Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey

The sources of ipsilateral projections from the amygdala to basoventral and mediodorsal prefrontal cortices were studied with retrograde tracers (horseradish peroxidase or fluorescent dyes) in 13 rhesus monkeys. The basoventral regions injected with tracers included the orbital periallocortex and proisocortex, orbital areas 13, 11, and 12, lateral area 12, and ventral area 46. The mediodorsal regions included portions of medial areas 25, 32, 14, and dorsal area 8. The above sites represent areas within two architectonic series of cortices referred to as basoventral or mediodorsal on the basis of their anatomic location. Each series consists of areas that show a gradual increase in the number of layers and their delineation in a direction from the caudal orbital and medial limbic cortices, which have an incipient laminar organization, towards the eulaminated periarcuate cortices (Barbas and Pandya, J. Comp. Neurol. 286: 353-375, '89). Labeled neurons projecting to the prefrontal cortex were found in the basolateral, basomedial (also known as accessory basal), lateral, and ventral cortical nuclei, and in the anterior amygdaloid and amygdalopiriform areas. The distribution of labeled neurons differed both quantitatively and qualitatively depending on whether the injection sites were in basoventral or mediodorsal prefrontal cortices. Cases with caudal orbital injections had the most labeled neurons in the amygdala, followed by cases with injections in cortices situated medioventrally. The latter received a high proportion of their amygdaloid projections from the basomedial nucleus. The lateral amygdaloid nucleus sent a robust projection to the least architectonically differentiated orbital periallocortex, and a weaker projection to the adjoining orbital proisocortical regions, but did not appear to project to either medial proisocortical sites or to the more differentiated ventrolateral or dorsolateral prefrontal cortices. In addition, there were topographical differences in the origin of projections from one amygdaloid nucleus directed to various prefrontal cortices. These differences were correlated either with the destination of the axons of afferent amygdaloid neurons to basoventral or to mediodorsal prefrontal cortices and/or with their projection to areas with varying degrees of laminar organization within the basoventral or mediodorsal sector. The clearest topography was observed for projections originating in the basolateral nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Prefrontal projections to the mediodorsal nucleus of the thalamus in the rhesus monkey.

The corticothalamic projections to the prefrontal cortex have been shown to be topographically organized. However, the underlying basis for this topography as it relates to the organization of the different architectonically defined areas of the prefrontal cortex has not been systematically studied. In the present investigation we have reassessed the thalamic projections from the different architectonic areas of the prefrontal cortex by using the technique of autoradiography in the rhesus monkey. The results show that the prefronto-mediodorsal projections are organized according to the architectonic differentiation of the prefrontal cortices. Thus architectonically less differentiated medial and orbital prefrontal regions project to the medial sector of the mediodorsal nucleus, the magnocellular subdivision. In contrast, highly differentiated prefrontal area 8 projects to the most lateral sector of the mediodorsal nucleus, the multiformis subdivision. Lateral prefrontal areas with intermediate architectonic features project to the central parvocellular sector of the mediodorsal nucleus. Additionally, these projections also reveal a dorsoventral topography. Thus areas in the medial and dorsolateral cortices project to the dorsal part of the mediodorsal nucleus. In contrast, areas in orbital and ventrolateral cortices project to the ventral part of the mediodorsal nucleus. The topographic organization of the corticothalamic connections described in this study corresponds to the progressive elaboration and differentiation of the architectonic features of the different prefrontal areas. This successive and dichotomous organization of prefrontothalamic connections may provide the basis for the observed differential functions of the prefrontal cortex and the mediodorsal nucleus.     

