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Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens
Brain Research 787 Ž1998. 304–310
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Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens Michael Bubser ) , Ariel Y. Deutch Departments of Psychiatry and Pharmacology, Vanderbilt UniÕersity School of Medicine, NashÕille, TN 37212, USA Accepted 4 November 1997
Abstract The prefrontal cortex and nucleus accumbens are primary recipients of medial thalamic inputs, prominently including projections from the thalamic paraventricular nucleus. It is not known if paraventricular neurons collateralize to innervate both the prefrontal cortex and nucleus accumbens. We used dual retrograde tract tracing methods to examine this question. A small population of paraventricular neurons was found to innervate the prefrontal cortex and medial nucleus accumbens. These data suggest that the thalamic paraventricular nucleus may coordinately influence activity in the prefrontal cortex and ventral striatum. q 1998 Elsevier Science B.V. Keywords: Nucleus accumbens; Paraventricular nucleus of the thalamus; Prefrontal cortex; Rat; Striatum; Thalamus
The paraventricular nucleus of the thalamus ŽPVT. and other midline intralaminar nuclei have extensive connections with limbic-related structures of the forebrain, including the prefrontal cortex ŽPFC., nucleus accumbens ŽNAS., amygdala, and hippocampus w4,5,16,18,40,44,49,52 x. The PVT sends projections to discrete regions within the PFC and NAS, innervating the shell and septal pole regions of the NAS and the infralimbic and prelimbic aspects of the PFC w4,5,40x. These regions of the PFC and NAS are anatomically and functionally connected w6,11,22,32,47x. It is not known if the PFC and NAS are innervated by separate neuronal populations in the PVT, or whether single PVT neurons collateralize to innervate both structures. Previous studies have revealed that some PVT neurons collateralize to innervate both the NAS and amygdala w28,49x or septum and entorhinal cortex w13x. Accordingly, some degree of collateralization of PVT afferents to the PFC and NAS might be expected. We examined this possibility in a dual retrograde-tracer study. Animal studies were carried out in accordance with the guidelines promulgated by the National Institutes of Health Guide for Care and Use of Laboratory Animals. Adult
) Corresponding author. Psychiatric Hospital at Vanderbilt, Suite 313, 1601 23rd Avenue South, Nashville, TN 37212, USA. Fax: q1-615-3277093; E-mail: [email protected]
0006-8993r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 7 . 0 1 3 7 3 - 5
male Sprague–Dawley rats Ž N s 8. were anaesthetized with pentobarbital and placed into a stereotaxic frame. 200–250 nl of a 2% suspension of the retrograde tracer Fast Blue ŽSigma Chemical, St. Louis, MO. was pressureinjected into the PFC. These injections were relatively large, covering both the infralimbic Žarea 25. and prelimbic Žarea 32. cortices, since such injections maximize the number of retrogradely labeled cells in the thalamus, and since the PVT innervates both of these prefrontal regions w40x. In contrast, the PVT projects predominantly to the NAS shell and septal pole, with other ventral striatal territories being innervated by different midlinerintralaminar nuclei w4x. In order to restrict tracer deposits to distinct NAS compartments, we used iontophoretic deposits of Mini Ruby Žtetramethylrhodamine–biotin dextran, lysine fixable, MW 10,000; Molecular Probes, Eugene, OR.. Mini Ruby was ejected through micropipettes with tip diameters of 20–30 m m filled with 10–15% Mini Ruby in 0.1 M phosphate buffer, pH 7.4; the tracer was deposited using 5.0 m A of pulsed positive current Ž7 s onroff. for 15–25 min. After a survival period of 10–21 days, the rats were deeply anaesthetized with pentobarbital and transcardially perfused with 0.1 M phosphate-buffered saline followed by 4% paraformaldehyde. 40–50 m m coronal sections were cut on a vibrating microtome. Mini Ruby-labeled cells were detected by overnight incubation in peroxidase-
M. Bubser, A.Y. Deutchr Brain Research 787 (1998) 304–310
