Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat

h%-uroscience Vol. 42, No. 1, pp. 73-102, 1991 Printed in Great Britain

0306-4522/91 $3.00 + 0.00 Pergamon Press plc

0 1991 IBRO

RESTRICTED CORTICAL TERMINATION FIELDS OF THE

MIDLINE AND INTRALAMINAR THALAMIC NUCLEI IN THE RAT

H. W. BERENDS? and H. J. GROEMWRGEN

Department of Anatomy and Embryology, Vrije Universiteit, Van der Boecborststraat 7, 1081 BT Amsterdam, The Netherlands

Abstract-The projections from the midline and intralaminar thalamic nuclei to the cerebral cortex were studied in the rat by means of anterograde tracing with Pheolus vulgar&leucoagglutinin.

The midline and intralaminar nuclear complex taken as a whole projects to widespread, predominantly frontal, cortical areas. Each of the constituent thalamic nuclei has a restricted cortical projection field that overlaps only slightly with the projection fields of adjacent midline and intralaminar nuclei. The projections of the intralaminar nuclei cover a larger cortical area than those of the midline nuclei. The laminar distributions of fibres from individual midline and intralaminar thalamic nuclei are different and include both deep and superficial cortical layers.

The parataenial, paraventricular and intermediodorsal midline nuclei each project to circumscribed parts of the prefrontal cortex and the hippocampal and parahippocampal regions. In the prefrontal cortex, the projections are restricted to the medial orbital, infralimbic, ventral prelimbic and agranular insular fields, and the rostral part of the ventral anterior cingular cortex. In contrast to the other midline nuclei, the rhomboid nucleus projects to widespread cortical areas. The rostra1 intral~inar nuclei innervate dorsal parts of the prefrontal cortex, i.e. the dorsal parts of the prelimbic, anterior cingular and dorsal agranular insular cortical fields, the lateral and ventrolateral orbital areas, and the caudal part of the ventral anterior cingular cortex. Additional projections are aimed at the agranular fields of the motor cortex and the caudal part of the parietal cortex. The lateral part of the parafascicular nucleus sends fibres predominantly to the lateral agranular field of the motor cortex and the rostral part of the parietal cortex. The medial part of the parafascicular nucleus projects rather sparsely to the dorsal part of the prelimbic cortex, the anterior cingular cortex and the medial agranular field of the motor cortex.

Individual midline and intralaminar thalamic nuclei are thus in a position to directly influence circumscribed areas of the cerebral cortex. In combination with previously reported data on the organization of the midline and intralaminar thalamostriatal projections and the prefrontal corticostriatal projections the present results suggest a high degree of differentiation in the convergence of thalamic and cortical afferent fibres in the striatum. Each of the recently described parallel basal ganglia-thalamocortical circuits can thus be expanded to include projections at both the cortical and striatal levels from a specific part of the midline and in~~aminar nuclear complex. The distinctive laminar dist~butions of the fibres originating from the different nuclei emphasize the specificity of the midline and intralaminar thalamocortical projections.

The midline and intralaminar thalamic nuclei constitute a conspicuous nuclear complex in the dorsal thalamus that receives afferents from a wide variety of sources25~26,8’ (for review see Ref. 88). The main targets of this complex include the cerebral cortex, the striatum, the reticular thalamic nucleus, the amygdala and the subthalamic nucteusU L273&7VW ~1,1w27.141 (for

review see Ref. 77). The ~lationship of the midline and intralaminar nuclei with the cerebral cortex is often characterized as non-specific, because of the widespread distribution of their projections over the cortex.69,80,‘27 Furthermore, the mode of termination in the cortex of the fibres originating from these nuclei is reminiscent of the laminar dis~bution of the “unspecific fibres” of Lorente de No.67*69,86 These anatomical data concur with the physiological

*To whom correspondence should be addressed. Abbreviations: CAI, field CA1 of Ammon’s horn; PHA-L,

Phaseolus u~lgaris-leucoagglutinin.

concept of a non-specific corticopetal system, parallel to the cortical projections from the specific or relay nuclei of the thalamus.6473*74,98 The concept is based on the results of experiments in which cortical recruit- ing and arousal reactions were elicited by electrical stimulation of several thalamic areas, including the midline and intralaminar nuclei.3’,73~74*97 The morphology of the neurons within these nuclei, observed in studies using the Golgi method,13’ has strengthened the above-mentioned assumption of non-specificity. However, an increasing body of evidence indicates a higher degree of specificity in the afferent and efferent connections of the midline and intralaminar nuclear complex than was assumed previously. The results of tracing studies have revealed that, in addition to their shared afferents, individual midline and intralaminar nuclei receive specific sets of inputs2S,26 (see references in Refs 11 and 88). Retrograde tracing studies have further shown that the midline and intralaminar projections to separate cortical areas come from

73

14 H. W. BERENDSE and H. J. GROENEWEGEN

different populations of neurons that are either inter- mingled or spatially segregated.9~‘5~78~89’90’1” Finally,

physiological and behavioural studies have provided evidence for the involvement of various nuclei in specific processes. 4,16,30,70,93,108.113,133135

The projections of the midline and intralaminar nuclei to the striatum constitute one of the two major striatal inputs8~‘1~75 and may consist of collaterals given off by the thalamocortical fibres. 22.23.76.'%124,139 The ot,,er

major input is derived from the entire cortical mantle and is arranged in such a way that functionally different cortical areas project to separate striatal regions.82~94,‘3*~‘5’,‘57 This suggests that these striatal sectors are functionally different, a notion substantiated by the results of physiological and behavioural studies, 18.32.39~42,103,109~110,121,122 In the monkey, Alexander

et al.’ have distinguished several parallel circuits lead- ing through the basal ganglia, each including distinct parts of the cerebral cortex, the striatum, the pallidum and the thalamus. In the rat, similarly organized basal ganglia-thalamocortical circuits may exist,5s but the precise organization of these circuits awaits further

elucidation.

prefrontal corticostriatal connections.12 In addition, the laminar distribution of the midline and intra-

laminar thalamic afferent fibres in the cerebral cortex will be described and, for the prefrontal cortex, related to the laminar origin of the patch- versus matrix- directed corticostriatal projections.47 To these aims, the anterograde tracer Phase&r vulgaris-leucoagglutinin (PHA-L), first introduced by Gerfen and Sawchenko,49 was used since it allows the placement of very small deposits of tracer and, furthermore, permits a differentiation between passing and terminating fibres.

EXPERIMENTAL PROCEDURES

Anierograde tracing

In line with the parallel arrangement of forebrain circuits involving cortex, thalamus and basal ganglia, we have demonstrated previously that inputs from the midline and intralaminar nuclei converge with functionally related cortical inputs in three distinct striatal sectors.” One of the objectives of the present study was to determine the degree of specificity in the projections of these thalamic nuclei to the cerebral cortex. For the prefrontal cortex, the organization

of these projections is compared with the parallel arrangement of the thalamostriatal” and that of the

Injections of 2.5% PHA-L49 (Vector Laboratories, U.S.A.) were placed stereotaxically in the thalamus of 38 female Wistar-rats (180-220 g), foilowing anaesthesia with a mixture (4: 3) of ketamine and 2-(2.6-xvlidine)5.6-dihvdro- 1,3-thiazine (dompun), in a dosage of -1 ml/kg. The tracer was applied iontophoretically through glass micropipettes (external tip diameter 15525 pm) using a positive-pulsed 7.5pA current (7 s on/7 s 0% CCS-3 current source, Midgard, U.S.A.) for 15-30min. The coordinates for the injections were derived from the atlas of Paxinos and Watson.‘o7 Survival times of the animals ranged between 6 and 20 days, after which the animals were reanaesthetized with pentobarbital and perfused transcardially with 100 ml saline, followed by 750ml of a fixative containing 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) either with or without 0.05% glutaraldehyde. Following a postfix- ation in the same fixative for 1-2 h, the brains were stored overnight at 4°C in 30% sucrose in 0. I M phosphate buffer (pH 7.4) or in a mixture of 20% glycerol and 2% dimethyl- sulphoxide in distilled water. Subsequently, sections were cut at 40 nm on a freezing microtome and collected in 0.1 M phosphate buffer (pH 7.4).