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)     

Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in Macaque monkeys

The origin and termination of prefrontal cortical projections to the periaqueductal gray (PAG) were defined with retrograde axonal tracers injected into the PAG and anterograde axonal tracers injected into the prefrontal cortex (PFC). The retrograde tracer experiments demonstrate projections to the PAG that arise primarily from the medial prefrontal areas 25, 32, and 10m, anterior cingulate, and dorsomedial areas 24b and 9, select orbital areas 14c, 13a, Iai, 12o, and caudal 12l, and ventrolateral area 6v. Only scattered cells were retrogradely labeled in other areas in the PFC. Caudal to the PFC, projections to the PAG also arise from the posterior cingulate cortex, the dorsal dysgranular, and granular parts of the temporal polar cortex, the ventral insula, and the dorsal bank of the superior temporal sulcus. Cells were also labeled in subcortical structures, including the central nucleus and ventrolateral part of the basal nucleus of the amygdala. The anterograde tracer experiments indicate that projections from distinct cortical areas terminate primarily in individual longitudinal PAG columns. The projections from medial prefrontal areas 10m, 25, and 32 end predominantly in the dorsolateral columns, bilaterally. Fibers from orbital areas 13a, Iai, 12o, and caudal 12l terminate primarily in the ventrolateral column, whereas fibers from dorsomedial areas 9 and 24b terminate mainly in the lateral column. The PFC areas that project to the PAG include most of the areas previously defined as the “medial prefrontal network.” The areas that comprise this network represent a visceromotor system, distinct from the sensory related “orbital network.” J. Comp. Neurol. 401:455–479, 1998. © 1998 Wiley-Liss, Inc.     

Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat

We utilised retrograde and anterograde tracing procedures to study the origin and termination of prefrontal cortical (PFC) projections to the periaqueductal gray (PAG) in the rat. A previous study, in the primate, had demonstrated that distinct subgroups of PFC areas project to specific PAG columns. Retrograde tracing experiments revealed that projections to dorsolateral (dlPAG) and ventrolateral (vlPAG) periaqueductal gray columns arose from medial PFC, specifically prelimbic, infralimbic, and anterior cingulate cortices. Injections made in the vlPAG also labeled cells in medial, ventral, and dorsolateral orbital cortex and dorsal and posterior agranular insular cortex. Other orbital and insular regions, including lateral and ventrolateral orbital, ventral agranular insular, and dysgranular and granular insular cortex did not give rise to appreciable projections to the PAG. Anterograde tracing experiments revealed that the projections to different PAG columns arose from specific PFC areas. Projections from the caudodorsal medial PFC (caudal prelimbic and anterior cingulate cortices) terminated predominantly in dlPAG, whereas projections from the rostroventral medial PFC (rostral prelimbic cortex) innervated predominantly the vlPAG. As well, consistent with the retrograde data, projections arising from select orbital and agranular insular cortical areas terminated selectively in the vlPAG. The results indicate: (1) that rat orbital and medial PFC possesses an organisation broadly similar to that of the primate; and (2) that subdivisions within the rat orbital and medial PFC can be recognised on the basis of projections to distinct PAG columns.     

Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey

An investigation of the architectonic organization and intrinsic connections of the prefrontal cortex was conducted in rhesus monkeys. Cytoarchitectonic analysis indicates that in the prefrontal cortex there are two trends of gradual change in laminar characteristics that can be traced from limbic periallocortex towards isocortical areas. The stepwise change in laminar features is characterized by the emergence and gradual increase in the width of granular layer IV, by an increase in the size of pyramidal cells in layers III and V, and by a higher cell-packing density in the supragranular layers. Myeloarchitectonic analysis reveals that the limbic areas are poorly myelinated, adjacent areas have a diffuse myelin content confined to the deep layers, and in isocortices the myelinated fibers are distributed in organized horizontal bands (of Baillarger) and a vertical plexus. Using the above architectonic criteria, we observed that one of the architectonic trends takes a radial basoventral course from the periallocortex in the caudal orbitofrontal region to the adjacent proisocortex and then to area 13. The next stage of architectonic regions includes orbital areas 12, 11, and 14, which is followed by area 10, lateral area 12, and the rostral part of ventral area 46. The last group includes the caudal part of ventral area 46 and ventral area 8. The other trend takes a mediodorsal course from the periallocortex around the rostral portion of the corpus callosum to the adjacent proisocortical areas 24, 25, and 32 and then to the medially situated isocortical areas 9, 10, and 14. The next stage includes lateral areas 10 and 9 and the rostral part of dorsal area 46. The last group includes the caudal part of dorsal area 46 and dorsal area 8. The interconnections of subdivisions of the basoventral and mediodorsal cortices were studied with the aid of anterograde and retrograde tracers. Within each trend a given area projects in two directions: to adjoining regions belonging to succeeding architectonic stages on the one hand, and to nearby regions from the preceding architectonic stage on the other. In each direction there is more than one region involved in this projection system, paralleling the radial nature of architectonic change. Periallo- and proisocortices have widespread intrinsic connections, whereas isocortices situated at a distance from limbic areas, such as area 8, have restricted connections. Most interconnections are limited to areas within the same architectonic trend. However, there are links between cortices from the two trends, and these seem to occur between areas that are at a similar stage of architectonic differentiation. The results suggest that there are two architectonically, and perhaps functionally, distinct axes within the prefrontal cortex. The earliest stages within each axis, which have widespread connections, may have a global role in neural processing. On the other hand, the latest stages, which have restricted connections, may have a more specific role in processes associated with the frontal lobe.     

