhinal cortex (EC) as well as moder- cortex to other parts of the brain. For instance, Llinas et ately to the dorsal subiculum, the parasubiculum, and the al. (1998) stated that the thalamus should not be simply lateral EC (Su and Bentivoglio, 1990; Wouterlood et al., viewed as a gateway to the cortex but rather “the thala- 1990; Wouterlood, 1991). RE fibers form asymmetric, pre- mus represents a hub from which any site in the cortex sumably excitatory connections (Uchizono, 1965) with dis- can communicate with any other such site or sites.” tal dendrites of pyramidal cells in stratum lacunosum- Supporting this view, Groenewegen and colleagues (Be- moleculare of CA1 (Wouterlood et al., 1990). rendse et al., 1988; Groenewegen et al., 1990; Berendse Several reports in various species have described prom- and Groenewegen, 1990, 1991; Groenewegen and Be- inent projections from HF to the prefrontal cortex (Swan- rendse, 1994; Wright and Groenewegen, 1995) have dem- son, 1981; Irle and Markowitsch, 1982; Cavada et al., onstrated that each of the dorsal midline and intralami- 1983; Goldman-Rakic et al., 1984; Ferino et al., 1987; Jay nar nuclei of thalamus receive input from discrete regions et al., 1989; van Groen and Wyss, 1990; Jay and Witter, of the prefrontal cortex and in turn project to specific, 1991; Carr and Sesack, 1996). In rats, hippocampal effer- largely nonoverlapping, zones in the . This find- ents to mPFC arise from temporal aspects of CA1 and the ing indicates that the midline thalamus represents an subiculum and terminate in a fairly restricted region of important relay in channeling information from mPFC to the ventral mPFC, including the medial orbital area, IL the striatum. In like manner, the present findings of and PL (Jay et al., 1989; Jay and Witter, 1991). HF fibers strong projections from mPFC to RE, together with well- form asymmetric synapses with pyramidal cells of mPFC documented RE projections to the HF (Wouterlood et al., (Carr and Sesack, 1996) and exert excitatory actions on 1990; Wouterlood, 1991), suggests that RE serves a simi- them (Ferino et al., 1987; Laroche et al., 1990; Jay et al., lar role for the hippocampus: a critical relay in the trans- 1995). The HF-mPFC projection supports long-term po- fer of information from mPFC to the hippocampus. tentiation at mPFC (Laroche et al., 1990; Jay et al., 1995, Role of mPFC projections to the 1996, 1998; Mulder et al., 1997; Gurden et al., 1999), hippocampus, by means of RE, on memory suggesting that the HF may exert enduring effects on the mPFC (Floresco et al., 1997; Seamans et al., 1998). processing functions Despite well documented HF to mPFC projections, there The medial prefrontal cortex has been linked to several are essentially no direct return projections from the mPFC higher order processes, including attention, working to the hippocampal formation (Beckstead, 1979; Goldman- memory, response selection, as well as the planning, se- Rakic et al., 1984; Room et al., 1985; Reep et al., 1987; quencing, and organization of behavior (Goldman-Rakic, Sesack et al., 1989; Hurley et al., 1991; Takagishi and 1987, 1994; Fuster, 1989; Kolb, 1990; Petrides, 1995, Chiba, 1991; Buchanan et al., 1994). The present findings 1998). The mPFC of rats is thought to be functionally 184 R.P. VERTES homologous to the dorsolateral prefrontal cortex of pri- structures. The medial temporal lobe may then function to mates (Kolb, 1984, 1990; O¨ ngu¨ r and Price, 2000). The bind together from frontal and other cortical regions to function most commonly associated with the prefrontal form lasting, recollectable memory traces. Thus, both re- cortex, and the one most extensively examined, is working gions would be critical to the conception of a memory, and memory; that is, the short-term storage and use of infor- lack of participation of either brain region would disrupt mation (Goldman-Rakic, 1987, 1995). For instance, it has memory.” been shown for monkeys that prefrontal lesions disrupt The presently described system of connections from performance on delayed response tasks (Goldman and mPFC to RE to HF may represent a critical route for the Rosvold, 1970; Passingham, 1975; Mishkin and Manning, transfer of information from mPFC to HF and the ento- 1978; Funahashi et al., 1993; Petrides, 2000) and prefron- rhinal cortex involved in converting information from tal cells discharge selectively during the delay period of short-term to long-term stores. delay tasks (Niki, 1974; Kojima and Goldman-Rakic, 1982; Finally, an accumulating body of evidence indicates that Funahashi et al., 1989; Quintana et al., 1988; Miller et al., the supramamillary nucleus (SUM) of the hypothalamus 1996; Chaffe and Goldman-Rakic, 1998; Romo et al., 1999; is directly involved in the modulation/generation of the Sawaguchi and Yamane, 1999). theta rhythm of the hippocampus (Kirk and McNaughton, A rather extensive body of research in rats has similarly 1991; Kocsis and Vertes, 1994; Bland et al., 1995; Vertes demonstrated that the prefrontal cortex serves a critical and Kocsis, 1997; Bland, 2000; Leranth and Vertes, 2000). role in tasks requiring the maintenance of information The theta rhythm serves a mnemonic function within the over time, including delayed alternation (Larsen and Di- hippocampus (for review, Vertes and Kocsis, 1997; Has- vac, 1978; Silva et al., 1986; van Haaren et al., 1988; Brito selmo, 2000). The SUM projects strongly to RE (Vertes, and Brito, 1990; Bubser and Schmidt, 1990; Kesner et al., 1992) and may relay a theta rhythmic signal from SUM to 1996; Delatour and Gisquet-Verrier, 1996, 1999) and de- RE (Vertes and Kocsis, 1997) possibly involved in gating layed matching and nonmatching to sample tasks (Shaw the flow of information from mPFC to HF, by means of RE, and Aggleton, 1993; Kolb et al., 1994; Granon et al., 1994; during theta-associated states or behaviors. Broersen et al., 1995; Seamans et al., 1995; Harrison and In summary, the infralimbic, prelimbic, and anterior Mair, 1996; Young et al., 1996; Porter and Mair, 1997). cingulate cortices selectively target midline/medial re- It has further been shown that lesions restricted to gions of the thalamus, whereas the medial agranular cor- ventral aspects of mPFC (PL and IL) produce the same tex predominantly projects to the intralaminar and lateral disruptive effects on delayed response tasks as do lesions nuclei of thalamus. All four divisions of the mPFC send of the entire medial wall of the mPFC, indicating that pronounced projections to the nucleus reuniens of the PL/IL may be the crucial mPFC region responsible for thalamus. The nucleus reuniens appears to be an impor- delayed response deficits (Brito and Brito, 1990; Seamans tant relay in the transfer of information from the mPFC to et al., 1995; Delatour and Gisquet-Verrier, 1996, 1999, the hippocampal formation. 2000; Floresco et al., 1997; Ragozzino et al., 1998). For example, Phillips and coworkers (Seamans et al., 1995) initially showed that bilateral inactivation of PL, but not ACKNOWLEDGMENTS of the dorsally adjacent anterior cingulate cortex, pro- We thank Nedialka Todorova for superb technical assis- duced pronounced deficits in the delayed version of an tance in all phases of this study and Sherri Von Hartman eight arm radial maze task and, subsequently, that the for excellent graphic work. same deficits were produced by disconnecting the hip- pocampus from PL (Floresco et al., 1997). The latter find- ings led them to propose that interconnections between LITERATURE CITED the HF, mPFC, and temporal lobe could represent, “a Beckstead RM. 1976. 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