Topographical organization of the afferent connections of the principal ventromedial thalamic nucleus in the cat

The afferent connections to the principal division of the ventromedial thalamic nucleus (VMP) were studied in the cat by means of the HRP retrograde transport technique. The large (40 nl) and small (20 nl) injections of this enzyme were delivered into the VMP using different stereotaxic approaches. The main afferents to VMP emanated bilaterally from the prefrontal, premotor, and rostral agranular insular cortices. Another important group of afferents to the VMP were those originating in the rostral third of the reticular thalamic nucleus, the entopeduncular nucleus, the substantia nigra pars reticulata, and the deep cerebellar nuclei. From the cerebellar nuclei, the contralateral lateral nucleus and the caudal third of both (ipsi and contralateral) medial cerebellar nuclei were the origin of afferents to the VMP. Other cortical areas projecting (in a lower density) to the VMP were the motor cortex, the cortex along the anterior ectosylvian sulcus, the granular insular cortex, the posterior agranular insular area, the prelimbic area, and the cortex along the posterior rhinal sulcus (SRP). Among other subcortical prosencephalic structures projecting to the VMP are the dorsal claustrum, substantia innominata, hypothalamic formations, and the zona incerta. Projections originated from the brainstem in the lateral part of the intermediate and deep layers of the superior colliculus, the central gray matter, the locus coeruleus, and the reticular formation. The nucleus tegmenti pedunculopontinus pars compacta, parabrachial nuclei, the vestibular complex, and the spinal trigeminal nucleus were also origins of projections to the VMP. We conclude by emphasizing the important bilateral cortical modulation of the different functions attributed to the VMP: recruiting-response mediation, reticular-activating system participation, and extrapyramidal motor integration. In light of the connections just described, the VMP may be considered as a point for impulses coming from complex association cortical areas and limbic formations to converge with those emanating from cortical and subcortical motor structures.     

Afferent projections to the thalamic mediodorsal nucleus in the cat studied by retrograde and anterograde axonal transport of horseradish peroxidase

The afferent pathways to the thalamic mediodorsal nucleus (MD) in the cat were studied using the methods of anterograde and retrograde axonal transport of horseradish peroxidase (HRP) and wheat germ agglutinin conjugated to HRP (WGA-HRP). The MD receives fibers from the prefrontal cortex in a topically organized manner in accordance with the thalamocortical projections. The medial or ventral portion of the MD receives afferents from the islands of Calleja of the olfactory tubercle, the nucleus of the diagonal band, the amygdala and the claustrum. The lateral hypothalamic nucleus sends a moderate number of fibers to the medial MD, but other hypothalamic nuclei send only a few fibers to the MD. The lateral or dorsal portion of the MD receives fibers from the nucleus of the diagonal band, the ventral pallidum and the entopeduncular nucleus, but only few from the olfactory tubercle and the amygdala. The thalamic reticular nucleus sends many fibers to the MD without showing any topography. The MD, particularly its lateral part, receives afferents from brainstem structures, such as the substantia nigra, superior colliculus, reticular formation, raphe nuclei and nucleus loci coerulei. Only the interpeduncular nucleus sends fibers mainly to the medial part of the MD. The cerebellar nuclei send only a few fibers to the lateral part of the MD at posterior levels.     

The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain-prefrontal cortex topography.

