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Previous Article | Next Article
Volume 17, Number 6, Issue of March 15, 1997 pp. 2143-2167
Copyright ©1997 Society for NeuroscienceInterconnected Parallel Circuits between Rat Nucleus Accumbens and Thalamus Revealed by Retrograde Transynaptic Transport of Pseudorabies Virus
Patricio O'Donnell1, Antonieta Lavín1, Lynn W. Enquist2, Anthony A. Grace1, and J. Patrick Card1 1 Departments of Neuroscience and Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and 2 Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544
ABSTRACT
One of the primary outputs of the nucleus accumbens is directed to the mediodorsal thalamic nucleus (MD) via its projections to the ventral pallidum (VP), with the core and shell regions of the accumbens projecting to the lateral and medial aspects of the VP, respectively. In this study, the multisynaptic organization of nucleus accumbens projections was assessed using intracerebral injections of an attenuated strain of pseudorabies virus, a neurotropic
Key words: transneuronal tracing; reticular thalamic nucleus; ventral pallidum; nucleus accumbens; mediodorsal thalamic nucleus; prefrontal cortex; globus pallidus; pseudorabies virusherpesvirus that replicates in synaptically linked neurons. Injection of pseudorabies virus into different regions of the MD or reticular thalamic nucleus (RTN) produced retrograde transynaptic infections that revealed multisynaptic interactions between these areas and the basal forebrain. Immunohistochemical localization of viral antigen at short postinoculation intervals confirmed that the medial MD (m-MD) receives direct projections from the medial VP, rostral RTN, and other regions previously shown to project to this region of the thalamus. At longer survival intervals, injections confined to the m-MD resulted in transynaptic infection of neurons in the accumbens shell but not in the core. Injections that also included the central segment of the MD produced retrograde infection of neurons in the lateral VP and the polymorph (pallidal) region of the olfactory tubercle (OT) and transynaptic infection of a small number of neurons in the rostral accumbens core. Injections in the lateral MD resulted in retrograde infection in the globus pallidus (GP) and in transynaptic infection in the caudate-putamen. Viral injections into the rostroventral pole of the RTN infected neurons in the medial and lateral VP and at longer postinoculation intervals, led to transynaptic infection of scattered neurons in the shell and core. Injection of virus into the intermediate RTN resulted in infection of medial VP neurons and second-order infection of neurons in the accumbens shell. Injections in the caudal RTN or the lateral MD resulted in direct retrograde labeling of cells within the GP and transynaptic infection of neurons in the caudate-putamen. These results indicate that the main output of VP neurons receiving inputs from the shell of the accumbens is heavily directed to the m-MD, whereas a small number of core neurons appear to influence the central MD via the lateral VP. Further segregation in the flow of information to the MD is apparent in the organization of VP and GP projections to subdivisions of the RTN that give rise to MD afferents. Collectively, these data provide a morphological basis for the control of the thalamocortical system by ventral striatal regions, in which parallel connections to the RTN may exert control over activity states of cortical regions.
INTRODUCTION
The nucleus accumbens, which is the ventral extension of the striatum, has been implicated in a number of psychiatric diseases such as schizophrenia (Snyder, 1973
; Matthysse, 1981
Two major subdivisions of the nucleus accumbens have been defined according to distinct anatomical connections (Heimer et al., 1991
The present study was designed to determine whether the pathways originating in the core and shell regions of the accumbens remain segregated within the VP and in the efferent projections of this area to the thalamocortical system. Although the primary thalamic target of the VP is the MD (Young et al., 1984
Parts of these data were presented at the 1995 Society for Neuroscience meeting (O'Donnell et al., 1995
MATERIALS AND METHODS
Animal handling and preparation. Adult male Sprague Dawley rats (200-420 gm at time of virus injection) were used in these experiments. They were housed in pairs with food and water available ad libitum, and under a 12:12 hr light/dark cycle (light on at 6:00 A.M.). Animal handling and experimental protocols were in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the University of Pittsburgh Animal Care and Use Committee. Injections of PRV were administered to anesthetized animals in a Biosafety Level 2 containment facility in accordance with regulations stipulated in Health and Human Services Publication No. 88-8395 entitled "Biosafety in Microbiological and Biomedical Laboratories". Animals were inoculated, housed, and killed in this facility.
Virus. An attenuated strain of PRV (Bartha strain) was used in this study. The virus, initially developed as a swine vaccine in 1961 (Bartha, 1961 80°C before use and thawed immediately before injection. Unused portions of each aliquot were inactivated with Chlorox and discarded.
Antibodies. A rabbit polyclonal antiserum (Rb134) generated against acetone-inactivated virus was used to localize infected neurons. The serum recognizes numerous virion proteins and produces robust immunohistochemical staining of the somata and dendrites of PRV-infected neurons (Card and Enquist, 1994 fragment of cholera toxin (CT), a conventional tracer that identifies one order of synaptic contact. A goat polyclonal antiserum (List Biochemicals, Campbell, CA) was used at a 1:20,000 dilution to localize CT in tissue from these animals.