Abbreviations used in the figures

MO mt oc Par I Par II

ACd ACv AGm AGI AId AIP AIv AM cc cg CL CM CPU Ent FL fr G hbc Hif HL IL IMD LHb LO LV MD MHb

anterior cingular cortex, dorsal part anterior cingular cortex, ventral part agranular field of motor cortex, medial part agranular field of motor cortex, lateral part agranular insular cortex, dorsal part agranular insular cortex, posterior part agranular insular cortex, ventral part anteromedial thalamic nucleus corpus callosum cingulum central lateral thalamic nucleus central medial thalamic nucleus caudate-putamen entorhinal cortex forelimb area fasciculus retroflexus gelatinosus thalamic nucleus habenular commissure hippocampal fissure hindlimb area infralimbic cortex intermediodorsal thalamic nucleus lateral habenular nucleus lateral orbital cortex lateral ventricle mediodorsal thalamic nucleus medial habenular nucleus

PC PF Pir PL PrC PRh PT PV PVA PVP Re Rh RSA RSG S

;r Tu VLO vo 3v

medial orbital cortex mammillothalamic tract occipital cortex parietal area I parietal area II paracentral thalamic nucleus parafascicular thalamic nucleus piriform cortex prelimbic cortex precommissural nucleus perirhinal cortex parataenial thalamic nucleus paraventricular thalamic nucleus paraventricular thalamic nucleus, anterior part paraventricular thalamic nucleus, posterior part nucleus reuniens thalami rhomboid thalamic nucleus agranular retrosplenial cortex granular retrosplenial cortex subiculum stria medullaris temporal cortex olfactory tubercle ventrolateral orbital cortex ventral orbital cortex third ventricle

Thalamocortical projections 15

Every third section was incubated in rabbit anti-PHA-L antiserum (1:2000; E-Y Labs, U.S.A. or Dakopatts, Denmark) for 18 hat 4”C, following three pre-rinses in 0.05 M Tris-buffered saline (pH 7.6) with 0.5% Triton X-100. Thereafter, sections were incubated in swine anti-rabbit whole serum (1: SO; Nordic Immunology, The Netherlands) and in rabbit ~ro~da~-ant~~roxidase (1: 800, Dakopatts, Denmark), successively, each for 1 h at 20°C. All incubations and intervening rinses were in 0.05 M T&-buffered saline (pH 7.6) with 65% Triton X-100. Finally, the sections were treated with diaminobenxidine (50 mg in 100 ml Tris-HCl. pH 7.6), preceded and followed ‘by th&e rinses in Tris-HCi (pH 7.6), and mounted from 0.2% gelatin in Tris-HCI (pH 7.6). Half the PHA-L-stained sections were counterstained with Cresyl Violet before coverslipping; the other sections

were coverslipped unstained. The distribution of PHA-L- labelled fibres and terminals was charted with the aid of a drawing tube on a standard Zeiss microscope.

RESULTS

For the dehneation of the various midline and intraiaminar thalamic nuclei, we refer to a previous study in which the striatal projections of these nuclei were described.” In the present study we adhere to the same nomenclature, adopted from Paxinos and Watson.“’

Fig. 1. (A)-(C) Photomicrographs of PHA-L injections in the midline and intralaminar thalamic nuclear complex. (A) Parataenial nucleus. (B) Inte~ediodorsal nucleus. (C) Rostrolateral part of the parafascicular nucleus. (D) High-power photomicro~aph illus~ating the mo~hology of PHA-L-la~ll~ thalamic fibres in the cerebral cortex. Scale bar in (A) = 2OOpm and also applies to (B) and (C). Scale bar in

(D) = 30 pm.

76 H.W. BEXENDSE and H.J. GROENEWEQEN

Prefrontal and other cortical areas

The parcellation of the prefrontal cortex largely follows the accounts of Krettek and Pricee4 and Van Eden and Uylings145 (see also Refs 55 and 114). According to these authors, the prefrontal cortex can be subdivided into medial and lateral portions. The medial prefrontal cortex includes the medial orbital, infralimbic, prelimbic, anterior cingular and medial precentral co&ices. The lateral prefrontal cortex encompasses the remaining orbital cortical fields and the agranular insular cortices. For the frontoparietal, retrosplenial and perirhinal cortical regions, the descriptions of Donoghue and Wise,37 Zilles and Wreersg and Reep et al. ‘I6 have been adopted. In these accounts, medial and lateral agranular fields are distinguished in the frontal cortex that correspond cytoarchitectonically to the medial and lateral precentral cortices of Krettek and Price,@ Van Eden and Uylings145 and Groenewegen. s5 In the present report, we will employ the terms medial and lateral agranular cortex. The first and secondary somatic sensory cortices are indicated as parietal area I and parietal area II, respectively; forelimb and hindlimb areas are identified as separate fields.37~“6,‘59 The temporal and occipital cortices will not be divided into subfields, since anterograde label was sparse in these areas following PHA-L injections in the midline and intralaminar nuclei.

Midline t~a~arno~ort~cal projections

PI-IA-L was injected in the paravent~cular, parataenial, inte~~iodo~al and rhom~id nuclei, Except for the injections in the parataenial nucleus, all PHA-L deposits involve the nuclei bilaterally. Examples of the injections are given in Fig. 1A and B. The diameter of the injection sites varies from 150 to 600 pm. With the exception of the fibres originating in the rhomboid nucleus (see corresponding paragraph), PHA-L-labelled fibres from all other nuclei terminate bilaterally in circumscribed areas of the prefrontal cortex and the hippocampal and/or parahippocampal cortices. The labelling is most dense ipsilaterally. The contralateral projection of the parataenial nucleus is negligible.

Most labelled fibres reach their cortical target via the inferior thalamic peduncle, the substantia innominata, the pallidum and the striatum. In the striatum, the thalamic fibres follow the fibre bundles of the internal capsule. A minority of fibres enter the striatum via the stria terminalis. It could not be determined whether the thalamocortical fibres give off collateral branches that terminate in the striatum. The majority of fibres destined for the posterior parts of the insular cortex, the perirhinal cortex and the entorhinal cortex follow a ventral route through the substantia innominata and the ~ygdaloid complex.

In the various cortical areas, the fibres o~~nating from the midline thalamic nuclei are not restricted to a single cortical layer, but rather distribute over two

or more layers. More importantly, the laminar distributions of the fibres from individual midline thalamic nuclei are different. Passing fibres, that can easily be distinguished from terminating fibres on the basis of their smooth appearance, are present in large numbers in the deeper cortical layers, coursing towards neigh- bouring cortical areas or more superficial cortical layers. In the layers that are most densely labelled, the fibres have a high density of varicosities, branch frequently and are oriented more or less parallel to the pial surface (Fig. ID). The fibres that terminate in sparsely labelled layers bear relatively few varicosities and follow a rather straight course (see for example Fig. 4B).

Parataenial nucleus. In case RP-88050, a very small injection of PHA-L was placed in the parataenial thalamic nucleus (Figs IA and 2). The resulting anterograde labelling in the medial prefrontal cortex pr~ominantly involves the medial orbital and infralimbic cortical areas (Figs 2A-C and 4). Sparse fibres terminate in the ventral part of the prelimbic cortex (Fig. 2B, C). The terminal plexus in the medial orbital cortex is concentrated in its dorsal part and involves layers I and III and, to a lesser extent, superficial layer V (Figs 2A and 4). The plexus is continuous with that in the rostra1 part of the infralimbic cortex which equally involves layers I and III and, though sparsely, layer V (Fig. 28, C). At caudal levels of the infralimbic cortex, the labelling is less dense. A few frbres from the parataenial nucleus terminate in the ventral agranular insular (Fig. 2C, D) and the perirhinal cortical fields (Fig. 21, J).

A sparse projection from the parataenial nucleus is directed to the entorhinal cortex and the ventral subiculum (Fig. 2J-L). The fibres in the entorhinal cortex are located predominantly in layers V and VI of the lateral subdivision; those in the ventral subiculum are confined to the molecular layer.