The medial and central segments of the mediodorsal nucleus of the thalamus (MD) receive afferents from the ventral forebrain, including the piriform cortex, the ventral pallidum, and the amygdaloid complex. Because MD is reciprocally interconnected with prefrontal and agranular insular cortical areas, it provides a relay of ventral forebrain activity to these cortical areas. However, there are also direct projections from the piriform cortex and the amygdala to the prefrontal and agranular insular cortices. This study addresses whether this system has a "triangular" organization, such that structures in the ventral forebrain project to interconnected areas in MD and the prefrontal/insular cortex. The thalamocortical projections of MD have been studied in experiments with injections of retrograde tracers into prefrontal or agranular insular cortical areas. In many of the same experiments, projections from the ventral forebrain to MD and to the prefrontal/insular cortex have been demonstrated with anterograde axonal tracers. The connections of the piriform cortex (PC) with MD and the prefrontal/insular cortex form an organized triangular system. The PC projections to the central and medial segments of MD and to the lateral orbital cortex (LO) and the ventral and posterior agranular insular cortices (AIv and AIp) are topographically organized, such that more caudal parts of PC tend to project more medially in MD and more caudally within the orbital/insular cortex. The central and medial portions of MD also send matching, topographically organized projections to LO, AIv and AIp, with more medial parts of MD projecting further caudally. The anterior cortical nucleus of the amygdala (COa) also projects to the dorsal part of the medial segment of MD and to its cortical targets, the medial orbital area (MO) and AIp. The projections of the basal/accessory basal amygdaloid nuclei to MD and to prefrontal cortex, and from MD to amygdaloceptive parts of prefrontal cortex, are not as tightly organized. Amygdalothalamic afferents in MD are concentrated in the dorsal half of the medial segment. Cells in this part of the nucleus project to the amygdaloceptive prelimbic area (PL) and AIp. However, other amygdaloceptive prefrontal areas are connected to parts of MD that do not receive fibers from the amygdala. Ventral pallidal afferents are distributed to all parts of the central and medial segments of MD, overlapping with the fibers from the amygdala and piriform cortex. Fibers from other parts of the pallidum, or related areas such as the substantia nigra, pars reticulata, terminate in the lateral and ventral parts of MD, where they overlap with inputs from the superior colliculus and other brainstem structures.(ABSTRACT TRUNCATED AT 400 WORDS)     

A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat.

Ascending projections from the dorsal raphe nucleus (DR) were examined in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). The majority of labeled fibers from the DR ascended through the forebrain within the medial forebrain bundle. DR fibers were found to terminate heavily in several subcortical as well as cortical sites. The following subcortical nuclei receive dense projections from the DR: ventral regions of the midbrain central gray including the 'supraoculomotor central gray' region, the ventral tegmental area, the substantia nigra-pars compacta, midline and intralaminar nuclei of the thalamus including the posterior paraventricular, the parafascicular, reuniens, rhomboid, intermediodorsal/mediodorsal, and central medial thalamic nuclei, the central, lateral and basolateral nuclei of the amygdala, posteromedial regions of the striatum, the bed nucleus of the stria terminalis, the lateral septal nucleus, the lateral preoptic area, the substantia innominata, the magnocellular preoptic nucleus, the endopiriform nucleus, and the ventral pallidum. The following subcortical nuclei receive moderately dense projections from the DR: the median raphe nucleus, the midbrain reticular formation, the cuneiform/pedunculopontine tegmental area, the retrorubral nucleus, the supramammillary nucleus, the lateral hypothalamus, the paracentral and central lateral intralaminar nuclei of the thalamus, the globus pallidus, the medial preoptic area, the vertical and horizontal limbs of the diagonal band nuclei, the claustrum, the nucleus accumbens, and the olfactory tubercle. The piriform, insular and frontal cortices receive dense projections from the DR; the occipital, entorhinal, perirhinal, frontal orbital, anterior cingulate, and infralimbic cortices, as well as the hippocampal formation, receive moderately dense projections from the DR. Some notable differences were observed in projections from the caudal DR and the rostral DR. For example, the hippocampal formation receives moderately dense projections from the caudal DR and essentially none from the rostral DR. On the other hand, virtually all neocortical regions receive significantly denser projections from the rostral than from the caudal DR. The present results demonstrate that dorsal raphe fibers project significantly throughout widespread regions of the midbrain and forebrain.     