Topographically specific hippocampal projections target functionally distinct prefrontal areas in the rhesus monkey

The sources of ipsilateral projections from the hippocampal formation, the presubiculum, area 29a-c, and parasubiculum to medial, orbital, and lateral prefrontal cortices were studied with retrograde tracers in 27 rhesus monkeys. Labeled neurons within the hippocampal formation (CA1, CA1′, prosubiculum, and subiculum) were found rostrally, although some were noted throughout the entire rostrocaudal extent of the hippocampal formation. Most labeled neurons in the hippocampal formation projected to medial prefrontal cortices, followed by orbital areas. In addition, there were differences in the topography of afferent neurons projecting to medial when compared with orbital cortices. Labeled neurons innervating medial cortices were found mainly in the CA1′ and CA1 fields rostrally, but originated in the subicular fields caudally. In contrast, labeled neurons which innervated orbital cortices were considerably more focal, emanating from the same relative position within a field throughout the rostrocaudal extent of the hippocampal formation. In marked contrast to the pattern of projection to medial and orbital prefrontal cortices, lateral prefrontal areas received projections from only a few labeled neurons found mostly in the subicular fields. Lateral prefrontal cortices, lateral prefrontal cortices received the most robust projections from the presubiculum and the supracallosal area 29a-c. Orbital, and to a lesser extent medial, prefrontal areas received projections from a smaller but significant number of neurons from the presubiculum and area 29a-c. Only a few labeled neurons were found in the parasubiculum, and most projected to medial prefrontal areas. The results suggest that functionally distinct prefrontal cortices receive projections from different components of the hippocampal region. Medial and orbital prefrontal cortices may have a role in long-term mnemonic process similar to those associated with the hippocampal formation with which they are linked. Moreover, the preponderance of projection neurons from the hippocampal formation innervating medial when compared with orbital prefrontal areas followed the opposite trend from what we had observed previously for the amygdala (Barbas and De Olmos [1990]) (J Comp Neurol 301:1–23). Thus, the hippocampal formation, associated with mnemonic processes, targets predominantly medial prefrontal cortices, whereas the amygdala, associated with emotional aspects of memory, issues robust projections to orbital limbic cortices. Lateral prefrontal cortices receive robust projections from the presubiculum and area 29a-c and sparse projections from the hippocampal formation. These findings are consistent with the idea that the role of lateral prefrontal cortices in memory is distinct from that of either medial or orbital cortices. The results suggest that signals from functionally distinct limbic structures to some extent follow parallel pathways to functionally distinct prefrontal cortices. © 1995 Wiley-Liss, Inc.     