Paraoentricular nucleus. PHA-L was injected at various rostrocaudal levels of the paraventricular nucleus. The deposit in case RP-86189 is located in the anterior part of the paraventricular nucleus and involves the dorsal portion of the nucleus only (Fig. 3). In the ventral part of the prelimbic cortex, anterogradely labelled fibres form a terminal plexus that is most dense caudally. The fibres terminate predominantly in layers I, V and VI (Figs 3A-C and SA). At the most caudal levels of the prelimbic cortex, the label in layer VI extends into the dorsal part of this cortical field (Fig. 3C). The agranular insular cortex receives paraventricular fibres as well. Rostrally, the fibres distribute over layers I, V and VI of the dorsal and, to a lesser extent, the ventral subfield (Fig. 3B-D). In the posterior agranular insular cortex, sparse thalamic flbres terminate predominantly in layer VI (Fig. 3E, F). The perirhinal cortex contains a moderate amount of anterogradely labelled fibres in layers V and VI and sparse fibres in layer III (Fig. 31-K). More dense anterograde label is present in the ventral subiculum, where the labelled fibres are organized in

Thalamocortical projections

Fig. 2. Chartings of PHA-L-labelled fibres in the cerebral cortex following an injection into the parataenial nucleus (case RP-88050). Passing and terminating fibres are differentially indicated, The injection site is drawn in the upper right hand comer and is shown photographically in Fig. 1A. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads

mark cytoarchitectonic boundaries between cortical fields.


Fig. 3. Chartings of PHA-L-labelled fibres in the cerebral cortex resulting from an injection into the anterior part of the paraventricular nucleus (case RP-86189). Passing and terminating fibres are differentially indicated. The injection site is drawn in the upper right hand corner. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads



two bands, one of which is located in the molecular densely labelled and the dorsal subiculum contains a layer and the other in the pyramidal cell layer few afferent thalamic fibres in the molecular layer. (Figs 3J-L and 5B-D). The deeper layers of the The anterograde label in the entorhinal cortex is entorhinal cortex, especially in its medial part, receive spread out equally over both medial and lateral a moderate amount of fibres (Fig. 3J-L). subdivisions.

Following injections in the anterior part of the paraventricular nucleus that encroach upon the mediodorsal thalamic nucleus, labelled fibres terminate in the same subfields of the medial and lateral prefrontal cortical areas as in the preceding case, but the laminar distribution of the fibres is different. In addition to the bands of terminating fibres in layers I, V and VI, there is a dense strip of afferent fibres with varicosities in layer III.

Tracer deposits in the ventral portion of the anterior part of the paraventricular nucleus always include the central medial and/or parataenial nuclei. If we exclude the cortical fields receiving projections from these adjacent nuclei, the ventral part of the anterior cingular cortex is the only cortical area that receives fibres from the ventral part of the paraventricular nucleus but not from its dorsal part (see above). In the cingular cortex, the majority of the fibres terminate in layers I, V and VI. Furthermore, in comparison to cases with injections in the dorsal part of the paraventricular nucleus, the ventral subiculum is less

After an injection more caudally in the paraventricular nucleus that may slightly involve the mediodorsal thalamic nucleus (case. RP-86445) the highest density of PHA-L-labelled fibres in the prefrontal cortex is present rostrally in the ventral part of the prelimbic cortex. Most fibres distribute over layers I and V, whereas layers VI and III are labelled in order of decreasing fibre density. As in case RP-86 189 (anterior paraventricular nucleus), labelled fibres are also present in the dorsal part of the agranular insular cortex where they terminate in layers I, III and the superficial part of layer V. A few fibres are present in the deep layers of the ventral and posterior parts of the agranular insular cortex and the lateral entorhinal cortex. Contrary to case RP-86189, the subiculum remains free of labelling.

Intermediodorsal nucleus. An injection of PHA-L in the intermediodorsal nucleus with minimal involvement of the mediodorsal nucleus (case RP-89358; Figs 1B and 6) produces dense fibre and terminal labelling in the ventral part of the dorsal agranular

Fig. 4. PHA-L labelling in the prefrontal cortex resulting from an injection in the parataenial nucleus. (A) Photomicrograph of a transverse section through the rostra1 part of the prefrontal cortex counterstained with Cresyl Violet. Labelled fibres terminate denselv in lavers I. III and sunerticial V of the medial orbital cortex. Note the smooth appearance of the labelied fibres in the other layers. (B) High-power photomicrograph of the PHA-L labelling in the medial orbital cortex. Scale bars = 200 pm (A); 50 pm (B).

80 H. W. BERENDSE and H. J. GROENR~EGEN

Fig. 5. Photomicrographs of PHA-L-labelied frbres in the prefrontal cortex (A) and the subiculum (ED) following an injection in the anterior part of the paraventrkadar nucleus. (A> LabaIled fibres in the ventral part of the prelimbic cortex. The tibres terminate in layers I, V and VI. Note that the labelling in layer I is confined to the deep Part. (B)-(D) In the ventral subiculum, PHA-L-labelled fibres are arranged in two bands (B). The inset in (B) is shown at a higher magnification in (D). A comparison with an adjacent section that was counterstained with Cresyl Violet (C) demonstrates that one of the two bands of labelled fibres is located deeply in the molecular layer, whereas the other involves the deep part of the pyramidal cell layer. Asterisks in (C) and (D) indicate corresponding blood vessels. Scale bar in (A) = 200 pm and

also applies to (B). Scale bar in (C) = 50pm and also applies to (D).


Fig. 6. Chartings of the anterograde labelling in the cerebral cortex resulting from a PHA-L injection in the intermediodorsal nucleus (case RP-89358). Passing and terminating fibres are differentially indicated. The tracer deposit is illustrated in the upper right hand corner of this figure and in Pig. 1B. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings.

Arrowheads mark cytoarchitectonic boundaries between cortical fields.


Fig. 7. Photomicrographs of two transverse sections through the dorsal agranular insular cortex illustrating the distribution of PHA-L-labelled fibres resulting from an injection in the intermediodorsal nucleus. The section in (A) was counterstained with Cresyl Violet. The fibres terminate in layers I, III and superficial V (A). Note in (B) the smooth appearance of the fibres in deep layer V. Scale bar in

(A) = 200 pm and also applies to (B).

insular cortex, throughout its rostrocaudal extent. The laminae with the highest density of labelling are layers I, III and the superficial part of layer V (Figs 6A-D and 7). The labelling is continuous with that in the rostra1 part of the posterior agranular insular cortex (Fig. 6E). At more caudal levels of the latter cortical field, label is sparse and restricted to the deep cortical layers (Fig. 6F-H). In the medial prefrontal cortex, labelled fibres are limited to the rostroventral part of the prelimbic cortex involving layers I, III and superficial V (Fig. 6A-C). Dense labelling is found throughout layer V of the lateral part of the entorhinal cortex. A few labelled fibres terminate in layers I and V of the ventral part of the perirhinal cortex (Fig. 61-K).

Rhomboid nucleus. Injections in the rhomboid nucleus (e.g. case RP-87157; Fig. 8) result in a quite different distribution of PHA-L-labelled fibres in the cerebral cortex than in the preceding cases. In case RP-87157, many fibres are present in layer I of the most ventral part of the infralimbic cortex which lies immediately adjacent to the taenia tecta and is some- times referred to as the dorsal peduncular cortex lo7 (Fig. 8C). Other concentrations of label involve layers I and V of the perirhinal cortex and the molecular layers of the dorsal parts of CA1 and the subiculum (Fig. 8G-L). In addition to these areas of dense labelling, there is diffuse and widespread labelling of virtually all cortical areas. The labelled fibres terminate in layers I and/or superficial V; in some areas the label extends from layer V into layer IV (Fig. 8). The fibres in layer VI are predominantly of the passing

type.

Intralaminar thalamocortical projections

Deposits of PHA-L were placed in the rostra1 and caudal intralaminar nuclei (see for example Fig. 1C). The range in size of the injections is similar to that of the midline injections. In all cases, the labelling in the cerebral cortex is restricted to the ipsilateral side of the brain, except for the central medial cases in which the injection sites extend across the midline. Most fibres reach the cerebral cortex along similar routes as the midline thalamic fibres. Following injections dorsolaterally in the intralaminar nuclei, the fibres enter the internal capsule directly from the reticular thalamic nucleus.