Efferent connections of the prelimbic (area 32) and the infralimbic (area 25) cortices: an anterograde tracing study in the cat

The projections from the caudal part of the medial frontal cortex, encompassing the prelimbic area (PL) and the infralimbic area (IL) (Brodmann's areas 32 and 25, respectively), were studied in the cat with the anterograde autoradiographic tracing technique. The results indicate that the projection fields of IL, in contrast to those of PL, are restricted almost exclusively to limbic structures. Whereas the major thalamic projections from PL reach the mediodorsal, anteromedial, and ventromedial nuclei, the medial part of the lateral posterior nucleus, and the parataenial and reticular nuclei, and weak projections from this area are directed to the nucleus reuniens and other midline nuclei, the nucleus reuniens is the major thalamic termination field of fibers arising from IL. Cortical areas that are reached by fibers originating in PL and, to a lesser degree, also in IL, include more rostral prefrontal areas (areas 8, 6, and 12), the agranular insular, and the rostral perirhinal cortices. In contrast, cortical areas that are more strongly related to IL include the cingulate, retrosplenial, caudal entorhinal, and perirhinal cortices and the subiculum of the hippocampal formation. Another prominent output of PL concerns projections to an extensive medial part of the caudate nucleus and the ventral striatum, whereas fibers from IL only distribute most ventrally in the striatum. In the amygdaloid complex, fibers from PL were found to reach the basolateral, basomedial, and central nuclei, and fibers from IL to distribute to the medial and central nuclei. PL furthermore projects to the claustrum and the endopiriform nucleus. Other structures in the basal forebrain, including the medial septum, the nuclei of the diagonal band, the preoptic area, and the lateral and dorsal hypothalamus are densely innervated by IL and only sparsely by PL. With respect to more caudal parts of the brainstem, projections from PL and IL appeared to be essentially similar. They reach the ventral tegmental area, the periaqueductal gray, the parabrachial nucleus, and in cases of PL injections were followed as far caudally as the pons.     

Efferent connections of the centromedian and parafascicular thalamic nuclei: an autoradiographic investigation in the cat

The efferent projections of the centromedian and parafascicular (CM-Pf) thalamic nuclear complex were analyzed by the autoradiographic method. Our findings show that the CM-Pf complex projects in a topographic manner to specific regions of the rostral cortex. These fibers distribute primarily to cortical layers I and III; however, the projection to layer I is more extensive. Following an injection into the rostral portion of the CM-Pf complex, label is found within the lateral rostral cortex, particularly within the presylvian, anterior ectosylvian, and anterior lateral sulci, and within the rostral medial cortex where label is present within the cruciate and anterior splenial sulci and anterior cingulate gyrus. An injection into the caudal dorsal portion of the CM-Pf complex results in label within the more ventral portions of the rostral lateral cortex where it is present within the anterior sylvian gyrus, presylvian regions, and gyrus proreus; and within the rostral medial cortex, where it is present within the rostral cingulate gyrus, and within the cruciate sulcus, and an extensive region ventral to the cruciate sulcus which includes the anterior limbic area. Injections into the caudal ventral portion of the CM-Pf complex result in virtually no cortical label, although a few labeled fibers are found in the subcortical white matter. The subcortical projection from the CM-Pf complex terminates within the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, zona incerta, fields of Forel, hypothalamus, thalamic reticular nucleus, and rostral intralaminar nuclei. Prominent silver grain aggregates are also present within the ventral lateral, ventral anterior, ventral medial, and lateral posterior nuclei, and ventrobasal complex. The aggregates in the thalamus appear to be fibers of passage, but whether these are also terminals cannot be determined with the techniques used in the present study.     