Calbindin immunolocalization provided a precise definition of the boundaries of the core and shell regions of the nucleus accumbens. This calcium-binding protein is densely concentrated in the accumbens core and absent in the shell (Zahm and Heimer, 1993
Injection procedures. Animals were anesthetized with ketamine and xylazine (60 mg/kg ketamine, 7 mg/kg xylazine, i.p.) before being placed in a stereotaxic apparatus (Kopf, Tujunga, CA). Virus was injected through a 1 µl Hamilton syringe lowered into target areas through a hole drilled in the skull. The stereotaxic coordinates used, obtained from a rat brain stereotaxic atlas (Paxinos and Watson, 1986
Two animals received an electrolytic lesion in the VP or the GP before receiving the PRV injection into the MD. The lesions were performed under deep anesthesia using a coated insect pin and a current generator (Grass, Quincy, MA). Monopolar current (4 mA for 20 sec) was passed though the electrode, placed in the rostral VP region (AP: 0.2, ML: 0.8, DV:
Tissue processing. After postinoculation periods ranging from 36 to 72 hr, the animals were deeply anesthetized with an overdose of ketamine and xylazine and perfused transcardially with a buffered aldehyde fixative (McLean and Nakane, 1974
RESULTS
PRV was injected intracerebrally in 52 rats. Twenty-nine of these animals contained injection sites that included one or more of the subdivisions of the MD or the RTN. Twelve animals contained injections that missed the MD or RTN. These cases were used as controls for the specificity of the results obtained from injection of virus into either the MD or the RTN. In two cases, electrolytic lesions of the VP or GP preceded injection of virus into the m-MD. Eleven cases were discarded because of poor placement of the injection (n = 7) or failure to detect viral immunoreactivity at short postinoculation intervals (n = 4; 36-44 hr survival). Temporal analysis of the extent of viral replication and transport indicated that postinoculation survival intervals of 36-50 hr were the most effective time span for characterizing the multisynaptic connections between the MD, RTN, and nucleus accumbens. At longer survival intervals, the more extensive transynaptic passage of virus made it more difficult to ascertain the routes of viral transport.Diffusion of PRV from the injection site
Controlled injection of PRV resulted in very little diffusion of virus from the site of injection, as demonstrated by the restricted distribution of infected cells at injection sites, even at the longest postinoculation intervals (Fig. 1A,C,E; see also Figs. 3A, 5A, 6A, 7A). Analysis of viral immunoreactivity at the injection sites in closely spaced sections revealed that infected neurons were confined to the immediate vicinity of the injection cannula. The effective area of viral injection, as defined by the distribution of neurons displaying viral immunoreactivity, ranged between 100 and 500 µm in diameter surrounding the tip of the cannula. Injection of equivalent volumes of PRV produced smaller injection sites in the m-MD compared with the l-MD (compare Figs. 3A and 5A), and the injections in any region of the RTN produced the largest injection sites (see Figs. 6A, 7A). Co-injection of the
Fig. 1. The diffusion of CT and PRV from a common site of injection is illustrated in this figure. The two tracers were mixed in equal parts, and 200 nl was injected into the mediodorsal nucleus (MDN) at 10 nl/min. A-F illustrate localization of PRV (A, C, E) or CT (B, D, F) in adjacent sections through rostral (A, B), intermediate (C, D), and caudal (E, F) levels of the MDN. PRV immunoreactivity is largely confined to the medial region of the MDN in the rostral half of the nucleus, whereas CT exhibits a larger sphere of diffusion throughout the rostrocaudal extent of the MDN. Scale bar (shown in F): 200 µm; all figures are of the same magnification.
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Fig. 3. Injection of PRV into the medial segment of the MD nucleus revealed a disynaptic connection with the basal forebrain. A and B demonstrate the restricted injection site resulting from injection of 100 nl of virus at 10 nl per minute. Neurons displaying PRV immunoreactivity are confined to the medial segment of the nucleus with no apparent spread to the central segment or adjacent thalamic nuclei. At short postinoculation intervals, infected neurons were present in the medial/rostral aspect of the VP (C, open block arrow, inset) but were not found in either division of the nucleus accumbens. The inset in C illustrates the region that is shown at higher magnification in D, in which calbindin immunoreactivity defines the limits of the core (NAco) and shell (NAsh) regions of the nucleus accumbens. With more advanced infection, more infected neurons were apparent in the medial VP, and they exhibited neuropathological changes characteristic of advanced viral replication (E, F). In addition, the virus passed transynaptically to infect neurons in the shell, but not in the core, of the nucleus accumbens (E, G). See text for additional details of the experiments and controls that established the route of viral transport through this circuitry. The area marked by the open and closed block arrows in E are shown at higher magnification in F and G, respectively. Scale bars: A, C, E, 200 µm; B, D, 100 µm; F, G, inset in C, 50 µm.
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Fig. 5. Injections of PRV that involved the c-MD and l-MD (A) produced a pattern of infection that differed from that produced by injection of virus into the m-MD. Infected first-order neurons were present in the intermediate and caudal RTN (B), the GP, (C), and the lateral VP (E, F). At longer postinoculation intervals, we did not observe transynaptic infection of neurons in the shell of the nucleus accumbens (D), but did observe occasional neurons in the core at rostral levels (G). The cells marked by the open block arrow in E are shown at higher magnification in F. The prominent viral immunoreactivity in the somatodendritic compartments of neurons in the GP and VP (C, E) and pathological changes in some of the infected cells (F, arrow) indicate that these cells are in an advanced stage of infection. Hb, Habenula; GP, globus pallidus; St, striatum; AC, anterior commissure. Scale bars: A-D (shown in C), 200 µm; E, 100 µm; F, G (shown in G), 20 µm.
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Fig. 6. Injection of PRV into the rostral and ventral portion of the RTN (A) labeled elements of the MD and basal forebrain circuitry revealed by injection of virus into the l-MD (compare with Fig. 5). The center of the injection site is marked by the asterisk in A. Retrogradely infected first-order neurons were observed in the lateral portion of the VP (B) as well as in the c-MD and l-MD (C). The morphology of the neurons marked by the large and small open block arrows in C are shown at higher magnification in D and E, respectively. Transynaptic infection of small numbers of neurons was apparent in the medial VP and nucleus accumbens shell (F) as well as in the rostral portion of the core (G). Scale bars: A, C, F, 200 µm; B, 100 µm; D, E, 20 µm.