The intralaminar nuclei project to restricted areas of the prefrontal cortex and the neocortex. A mediolateral gradient in the thalamus corresponds to a mediolateral gradient in the cerebral cortex. Further- more, rostra1 injections produce a terminal plexus in the cortex characterized by an extensive rostrocaudal distribution, with relative sparing of extreme rostra1 levels, whereas caudal injections result in labelling that is largely confined to rostra1 cortical areas. In general, the projections to the caudolateral parts of the cerebral cortex are less dense and cover larger areas. The laminar distribution of the fibres in the cortex is dependent upon the thalamic nucleus injected. The morphology of the fibres that arise from the intralaminar nuclei is similar to that of the fibres originating in the midline nuclei (see above).

Central medial nucleus. In case RP-86108, the PHA-L injection was placed in the central medial nucleus (Fig. 9). The resulting label in the cerebral

Thalam~orti~l projections

. AGm

m

Fig. 8. Chartings of PHA-L-lazily fibres in the cerebral cortex foilowi~g an injection in the rhomboid nucleus (case RP-87157). Passing and terminating fibres are differentially indicated. The injection site is drawn in the upper right hand comer. Note that the labelled fibres are present in widespread cortical areas. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other

chartings. Arrowheads mark cytoarchitectonic boundaries between cortical fields.

H. W. BEREND~E and H. 1. GROENEWEGEN

Fig. 9. Chartings of PHA-L-labelled fibres in the cerebral cortex that result from an injection in the rostra1 part of the central medial nucleus (case RP-86108). Passing and terminating fibres are differentially indicated. The injection site is drawn in the upper right hand corner. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads mark

cytoarchitectonic boundaries between cortical fields.


r SnJ

j&” pIATPc

:= \ j

CM L____ ____ ___-..-.._ ____- __I

d

Fig. 10. Chartings of PHA-L-labelled fibres in the cerebral cortex following an injection in the rostra1 part of paracentral nucleus (case RP-88251). Passing and terminating fibres are differentially indicated. The tracer deposit is drawn in the upper right hand comer. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads mark cytoarchitectonic

boundaries between cortical fields.


cortex is largely confined to prefrontal areas. A dense plexus of te~inating tibres covers the rostrocaudal extent of the dorsal part of the prelimbic cortex and the rostra1 two-thirds of the dorsal anterior cingular cortex (Figs 9A-E and llA, B). At the level of the forceps minor of the corpus callosum, the field of terminations breaks up into two separate areas, with a narrow intervening zone that is unlabelled and coincides with the border zone between the prelimbic and the anterior cingular cortical fields (Fig. 9B). In both cortical fields, the labelled fibres terminate most densely in layers I and V. The superficial part of layer V is more densely labelled than its deep part. Layer III is only slightly involved (Fig. 11 A, B). At caudal levels of the anterior cingular cortex, the terminal plexus shifts from the dorsal into the ventral subfield (Figs 9E, F and llC, D). A few scattered fibres terminate in the deep layers of the perirhinal cortex (Fig. 91, J). In other cases with similarly placed but somewhat larger injections, sparse labelling can also be observed in the deep layers of the occipital cortex.

Paracentral nucleus. The PHA-L injection in case RP-88251 is centred in the rostra1 part of the paracentral nucleus. At this thalamic level the central lateral nucleus is not present.“*ro7 As a consequence of the small size of the rostra1 part of the paracentral nucleus, the PHA-L deposit involves the adjacent anteroventral and mediodorsal thalamic nuclei (Fig. 10). The injection produces dense fibre and terminal labelling in the dorsal anterior cingular cortex that extends into the medial part of the medial agranular cortex (Fig. IOB-F). The labelling is strongest at intermediate rostrocaudal levels and is concentrated in layers I and superficial V. A few fibres terminate in layer III. An additional plexus of labelled fibres in layers I and III of the retrosplenial area (Fig. IOG, H) probably results from the involvement of the anteroventral nucleus in the injection site. A few smooth fibres pass through the deep layers of the occipital cortex (Fig. IOJ).

In case RP-86041, the PHA-L deposit involves the caudal part of the paracentral nucleus and the adjacent ventral part of the mediodorsal nucleus. Three areas of termination are present in the cerebral cortex. The first and most dense area occupies the rostra1 part of the dorsal agranular insular cortex, where the majority

of labelled fibres terminate in layers I, III and V. Layer VI contains pr~ominantly passing ftbres. At the rostra1 tip of the hemisphere, the labelling extends from the dorsal agranular insular cortex into the lateral orbital cortex (Fig. 11F). The second plexus of terminating fibres is situated rostrally in the lateral agranular and the lateral part of the medial agranular cortical fields. The labelled fibres terminate in layer I and at the border between layers IV and V (Fig. 1lE). The last and least densely labelled area involves the posterior agranular insular and the perirhinal cortices,

Central lateral nucleus. The PHA-L deposit in case RP-88277, placed at a more caudal thalamic level compared to that in case RP-88251, is centred in the rostra1 part of the central lateral nucleus (Fig. 12) and may slightly involve the adjacent mediodorsal and ventrolateral nuclei. Subsequent to this injection labelled fibres are present in the frontal and parietal cortices. In the frontal cortex, the labelling is restricted to the medial agranular field and the adjacent medial part of the lateral agranular field. The fibres in the frontal cortex are organized in three bands (Figs 12B-F and 14A). One of these bands is only weak and consists of a few fibres in layer I that course parallel to the pial surface. Other fibres terminate at the border of layers III and IV and are oriented perpendicular to the pial surface. The third band of labelling has the highest density of fibres and resides in the deep part of layer V. The other cortical layers predominantly contain passing fibres (Fig. 14A). At the caudal end of the prefrontal cortex, the label extends into the rostra1 part of the retrosplenial cortex where it tapers off rapidly in a caudal direction (Fig. 12G, H). The labelling of the parietal cortex is restricted to the caudal part of parietal area I (Fig. 12F-I). A small number of fibres terminate in layer I, whereas one band of more extensive labelling involves layer IV, and another deep layer V and superficial layer VI (Fig. 14B). The sparse fibres observed rostrally in the occipital cortex bear only very few varicosities (Fig. 12H, I). A few fibres terminate in the deep layers of the ventrolateral orbital cortex (Fig. 12A, B).

Following an injection of PHA-L in the caudal part of the central lateral nucleus, that involves the lateral part of the mediodorsal nucleus (case RP-87219) the

Fig. 1 I. (A)-(D) PHA-L-la~ll~ fibres in frontal sections through the prefrontal cortex following an injection in the central medial nucleus. In both the dorsal part of the prelimbic (A) and the dorsal anterior cingular cortex (B) labelled fibres terminate densely in layers I and superficial V. Smooth fibres of passage are present in the other layers. The labelling in the ventral anterior cingular cortex is sparse (C). A high-power photomicrograph of a section counterstained with Cresyl Violet (D) demonstrates that the fibres terminate in layers I and superficial V. (E),(F) Photomicrographs of the PHA-L labelling in the cerebral cortex that results from an injection in the caudal part of the paracentral nucleus. In the lateral agranular field of the motor cortex, labelled fibres terminate predominantly in layer I and at the border between layers IV and V (E). The extremely dense labelling of the lateral orbital and dorsal agranular insular cortical fields is concentrated in layers III and V. A few fibres terminate in layer I. Scale bar in

(A) = 2OOpm and also applies to (B), (C), (E) and (F). Scale bar in (D) = 50 pm.


Fig. 11 (A-F).

H. W. BERENDSE and H. J. GROENEWEGEN

Fig. 12. Chartings of the anterograde labelling in the cerebral cortex following a PHA-L injection into the rostra1 part of the central lateral nucleus (case RP-88277). Passing and terminating fibres are differentially indicated. The injection site is illustrated in the upper right hand corner. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads



highest density of labelling is present rostrally in layer III of the dorsal anterior cingular and agranular cortical fields. Very few fibres terminate in layer I. In the agranular fields, some fibres terminate in&tperIicial layer V. Contrary to case RP-88277, no labelled fibres are found in the parietal cortex in case RP-87219, but the labelling in the ventrolateral orbital cortex, which includes layers I, III and V, is more dense than that in case RP-88277.