labeled streptavidin Ž1:400; Vector, Burlingame, CA. in Tris-buffered saline ŽTBS. containing 0.2% Triton X-100, followed by incubation in TBS containing 0.025% 3,3X-diaminobenzidine, 0.001% H 2 O 2 , 0.4% nickel ammonium sulfate and 0.04% cobalt chloride to yield a black precipitate. After the reaction was stopped, sections were taken through an ascending–descending series of methanol washes followed by incubation in methanolic peroxide to eliminate any residual peroxidase activity w2x. Fast Blue-labeled cells were detected after incubation in a rabbit anti-Fluoro Gold antibody that also recognizes Fast blue Ž1:3000; Chemicon, Temecula, CA. and developed using the peroxidase anti-peroxidase method w43x. Fast Blue was visualized by incubation in an acetate buffer
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ŽpH 5.6. containing 0.033% 3-amino-9-ethyl-carbazole ŽAEC., 7.1% dimethylformamide and 0.025% H 2 O 2 to yield a bright red reaction product. In order to differentiate clearly the PVT from the contiguous parataenial nucleus, which also sends efferents to the NAS and PFC w5,35x, and the mediodorsal thalamic nucleus, which projects to the PFC w38x, sections were also processed to reveal tyrosine hydroxylase-like immunoreactivity ŽTH-li.. A dense TH-li fiber innervation is present in the PVT, but not in the adjacent parataenial or mediodorsal thalamic nuclei w28x. TH-li was detected using a primary mouse monoclonal antibody Ž1:2500; Incstar, Stillwater, MN., and developed by the peroxidase anti-peroxidase method using diaminobenzidine without heavy
Fig. 1. Retrogradely labeled cells in the thalamic paraventricular nucleus ŽPVT.. The PVT can be distinguished from other dorsomedial thalamic nuclei by a relatively dense tyrosine hydroxylase innervation Žbrown fibers in top panel.. Mini Ruby-labeled cells projecting to the nucleus accumbens Žblack granular reaction product, marked by arrow in lower left panel. are confined to the PVT at this level, while Fast blue-labeled cells that innervate the prefrontal cortex Žsmall arrowhead pointing to bright red cells. are seen in both the PVT and contiguous mediodorsal thalamic nucleus ŽMD.. Double-labeled cells Žlarge arrowhead, bottom panels. that project to both forebrain sites can be clearly distinguished. Scale bar s 10 m m Žbottom panels..
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metal intensification, resulting in brown TH-li axons being stained. The processing of the sections for TH-li was performed after the Mini Ruby procedure, but before the Fast Blue immunohistochemical procedure. The accumbal site of Mini Ruby deposits was determined by first processing sections to reveal Mini Ruby, with the tissue then processed to reveal calbindin-li, using a mouse monoclonal calbindin antibody Ž1:4000; Sigma Chemical.. Calbindin expression is high in cells in the NAS core, but not the shell and septal pole regions w25x. Injections of Mini Ruby into the medial shell and septal pole regions of the NAS resulted in retrogradely-labeled cells in the PVT; injections more laterally in the NAS yielded very sparse PVT labeling. The relatively large PFC injections resulted in retrogradely-labeled cells throughout the anteroposterior extent of the PVT. Double-labeled cells that projected to both the NAS and PFC comprised a minority of the total number of cells that were retrogradely labeled from the NAS. These neurons were typically seen in the lateral aspects of the PVT. Mini Ruby and Fast Blue labeling of neurons could be easily distinguished ŽFig. 1.. The black granular reaction product defining Mini Ruby-labeled cells was seen against the homogenous bright red staining of Fast Blue-labeled cells. In addition, these cells could be clearly seen against the background of catecholamine axons defining the PVT ŽFig. 1.. PFC Fast Blue injections were confined primarily to prelimbic Žarea 32. and dorsal aspects of the infralimbic Žarea 25. cortices ŽFig. 2.. NAS tracer deposits differentially involved the septal pole, medial shell, and the core regions. Three cases will be briefly discussed; these animals displayed different patterns of retrograde labeling in the PVT that was attributable to involvement of the different accumbal compartments.