Orbitomedial prefrontal cortical projections to hypothalamus in the rat

A previous study in the rat revealed that distinct orbital and medial prefrontal cortical (OMPFC) areas projected to specific columns of the midbrain periaqueductal gray region (PAG). This study used anterograde tracing techniques to define projections to the hypothalamus arising from the same OMPFC regions. In addition, injections of anterograde and retrograde tracers were made into different PAG columns to examine connections between hypothalamic regions and PAG columns projected upon by the same OMPFC regions. The most extensive patterns of hypothalamic termination were seen after injection of anterograde tracer in prelimbic and infralimbic (PL/IL) and the ventral and medial orbital (VO/MO) cortices. Projections from rostral PL/IL and VO/MO targeted the rostrocaudal extent of the lateral hypothalamus, as well as lateral perifornical, and dorsal and posterior hypothalamic areas. Projections arising from caudal PL/IL terminated within the dorsal hypothalamus, including the dorsomedial nucleus and dorsal and posterior hypothalamic areas. There were also projections to medial perifornical and lateral hypothalamic areas. In contrast, it was found that anterior cingulate (AC), dorsolateral orbital (DLO), and agranular insular (AId) cortices projected to distinct and restricted hypothalamic regions. Projections arising from AC terminated within dorsal and posterior hypothalamic areas, whereas DLO and AId projected to the lateral hypothalamus. The same OMPFC regions also projected indirectly, by means of specific PAG columns, to many of the same hypothalamic fields. In the context of our previous findings, these data indicate that, in both rat and macaque, parallel but distinct circuits interconnect OMPFC areas with specific hypothalamic regions, as well as PAG columns.     

Organization of anterior cingulate and frontal cortical projections to the retrosplenial cortex in the rat

The retrosplenial cortex (areas 29a-d), which plays an important role in spatial memory and navigation, is known to provide massive projections to frontal association and motor cortices, which are also essential for spatial behavior. The reciprocal projections originating from these frontal cortices to areas 29a-d, however, have been analyzed to only a limited extent. Here, we report an analysis of the anatomical organization of projections from anterior cingulate area 24 and motor and prefrontal cortices to areas 29a-d in the rat, using the axonal transport of cholera toxin B subunit and biotinylated dextran amine. Area 29a receives projections from rostral area 24a, area 24b, the ventral orbital area, and the caudal secondary motor area. Rostral area 29b receives projections from caudal area 24a, whereas caudal area 29b receives projections from rostral area 24a. Area 29b also receives projections from area 24b and the ventral orbital area. Areas 29c and 29d receive projections from areas 24a and 24b and the secondary motor area in a topographic manner such that the rostrocaudal axis of areas 29c and 29d corresponds to the caudorostral axis of areas 24a and 24b and the secondary motor area. Rostral areas 29c and 29d also receive projections from the caudal primary motor area, and area 29d receives projections from the ventral, lateral, and medial orbital areas. These differential frontal cortical projections to each area of the retrosplenial cortex suggest that each area may contribute to different aspects of retrosplenial cortical function such as spatial memory and behavior.     

Contralateral thalamic projections predominantly reach transitional cortices in the rhesus monkey

Connections between the thalamus and the cortex are generally regarded as ipsilateral, even though contralateral connections exist as well in several adult mammalian species. It is not known however, whether contralateral thalamocortical projections reach particular cortices or whether they emanate from specific nuclei. In the rhesus monkey different types of cortices, ranging from transitional to eulaminate, vary in their cortical connectional pattern and may also differ in thier thalamic connections. Because olfactory and transitional prefrontal cortices receive widespread projections, we investaged whether they are the target of projections from the contralateral thalamus as well. With the aid of retrograde tracers, we studied the thalamic projections of primary olfactory (olfactory tubercle and prepiriform cortex) and transitional orbital (areas PAPP, Pro 13) and medial (areas 25, 24, 32) areas, and of eulaminate (areas 11, 12, 9) cortices for comparison. To determine the prevalence of neurons in the contralateral thalamus, we compared them with the ipsilateral in each case. The pattern of ipsilateral thalamic projections differed somewhat among orbital, medial, and olfactory cortices. The mediodorsal nucleus was the predominant source of projections to orbital areas, midline nuclei included consistently about 25% of the thalamic neurons directed to medial transitional cortices, and primary olfactory areas were distinguished by receiving thalamic projections predominantly from neurons in midline and intralaminar nuclei. Notwithstanding some broad differences in the ipsilateral thalamofrontal projections, which appeared to depend on cortical location, the pattern of contralateral projections was thalamus were noted in midline, the magnocellular sector of the mediodorsal nucleus, the anterior medial and intralaminar nuclei, and ranged from 0 to 14% of the ipsilateral; they were directed primarily to olfactory and transitional orbital and medical cortices but rarely projected to eulaminate areas. Several thalamic nuclei projected from both sides to olfactory and transitional areas, but issued only ipsilateral projections to eulaminate areas. Though ipsilateral thalamocortical projections predominate in adult mammalian species, crossed projections are a common feature in development. The results suggest differences in the persistence of contralateral thalamocortical interactions between transitional and eulaminate cortices. © 1994 Wiley-Liss, Inc.     

Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers

This paper describes the quantitative areal and laminar distribution of identified neuron populations projecting from areas of prefrontal cortex (PFC) to subcortical autonomic, motor, and limbic sites in the rat. Injections of the retrograde pathway tracer wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) were made into dorsal/ventral striatum (DS/VS), basolateral amygdala (BLA), mediodorsal thalamus (MD), lateral hypothalamus (LH), mediolateral septum, dorsolateral periaqueductal gray, dorsal raphe, ventral tegmental area, parabrachial nucleus, nucleus tractus solitarius, rostral/caudal ventrolateral medulla, or thoracic spinal cord (SC). High-resolution flat-map density distributions of retrogradely labelled neurons indicated that specific PFC regions were differentially involved in the projections studied, with medial (m)PFC divided into dorsal and ventral sectors. The percentages that WGA-HRP retrogradely labelled neurons composed of the projection neurons in individual layers of infralimbic (IL; area 25) prelimbic (PL; area 32), and dorsal anterior cingulate (ACd; area 24b) cortices were calculated. Among layer 5 pyramidal cells, approximately 27.4% in IL/PL/ACd cortices projected to LH, 22.9% in IL/ventral PL to VS, 18.3% in ACd/dorsal PL to DS, and 8.1% in areas IL/PL to BLA; and 37% of layer 6 pyramidal cells in IL/PL/ACd projected to MD. Data for other projection pathways are given. Multiple dual retrograde fluorescent tracing studies indicated that moderate populations (<9%) of layer 5 mPFC neurons projected to LH/VS, LH/SC, or VS/BLA. The data provide new quantitative information concerning the density and distribution of neurons involved in identified projection pathways from defined areas of the rat PFC to specific subcortical targets involved in dynamic goal-directed behavior.     

Projections of the medial orbital and ventral orbital cortex in the rat

The medial orbital (MO) and ventral orbital (VO) cortices are prominent divisions of the orbitomedial prefrontal cortex. To our knowledge, no previous report in the rat has comprehensively described the projections of MO and VO. By using the anterograde tracer Phaseolus vulgaris leucoagglutinin and the retrograde tracer Fluoro-Gold, we examined the efferent projections of MO and VO in the rat. Although MO and VO projections overlap, MO distributes more widely throughout the brain, particularly to limbic structures, than does VO. The main cortical targets of MO were the orbital, ventral medial prefrontal (mPFC), agranular insular, piriform, retrosplenial, and parahippocampal cortices. The main subcortical targets of MO were the medial striatum, olfactory tubercle, claustrum, nucleus accumbens, septum, substantia innominata, lateral preoptic area, and diagonal band nuclei of the basal forebrain; central, medial, cortical, and basal nuclei of amygdala; paratenial, mediodorsal, and reuniens nuclei of the thalamus; posterior, supramammillary, and lateral nuclei of the hypothalamus; and periaqueductal gray, ventral tegmental area, substantia nigra, dorsal and median raphe, laterodorsal tegmental, and incertus nuclei of the brainstem. By comparison, VO distributes to some of these same sites, notably to the striatum, but lacks projections to parts of limbic cortex, to nucleus accumbens, and to the amygdala. VO distributes much more strongly, however, than MO to the medial (frontal) agranular, anterior cingulate, sensorimotor, posterior parietal, lateral agranular retrosplenial, and temporal association cortices. The patterns of MO projections are similar to those of the mPFC, whereas the projections of VO overlap with those of the ventrolateral orbital cortex (VLO). This suggests that MO serves functions comparable to those of the mPFC, such as goal-directed behavior, and VO performs functions similar to VLO such as directed attention. MO/VO may also serve as a link between lateral orbital and medial prefrontal cortices.     