Organization of cortical and subcortical projections to anterior cingulate cortex in the cat

The aim of the experiments reported here was to identify cortical and subcortical forebrain structures from which anterior cingulate cortex (CGa) receives input in the cat. Deposits of retrograde tracers were placed at nine sites spanning the anterior cingulate area and patterns of retrograde transport were analyzed. Thalamic projections to CGa, in descending order of strength, originate in the anteromedial nucleus, lateroposterior nucleus, ventroanterior nucleus, rostral intralaminar complex, reuniens nucleus, mediodorsal nucleus, and laterodorsal nucleus. Minor and inconsistent ascending pathways arise in the paraventricular, parataenial, parafascicular, and subparafascicular thalamic nuclei. The basolateral nucleus of the amygdala, the hypothalamus, the nucleus of the diagonal band, and the claustrum are additional sources of ascending input. Cortical projections to CGa, in descending order of strength, derive from posterior cingulate cortex, prefrontal cortex, motor cortex (areas 4 and 6), parahippocampal cortex (entorhinal, perirhinal, postsubicular, parasubicular, and subicular areas), insular cortex, somesthetic cortex (areas 5 and SIV), and visual cortex (areas 7p, 20b, AMLS, PS and EPp). In general, the limbic, sensory, and motor afferents of CGa are weak. The dominant sources of input to CGa are other cortical areas with high-order functions. This finding calls into question the traditional characterization of cingulate cortex as a bridge between neocortical association areas and the limbic system.     

Organization of afferents to the orbitofrontal cortex in the rat

The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas.     

Cortical and subcortical, including sensory-related, afferents to the thalamic mediodorsal nucleus of the cat

Cortical and subcortical afferents to the cat's thalamic mediodorsal nucleus (MD) were investigated using the method of retrograde transport of horseradish peroxidase (HRP). HRP was applied using vertical or oblique approaches and either a microsyringe or implanted pipettes filled with HRP-powder. A wide variety of cortical afferents to MD was detected: Aside from afferents from the cat's classical prefrontal cortex (gyri proreus, rectus, frontalis), from adjacent areas of the premotor and cingulate cortex and from portions of the insular cortex, afferents were found from cortical areas related to the processing of somatosensory, gustatory, auditory and visual information and from portions of the parietal and temporal association cortex. A considerable number of afferents arose from the diagonal band of Broca and a small number from the precommissural septum, periamygdaloid , prepiriform , entorhinal, subicular and amygdalar regions. The preoptic region and hypothalamic areas contained some labeled cells. All brains, with the exception of one with a very small dorsomedial injection, contained labeled cells in the mamillary bodies. The reticular nuclear complex and the ventral lateral geniculate nucleus were the main sources of afferents on the thalamic level. In the brain stem the substantia nigra, the ventral tegmental area, the deep layers of the superior colliculus, pretectal and tegmental regions contained labeled cells. These results show that MD receives afferents from a large variety of structures. Among them are several cortical as well as subcortical regions related to the processing of sensory and motor information. Taken together, these connections and the numerous afferents to MD from regions related to emotional and motivational behavior confirm the view that MD has to be termed association nucleus.     

The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat

Direct projections from the forebrain to the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus in the rat medulla were mapped in detail using both retrograde axonal transport of the fluorescent tracer True Blue and anterograde axonal transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). In the retrograde tracing studies, cell groups in the medial prefrontal cortex, lateral prefrontal cortex (primarily ventral and posterior agranular insular cortex), bed nucleus of the stria terminalis, central nucleus of the amygdala, paraventricular, arcuate, and posterolateral areas of the hypothalamus were shown to project to the NTS and in some cases also to the dorsal motor nucleus of the vagus. The prefrontal cortical areas projecting to the NTS apparently overlap to a large degree with those cortical areas receiving mediodorsal thalamic and dopaminergic input. The retrogradely labeled cortical cells were situated in deep layers of the rat prefrontal cortex. The anterograde tracing studies revealed a prominent topography in the mediolateral termination pattern of forebrain projections to the rostral part of the NTS and to the dorsal pons. The projections to the NTS were generally bilateral, except for projections from the central nucleus of the amygdala and bed nucleus of the stria terminalis which were predominantly ipsilateral. The prefrontal cortical projections to the NTS travel through the cerebral peduncle and pyramidal tract and terminate throughout the rostrocaudal extent of the NTS. Specifically, the prefrontal cortex innervates dorsal portions of the NTS (lateral part of the dorsal division of the medial solitary nucleus, dorsal part of the lateral solitary nucleus and the caudal midline region of the commissural nucleus), areas which receive relatively sparse subcortical projections. These dorsal portions of the NTS receive major primary afferent projections from the vagal and glossopharyngeal nerves. In contrast, the subcortical projections, which travel through the midbrain and pontine tegmentum, terminate most heavily in the ventral portions of the NTS, i.e., the area immediately dorsal and lateral to the dorsal motor nucleus of the vagus. Only the paraventricular hypothalamic nucleus has substantial terminals throughout the dorsal motor nucleus of the vagus. Hypothalamic cell groups innervate the area postrema and, along with the prefrontal cortex, innervate the zone subjacent to the area postrema.(ABSTRACT TRUNCATED AT 400 WORDS)     