One animal received a small Mini Ruby injection confined to the dorsal aspect of the septal pole region of the NAS Žsee Fig. 2.. While cells that were retrogradely labeled from the PFC were present throughout the PVT, Mini Ruby-labeled cells were abundant in the anterior PVT but very sparse more caudally. In this case, doublelabeled cells were seen only in the anterior PVT ŽFig. 3A., being predominantly located along the lateral border of the PVT, adjacent to the parataenial nucleus. The doublelabeled cells were seen only in the area invested with TH-li fibers, consistent with these cells being in the PVT rather than parataenial nucleus. Of the 141 PVT cells that were retrogradely labeled from the NAS, 14 Ž10%. were double-labeled. Another rat had a Mini Ruby injection restricted to the medial shell Žsee Fig. 2.. PVT cells retrogradely labeled from the NAS or PFC were seen throughout the anteroposterior extent of the PVT, as were neurons that were double-labeled from both the PFC and NAS ŽFig. 3B.. In this case, the number of double-labeled cells was somewhat higher in the posterior and middle levels Ž15–19%. of the PVT than in the anterior PVT Ž10%.. Double-labeled cells were again most frequently encountered at the lateral border of the PVT. 240 Mini Ruby-labeled cells were counted in the PVT, of which 38 Žf 16%. also contained Fast Blue. One Mini Ruby injection involved only the ventrolateral shell and the core. In this animal, very few PVT cells were retrogradely labeled from the NAS, and no double-labeled cells were seen in the PVT. However, some double-labeled cells were present more ventrally in the intermediodorsal and centromedial thalamic nuclei Ždata not presented.. Cells retrograde labeled from the PFC and NAS were easily distinguished by color as well as intracellular distribution of reaction product. Fast Blue has been used exten-
Fig. 2. Representative retrograde tracer deposits into the prefrontal cortex ŽFast Blue, left. and the septal pole ŽMini Ruby, center. or the medial shell ŽMini Ruby, right. of the nucleus accumbens. Sections were first stained for the tracer and then counterstained with Cresyl violet Žleft, center. or immunostained for calbindin Žright..
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Fig. 3. Chartings of retrogradely labeled cells in the paraventricular thalamic nucleus ŽPVT. following Fast Blue and Mini Ruby injections into the medial prefrontal cortex and subregions of the nucleus accumbens, respectively. ŽA. Tracer injections into the prefrontal cortex and septal pole Žsee Fig. 2, left and center. or ŽB. prefrontal cortex and medial shell Žsee Fig. 2, right. show contrasting patterns of retrograde labeling. Open circles represent Mini Ruby-labeled cells projecting to the nucleus accumbens, while small dots are Fast blue labeled cells innervating the prefrontal cortex. Double-labeled cells that project to both the cortex and accumbens Žfilled circles. are concentrated in the lateral aspects of the PVT. lHb: lateral habenula; mHb: medial habenula; PT: parataenial thalamic nucleus; sm: stria medularis.