Connections underlying the synthesis of cognition, memory, and emotion in primate prefrontal cortices

Distinct domains of the prefrontal cortex in primates have a set of connections suggesting that they have different roles in cognition, memory, and emotion. Caudal lateral prefrontal areas (areas 8 and 46) receive projections from cortices representing early stages in visual or auditory processing, and from intraparietal and posterior cingulate areas associated with oculomotor guidance and attentional processes. Cortical input to areas 46 and 8 is complemented by projections from the thalamic multiform and parvicellular sectors of the mediodorsal nucleus associated with oculomotor functions and working memory. In contrast, caudal orbitofrontal areas receive diverse input from cortices representing late stages of processing within every unimodal sensory cortical system. In addition, orbitofrontal and caudal medial (limbic) prefrontal cortices receive robust projections from the amygdala, associated with emotional memory, and from medial temporal and thalamic structures associated with long-term memory. Prefrontal cortices are linked with motor control structures related to their specific roles in central executive functions. Caudal lateral prefrontal areas project to brainstem oculomotor structures, and are connected with premotor cortices effecting head, limb and body movements. In contrast, medial prefrontal and orbitofrontal limbic cortices project to hypothalamic visceromotor centers for the expression of emotions. Lateral, orbitofrontal, and medial prefrontal cortices are robustly interconnected, suggesting that they participate in concert in central executive functions. Prefrontal limbic cortices issue widespread projections through their deep layers and terminate in the upper layers of lateral (eulaminate) cortices, suggesting a predominant role in feedback communication. In contrast, when lateral prefrontal cortices communicate with limbic areas they issue projections from their upper layers and their axons terminate in the deep layers, suggesting a role in feedforward communication. Through their widespread connections, prefrontal limbic cortices may exercise a tonic influence on lateral prefrontal cortices, inextricably linking areas associated with cognitive and emotional processes. The integration of cognitive, mnemonic and emotional processes is likely to be disrupted in psychiatric and neurodegenerative diseases which preferentially affect limbic cortices and consequently disconnect major feedback pathways to the neuraxis.     

Prefrontal cortical projections to the striatum in macaque monkeys: evidence for an organization related to prefrontal networks

The organization of projections from the prefrontal cortex (PFC) to the striatum in relation to previously defined "orbital" and "medial" networks within the PFC were studied in monkeys using anterograde and retrograde tracing techniques. The results indicate that the orbital and medial networks connect to different striatal regions. The ventromedial striatum (the medial caudate nucleus, accumbens nucleus, and ventral putamen) receives input predominantly from the medial PFC (mPFC) and orbital areas 12o, Iai, and 13a, which constitute the "medial" network. More specifically, caudal medial areas 32, 25, and 14r project to the medial edge of the caudate nucleus, accumbens nucleus, and ventromedial putamen, whereas rostral areas 10o, 10m, and 11m are restricted to the medial edge of the caudate. Projections from orbital areas 12o, 13a, and Iai extend more laterally into the lateral accumbens and the ventral putamen. Area 24 gives rise to a divided pattern of projections, including fibers to the ventromedial striatum, apparently from area 24b, and fibers to the dorsolateral striatum, apparently from area 24c. Other areas of orbital cortex (11l, 12m, 12l, 13m, 13l, Ial, and Iam) that constitute the "orbital" network project primarily to the central part of the rostral striatum. This region includes the central and lateral parts of the caudate nucleus, and the ventromedial putamen, on either side of the internal capsule. The results support the subdivision of the orbital and medial PFC into "medial" and "orbital" networks and suggest that the prefrontostriatal projections reflect the functional organization of the PFC rather than topographic location.     

Differential connections of the perirhinal and parahippocampal cortex with the orbital and medial prefrontal networks in macaque monkeys