Afferent connections of the lateralis medialis thalamic nucleus in the cat

We have used anterograde and retrograde horseradish peroxidass tracing methods in this study. Peroxidase injections in the lateralis medialis thalamic nucleus (LIB of the cat resulted in labeled neurons in cortical and subcortical structures that averaged 71 % and 29%, respectively. Every LM sector receives abundant projections from the polymodal sylvian anterior cortical area, the reticular thalamic nucleus, and the stratum opticum and intermediate layer of the superior colliculus. Less abundant but consistent projections were detected in cingular, auditory II, lateral suprasylvian and anterior ectosylvian visual cortices, and cortical area 7. A topographical distribution of afferent connections to different LM sectors arising from other cortical and subcortical structures could be established. The ventromedial sector receives connections mainly from the insular agranular, limbic and prefrontal cortical areas, as well as from brain stem structures and the contralateral pretectal region. The dorsolateral sector is mainly related to cortical areas and subcortical strictures processing visual information. The existence of overlap among neuronal LM populations receiving and sending connections to and from various cortical areas suggests that this nucleus is an appropriate substrate for effective interaction between different and distant cortical areas.     

Heterotopic Cortical Afferents to the Medial Prefrontal Cortex in the Rat. A Combined Retrograde and Anterograde Tracer Study

Cortical afferent projections towards the medial prefrontal cortex (mPFC) were investigated with retrograde and anterograde tracer techniques. Heterotopical afferent projections to the medial prefrontal cortex arise in secondary, or higher order, sensory areas, motor areas and paralimbic cortices. On the basis of these projections three subfields can be discriminated within the mPFC. (1) The ventromedial part of mPFC, comprising the pre- and infralimbic areas, receives mainly projections from the perirhinal cortex. (2) The caudal two-thirds of the dorsomedial PFC, comprising frontal area 2 and the dorsal anterior cingulate area, receives projections from the secondary visual areas, the posterior agranular insular area and the retrosplenial areas. (3) The rostral one-third of the dorsomedial PFC is the main recipient of projections from the somatosensory and motor areas and the posterior agranular insular area. The laminar distribution of cells projecting to the mPFC varies considerably in the different cortical areas, just as the laminar distribution of termination of their fibres within the mPFC does. It is concluded that the corticocortical connections corroborate with subcortical connectivity in attributing to the mediodorsal projection cortex of the rat functions which are comparable to those of certain prefrontal, premotor and anterior cingulate areas in the monkey.     