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Fig. 7. Injection of virus into the caudal RTN produced a pattern of infection distinct from that produced by injection of the rostral RTN. The site of injection is illustrated in A and B, with the asterisks marking the position of the tip of the injection cannula. Scattered infected first-order neurons were present in the l-MD (C); the neuron marked by the open block arrow in C is shown at higher magnification in the inset. Larger numbers of first-order neurons were present in the GP (D, E). At longer survival times, striatal medium spiny neurons were heavily infected (G, bottom of field), and we also noted viral immunoreactivity in large spiny interneurons of the striatum that exhibited a morphology similar to that of cholinergic interneurons (F, open block arrow). The appearance of viral immunoreactivity in these cells at long survival intervals is consistent with them becoming infected by retrograde transynaptic passage of virus from the medium spiny neurons. No infected neurons were observed in either the core or the shell of the nucleus accumbens in these animals. Scale bars: A-C, 200 µm; D, 50 µm; E, F, inset in C, 20 µm.
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Temporal analysis and specificity of transynaptic passage of PRV
Intracerebral injection of PRV produced patterns of neuronal infection consistent with retrograde transneuronal passage of virus from the site of injection, as shown by temporal analysis of viral replication and transport and the co-extensive distribution of PRV- and CT-labeled neurons at sites of first-order projection. We analyzed the distribution of viral infection at various postinoculation intervals as an initial means of determining first- and second-order infections and used the co-injection of a classical tracer (the
Fig. 2. Examination of the cingulate cortex after injection of PRV into the lateral subdivision of the MDN demonstrates that this strain of virus is only transported retrogradely from the site of intracerebral injection. In A, the most prominent viral immunoreactivity is present in neurons found in deep layers of the cortex. Densely staining somata and dendrites of these neurons reveal the clear morphological features of pyramidal neurons and also demonstrates that these neurons are in an advanced stage of infection. In contrast, only scattered neurons in an early stage of infection are apparent in superficial layers. In many of these cells, viral immunoreactivity is confined to the cell nuclei (B, small arrows), and when it is apparent in the cytoplasm (open block arrow), the staining reveals that the cells are small interneurons rather than projection neurons. These data indicate that retrograde transport of virus from the MDN produced the first-order infection of pyramidal neurons in deeper layers of cingulate cortex and that transynaptic passage of virus from these cells produced the temporally delayed infection of interneurons in superficial layers. Scale bars: A, 100 µm; B, 50 µm.
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The temporal aspects of viral replication allowed us to distinguish first- and second-order infection in neurons. Continued replication of virus in neurons that projected directly to the injection sites (first-order neurons) eventually produced pathological changes in the neurons and, at the longest postinoculation intervals, such neurons were associated with immunoreactive glia (Fig. 3E,F). In contrast, neurons in synaptic contact with the initially infected neurons (second-order neurons) exhibited fewer pathological changes (Fig. 3E,G), because the virus had undergone replication in these neurons for a shorter period of time. Thus, temporal order can be inferred by the degree of pathological changes in the infected neurons and the association of infected glia. The significance of the glial response in maintaining specific transynaptic passage of PRV has been published (Card et al., 1993 Transport of virus from the MD
m-MD (n = 8) PRV was confined to the m-MD in two animals that survived 49 hr. The injection site in one case (94-H38; Fig. 3A,B) covered the m-MD throughout most of its rostrocaudal extent, whereas in the other animal (94-H39), the injection site was limited to the caudal third of the m-MD. Although the survival times were similar in both animals, the extent of infection was less in the case in which the injection was restricted to the caudal m-MD. Large numbers of infected neurons were observed in the VP in both animals, particularly in the ventral and medial aspects of its rostral extent, at the region bordering the nucleus of the diagonal band of Broca (NDBB) (Fig. 3E,F). Infected neurons were also found in the rostral and intermediate regions of the RTN, but not in its caudal region. All these cells showed signs of advanced viral infection and were associated with infected glia, suggesting that they gave rise to a first-order, direct projection to the m-MD. Labeling in the striatal regions involved only the accumbens shell, predominantly in its caudal aspect (Fig. 3E,G), as defined by the distribution of calbindin immunoreactivity (Fig. 3D). A clear temporal organization was observed in the infection of these neurons compared with neurons in the medial VP. Infection of medial VP neurons always preceded infection of shell neurons (compare Fig. 3, C and E). Similarly, when both populations were infected, neurons in the medial VP always showed signs of more advanced viral replication (Fig. 3E-G). No infected neurons were present in the CPu and accumbens core of these cases.
Injection in the m-MD also revealed a first-order infection of the RTN. In cases in which the injection site was confined to the m-MD, we observed a large number of infected neurons in the rostral and intermediate RTN and no infected neurons at caudal levels of the RTN (compare Fig. 4, A and B). Furthermore, infected neurons in rostral and intermediate regions of the RTN were confined to the ventral third of the nucleus (Fig. 4B). 
Fig. 4. Injection of the m-MD also revealed a topographically organized afferent input from neurons in the RTN. After restricted injections of this subdivision, infected neurons were present in the ventromedial portion of the rostral RTN (B), but were not present in the caudal RTN (A, arrowheads). Scale bars: A, 200 mm; B, 100 mm.