Parafascicular nucleus, lateral part. Following injections of PHA-L in the parafascicular nucleus, labelled fibres distribute over the lateral agranular field of the frontal cortex and the parietal cortex. The majority of the fibres terminate rostrally in these cortical areas and are concentrated in four bands situated in layers I, IV, deep V and deep VI (Fig. 14C, D). Layers V and VI are most densely labelled. In the agranular field of the frontal cortex the strip of label in layer IV is uninterrupted, whereas in the dorsolateral part of the parietal cortex it is more sparse and discontinuous.

The tracer deposit in case RP-88049 is located in the centre of the lateral part of the parafascicular nucleus (Fig. 13). In the cerebral cortex, the PHA-L- labelled fibres occupy the lateral agranular cortex, the most lateral part of the medial agranular cortex and the dorsolateral part of parietal area I (Figs 13AG and 14C, D). A minority of fibres terminate in the forelimb and hindlimb areas. The labelling in the caudal part of the parietal cortex is weak and restricted to the deep cortical layers. A few fibres are present in the rostra1 part of the occipital cortex (Fig. 13H, I). In case RP-88090, the PHA-L deposit is smaller than that in case RP-88049 and involves only the most rostrolateral part of the parafascicular nucleus (Fig. 1C). In the cerebral cortex, the labelled fibres have a more medial position than in case RP-88049 and thus occupy the rostrolateral part of the lateral agranular cortex and the rostra1 part of the parietal cortex. The most caudally located fibres in the parietal cortex are concentrated in parietal area II. The laminar distribution in the latter cortical area is somewhat different from that described above. Two bands of terminating fibres are present, the first in layer I and the other at the border between layers IV and V. The label in layer VI consists of smooth passing fibres.

Parafascicular nucleus, medial part. The cortical projections of the medial part of the parafascicular nucleus are rather sparse. The highest density of labelled fibres is present in the dorsal part of the prelimbic cortex, the anterior cingular cortex, and the caudal part of the medial agranular cortex. In the latter areas, the label is restricted to layers I, V and VI. It is interesting to note that the projections to these areas overlap to a large extent with those of the central medial nucleus (cf. case RP-86108). A few fibres are further observed in the deep layers of the agranular insular cortex, the occipital, perirhinal and entorhinal cortices, the subiculum, and the parasubiculum.

DISCUSSION

The most striking finding of the present study of the midline and intralaminar thalamocortical projections in the rat is that, contrary to the results of previous anterograde tracing studies in rat@‘@ and cats,80,‘27 the individual nuclei of the midline and intralaminar nuclear complex project to specific parts of the cerebral cortex. Thus far, a topographically organized projection to the cerebral cortex has been reported only for the centromedian-parafascicular complex in the cat.‘26 Of equal importance is the present observation that the laminar distributions in the cerebral cortex of the midline and intralaminar fibres are not the same for all nuclei. Both findings support the notion that there is a high degree of specificity in the connections of the midline and intralaminar nuclear complex, li,25,26@ A combination of the present results with those of studies on the thalamostriatal” and the prefrontal corticostriatal projections’* reveals that particular parts of the midline and intralaminar thalamic nuclear complex project to specific cortical areas as well as to the striatal targets of these areas. The implication of this arrangement is that each of the recently proposed basal ganglia-thalamocortical circuits3@ can be influenced both at the cortical and the striatal level by the same part of the midline and intralaminar nuclear complex.

Area1 organization of midline thalamocortical projections

Previous studies have demonstrated that the cortical projections of the midline thalamic nuclei are predominantly ipsilateral; only a small number of neurons in the midline of the thalamus project contralaterally.96~“2~‘42 In agreement with this, the present PHA-L injections in the midline nuclei gave rise to bilateral labelling. Following injections in the parataenial nucleus, well outside the midline, labelhng was virtually absent from the contralateral hemisphere. The major cortical targets of the midline thalamic nuclei, not including the rhomboid and reuniens nuclei, are the ventral part of the medial prefrontal cortex, several subfields of the lateral prefrontal cortex, and the hippocampal and parahippocampal regions. A sparse innervation of the perirhinal cortex was found to originate from the paraventricular and intermediodorsal nuclei (cf. Refs 29 and 63). The projections to the prefrontal cortex are virtually non- overlapping, which is at variance with the results of a recent retrograde tracing study with fluorescent tracers in the rat by Conde et af.24 In the present anterograde tracing study, it could be demonstrated that many passing fibres course through the ventral parts of the medial prefrontal cortex on their way to more dorsal cortical areas. The uptake of fluorescent tracer by these fibres is a likely explanation for the more widespread and overlapping projections from the midline and intralaminar thalamic nuclei to the medial prefrontal cortex, as found by CondC et a1.24

H. W. BERENDSE and H. J. GROENEWEGEN

Fig. 13. Chartings of PHA-L-labelled fibres in the cerebral cortex resulting from an injection in the lateral part of the parafascicular nucleus (case RP-88049). Passing and terminating fibres are differentially indicated. The injection site is drawn in the upper right hand corner. Sections (A)-(L) correspond approximately to the sections indicated by the same letters in the other chartings. Arrowheads mark

cytoarchitectonic boundaries between cortical fields.

Fig. 14. Photomicrographs of the PHA-L labelling in the cerebral cortex following injections in the rostra1 part of the central lateral (A, B) and in the lateral part of the parafascicular nucleus (C, D). (A) Transverse section through the agranular fields of the motor cortex. Labelled fibres terminate in layer I, at the border between layers III and IV, and in deep layer V. Note that the highest density of terminating iibres is in layer V. (B) High-power photomicrograph of PHA-L-labelled fibres in layer V of the parietal cortex. Countemtained with Cresyl Violet. (C) In the lateral agranular field of the motor cortex and in the parietal cortex, PHA-L-la~ll~ fibres from the parafascicular nucleus distribute over layers I, IV, deep V and deep VI. Many smooth passing fibres intermingle with the te~inating fibres in layer VI. Note that the fibres terminating in layer IV are oriented perpendicular to the pial surface. (D) High-power photomicrograph of PHA-L-labelled hbres from the parafascicular nucleus in deep layer V of the parietal cortex. Counterstained with Cresyl Violet. Scale bar in (A) = 200 pm

and also applies to (C). Scale bar in (B) = 50 ym and also applies to (D).


For the parataenial nucleus we found a projection to the medial orbital and infralimbic subfields of the medial prefrontal cortex. Previous retrograde tracing studies have shown a projection from the parataenial nucleus to the infralimbic cortex,33,78,‘46 whereas a projection to the medial orbital cortex was inferred from the results of several large injections of tritiated proline in the mediodorsal and adjacent thalamic nuclein4 Interestingly, the parataenial nucleus has been related to the basal parts of the medial surface of the hemisphere as early as 1951 by Droogleever- Fortuyn,” who noted degenerative changes in this nucleus following lesions of the cerebral cortex in the rabbit. The absence of a projection from the mediodorsal nucleus to the medial orbital and infralimbic cortices55,84 suggests that the relationship of the parataenial nucleus with these cortical areas may be partly comparable to the relationship of the mediodorsal nucleus with the other prefrontal cortical areas (see Laminar organization of midline and intralaminar thalamocortical projections). The presence of sparse labelling in the ventral subiculum and the entorhinal cortex in our experiments is in accord with the results of retrograde tracing studies on the thalamic afferents of the hippocampal and parahippocampal regions.7~71~119~'"

In the cat, retrograde labelling of neurons in the paraventricular nucleus has been reported following tracer injections in the cingular and medial prefrontal cortices.‘OO~‘O’ In the rat, projections from the paraventricular nucleus to the cerebral cortex have either been denied’* or were considered to be sparse and widespread.69 The present anterograde tracing study is the first to demonstrate that the projections from the paraventricular nucleus are substantial but, neverthe- less, restricted to a few cortical areas. These areas include the ventral part of the prelimbic cortex and, though to a lesser extent, the agranular insular cortex and the ventral part of the anterior cingular cortex. Furthermore, our results indicate that the projection to the latter area is probably derived from the ventral part of the paraventricular nucleus. In agreement with the results of previous retrograde tracing studies 7~71~“9~‘37~‘40~‘54~‘55 we found projections from the anterior part of the paraventricular nucleus to the subiculum and the entorhinal cortex. The posterior part of the nucleus does not seem to provide any significant contribution to either of these projections. The paraventricular nucleus projects sparsely to the perirhinal cortex (present results).