sively in retrograde tracing studies. More recently, modified dextrans have been used as both retrograde and anterograde tracers w9,34,45,46,54x. The present results revealed strong retrograde labeling after Mini Ruby injections. The use of Mini Ruby permitted iontophoretic deposits into discrete regions of the NAS, and therefore allowed us to determine if accumbal subregions were differential recipients of branched neurons from the PVT, consistent with the topographical organization of medial thalamic projections to the ventral striatum w4,40x. Moreover, the ability to make iontophoretic deposits decreased the likelihood of uptake of the tracer by axons traversing the NAS as they project to the frontal cortices. Under the conditions used in the present study, we did not see any evidence of uptake of Mini Ruby by fibers of passage. Thus, medial NAS injections did not retrogradely label cells in the mediodorsal thalamic nucleus, although these
thalamic neurons send axons coursing through the region near the injection sites to enter the PFC. Moreover, in a single case in which a Mini Ruby deposit was restricted to the temporal limb of the anterior commissure, there was no labeling in other parts of the brain, contra- or ipsi-lateral to the site of injection. The distribution of neurons retrogradely labeled from the PFC and NAS is consistent with previous reports concerning the topographical organization of thalamocortical and thalamostriatal projections w4,5,16,18,35,40,44,49 x. This is the first report of PVT cells that collateralize to innervate the PFC and NAS. Previous reports have indicated that single PVT neurons collateralize to innervate the NAS and amygdala w28,49x and the septum and entorhinal cortex w13x. In contrast, a recent report stated that PVT neurons do not collateralize to innervate the PFC and NAS w48x. However, this study involved tracer deposits re-
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stricted to the lateral aspects of the NAS, an area from which we obtained little retrograde labeling in the PVT. Previous anterograde and retrograde tract tracing studies have also indicated that PVT projections to the lateral NAS, including the core, are very sparse w4,10,40,55x. We found that the percentage of double-labeled cells to the number of PVT cells labeled from the NAS, was relatively small, averaging about 15%. Double-labeled cells were detected at all rostro-caudal levels of the PVT in which significant retrograde labelling from the NAS was seen. The double-labeled cells were restricted to the region invested by a relatively dense plexus of TH-li fibers, and were seen most frequently in the lateral aspects of the PVT. These data correspond well with other studies examining collateralization of PVT neurons to forebrain sites, in which investigators have found a similar percentage of double-labeled cells w13,28,49x. It is interesting to note that in those areas in which neurons are found that branch to innervate both the NAS and PFC, including the ventral tegmental area, dorsal raphe, and basolateral amygdala, only a small percentage of the cells collateralize w27,48,53x. It is likely that PVT neurons that collateralize to innervate both the PFC and NAS exert some coordinated functional effect on the two targets, but it is not known to which degree such effects are realized; future studies will be required to examine this issue. The PVT receives widespread afferents, including those from the reticular formation w7,15,19,42x. Brainstem dopaminergic neurons also project to the PVT w53x. The strong afference from reticular formation structures coupled with the efferent projections of the PVT to limbic forebrain sites w40x indicate that the PVT is strategically positioned to integrate activity in the limbic forebrain as a function of arousal and attention. Consistent with such a functional role is the observation that the midline intralaminar nuclei are activated during attention-demanding tasks w36x. Thus, the PVT may be involved in alerting cortical ŽPFC. and limbic ŽNAS. areas to novel situations w32x. The current data indicate that certain PVT neurons collateralize to innervate both the PFC and NAS, two sites proposed to be central to the pathophysiology of schizophrenia w3,11,22,23,24,30x. The thalamus has also been implicated in the pathophysiology of schizophrenia w1,12,31,41,50x, and the PVT has recently been shown to be a site of action of antipsychotic drugs w17,26x. In view of the dominant Žalbeit challenged. dopamine hypothesis of schizophrenia w29,33x, it is interesting to note that the PVT receives a dopaminergic innervation derived in part from the midbrain A10 dopamine neurons w51x, others of which also innervate the PFC and NAS. Accordingly, the PVT is well situated to integrate dopaminergic activity in diverse areas by virtue of both receiving a dopamine input and sending glutamatergic projections to forebrain sites w16x. While any specific role of the PVT in schizophrenia is speculative, a likely role for the thalamus is in relation to changes in attention and distractibility seen in
schizophrenic patients w1,8,20,37,39x. Moreover, since stress may lead to an acute exacerbation of the psychotic process, and since stress activates the PVT as well as the PFC and NAS shell w14,21,23x, the PVT may be part of an extended stress circuit involving the PFC and its subcortical targets. The current data suggest that PVT neurons may concurrently or differentially influence activity in the PFC and NAS. Uncovering the mechanisms that regulate the activity in the two different types of PVT neurons Žthose projecting to only one target and those innervating two, or potentially more, targets. should be a focus of future work, and is likely to involve extended corticofugal circuits w25,32x.