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C-MD (n = 5) Five animals received viral injections in regions that included the c-MD and were killed 39 to 52 hr after the viral injection. However, none of the injection sites were actually restricted to this relatively small subdivision. The injection sites covered most of the c-MD and part of l-MD in two animals (95-H149 and 96-H6) (Fig. 5A) and most of c-MD and part of m-MD in the other three cases (95-H7, 94-H21, and 96-H5). All of these animals showed advanced infection of a large number of neurons in the polymorph region of the OT (Fig. 5D) as well as in the lateral, subcommissural region of the caudal VP (Fig. 5E,F). In cases including the l-MD in the injection site (Fig. 5A), first-order projection cells were also detected in the GP (Fig. 5C), and in cases in which the injection also involved the m-MD, cells with advanced infection were detected in the medial, rostral VP. Infection in striatal regions varied according to the extent of the injection site in these cases. We never observed infection of accumbens shell neurons when the injection was restricted to the c-MD and l-MD (Fig. 5D). When injections involved the c-MD along with either the lateral or medial segments, we observed a limited number of infected core neurons that were found almost exclusively at rostral levels in the core (Fig. 5G). In contrast, when the viral injection was confined to the l-MD, we never observed infected neurons in either of the accumbens regions (see below). A few scattered infected cells at an early stage of infection at the septal border of the shell region of the accumbens, as well as some infected cells in the core region of the accumbens, were found in the cases in which the injection included the m-MD and the c-MD. A few infected cells in the core and the CPu were observed in the cases in which injections covered both the c-MD and l-MD.
Several injections that included the m-MD also extended into neighboring regions. Two animals received PRV injections that involved the paraventricular nucleus of the thalamus (PVT) (94-H40 and 94-H41). These animals were killed at 39 and 51 hr after injection and, as in the MD injected cases, they contained first-order infected neurons in the medial VP and rostral RTN and second-order neurons in the shell region of the accumbens. Two additional animals with an injection site that involved the m-MD, PVT, and habenula (cases 94-H22 and 95-H6) exhibited a similar pattern of infection, as seen in other animals in which the injection involved the m-MD along with either the lateral habenula (94-H13) or the anteromedial thalamic nucleus (95-H148). All these cases also exhibited infected neurons consistent with projections to these other thalamic nuclei. For example, cases involving the PVT contained large numbers of infected neurons in the hypothalamic suprachiasmatic nuclei, consistently with the recently demonstrated projection between these nuclei (Moga et al., 1995 L-MD (n = 5) Five animals received injections within the l-MD that largely excluded the c-MD. Four animals were examined after survival periods of 44 to 50 hr. In one of these cases (94-H18), the injection site encompassed the caudal half of the l-MD, whereas the other two animals (94-H12 and 95-H150) received the PRV injection in the l-MD and the lateral habenula. Infected neurons at an advanced stage were detected in the GP, but no infected cells were seen in the VP. In addition, neurons at an early stage of infection were detected in the CPu but not in the accumbens. In these cases, cells in advanced stages of infection were also seen in the caudal aspects of the RTN.
Cells in the RTN were also infected after injections that included the c-MD (Fig. 5B). The distribution of infected RTN neurons was different depending on the involvement of the m-MD or l-MD in the injection site. The animals in which PRV was injected in the m-MD and c-MD showed infected neurons in the rostral pole of the RTN, similar to those with an injection selectively placed within the m-MD. On the other hand, injections in the l-MD and c-MD resulted in infection of neurons in more caudal parts of the RTN (Fig. 5B), similar to that observed after injections restricted to the l-MD (see below). Thus, these patterns appear to be the result of transynaptic passage after m-MD and l-MD PRV rather than after c-MD PRV. Control experiments (n = 8) In two cases, PRV injections were made into the m-MD in rats that had received an electrolytic lesion of the medial VP or the GP. The injection sites in these cases were restricted to the m-MD. These animals were killed after long incubation periods of 60 and 62 hr. In one case with a GP lesion that spared most of the VP (95-H63), neurons at an advanced stage of infection were observed in the medial VP, and neurons earlier in the course of infection were detected in the accumbens shell. In the case with an extensive lesion of the VP (95-H64), PRV injection in the m-MD failed to label neurons in the shell.
Two animals were killed after relatively long survival periods (~68 hr) that yielded a widespread infection that was extensive across most of the structures studied. The injection site in one of these animals (94-H7) was centered in the caudal third of the l-MD and extended into the lateral habenula in the other (94-H9). Both animals exhibited infected neurons in the VP at different stages of infection. Several neurons showing signs of advanced infection could be observed in the GP as well. Few scattered infected cells could be observed in both the core and the shell regions of the nucleus accumbens in one case (94-H7), and only in the shell in the other (94-H9). The sparse number of infected neurons in the nucleus accumbens contrasted to the heavy labeling throughout most other structures in these cases.
Three animals received viral injections in regions adjacent to, but avoiding entirely, the m-MD. In one of the cases, the injection included the medial habenula and the overlying dentate gyrus of the hippocampus (94-H17), and no infected neurons could be detected in striatal or pallidal regions. In another animal (95-H11), PRV was injected in the dentate gyrus of the hippocampus, and no viral immunoreactivity was observed in any basal ganglia or thalamic region. A third case received the PRV injection into the lateral septum with spread of virions into the lateral ventricle (95-H78), but no viral infection could be detected in the basal ganglia.
Two additional animals received PRV injections in structures close to, but not in, the l-MD. In one case (95-H8), PRV was injected into the ventricle. No labeling was found in the basal ganglia in this animal. In another animal (94-H47), PRV was injected in the laterodorsal thalamic nucleus, which is located laterally to the MD. In this case, infected neurons were observed in the septum and NDBB but not in the basal ganglia.