Contrary to the parataenial and paraventricular nuclei, the intermediodorsal nucleus projects most densely to the lateral part of the prefrontal cortex. In our experiments, labelled fibres were observed in layers I, III and superficial V of the posterior agranular insular cortex and the ventral part of the dorsal agranular insular cortex. A comparison with retrograde tracing studies is difficult, since in these studies the intermediodorsal nucleus was not identified as a separate entity but was instead included in the caudo-

medial part of the mediodorsal nucleus48s55 or in the central medial nucleus.“4 Some retrogradely labelled neurons illustrated in these studies appear to lie quite close to or even in that part of the thalamus which we identify as intermediodorsal nucleus. Moreover, a fluorescent tracer injection, which is located super- ficially in the dorsal agranular insular cortex, results in extensive retrograde labelling of both the caudomedial part of the mediodorsal nucleus and the intermediodorsal nucleus (Groenewegen, unpublished observations). The projection to layer V of the agranular insular cortex that we presently observed most probably originates from the intermediodorsal nucleus. The labelling in layers I and III may derive from the caudomedial part of the mediodorsal nucleus for which a projection to these layers has been reported.55,84 As the projection to layer I from the caudomedial part of the mediodorsal nucleus in the experiments of Krettek and Pric@“ and Groenewegen55 is quite sparse compared to that demonstrated in the present experiments, this layer presumably receives projections from both the mediodorsal and intermediodorsal nuclei.

The presence of a sparse projection from the intermediodorsal nucleus to the ventral part of the prelimbic cortex is in agreement with the results of retrograde tracing studies.24*55’46 As we discussed for the agranular insular cortex, the involvement in the injection site of the caudomedial part of the mediodorsal nucleus probably accounts partly or entirely for the labelling in layers I and III (see preceding paragraph). The projection to the lateral entorhinal area, which we observed in our material, has not been reported in retrograde tracing studies in rats or cats.7,‘54,‘55 In the monkey, many retrograde neurons have been described in the centralis complex of the thalamus following tracer injections in lateral parts of the entorhinal cortex.” According to Jones,” part of this complex in the monkey is comparable to the intermediodorsal nucleus of the rat.

The pattern of cortical projections of the rhomboid and reuniens nuclei is quite different from that described above which emphasizes that the group of midline nuclei is heterogeneous as far as their connections are concerned (see also Refs 11, 140 and 153). The rhomboid nucleus projects densely to only a few cortical areas, including the most ventral part of the infralimbic cortex, the perirhinal cortex, and the dorsal parts of the subiculum and CAI. Additionally, there is a diffuse projection to widespread areas of the cerebral cortex, most strongly to the frontopari- eta1 areas (present results; cf. Ref. 104). Consistent with these results, retrograde tracing studies have demonstrated the labelling of neurons in the rhomboid nucleus subsequent to injections in various parts of the medial and lateral prefrontal cortical areas.7*~‘oo~‘o’~“4~120~‘46 Like the rhomboid nucleus, the nucleus reuniens projects densely to a few cortical areas and more diffusely to a larger cortical area. The dense projections involve the ventral part of the infra-

Thalamocorticsl projections 93

limbic cortex, the ventral anterior cingular cortex, the subiculum, and CAl.66*‘04,‘53

Area1 organization of intralaminar thalamocortical projections

The rostra1 and caudal intralaminar nuclei project pr~omin~tly to the ipsilateral cerebral cortex (present results and Refs 67, 69, 78, 80, 89, 90, 126, 127 and 144). In the central medial nucleus, ipsi- and contralaterally projecting neurons intermingle in the midline.~“2~‘42 Except for the centromedian- parafascicular complex of the cat, which was found to project topographically to specific regions of the rostra1 cerebral cortex,‘26 anterograde tracing experiments have so far failed to demonstrate any substantial differences in the cortical projections of the intralaminar nuclei.67~69~80~‘27 A rough topographical organization in the intralaminar thalamocortical projections was already demonstrated with the retrograde degeneration method in 1966 by Murray.* Furthermore, the results of retrograde tracing studies in several mammalian species suggest that the intralaminar nuclei have preferential zones of termination in the cerebral cortex72~78**3**g~‘4 (for further references see Ref. 88). This is substantiated by the finding in anatomical and physiological studies that branching of single intralaminar neurons to separate cortical areas is either minimal or entirely absent.9~1J~80~90~139 The present study is the first to substantiate the results of the retrograde tracing experiments by means of anterograde tract tracing. As a group, the intralaminar nuclei project predominantly to rostra1 parts of the cerebra1 cortex, including the frontal and parietal areas. The projections to the prefrontal cortex are restricted to the dorsal parts of the prelimbic and the agranular insular cortical fields, the caudal part of the ventral anterior cingular cortex, and the lateral and ventrolateral orbital areas, and are thus complementary to those of the midline nuclei (see above).

The central medial nucleus densely innervates the dorsal part of the prelimbic cortex and the rostra1 two-thirds of the dorsal anterior cingular cortex. A less dense projection is aimed at the caudal part of the ventral anterior cingular cortex. These data are in agreement with the results of retrograde tracing studies in rats and cats,‘s89*‘oo.‘43~‘” Since our injections involve only the rostra1 part of the central medial nucleus, we could not con&m the existence of thalamic inputs from this nucleus to the agranular insular cortex, the temporal cortex and the face representa- tion of the motor cortex, which appear to originate exclusively from the caudal part of central medial nucleusz~1’4~13’~‘44 (see also references in Ref. 88). In the present study, the perirhinal cortex is the only temporal cortical area that receives a sparse projection from the central medial nucleus. The presence of sparse labelling in the occipital cortex in our experiments with large injections in the central nucleus substantiates the results of previous studies.@J2’ Using

anterograde tracing of tritiated amino acids from the rostra1 part of the central medial nucleus in the rat, Herkenham67,6g reported that this nucleus projects to virtually all cortical areas. The discrepancy with the results of our PHA-L injections can be explained by the fact that Herkenham@ includes the ventrally adjacent rhomboid nucleus in his central medial nucfeus. The involvement of the rhomboid nucleus may account for the observed widespread projections (present results). In the cat, the cortical projections of the central medial nucleus heavily involve the orbitofrontal and cingular fields.127 The additional projections to other cortical areas may be the result of the involvement in the injection site of the ventral part of the central medial nucleus which corresponds to the rhomboid nucleus of the rat.“*77*‘07

The cortical projection field of the paracentral nucleus comprises the dorsal anterior cingular cortex, the agranular fields of the frontal cortex, the agranular insular cortex, the perirhinal cortex and the lateral orbital cortex. Involvement of the mediodorsal nucleus in the injection site probably accounts for the fibres in layer III of the dorsal anterior cingular and agranular insular cortical fields, and may contribute to the projections to layer Iss@ (see also Laminar organization of midline and intralaminar thalamocortical projections). Rostra1 parts of the paracentral nucleus project to intermediate rostrocaudal levels of the dorsal anterior cingular cortex and the medial part of the medial agranular field. The presence of PHA-L-labelled fibres in layers I and III of the retrosplenial cortex in case RP-8825 I probably results from the involvement of the adjacent anteroventral thalamic nucleus in the injection site.?’ Fibres from the caudal parts of the paracentral nucleus terminate rostrally in the lateral orbital cortex, the dorsal agranular insular cortex, the lateral agranular field and the lateral part of the medial agranular field. Minor projections were found to the posterior agranular insular and perirhinal cortices. These findings are largely consistent with observations in retrograde tracing studies 2~35~‘8~8~~‘~~‘20~130~‘~3,161 however, he projections to

visual, auditory and temporal cortical areas that have been reported in the cat’@‘” (see also references in Ref. 88) could not be co&rned in the rat. The projections described in the present study are more restricted than those reported in previous anterograde tracing studies.67@~80*‘27 This may be explained by the fact that with PHA-L, in contrast to tritiated amino acids, very small deposits of tracer can be made and that terminating fibres can be distinguished from passing fibres. Alternatively, the fact that the small PHA-L deposits in the present study do not involve the total rostrocaudal extent of the paracentral nucleus may have caused us to underestimate the total projection of this nucleus. However, this could only have been the case if specific subgroups of neurons with projections different from the ones described in the present study were unevenly distributed over the rostrocaudal axis, as our injections were placed at


several rostrocaudal levels. The discrepancies with the studies in the cat80~‘27 could be explained by species differences. However, the high degree of differentiation in the projections to the striatum from the same nuclei in both rat and cat8*n,75 render the latter explanation quite unlikely.