Acknowledgements This research was supported by MH 45124 and MH 57995.
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Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens Michael Bubser ) , Ariel Y. Deutch Departments of Psychiatry and Pharmacology, Vanderbilt UniÕersity School of Medicine, NashÕille, TN 37212, USA Accepted 4 November 1997
Abstract The prefrontal cortex and nucleus accumbens are primary recipients of medial thalamic inputs, prominently including projections from the thalamic paraventricular nucleus. It is not known if paraventricular neurons collateralize to innervate both the prefrontal cortex and nucleus accumbens. We used dual retrograde tract tracing methods to examine this question. A small population of paraventricular neurons was found to innervate the prefrontal cortex and medial nucleus accumbens. These data suggest that the thalamic paraventricular nucleus may coordinately influence activity in the prefrontal cortex and ventral striatum. q 1998 Elsevier Science B.V. Keywords: Nucleus accumbens; Paraventricular nucleus of the thalamus; Prefrontal cortex; Rat; Striatum; Thalamus
The paraventricular nucleus of the thalamus ŽPVT. and other midline intralaminar nuclei have extensive connections with limbic-related structures of the forebrain, including the prefrontal cortex ŽPFC., nucleus accumbens ŽNAS., amygdala, and hippocampus w4,5,16,18,40,44,49,52 x. The PVT sends projections to discrete regions within the PFC and NAS, innervating the shell and septal pole regions of the NAS and the infralimbic and prelimbic aspects of the PFC w4,5,40x. These regions of the PFC and NAS are anatomically and functionally connected w6,11,22,32,47x. It is not known if the PFC and NAS are innervated by separate neuronal populations in the PVT, or whether single PVT neurons collateralize to innervate both structures. Previous studies have revealed that some PVT neurons collateralize to innervate both the NAS and amygdala w28,49x or septum and entorhinal cortex w13x. Accordingly, some degree of collateralization of PVT afferents to the PFC and NAS might be expected. We examined this possibility in a dual retrograde-tracer study. Animal studies were carried out in accordance with the guidelines promulgated by the National Institutes of Health Guide for Care and Use of Laboratory Animals. Adult
) Corresponding author. Psychiatric Hospital at Vanderbilt, Suite 313, 1601 23rd Avenue South, Nashville, TN 37212, USA. Fax: q1-615-3277093; E-mail: [email protected]
0006-8993r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 7 . 0 1 3 7 3 - 5
male Sprague–Dawley rats Ž N s 8. were anaesthetized with pentobarbital and placed into a stereotaxic frame. 200–250 nl of a 2% suspension of the retrograde tracer Fast Blue ŽSigma Chemical, St. Louis, MO. was pressureinjected into the PFC. These injections were relatively large, covering both the infralimbic Žarea 25. and prelimbic Žarea 32. cortices, since such injections maximize the number of retrogradely labeled cells in the thalamus, and since the PVT innervates both of these prefrontal regions w40x. In contrast, the PVT projects predominantly to the NAS shell and septal pole, with other ventral striatal territories being innervated by different midlinerintralaminar nuclei w4x. In order to restrict tracer deposits to distinct NAS compartments, we used iontophoretic deposits of Mini Ruby Žtetramethylrhodamine–biotin dextran, lysine fixable, MW 10,000; Molecular Probes, Eugene, OR.. Mini Ruby was ejected through micropipettes with tip diameters of 20–30 m m filled with 10–15% Mini Ruby in 0.1 M phosphate buffer, pH 7.4; the tracer was deposited using 5.0 m A of pulsed positive current Ž7 s onroff. for 15–25 min. After a survival period of 10–21 days, the rats were deeply anaesthetized with pentobarbital and transcardially perfused with 0.1 M phosphate-buffered saline followed by 4% paraformaldehyde. 40–50 m m coronal sections were cut on a vibrating microtome. Mini Ruby-labeled cells were detected by overnight incubation in peroxidase-