Previous anatomical studies indicate that the orbital and medial prefrontal cortex (OMPFC) of monkeys is organized into an "orbital" network, which appears to be related to feeding and reward, and a "medial" network, related to visceral control and emotion. In this study, we examined the connections of the orbital and medial prefrontal networks with the perirhinal (areas 35 and 36) and parahippocampal (areas TF and TH) cortex with anterograde and retrograde axonal tracers. The perirhinal cortex is reciprocally connected with orbital network areas Iapm, Iam, Ial, 13m, 13l, 12r, and 11l. In contrast, the parahippocampal cortex is reciprocally connected with the medial network, especially areas around the corpus callosum (areas 24a/b, caudal 32, and 25), and with area 11m. Projections from the parahippocampal cortex also extend to areas 10m, 10o, Iai, and rostral area 32, as well as to dorsolateral areas 9 and 46. In addition, both the perirhinal and parahippocampal cortex are reciprocally connected with areas that are intermediate between the orbital and medial networks (areas 13a, 13b, and 14c) and with the supracallosal area 24a'/b'. Outside the frontal cortex, the perirhinal cortex and the orbital prefrontal network are both interconnected with the ventral part of the temporal pole (TG), area TE and the ventral bank and fundus of the superior temporal sulcus (STS), and the dysgranular insula. In contrast, the parahippocampal cortex and the medial prefrontal network are connected with the dorsal TG, the rostral superior temporal gyrus (STG) and dorsal bank of STS, and the retrosplenial cortex.     

Projections from the parahippocampal region to the prefrontal cortex in the rat: evidence of multiple pathways

The purpose of the present study was to investigate, by means of anterograde tracing methods, the detailed organization of the parahippocampal-prefrontal projections in the rat brain. Efferents from the perirhinal cortex were found to terminate principally in both the ventromedial (prelimbic and infralimbic cortices) and lateral (agranular insular cortex) regions of the prefrontal cortex. Terminal fields were observed mainly in the superficial layers of the prefrontal cortex. Projections arising from the dorsolateral entorhinal cortex, which borders the perirhinal cortex along its ventral extent, were similarly directed to the ventromedial and lateral prefrontal cortices but also encompassed other frontal areas (dorsomedial and orbital prefrontal regions). Terminal fields of entorhinal projections were also found in the superficial layers of the prefrontal cortex. A third pathway, taking its source in the post-rhinal cortex, presented striking topographical differences with the two other output systems. Hence, post-rhinal efferences terminated only in the ventrolateral orbital area. The results indicate that two main routes originate from the parahippocampal region to reach the prefrontal cortex. One pathway involves the rostral and lateral portions of the parahippocampal region (perirhinal and dorsolateral entorhinal cortices), and the other relies on its most caudal region, the post-rhinal cortex. The presence of such different multiple parahippocampal-prefrontal pathways may have functional relevance for learning and memory processes.     

Sensory and premotor connections of the orbital and medial prefrontal cortex of macaque monkeys

Sensory and premotor inputs to the orbital and medial prefrontal cortex (OMPFC) were studied with retrograde axonal tracers. Restricted areas of the lateral and posterior orbital cortex had specific connections with visual-, somatosensory-, olfactory-, gustatory-, and visceral-related structures. More medial areas received few direct sensory inputs. Within the lateral and posterior orbital cortex, area 121 received a substantial projection from visual areas in the inferior temporal cortex (TE). Area 12m received somatosensory input from face, digit, or forelimb regions in the opercular part of area 1–2, in area 7b, in the second somatosensory area (SII), and in the anterior infraparietal area (AIP). Areas 13m and 131 also received a projection from the opercular part of areas 1–2 and 3b. The posteromedial and lateral agranular insular areas (Iapm and Ial, respectively) received fibers from the ventral part of the parvicellular division of the ventroposterior medial nucleus of the thalamus (VPMpc) that may represent a visceral afferent system. The dorsal part of VPMpc projected to the adjacent gustatory cortex. These restricted inputs from several sensory modalities and the convergent corticocortical connections to orbital areas 13l and 13m suggest a network related to feeding. The OMPFC was also connected to premotor cortex in ventral area 6 (areas 6va and 6vb), in cingulate area 24c, and probably in the supplementary eye field. Area 6va projected to area 12m, whereas a region of area 6vb projected to area 131. The region of the supplementary eye field projected to areas 121, 120, and 12r. Area lal received fibers from area 24c. Lighter and more diffuse projections also reached wider areas of the OMPFC. For example, injections in several orbital areas labeled a few cells scattered through the anterior part of area TE and the superior temporalrus. There was also a projection to the intermediate agranular insular area (Iai) and to areas 13a and 12o from the apparently multimodal areas in the superior temporal sulcus and gyrus. © 1995 Wiley-Liss, Inc.     

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.     

Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin

The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examine the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental-cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.