The central lateral nucleus is considered to be a source of input to the frontal and parietal cortical gelds ~6,21.35.3~~,65,72~,89,105.115,128,132.144 me present data

confirm the presence of projections to the agranular fields of the frontal cortex and to caudal parts of the parietal cortex and give some indication that a rostral-to-caudal gradient in the central lateral nucleus corresponds to a caudal-to-rostra1 gradient in the cerebral cortex. The projection to the parietal cortex originates exclusively from the rostra1 part of the central lateral nucleus. Since the lateral part of the mediodorsal nucleus projects to layers I and III of the anterior cingular and medial agranular cortical fields, the involvement of this part of the mediodorsal nucleus in the injection sites can explain the projections to layers I and III of these cortical areas.ss,84 Projections to widespread frontal and parietal cortical areas have been reported for the paralaminar part of the ventrolateral nucleus,69 which lies immediately adjacent to the central lateral nucleus and may have been involved slightly in our rostra1 central lateral injection. How- ever, retrograde tracing studies have demonstrated that the populations of neurons in the ventrolateral nucleus projecting to the lateral agranular field of the motor cortex and the first somatosensory area are not adjacent to the rostra1 part of the central lateral nucleus.2’s36 Neurons projecting to the medial agranular field of the motor cortex are located both in the rostra1 part of the central lateral nucleus and in the adjacent part of the ventrolateral nucleus.“’ There- fore, the involvement of the ventrolateral nucleus in our injection in the rostra1 part of the central lateral nucleus may have contributed to the projection to the medial agranular field of the motor cortex. The present observation of a projection to the agranular part of the retrosplenial cortex is consistent with the results of previous retrograde tracing studies.‘aC,‘20,‘43,is6 Finally, a sparse projection from the central lateral nucleus to the ventrolateral orbital cortex was present in our material. In the cat and the monkey, a more fine- grained topography of the cortical projections of the central lateral nucleus has been demonstrated with retrograde tracing methods.72~132

In the present study, we have demonstrated that in the rat the lateral part of the parafas~icular nucleus, corresponding to the centromedian nucleus of the cat,77 projects more densely to the cerebral cortex than the medial part, which is comparable to the parafascicular nucleus of the cat.77 The projections from the lateral part of the parafascicular nucleus predominantly involve the rostra1 portions of the lateral agranular and parietal cortical areas. The forelimb and hindlimb areas and the occipital cortex are only sparsely innervated. The above-mentioned

projections thus appear to converge with those of the adjacent posterior nucleus, for which projections to both motor and parietal cortical areas have been demonstrated in the anterograde tracing study of Herkenham.69 Retrograde tracing studies confirm that both the parafascicular and the posterior nucleus project to the parietal cortex and the lateral agranular field of the motor cortex.s,2’,36 The cortical projections of the medial part of the parafasci~ular nucleus are to some extent complementary to those of the lateral part and include the prelimbic cortex, the anterior cingular cortex and the medial agranular cortex. Minor projections reach the agranular insular, occipital, perirhinal and entorhinal cortices, and the hippocampus. The above-mentioned findings are consistent with the results of the anterograde tracing study in the cat by Royce and Mourey.iz6 In their study, the motor and premotor cortical fields constitute the major target of the centromedian-parafascicular complex, but non- motor areas are involved as welln6 In particular, the parafascicular nucleus has been mentioned as a source of afferents to the medial prefrontal cortex in cats and monkeys. ‘01,‘46 In the rat, projections from the parafascicular nucleus to the motor cortex have been reported using both anterograde and retrograde tracing techniques (Refs 2, 34, 67 and present results). Jones and Leavitt” related the parafascicular nucleus to the ventrolateral surface of the hemisphere, near the frontal pole, whereas Ullbn’” reported widespread cortical projections with a frontal predominant. In studies of the afferent connections of the agranular insular cortex in rodents, retrograde labelling of neurons in the medial part of the parafascicular nucleus has been reported.48.“4

Relationship with the parallel arrangement of basal ganglia-thalamocortical circuits

The midline and intralaminar nuclei each project to a specific part of the cerebral cortex, although there is some overlap with the projections from neighbour- ing nuclei. The cortical targets of the midline nuclei are located in the ventral parts of the cerebral cortex, whereas the intralaminar nuclei predominantly target more dorsally located cortical areas. Furthermore, rostra1 parts of the midline and intralaminar complex are related to the medial and dorsomedial surface of the hemisphere, whereas caudal parts innervate the ventrolateral, lateral and dorsolateral surfaces of the cerebral cortex. Lastly, a rostral-to-caudal gradient in the thalamus corresponds to a caudal-to-rostra1 gradient in the cerebral cortex.

In a previous report, we have described the topographical organization of the projections from the midline and intralaminar nuclei to the striatum in the rat” (see also Refs 8, 75 and 129). On the basis of the available literature on the afferent connections of these nuclei, we distinguished three nuclear groups, of which the limbic-afferented group of midline nuclei projects to medial parts of the striatum. The motor- related lateral parafascicular nucleus issues flbres


PV

lss CM m pc

m ,MD

CMlPC

MD/PC

Fig. 15. Schematic drawing illustrating the main termination fields of the midline and intralaminar nuclei in the prefrontal cortex. The minor projections from the paraventricular nucleus to the agranular insular cortex and from the intermediodorsal nucleus to the ventral part of the prelimbic cortex are not indicated. The sparsely innervated termination field of the medial part of the parafascicular nucleus (not illustrated)

overlaps largely with that of the central medial nucleus (cf. Ref. 11).

to the most lateral part of the striatum, whereas the rostra1 intralaminar nuclei, which receive prominent sensory inputs, innervate intermediate striatal areas. As this arrangement of thalamostriatal projections from nuclei with functionally distinct sets of afferents is similar to that of the corticostriatal projections originating in functionally different cortical areas,94,138 it was tentatively concluded that functionally related cortical and thalamic inputs converge in three distinct, large striatal regions. The organization of the thalamocortical projections, demonstrated in the present study, makes it tempting to suggest a further differentiation in the coupling of thalamostriatal and corticostriatal projections in the rat. A comparison of the projections from the midline and intralaminar nuclei to the prefrontal cortex (summarized in Fig. 15) with the thalamostriatal” and prefrontal corticostriatal’* projections reveals that a particular part of this nuclear complex projects to both a specific prefrontal cortical field and the striatal target area of this field. A similar arrangement has recently been described for the connections of the pulvinar with the caudal part of the putamen and the visual cortex in Tupuia?* The consequence of the present findings is that each of the basal ganglia-thalamocortical circuits that have recently heen proposed in the monkey’ and the rata may be under the influence of the same part of the midline

NSC 4211-D

and intralaminar nuclear complex at two different way stations of the circuit.

It is noteworthy that the projections from the midline nuclei to the hippocampus and parahippocampal areas and to their ventral striatal target areas are organized according to similar principles. The anterior part of the paraventricular nucleus, for example, projects to both the ventral subiculum and the caudomedial part of the nucleus accumbens (Refs 11, 57 and present results).