The injection site in another animal encompassed all three segments of the MD (case 95-H9), and the pattern of viral infection was similar to that of the cases of injection in each segment combined. Thus, heavily infected neurons were observed in the medial and lateral VP as well as in the GP, and second-order neurons were detected in the shell and core regions of the accumbens as well as in the CPu. Transport of virus from the RTN
The injection sites that included the RTN were distributed along most of the rostrocaudal axis of this thalamic nucleus. To analyze the results without losing any potential topographic information, the cases were sorted according to the location of the center of injection along the rostrocaudal axis. Rostral RTN (n = 2) Two animals received PRV injections in the rostral pole of the RTN and were killed 48 and 50 hr after the injection. The injection site included the ventral aspect of the rostral RTN in one case (94-H45; Fig. 6A), in the same region of the RTN that showed infection after m-MD injections. In this case, neurons at a comparatively advanced stage of infection were observed in the medial/rostral VP (Fig. 6F) as well as in the lateral and caudal aspects of the VP (Fig. 6B). Also, scattered neurons very early in their infection were observed in both the accumbens core and shell (Fig. 6F,G). The other animal (case 95-H143) received the PRV injection into the ventral and dorsal aspects of the RTN rostral pole. In this case, first-order projection neurons were observed in the lateral and caudal VP as well as in the GP. Neurons at an early stage of infection were detected in the accumbens core and CPu. No infected cells were found in the accumbens shell in any of these cases. In the animal injected in the ventral aspect of the rostral RTN, neurons advanced in infection were detected in the c-MD but not in the m-MD. In the other, more extensively injected, case, heavily infected neurons were detected in the c-MD and l-MD (Fig. 6C-E). Intermediate RTN (n = 2) Two cases were injected in the intermediate region of the RTN. In one of them (95-H145), neurons advanced in infection were observed in the medial and rostral VP and in the m-MD. The distribution of first-order projection neurons was matched by CT immunoreactivity in this animal (see Fig. 10). Neurons at an early stage of infection were detected in the accumbens shell. In the other case (95-H75), which received the PRV injection at a more dorsal location within the intermediate RTN, no viral infection could be found in any pallidal or striatal region.
Fig. 10. Structures infected after a viral injection restricted to the l-MD. The injection site of this representative case is shown as a hatched area; solid circles represent the distribution of first-order projection neurons; open circles show the location of second-order projection neurons.
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Caudal RTN (n = 4) Four animals received the PRV injection at caudal locations within the RTN. Two of these animals received the injections at 2.0-2.5 mm caudal to bregma. In one of them (case 94-H46), the injection site was tightly confined to the RTN (Fig. 7A,B), and no detectable infection was observed in the accumbens or VP. The other case with a similar injection site (95-H12) extending medially into the VPL thalamic nucleus did not result in viral infection in the accumbens or VP. However, both cases exhibited a large number of neurons advanced in infection within the GP (Fig. 7D,E) and some infected neurons in the l-MD (Fig. 7C). Cells in early stages of infection were detected in the CPu (Fig. 7F). In two other animals, the injection site was placed at even more caudal locations within the RTN; i.e., 3.0 or 3.3 mm caudal to bregma. In these cases (95-H76 and 95-H146), no infected cells were labeled in any region within the basal ganglia. Control injections for the RTN (n = 7) A group of animals received PRV injection in the vicinity of the RTN rostral pole but without including the RTN. Three cases involved the bed nucleus of the stria terminalis (BNST) rostral to the RTN (cases 94-H44, 94-H49, and 94-H51). In these cases, neurons at an advanced stage of infection were detected in the medial and rostral VP, and neurons with early infections were seen in the accumbens shell, but not in the core, which is a different pattern from that of rostral RTN injections. In two additional animals (cases 94-H48 and 95-H14), the injection sites were restricted to the internal capsule with a little involvement of the GP in one, just lateral to where the rostral RTN injections were placed. Although widespread infection was seen throughout most of the neocortex in those cases in which tissue damage was present at the injection sites, no infected neurons were detected in the accumbens or VP. In the case in which the GP was included in the injection site, however, heavily infected cells were detected in the CPu.
Two animals received PRV injection in regions adjacent to the caudal RTN. One of them received the viral injection in the lateral geniculate nucleus and dentate gyrus of the hippocampus (case 95-H13). In this animal, neurons advanced in infection were observed in the dorsomedial hypothalamus but not in the basal ganglia. Another animal (case 95-H77) received the injection in the internal capsule, in a site located laterally to that of the caudal RTN injection cases. In this animal, no evidence of infected neurons was observed in the basal ganglia, although extensive labeling was detected in most cortical regions. Other circuits labeled after MD and RTN injections
The cortical regions retrogradely infected after PRV injections in the MD also differ according to the segment injected. Thus, injections in the m-MD resulted in viral infection in the infralimbic, medial orbital, and agranular insular cortices. In the cases in which the injection sites included the c-MD, neurons advanced in infection were detected in orbital and PL cortices. In addition, selective injections in the l-MD resulted in first-order infected neurons in the piriform and cingulate cortices. Injections in the rostral RTN resulted in infected neurons in cingulate and PL cortices, whereas injections in the caudal RTN labeled the cingulate cortex.