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labeled streptavidin Ž1:400; Vector, Burlingame, CA. in Tris-buffered saline ŽTBS. containing 0.2% Triton X-100, followed by incubation in TBS containing 0.025% 3,3X-diaminobenzidine, 0.001% H 2 O 2 , 0.4% nickel ammonium sulfate and 0.04% cobalt chloride to yield a black precipitate. After the reaction was stopped, sections were taken through an ascending–descending series of methanol washes followed by incubation in methanolic peroxide to eliminate any residual peroxidase activity w2x. Fast Blue-labeled cells were detected after incubation in a rabbit anti-Fluoro Gold antibody that also recognizes Fast blue Ž1:3000; Chemicon, Temecula, CA. and developed using the peroxidase anti-peroxidase method w43x. Fast Blue was visualized by incubation in an acetate buffer
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ŽpH 5.6. containing 0.033% 3-amino-9-ethyl-carbazole ŽAEC., 7.1% dimethylformamide and 0.025% H 2 O 2 to yield a bright red reaction product. In order to differentiate clearly the PVT from the contiguous parataenial nucleus, which also sends efferents to the NAS and PFC w5,35x, and the mediodorsal thalamic nucleus, which projects to the PFC w38x, sections were also processed to reveal tyrosine hydroxylase-like immunoreactivity ŽTH-li.. A dense TH-li fiber innervation is present in the PVT, but not in the adjacent parataenial or mediodorsal thalamic nuclei w28x. TH-li was detected using a primary mouse monoclonal antibody Ž1:2500; Incstar, Stillwater, MN., and developed by the peroxidase anti-peroxidase method using diaminobenzidine without heavy
Fig. 1. Retrogradely labeled cells in the thalamic paraventricular nucleus ŽPVT.. The PVT can be distinguished from other dorsomedial thalamic nuclei by a relatively dense tyrosine hydroxylase innervation Žbrown fibers in top panel.. Mini Ruby-labeled cells projecting to the nucleus accumbens Žblack granular reaction product, marked by arrow in lower left panel. are confined to the PVT at this level, while Fast blue-labeled cells that innervate the prefrontal cortex Žsmall arrowhead pointing to bright red cells. are seen in both the PVT and contiguous mediodorsal thalamic nucleus ŽMD.. Double-labeled cells Žlarge arrowhead, bottom panels. that project to both forebrain sites can be clearly distinguished. Scale bar s 10 m m Žbottom panels..
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metal intensification, resulting in brown TH-li axons being stained. The processing of the sections for TH-li was performed after the Mini Ruby procedure, but before the Fast Blue immunohistochemical procedure. The accumbal site of Mini Ruby deposits was determined by first processing sections to reveal Mini Ruby, with the tissue then processed to reveal calbindin-li, using a mouse monoclonal calbindin antibody Ž1:4000; Sigma Chemical.. Calbindin expression is high in cells in the NAS core, but not the shell and septal pole regions w25x. Injections of Mini Ruby into the medial shell and septal pole regions of the NAS resulted in retrogradely-labeled cells in the PVT; injections more laterally in the NAS yielded very sparse PVT labeling. The relatively large PFC injections resulted in retrogradely-labeled cells throughout the anteroposterior extent of the PVT. Double-labeled cells that projected to both the NAS and PFC comprised a minority of the total number of cells that were retrogradely labeled from the NAS. These neurons were typically seen in the lateral aspects of the PVT. Mini Ruby and Fast Blue labeling of neurons could be easily distinguished ŽFig. 1.. The black granular reaction product defining Mini Ruby-labeled cells was seen against the homogenous bright red staining of Fast Blue-labeled cells. In addition, these cells could be clearly seen against the background of catecholamine axons defining the PVT ŽFig. 1.. PFC Fast Blue injections were confined primarily to prelimbic Žarea 32. and dorsal aspects of the infralimbic Žarea 25. cortices ŽFig. 2.. NAS tracer deposits differentially involved the septal pole, medial shell, and the core regions. Three cases will be briefly discussed; these animals displayed different patterns of retrograde labeling in the PVT that was attributable to involvement of the different accumbal compartments.