Organization of the Visual Reticular Thalamic Nucleus of the Rat

The visual sector of the reticular thalamic nucleus has come under some intense scrutiny over recent years, principally because of the key role that the nucleus plays in the processing of visual information. Despite this scrutiny, we know very little of how the connections between the reticular nucleus and the different areas of visual cortex and the different visual dorsal thalamic nuclei are organized. This study examines the patterns of reticular connections with the visual cortex and the dorsal thalamus in the rat, a species where the visual pathways have been well documented. Biotinylated dextran, an anterograde and retrograde tracer, was injected into different visual cortical areas [17; rostral 18a: presumed area AL (anterolateral); caudal 18a: presumed area LM (lateromedial); rostral 18b: presumed area AM (anteromedial); caudal 18b: presumed area PM (posteromedial)] and into the different visual dorsal thalamic nuclei (posterior thalamic, lateral posterior, lateral geniculate nuclei), and the patterns of anterograde and retrograde labelling in the reticular nucleus were examined. From the cortical injections, we find that the visual sector of the reticular nucleus is divided into subsectors that each receive an input from a distinct visual cortical area, with little or no overlap. Further, the resulting pattern of cortical terminations in the reticular nucleus reflects largely the patterns of termination in the dorsal thalamus. That is, each cortical area projects to a largely distinct subsector of the reticular nucleus, as it does to a largely distinct dorsal thalamic nucleus. As with each of the visual cortical areas, each of the visual dorsal thalamic (lateral geniculate, lateral posterior, posterior thalamic) nuclei relate to a separate territory of the reticular nucleus, with little or no overlap. Each of these dorsal thalamic territories within the reticular nucleus receives inputs from one or more of the visual cortical areas. For instance, the region of the reticular nucleus that is labelled after an injection into the lateral geniculate nucleus encompasses the reticular regions which receive afferents from cortical areas 17, rostral 18b and caudal 18b. These results suggest that individual cortical areas may influence the activity of different dorsal thalamic nuclei through their reticular connections.     

Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat: an anterograde tracer PHA-L study

The efferent projections of the infralimbic region (IL) of the medial prefrontal cortex of the rat were examined by using the anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). Major targets of the IL were found to include the agranular insular cortex, olfactory tubercle, perirhinal cortex, the whole amygdaloid complex, caudate putamen, accumbens nucleus, bed nucleus of the stria terminalis, midline thalamic nuclei, the lateral preoptic nucleus, paraventricular nucleus, supramammillary nucleus, medial mammillary nucleus, dorsal and posterior areas of the hypothalamus, ventral tegmental area, central gray, interpeduncular nucleus, dorsal raphe, lateral parabrachial nucleus and locus coeruleus. Previously unreported projections of the IL to the anterior olfactory nucleus, piriform cortex, anterior hypothalamic area and lateroanterior hypothalamic nucleus were observed. The density of labeled terminals was especially high in the agranular insular cortex, olfactory tubercle, medial division of the mediodorsal nucleus of the thalamus, dorsal hypothalamic area and the lateral division of the central amygdaloid nucleus. Several physiological and pharmacological studies have suggested that the IL functions as the 'visceral motor' cortex, involved in autonomic integration with behavioral and emotional events. The present investigation is the first comprehensive study of the IL efferent projections to support this concept.     

The primate mediodorsal (MD) nucleus and its projection to the frontal lobe

The frontal lobe projections of the mediodorsal (MD) nucleus of the thalamus were examined in rhesus monkey by transport of retrograde markers injected into one of nine cytoarchitectonic regions (Walker's areas 6, 8A, 9, 10, 11, 12, 13, 46, and Brodmann's area 4) located in the rostral third of the cerebrum. Each area of prefrontal, premotor, or motor cortex injected was found to receive a topographically unique thalamic input from clusters of cells in specific subdivisions within MD. All of the prefrontal areas examined also receive topographically organized inputs from other thalamic nuclei including, most prominently, the ventral anterior (VA) and medial pulvinar nuclei. Conversely, and in agreement with previous findings, MD projects to areas of the frontal lobe beyond the traditional borders of prefrontal cortex, such as the anterior cingulate and supplementary motor cortex. The topography of thalamocortical neurons revealed in coronal sections through VA, MD, and pulvinar is circumferential. In the medial part of MD, for example, thalamocortical neurons shift from a dorsal to a ventral position for cortical targets lying medial to lateral along the ventral surface of the lobe; neurons in the lateral MD move from a ventral to a dorsal position, for cortical areas situated lateral to medial on the convexity of the hemisphere. The aggregate evidence for topographic specificity is supported further by experiments in which different fluorescent dyes were placed in multiple areas of the frontal lobe in each of three cases. The results show that very few, if any, thalamic neurons project to more than one area of cortex. The widespread cortical targets of MD neurons together with evidence for multiple thalamic inputs to prefrontal areas support a revision of the classical hodological definition of prefrontal cortex as the exclusive cortical recipient of MD projections. Rather, the prefrontal cortex is defined by multiple specific relationships with the thalamus.     