In addition to structures in the basal ganglia, basal forebrain, and cortex, a number of other brain regions exhibited viral immunoreactivity after PRV injections in the different divisions of the MD or RTN. These were different for each of the regions studied, and they were consistent with previously reported data using conventional tract tracing techniques. The brain regions in which we observed neurons with advanced infection (first order) and neurons with early stages of infection (second order) are listed in Tables 1 and 2. Briefly, injections in the m-MD resulted in viral infection in NDBB, VTA, and laterodorsal tegmental nucleus (LDTg) (Fig. 8). In the cases in which the injections sites extended into the PVT, cells at an advanced stage of infection were also found in the suprachiasmatic nucleus and dorsomedial hypothalamus. In the cases in which the injection sites included the c-MD, neurons advanced in infection were detected in the lateral septum, OT, NDBB, and LDTg (Fig. 9). In the cases injected in the l-MD, infected neurons were seen in lateral septum, NDBB, raphe magnus, substantia nigra pars reticulata, and LDTg (Fig. 10).
Table 1. Brain regions showing labeling after PRV injections in different regions of the MD thalamic nucleus
m-MD c- + m-MD l- + c-MD l-MD Forebrain Isocortex Agranular insular cortex 1 Cingulate cortex 1* 1* 1 Entorhinal cortex 1 Infralimbic prefrontal cortex 1 1* Orbital cortex 1 1* * Prelimbic prefrontal cortex 1* 1* Claustrum 1* 1* 1 Olfactory cortex Anterior olfactory nucleus 2 1* Olfactory tubercle (polymorph region) 1* 1* Islands of Calleja 2 2 Piriform cortex 2 2 2 1 Hippocampal formation Subiculum, ventral 1 CA1/CA2 2 2 2 Amygdala Medial nucleus * 2 Cortical nucleus 2 1 Basolateral nucleus 2 2 Septal region Lateral septal nucleus 1 1* 1* 1 Medial septal nucleus 1 1* 1* Nucleus of the diagonal band of Broca 1 1* 1* 1 Bed nucleus of the stria terminalis 2 1* 2 2 Basal ganglia Caudate-putamen 2 2 Accumbens core 2 2 Accumbens shell 2 2 Ventral pallidum (rostral/medial) 1 1* 1* Ventral pallidum (caudal/lateral) 1* 1* Globus pallidus 1* 1 Entopeduncular 2 1 Fundus striatum 1* Thalamus AV nucleus 2 Intergeniculate leaf 2 2 2 Centromedian-parafascicular 2 2 Habenula, medial 2 2 Reticular thalamic nucleus, rostral 1 1* 1* 1 Reticular thalamic nucleus, intermediate 1* 1* 1 Reticular thalamic nucleus, caudal 1 1 1 1 Zona incerta 2 2 2 1 Subthalamic nucleus 2 Hypothalamus Preoptic area 1 1* 1* 1 Suprachiasmatic nucleus 2 Dorsomedial hypothalamus 2 2 Ventromedial hypothalamus 1 1* 1* Lateral hypothalamus 2 1* 1* 2 Arcuate nucleus 2 2 Brainstem Superior colliculus 1 Pretectal area 2 2 Spinal trigeminal nucleus 2 Nucleus of the solitary tract 1 Parabrachial 2 1* 1* 1 Area postrema 2 Laterodorsal tegmental nucleus 1 1* 1* 1 Substantia nigra, pars compacta (A9) 2 2 2 2 Substantia nigra, pars reticulata 1 Retrorubral formation (A8) 2 2 Ventral tegmental area (A10) 1 1* 1* 2 Raphe magnus 1* 1 Dorsal raphe 1 1* 2 Locus coeruleus 2 1 Periacqueductal gray 2 1* 1* 1 (A5) 2 Nucleus Darkschewitz 2 Vestibular nucleus, lateral 2 1, Cells labeled by direct retrograde transport; 2, second-order retrograde labeling, after transynaptic passage; * presence of neurons with CT immunoreactivity.
Table 2. Brain regions showing labeling after PRV injections in different RTN regions
Rostral RTN Intermediate RTN Caudal RTN Forebrain Isocortex Agranular insular cortex 2 Cingulate cortex 1* 1* 1 Entorhinal cortex 1 Infralimbic prefrontal cortex 1* Orbital prefrontal cortex * * Perirhinal cortex * 2 Prelimbic prefrontal cortex 1* 1* 1 Claustrum * 1* 1 Olfactory cortex Olfactory tubercle 1* 2 Piriform cortex 2 Endopiriform nucleus 1* 1* Hippocampal formation Subiculum, dorsal * * Amygdala Medial nucleus 1* 1* 1 Basolateral nucleus 1* 2 Cortical nucleus 2 Septal region Lateral septal nucleus 2 1* Medial septal nucleus 2 Nucleus of the diagnoal band of Broca 1* 1* 1 Bed nucleus of the stria terminalis 2 2 1 Basal ganglia Caudate-putamen 2 2 Accumbens core 2 2 Accumbens shell 2 Ventral pallidus (rostral/medial) 1* Ventral pallidus (caudal/lateral) 1* 1 Globus pallidus 1* 2 1 Entopeduncular 1* 1* 1 Substantia innominata 1* 1* 1 Thalamus AD nucleus 1 Mediodorsal, medial segment 1* 1* Mediodorsal, central segment 1* VA-VL 1 VPL-VPM 1 Intergeniculate leaf 1* Centromedian-parafascicular 1* Zona incerta 1* 1* Subthalamic nucleus 2 2 Hypothalamus Preoptic area 2 1* Dorsomedial hypothalamus 2 2 Ventromedial hypothalamus 1 Lateral hypothalamus 2 1* Brainstem Parabrachial 1* 1 Laterodorsal tegmental nucleus 1* 1* 1 Pedunculopontine 1* 1* 1 Substantia nigra, pars compacta (A9) 1 Retrorubral field (A8) 2 1 Ventral tegmental area (A10) 2 Dorsal raphe 2 Periacqueductal gray 2 1, Cells labeled by direct retrograde transport; 2, second-order retrograde labeling, after transynaptic passage; * neurons immunoreactive for CT. 