One animal received a small Mini Ruby injection confined to the dorsal aspect of the septal pole region of the NAS Žsee Fig. 2.. While cells that were retrogradely labeled from the PFC were present throughout the PVT, Mini Ruby-labeled cells were abundant in the anterior PVT but very sparse more caudally. In this case, doublelabeled cells were seen only in the anterior PVT ŽFig. 3A., being predominantly located along the lateral border of the PVT, adjacent to the parataenial nucleus. The doublelabeled cells were seen only in the area invested with TH-li fibers, consistent with these cells being in the PVT rather than parataenial nucleus. Of the 141 PVT cells that were retrogradely labeled from the NAS, 14 Ž10%. were double-labeled. Another rat had a Mini Ruby injection restricted to the medial shell Žsee Fig. 2.. PVT cells retrogradely labeled from the NAS or PFC were seen throughout the anteroposterior extent of the PVT, as were neurons that were double-labeled from both the PFC and NAS ŽFig. 3B.. In this case, the number of double-labeled cells was somewhat higher in the posterior and middle levels Ž15–19%. of the PVT than in the anterior PVT Ž10%.. Double-labeled cells were again most frequently encountered at the lateral border of the PVT. 240 Mini Ruby-labeled cells were counted in the PVT, of which 38 Žf 16%. also contained Fast Blue. One Mini Ruby injection involved only the ventrolateral shell and the core. In this animal, very few PVT cells were retrogradely labeled from the NAS, and no double-labeled cells were seen in the PVT. However, some double-labeled cells were present more ventrally in the intermediodorsal and centromedial thalamic nuclei Ždata not presented.. Cells retrograde labeled from the PFC and NAS were easily distinguished by color as well as intracellular distribution of reaction product. Fast Blue has been used exten-
Fig. 2. Representative retrograde tracer deposits into the prefrontal cortex ŽFast Blue, left. and the septal pole ŽMini Ruby, center. or the medial shell ŽMini Ruby, right. of the nucleus accumbens. Sections were first stained for the tracer and then counterstained with Cresyl violet Žleft, center. or immunostained for calbindin Žright..
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Fig. 3. Chartings of retrogradely labeled cells in the paraventricular thalamic nucleus ŽPVT. following Fast Blue and Mini Ruby injections into the medial prefrontal cortex and subregions of the nucleus accumbens, respectively. ŽA. Tracer injections into the prefrontal cortex and septal pole Žsee Fig. 2, left and center. or ŽB. prefrontal cortex and medial shell Žsee Fig. 2, right. show contrasting patterns of retrograde labeling. Open circles represent Mini Ruby-labeled cells projecting to the nucleus accumbens, while small dots are Fast blue labeled cells innervating the prefrontal cortex. Double-labeled cells that project to both the cortex and accumbens Žfilled circles. are concentrated in the lateral aspects of the PVT. lHb: lateral habenula; mHb: medial habenula; PT: parataenial thalamic nucleus; sm: stria medularis.