Diverse thalamic projections to the prefrontal cortex in the rhesus monkey.

We studied the sources of thalamic projections to prefrontal areas of nine rhesus monkeys with the aid of retrograde tracers (horseradish peroxidase or fluorescent dyes). Our goal was to determine the proportion of labeled neurons contributing to this projection system by the mediodorsal (MD) nucleus compared to those distributed in other thalamic nuclei, and to investigate the relationship of thalamic projections to specific architectonic areas of the prefrontal cortex. We selected areas for study within both the basoventral (areas 11, 12, and ventral 46) and the mediodorsal (areas 32, 14, 46, and 8) prefrontal sectors. This choice was based on our previous studies, which indicate differences in cortical projections to these two distinct architectonic sectors (Barbas, '88; Barbas and Pandya, '89). In addition, for each sector we included areas with different architectonic profiles, which is also relevant to the connectional patterns of the prefrontal cortices. The results showed that MD included a clear majority (over 80%) of all thalamic neurons directed to some prefrontal cortices (areas 11, 46, and 8); it contributed just over half to some others (areas 12 and 32), and less than a third to area 14. Clusters of neurons directed to basoventral and mediodorsal prefrontal areas were largely segregated within MD: the former were found ventrally, the latter dorsally. However, the most striking findings establish a relationship between thalamic origin and laminar definition of the prefrontal target areas. Most thalamic neurons directed to lateral prefrontal cortices, which are characterized by a high degree of laminar definition (areas 46 and 8), originated in the parvicellular and multiform subdivisions of MD, and only a few were found in other nuclei. In contrast, orbital and medial cortices, which have a low degree of laminar differentiation, were targeted by the magnocellular subdivision of MD and by numerous other limbic thalamic nuclei, including the midline and the anterior. Thus topographic specificity in the origin of thalamic projections increased as the laminar definition of the target area increased. Moreover, the rostrocaudal distribution of labeled neurons in MD and the medial pulvinar also differed depending on the degree of the laminar definition of the prefrontal target areas. The rostral parts of MD and the medial pulvinar projected to the eulaminate lateral prefrontal cortices, whereas their caudal parts projected to orbital and medial limbic cortices. Selective destruction of caudal MD is known to disrupt mnemonic processes in both humans and monkeys, suggesting that this thalamic-limbic prefrontal loop may constitute an important pathway for memory.     

Subcortical projections to the frontal pole in the marmoset monkey

The subcortical projections to the marmoset frontal pole were mapped with the use of fluorescent tracer injections. The main thalamic projections, which originated in both the magnocellular and parvocellular subdivisions of the mediodorsal nucleus, were topographically organized. Our results suggest the existence of a third, caudal subdivision of this nucleus, which is likely to be homologous to the macaque's pars densocellularis. A substantial, but not topographically organized, projection to Brodmann's area 10 originated in the medial part of the ventral anterior nucleus. Minor thalamic projections originated in the medial pulvinar nucleus and in the midline/intralaminar nuclei. Finally, the posterior thalamic group (including the limitans and suprageniculate nuclei) sent a small projection to rostral area 10 that has not previously been documented in primates. The main extrathalamic projections stemmed from the claustrum, which contained as many as 50% of all subcortical labelled neurons. Minor connections originated in the hypothalamus (mainly in the lateral anterior and lateral tuberal regions), dorsal periaqueductal grey matter, basal forebrain (nucleus basalis of Meynert and horizontal limb of the diagonal band of Broca), and amygdala (basal, accessory basal and lateral nuclei). The present results, combined with recent data on the cortical projections to area 10, reveal the frontal pole as a region that integrates information from multiple neural processing systems, including high-level sensory, limbic and working memory-related structures. Although the pattern of subcortical projections is similar to that previously described in the macaque, suggesting a homologous organization, the present data also suggest functional distinctions between medial and lateral sectors of area 10.     