Fig. 8. PRV injection in the m-MD resulted in a consistent pattern of infection across structures. Symbols represent infected neurons and their placement in 12 representative drawings of coronal sections of the rat brain, modified from a stereotaxic rat brain atlas (Paxinos and Watson, 1986
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Fig. 9. Injection of virus that included the c-MD exhibited infection of some common structures. Symbols represent the distribution of infected neurons after injection of PRV in selected cases. Circles show the distribution of infection after an injection including both the m-MD and the c-MD (injection site shown with vertical hatch). Triangles represent the distribution of infected neurons after an injection that included both the c-MD and the l-MD (injection site represented with horizontal hatch). The distribution of infection in structures labeled in both cases is shown in bold; the distribution of infection observed in any of the cases but not on the other is shown in gray.
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Injections in the rostral RTN resulted in infected neurons at a relatively advanced stage in the medial nucleus of the amygdala, SI, NDBB, septum, VPL and VPM thalamic nuclei, pedunculopontine nucleus, LDTg, and contralateral RTN (Fig. 11). Injections in the intermediate RTN labeled the m-MD and LDTg (Fig. 12). Also, injections in the caudal RTN resulted in advanced neuronal infection in the medial nucleus of the amygdala, SI, BNST, VPL-VPM thalamic nuclei, and SNc (Fig. 13). 
Fig. 11. Injections of virus in the rostral RTN resulted in a specific pattern of infection. Circles and triangles represent first-order infected neurons (solid) and second-order infected neurons (open) for two selected cases. The distribution of infected neurons after the small injection (gray) is shown with triangles, whereas the location of infected cells after the larger injection (hatched) is shown with circles.
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Fig. 12. Co-injection of PRV and CT in the intermediate RTN results in similar first-order projections. Circles represent PRV-infected neurons (solid, first order; open, second order). Small × symbols represent the distribution of CT-labeled neurons. The extension of PRV infection in the injection site is shown as a dark area, and the larger extension of CT around the injection site is shown as a hatched area.
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Fig. 13. Distribution of infected neurons in a case representative of injections in the caudal RTN. The injection site is shown as a hatched area; solid triangles represent the distribution of first-order projection neurons, and open triangles show the distribution of second-order projection neurons.
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DISCUSSION
An important issue in correlating the anatomy of the limbic system with psychiatric disorders lies in the specificity of connections among key components of these systems. Although studies using sequential labeling of retrogradely transported compounds have been powerful in assessing such connections, the existence of several multisynaptic pathways presents unique constraints that render such an approach problematic. For this reason, we used PRV for tracing transynaptic projections from the core and shell regions of the nucleus accumbens to the VP and thalamus. The affinity of the virus for axon terminals and astrocytes (Vahlne et al., 1978Specificity of viral labeling
Controlled intracerebral injection of PRV into the MD or RTN produced highly restricted cell labeling at the site of injection that was confined to the subdivisions of the MD or RTN in many cases. This technique has been used previously to assess the central neural connections labeled after injections of virus into peripheral structures (for review, see Card and Enquist, 1994
The direction of viral transport was an important consideration in interpreting our findings. Zemanick and colleagues (1991) have reported differential transport of two strains of HSV from the primate motor cortex after intracerebral injection, with one strain passing only in an anterograde transynaptic direction and the other exclusively in a retrograde transynaptic direction. In preliminary studies (Enquist et al., 1993
A potential source of concern relates to whether viral uptake by fibers of passage may have confounded our results. As mentioned above, the virus has a high affinity for axon terminals and astrocytes. Thus, if substantial tissue damage is avoided at the injection site, virions are not likely to enter intact fibers of passage. Our cases involving internal capsule injections show widespread cortical infection. However, these were designed to test whether the spread of virus beyond the injection site could account for any of our results; and furthermore were provided by exceedingly large injections coupled with long survival times. Thus, the presence of tissue damage in the internal capsule in cases with long incubation periods did indeed result in viral uptake and cortical infection, but nonetheless did not result in infection in the VP. Furthermore, none of the cases involving MD- or RTN-selective injections that were included in the results exhibited signs of tissue damage in the injection sites. First- and second-order projection neurons
The morphology of infected neurons allowed us to identify first- and second-order projection neurons. First-order neurons are infected by preferential uptake of virions at axon terminals at the site of intracerebral injection. Indeed, previous in vitro studies (Vahlne et al., 1978
The reliability of the labeling observed with these viral injections is remarkable. We compared our findings with the large body of literature using conventional retrograde and anterograde tracers in these regions. With a few exceptions, our findings involving direct, first-order projections are consistent with those reported previously (Mogenson, 1987 Organization of connections between the accumbens and MD
Injections of virus into subdivisions of the MD and RTN revealed distinct patterns of infection, suggesting the presence of parallel circuits between the basal forebrain and thalamus. First, multisynaptic projections arising in the accumbens shell relay via the medial VP and terminate selectively within the m-MD. The retrograde infection of neurons in the ventromedial part of the rostral VP after PRV injection in the m-MD is consistent with what has been reported by several groups using conventional tracers (Young et al., 1984