sively in retrograde tracing studies. More recently, modified dextrans have been used as both retrograde and anterograde tracers w9,34,45,46,54x. The present results revealed strong retrograde labeling after Mini Ruby injections. The use of Mini Ruby permitted iontophoretic deposits into discrete regions of the NAS, and therefore allowed us to determine if accumbal subregions were differential recipients of branched neurons from the PVT, consistent with the topographical organization of medial thalamic projections to the ventral striatum w4,40x. Moreover, the ability to make iontophoretic deposits decreased the likelihood of uptake of the tracer by axons traversing the NAS as they project to the frontal cortices. Under the conditions used in the present study, we did not see any evidence of uptake of Mini Ruby by fibers of passage. Thus, medial NAS injections did not retrogradely label cells in the mediodorsal thalamic nucleus, although these
thalamic neurons send axons coursing through the region near the injection sites to enter the PFC. Moreover, in a single case in which a Mini Ruby deposit was restricted to the temporal limb of the anterior commissure, there was no labeling in other parts of the brain, contra- or ipsi-lateral to the site of injection. The distribution of neurons retrogradely labeled from the PFC and NAS is consistent with previous reports concerning the topographical organization of thalamocortical and thalamostriatal projections w4,5,16,18,35,40,44,49 x. This is the first report of PVT cells that collateralize to innervate the PFC and NAS. Previous reports have indicated that single PVT neurons collateralize to innervate the NAS and amygdala w28,49x and the septum and entorhinal cortex w13x. In contrast, a recent report stated that PVT neurons do not collateralize to innervate the PFC and NAS w48x. However, this study involved tracer deposits re-
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stricted to the lateral aspects of the NAS, an area from which we obtained little retrograde labeling in the PVT. Previous anterograde and retrograde tract tracing studies have also indicated that PVT projections to the lateral NAS, including the core, are very sparse w4,10,40,55x. We found that the percentage of double-labeled cells to the number of PVT cells labeled from the NAS, was relatively small, averaging about 15%. Double-labeled cells were detected at all rostro-caudal levels of the PVT in which significant retrograde labelling from the NAS was seen. The double-labeled cells were restricted to the region invested by a relatively dense plexus of TH-li fibers, and were seen most frequently in the lateral aspects of the PVT. These data correspond well with other studies examining collateralization of PVT neurons to forebrain sites, in which investigators have found a similar percentage of double-labeled cells w13,28,49x. It is interesting to note that in those areas in which neurons are found that branch to innervate both the NAS and PFC, including the ventral tegmental area, dorsal raphe, and basolateral amygdala, only a small percentage of the cells collateralize w27,48,53x. It is likely that PVT neurons that collateralize to innervate both the PFC and NAS exert some coordinated functional effect on the two targets, but it is not known to which degree such effects are realized; future studies will be required to examine this issue. The PVT receives widespread afferents, including those from the reticular formation w7,15,19,42x. Brainstem dopaminergic neurons also project to the PVT w53x. The strong afference from reticular formation structures coupled with the efferent projections of the PVT to limbic forebrain sites w40x indicate that the PVT is strategically positioned to integrate activity in the limbic forebrain as a function of arousal and attention. Consistent with such a functional role is the observation that the midline intralaminar nuclei are activated during attention-demanding tasks w36x. Thus, the PVT may be involved in alerting cortical ŽPFC. and limbic ŽNAS. areas to novel situations w32x. The current data indicate that certain PVT neurons collateralize to innervate both the PFC and NAS, two sites proposed to be central to the pathophysiology of schizophrenia w3,11,22,23,24,30x. The thalamus has also been implicated in the pathophysiology of schizophrenia w1,12,31,41,50x, and the PVT has recently been shown to be a site of action of antipsychotic drugs w17,26x. In view of the dominant Žalbeit challenged. dopamine hypothesis of schizophrenia w29,33x, it is interesting to note that the PVT receives a dopaminergic innervation derived in part from the midbrain A10 dopamine neurons w51x, others of which also innervate the PFC and NAS. Accordingly, the PVT is well situated to integrate dopaminergic activity in diverse areas by virtue of both receiving a dopamine input and sending glutamatergic projections to forebrain sites w16x. While any specific role of the PVT in schizophrenia is speculative, a likely role for the thalamus is in relation to changes in attention and distractibility seen in
schizophrenic patients w1,8,20,37,39x. Moreover, since stress may lead to an acute exacerbation of the psychotic process, and since stress activates the PVT as well as the PFC and NAS shell w14,21,23x, the PVT may be part of an extended stress circuit involving the PFC and its subcortical targets. The current data suggest that PVT neurons may concurrently or differentially influence activity in the PFC and NAS. Uncovering the mechanisms that regulate the activity in the two different types of PVT neurons Žthose projecting to only one target and those innervating two, or potentially more, targets. should be a focus of future work, and is likely to involve extended corticofugal circuits w25,32x.
Acknowledgements This research was supported by MH 45124 and MH 57995.
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