Cortical,thalamic, and amygdaloid connections of the anterior and posterior insular cortices

Cortical, thalamic, and amygdaloid projections of the rat anterior and posterior insular cortices were examined using the anterograde transport of biocytin. Granular and dysgranular posterior insular areas between bregma and 2 mm anterior to bregma projected to the gustatory thalamic nucleus. Granular cortex projected to the subjacent dysgranular cortex which in turn projected to the agranular (all layers) and granular cortices (layers I and VI). Both granular and dysgranular posterior areas projected heavily to the dysgranular anterior insular cortex. Agranular posterior insular cortex projected to medial mediodorsal nucleus, agranular anterior insular and infralimbic cortices as well as granular and dysgranular posterior insula. No projections to the amygdala were observed from posterior granular cortex, although dysgranular cortex projected to the lateral central nucleus, dorsolateral lateral nucleus, and posterior basolateral nucleus. Agranular projections were similar, although they included medial and lateral central nucleus and the ventral lateral nucleus. Dysgranular anterior insular cortex projected to lateral agranular frontal cortex and granular and dysgranular posterior insular regions. Agranular anterior insular cortex projected to the dysgranular anterior and prelimbic cortices. Anterior insuloamygdaloid projections targeted the rostral lateral and anterior basolateral nuclei with sparse projections to the rostral central nucleus. The data suggest that the anterior insula is an interface between the posterior insular cortex and motor cortex and is connected with motor-related amygdala regions. Amygdaloid projections from the posterior insular cortex appear to be organized in a feedforward parallel fashion targeting all levels of the intraamygdaloid connections linking the lateral, basolateral, and central nuclei . J. Comp. Neurol. 399:440–468, 1998. © 1998 Wiley-Liss, Inc.     

Origin and topography of fibers contributing to the fornix in macaque monkeys

The distribution of neurons contributing to the fornix was mapped by placing the retrograde tracer horseradish peroxidase (HRP) in polyacrylamide gels in different medial to lateral locations within the fornix of three rhesus monkeys (Macaca mulatta). The HRP was placed from 3 to 5 mm caudal to the descending columns of the fornix. Additional information came from a series of rhesus and cynomolgus monkeys (Macaca fasciculata) with anterograde tracer injections in the medial temporal lobe. The hippocampal formation, including the subiculum and presubiculum, together with the entorhinal cortex (EC) and perirhinal cortex (area 35) contribute numerous axons to the fornix in a topographical manner. In contrast, the lateral perirhinal cortex (area 36) and parahippocampal cortical areas TF and TH only contained a handful of cells labeled via the fornix. The medial fornix originates from cells in the caudal half of the subiculum, the lamina principalis interna of the caudal half of the presubiculum, and from the perirhinal cortex (area 35). The intermediate portion of the fornix (i.e., that part midway between the midline and most lateral parts of the fornix) originates from cells in the rostral half of the subiculum and prosubiculum, the anterior presubiculum (only from the lamina principalis externa), the caudal presubiculum (primarily from lamina principalis interna), the rostral half of CA3, the EC (primarily 28I and 28M), and the perirhinal cortex (area 35). The lateral parts of the fornix arise from the rostral EC (28L only) and the most rostral portion of CA3. Subcortically, the medial septum, nucleus of the diagonal band, supramammillary nucleus, lateral hypothalamus, dorsal raphe nucleus, and the thalamic nucleus reuniens all send projections through the fornix, which presumably terminate in the hippocampus and adjacent parahippocampal region. These results not only help to define those regions that project via the fornix, but also reveal those subcortical projections to the hippocampal formation most likely to rely entirely on nonfornical pathways.