A second circuit involves projections from the accumbens core to the lateral VP and the pallidal region of the OT, then to the c-MD and rostral RTN. Injections that included the c-MD resulted in first-order infection of neurons in the polymorph (pallidal) region of the OT and in the caudal and lateral subcommissural region of the VP and in second-order infection of neurons in the core and striatal OT. It should be noted that in all these cases, the injections also extended into the neighboring m-MD or l-MD, and the pallidal and striatal infection patterns were a combination of those typical of m-MD and l-MD injections with the lateral VP and accumbens core. This projection arising from the core should be taken with caution, because in all cases, the number of cells infected in the core was very sparse. It is possible that the primary thalamic target of core-originated projections was missed in this study. Indeed, it has been proposed that neurons in the laterodorsal VP receiving input from the core project to the caudal and ventral parts of the m-MD (Groenewegen et al., 1990
A third circuit shown by our data involves projections from the CPu to the GP to the l-MD. Injections in the l-MD resulted in a pattern of retrograde labeling consistent with that reported previously (Haber et al., 1985 Organization of connections between accumbens and RTN
Different regions within the RTN were also targets of striatal and accumbal projections via the GP and VP. Injections into the ventral part of the rostral RTN resulted in an extensive infection of VP neurons and in second-order infection in the nucleus accumbens core and shell. In the animals injected in more dorsal and caudal regions of the rostral RTN, infected cells were detected in the VP, and second-order neurons were observed in the accumbens shell and not in the core. This suggests that the shell, in addition to its projection to the m-MD via the VP, may also target a discrete region within the RTN, whereas the core, in addition to targeting the c-MD via the VP, also projects to a different RTN region. The absence of this pattern of infection in cases in which the injection was close to, but did not involve, the RTN supports this conclusion.
PRV injections into the caudal RTN resulted in infection of cells in the GP that had the characteristic labeling pattern of first-order projection cells. In addition, second-order projection neurons were labeled in the CPu but were absent in the accumbens. These findings are consistent with results from injections of anterograde tracers in the GP that yielded labeling of terminals in the caudal RTN (Gandia et al., 1993 Parallel circuits involving the MD and RTN
The results presented here reveal a substantial degree of segregation in the projections from the accumbens core and shell regions to the thalamus. Indeed, while efferents from the shell region of the accumbens, via its projections to the medial VP, contact the m-MD and rostral-intermediate regions of the RTN, the projections from the core region, via the lateral VP, affect primarily the c-MD and rostral pole of the RTN. In addition, CPu efferents target the l-MD and a caudal region of the RTN via the GP. These parallel circuits revealed by the transynaptic passage of this neurotropic virus are a confirmation of what has been proposed by the analysis of separate conventional tracer studies (Groenewegen et al., 1990
Fig. 14. Parallel circuits linking the CPu, accumbens core, and accumbens shell with pallidal and thalamocortical systems. The arrows summarize the most consistent data obtained after PRV injections into the MD or RTN regions. Green arrows represent circuitry involving the accumbens shell and medial VP, red arrows show circuits involving the accumbens core and lateral VP/pallidal OT, and blue arrows represent circuits originated from the CPu and GP. Gray arrows show cortico-thalamic and cortico-striatal projections not assessed in this study. The m-MD receives very heavy projections via the shell/medial VP-axis. The c-MD receives much weaker projections from the core/lateral VP system and through the polymorph layer of the OT. The l-MD receives projections from the dorsal striatum-GP. In addition, the three striatal regions also project (via VP and GP) to relatively segregated regions within the RTN. In turn, these RTN areas project to different MD segments. Also, the three MD segments receive relatively segregated inputs from prefrontal cortical areas. Overall, these data provide strong evidence for the presence of parallel circuits within the basal ganglia-thalamic projections, which are not completely closed, allowing for interactions among them.
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As suggested by in vivo intracellular recordings in the RTN (Lavín and Grace, 1994
Even though core and shell neurons project to different thalamic target areas, there are some interactions between these parallel circuits (Fig. 14). The MD itself is not likely to be a site for interactions between these parallel circuits, because dendritic trees of cells located in the different segments of the MD were found to be confined to each MD subdivision (Kuroda et al., 1992 Functional implications
The MD regions targeted by the striatal regions have been demonstrated to be the origin of projections to cortical regions that in turn project back to the accumbens and striatum. Thus, the m-MD projects to the PL and IL PFC, the c-MD to the lateral orbital and ventral agranular insular cortex, and the l-MD to the anterior cingulate cortex (Leonard, 1972
The RTN is known to exert a control on the oscillatory activity of thalamocortical projections (Steriade et al., 1993a
In summary, our data show that multisynaptic circuits from the CPu and accumbens core and shell to the MD and reticular thalamic nuclei via the VP are organized in a series of parallel loops that nonetheless exhibit some interactions. The accumbens shell is the primary source of transynaptic striatal input to the MD, whereas the sparse accumbens core transynaptic projections to the thalamus appear to be primarily directed to the RTN.
FOOTNOTES
Received July 19, 1996; revised Dec. 3, 1996; accepted Dec. 31, 1996.
This work was supported by National Institutes of Health Grants MH53574 (J.P.C.), NINDS33506 (L.W.E.), and MH45156 and MH01055 (A.A.G.); and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (P.O.). We thank Ms. Jen-Shew Yen for her excellent technical assistance and Dr. Susan R. Sesack and Dr. Holly Moore for comments on this manuscript. We also thank Dr. Robert Y. Moore for generously providing the use of his BSL-2 facility.
Correspondence should be addressed to Dr. Patricio O'Donnell, Department of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260.
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