Laminar organization of midline and intralaminar thalamocortical projections

The laminar distribution of the midline and intralaminar thalamic fibres in the cerebral cortex is still a controversial issue. In a recent classification of thalamic nuclei based upon the laminar distribution patterns in the cerebral cortex, the midline and intralaminar nuclei form a class of nuclei which project to layers V and/or VI.67,69 The other classes of nuclei in this tripartite division of thalamic nuclei encompass the thalamic relay nuclei for vision, audition and somesthesis, which project to layers III, IV, or both, and the paralaminar nuclei of which the projections terminate densely in layer I and additionally may include other layers. However, in the cat and the monkey, projections from the midline and intralaminar


nuclei to superficial cortical layers, including layers I and III, have been reported repeatedly using the anterograde transport of both tritiated amino acids43s0~‘26~‘27 and PHA-L.‘25 Although these results may reflect species differences or spread of tracer in the adjacent paralaminar thalamic nuclei, superficial applications of horseradish peroxidase to the parietal cortex lead to labelling of intralaminar neurons in both cats and rat.“’ The relatively sparse labelling of the intralaminar nuclei in the latter study is quite compatible with the sparse layer I projections to the parietal cortex observed in the present study. Contra- dictory results have been obtained with superficial horseradish peroxidase applications to the visual cortex.‘9,“8 The present findings using the sensitive PHA-L technique establish that the midline and intralaminar nuclei in the rat project to deep as well as to superficial cortical layers. Physiological data are consistent with a superficial termination of afferents from the central lateral thalamic nucleus in the rat and the cat.10s~‘28

In the prefrontal cortex, the fibres from all midline and intralaminar nuclei, except for those from the paraventricular thalamic nucleus, terminate predominantly in layers I and superficial V. Many passing fibres are present in layer VI and deep layer V. The additional plexus of terminating fibres in layer III, which is found in some cases, probably results from involvement of the mediodorsal nucleus in the injection site.55@ In these cases, the mediodorsal nucleus may also contribute to the layer I projections.55T84 The parataenial nucleus projects to layers I, III and V of the medial orbital and infralimbic cortical fields. Interestingly, until now a projection of the mediodorsal nucleus to the projection field of the parataenial nucleus has not been demonstrated.55~84 It may therefore be concluded that the parataenial nucleus has characteristics of both the mediodorsal nucleus and the midline and intralaminar nuclear complex. The projections from the paraventricular nucleus have a different laminar organization than those from the other nuclei, as the fibres from this nucleus terminate not only in layers I and superficial V, but also in deep layer V and in layer VI. The projections from the midline nuclei to the entorhinal and perirhinal cortices are largely confined to layers V and VI. The widespread projections from the rhomboid nucleus to the prefrontal cortex predominantly involve layer I. The fibres from the rhomboid nucleus in other parts of the cerebral cortex terminate in layers I and V; in some cortical areas the fibres from the rhomboid nucleus terminate in deep layer IV (cf. Ref. 104).

The laminar distribution of the intralaminar thalamic fibres in the agranular fields of the frontal cortex and the parietal cortex as well as the relative density of labelhng in each of the layers involved are dependent upon the nuclear origin of the fibres. All nuclei project relatively sparsely to layer I. A second plexus of terminating fibres is present in layer IV and may extend into layer III. The fibres in deep layer V

may extend into the superficial part of layer VI. A projection to deep layer VI is found only for the parafascicular nucleus.

The most striking difference between the rat and the cat with respect to the laminar organization of the projections of the intralaminar nuclei is the absence of a projection to layer V in the latter species. Instead, a dense innervation of layer III has been described.80~‘26’27 Taking into consideration the intimate relationship of the midline and intralaminar nuclei with the striatum,8*“~75 the observed discrepancy may be related to the fact that most corticostriatal projection neurons in the cerebral cortex of the cat reside in layer III,‘23 whereas in the rat these projections originate predominantly from neurons in layer V.94

Relationship with the compartmental organization of the striatum

A characteristic feature of the striatum is its compartmental organization, which is reflected in the heterogeneous distribution of virtually all histo- chemical markers, receptors, uptake sites, and alTerent and efferent systems. ‘4.45,46,53,54,58,59,68,147 Recently, it has

been demonstrated that in the rat the cortical afferents of the patch versus the matrix compartments in the dorsal striatum, as defined by immunohistochemistry for calbindin D,,,,, are derived from different cortical layers.47 Corticostriatal neurons in deep layer V and layer VI project principally to the patches, whereas superficial layer V and layer III and II corticostriatal neurons show a preference for the matrix. The laminar organization of the cortical projections from the midline and intralaminar thalamic nuclei could well be in register with this arrangement in the corticostriatal system. The striatal projections from the thalamic nuclei that are related to layers I and superficial V of the prefrontal cortex avoid areas of high immunoreactivity for enkephalin in the ventromedial part of the caudate-putamen and the adjacent part of the nucleus accumbens.“*13 These areas coincide with areas of low immunoreactivity for calbindin D28,,.‘47 The paraventricular nucleus, which projects to the areas of high immunoreactivity for enkephalin in the aforementioned striatal regions, is the sole representa- tive of the midline and intralaminar nuclei that issues fibres to deep layer V and layer VI of the prefrontal cortical areas projecting to these striatal areas. Although these data are by no means conclusive without information on the microcircuitry at the cortical level, it is tempting to suggest that a particular midline or intralaminar thalamic nucleus, projecting to a distinct compartment in the striatum,‘1,‘3 can most directly inIluence those prefrontal corticostriatal neurons that project to the same striatal compartment. More detailed knowledge of the prefrontal corticostriatal projections and the cortical microcircuitry is necessary to substantiate this assumption and to generalize it for the entire ventral striatum.

Thaiamocortical projections 97

Functional considerations

Over the past decade, the ideas about the midline and intralaminar nuclear complex of the thalamus have changed considerably. The original concept of a non-specific corticopetal system that relays the activity of the reticular formation to widespread areas of the cerebral cortexS2,M,73,74,98*139 has been replaced by a more differentiated view of a system of distinguishable nuclei, which each receive specific sets of afferents, project to specific parts of the striatum and the cerebral cortex, and are involved in quite specific processes. 4.8,10,11,16,25,26,30,70,87,88,93,108,113.131-135

The concept of a highly differentiated group of midline and intralaminar nuclei does not necessarily imply that these nuclei process the same type of info~ation as the relay nuclei. For example, extero- ceptive information is conveyed via separate populations of neurons in the spinal cord to the midline and intralaminar nuclei, and to the relay nuclei.28~50~91~‘02~IJ2 More importantly, the spinal cord neurons projecting to the latter nuclei have small receptive fields, whereas those projecting to the midline and intralaminar nuclei have large, often bilateral, receptive fields, are not somatotopically organized, and may be polymoda11~“*5’~‘08 (cf. Ref. 17). Therefore, the relay nuclei probably subserve discriminative aspects of the ascending information, contrary to the midline and intralaminar nuclei which may be committed to non- di~~minative or affective aspects of the information.‘*20*95*‘58 These features may be required to alert

the organism of the occurrence of new and potentially dangerous situations. 61~Lo8 Since the relay nuclei of the thalamus project only sparsely to the striatum,B~*‘~7s di~~minative aspects of the ascending info~ation are relayed mainly to the cerebral cortex. The non- discriminative aspects of the information are conveyed to both the striatum and the cerebral cortex (Refs 8, 11,67, 69, 75, 80, 126, 127 and present results), either by the same or by closely adjacent neurons.Z23~7690~124,139 At the level of the cerebral cortex, both aspects of the info~ation can be integrated and an adequate response planned. Depending on the affective value, the non-discriminative aspects of the ascending information that reach the striatum by way of the midline and intralaminar nuclei can either prepare the striatum for an imminent cortical input or induce a timely first behaviouraf response to be modified by the integrated cortical input. The importance of the midline and intralaminar nuclear complex for spontaneous and reactive behaviour is stressed by the reduction in responsiveness to external stimuli (neglect) and the lack of spontaneous behaviour (hypokinesia, mutism, brad~hrenia) following damage to these nuclei both in human patients62,85,1~,i48,*~ and in animals.‘W*‘49

Acknowledgemenrs-We would like to thank Prof. Dr A. H. M. Lohman for his critical review of this manuscript, Mmes Anita Hartog-te Kortschot and Yvon Galis-de Graaf for technical assistance, Mr Dirk de Jong for his invaluable photo~phi~al skills and MS Joan Hage for secretarial support.

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(Accepted 3 1 October 1990)

Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat

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