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Topographic organization of the striatal and thalamic connections of rat medial agranular cortex
Brain Research 841 Ž1999. 43–52 www.elsevier.comrlocaterbres
Research report
Topographic organization of the striatal and thalamic connections of rat medial agranular cortex R.L. Reep a
a, )
, J.V. Corwin
b
Department of Physiological Sciences and Brain Institute, UniÕersity of Florida, GainesÕille, FL 32610, USA b Department of Psychology, Northern Illinois UniÕersity, De Kalb, IL, USA Accepted 22 June 1999
Abstract The rostral and caudal portions of rat medial agranular cortex ŽAGm. play different functional roles. To refine the anatomical framework for understanding these differences, axonal tracers were used to map the topography of the connections of AGm with the striatum and thalamus. The striatal projections follow mediolateral and rostrocaudal gradients that correspond to the locations of the neurons of origin within AGm. Projections from rostral AGm are widespread and dense rostrally, then coalesce into a circumscribed dorsocentral region at the level of the pre-commissural septal nuclei. Projections from mid and caudal AGm are less widespread and less dense, and are focused more caudally. Striatal projections from the adjacent anterior cingulate and lateral agranular areas overlap those of AGm but are concentrated more medially and laterally, respectively. Thalamic connections of AGm are organized so that more caudal portions of AGm have connections with progressively more lateral and caudal regions of the thalamus, and the full extent of AGm is connected with the ventrolateral ŽVL. nucleus. Rostral AGm is interconnected with the lateral portion of the mediodorsal nucleus ŽMDl., VL, and the central lateral ŽCL., paracentral ŽPC., central medial, rhomboid and ventromedial nuclei. Caudal AGm has robust connections with VL, the posterior, lateral posterior and lateral dorsal nuclei, but little or none with MDl, CLrPC and VM. These differences in the subcortical connections of rostral and caudal AGm parallel their known differences in corticocortical connections, and represent another basis for experimental explorations of the functional roles of these cortical territories. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Cerebral cortex; Striatum; Thalamus; Connection; Medial agranular
1. Introduction Recent studies have pointed to medial agranular cortex ŽAGm. as one component of a cortical–subcortical network subserving directed spatial attention in rats, and have shown that the rostral ŽrAGm. and caudal ŽcAGm. portions of AGm play differing functional roles w6,7x. Anatomical and microstimulation findings w12,14,16,27,31,32, 34,35x suggest that AGm may represent the homolog of primate area 8, which also plays a pivotal role in spatial processing and directed attention w17x. Unilateral lesions of AGm result in severe multimodal neglect of visual, auditory, and tactile stimuli that is qualitatively similar to
) Corresponding author. Department of Physiological Sciences, Box 100144, HSC, University of Florida, Gainsville, FL 32610, USA. Fax: q1-352-392-5145; E-mail: [email protected]
neglect in primates w8,10x. Whereas small unilateral lesions of cAGm result in severe multimodal neglect, larger rAGm lesions produce allesthesiarallokinesia in which the animal demonstrates inappropriate contralateral orientations to stimulation w21x. Bilateral lesions of AGm produce deficits in egocentric spatial processing w20,22x. The functional distinctions between rAGm and cAGm are reflected in their distinct but partially overlapping patterns of connections with cortex w34x, thalamus w18x, brainstem w23,24,40x and spinal cord w12,26x. In addition, rAGm is selectively involved in head orientation movements w39x. The dorsocentral striatum, the major site of corticostriatal projections from rAGm w32x, appears to play a pivotal role in directed attention and recovery of function from lesion-induced attentional disorders. Axon-sparing lesions of the dorsocentral striatum produce severe multimodal neglect of stimuli presented contralesionally, whereas lesions placed more laterally and ventrally do not w43x. The dopamine agonist apomorphine, which induces acute re-
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covery in animals with severe neglect produced by cortical lesions w8,9,21x, does not result in recovery when administered to animals with lesions of the dorsocentral striatum w43x. This finding suggests that the dorsocentral striatum may be the site of action for drug-induced recovery from neglect. In view of the crucial role of the striatum in the dynamics of directed attention, neglect, and behavioral recovery from neglect, and the different functional roles of rAGm and cAGm, it is important to understand the topography of the projections from AGm to the striatum. In an earlier anatomical study, we found that rostral Žpregenual. AGm projects to the dorsocentral region of the caudatoputamen w32x. However, the striatal projections of more caudal portions of AGm have not been described sytematically. Berendse et al. w5x confirmed the dorsocentral location of projections from AGm to the caudatoputamen, and noted that caudal Žsupragenual. AGm projected more dorsally and caudally to the striatum than rostral AGm. However, this topography was not presented in any detail. Thalamic afferents to AGm were reported to be topographically organized w18x but no information has been available concerning corticothalamic projections. Therefore, in the present study, we examined the topography of the striatal and thalamic connections of AGm throughout its mediolateral and rostrocaudal extent. Because AGm is narrow in the mediolateral dimension and elongated in the rostrocaudal dimension, we hypothesized that there was rostrocaudal topography in these subcortical connections, as had been found for its corticocortical connections w34x. This seemed particularly likely because of the functional heterogeneity of AGm along the rostrocaudal dimension, as outlined above.
tion, and the two neighboring series were processed for autoradiography or fluorescence. From the cresyl violet stained sections, drawings were traced using a macroprojector. Cortical, striatal and thalamic boundaries were identified, as were landmarks such as blood vessels. The locations of cortical injection sites were determined in each brain by mapping the boundaries of area AGm and surrounding cortical areas, using the Nissl stained series of sections and according to cytoarchitectural criteria previously reported w30,34x. The terms AGm and AGl are synonymous with areas Fr2 and Fr1 w47x, respectively. Thalamic nuclei were identified and demarcated according to the criteria and maps of Jones w19x and Paxinos and Watson w28x. An Olympus BH-2 microscope was used in darkfield mode for viewing autoradiographic silver grain labeling, and in epifluorescence mode for visualizing fluorescent labeled somata, axons and terminal fields. The distributions of labeled profiles of interest were plotted on drawings made from the corresponding adjacent Nissl stained sections. Within the caudatoputamen, labeling associated with axon bundles was distinguished in autoradiographic material as tightly packed groups of silver grains overlying white matter bundles, the latter visible when viewing the cresyl violet stained sections with brightfield illumination. Terminal field labeling appeared as more uniformly scattered grains overlying gray matter zones rather than bundles of white matter. In fluororuby material, axonal and terminal field labeling were readily distinguished by the threadlike appearance of the former and the fine granular appearance of the latter.
3. Results 2. Materials and methods
3.1. Projections from AGm to the caudatoputamen
A total of 21 albino and hooded rats was used for analysis in this study. All animal procedures were done according to institutional protocols that meet or exceed NIH and Society for Neuroscience guidelines. Each rat received one injection of an axonal tracer into the cerebral cortex, using procedures and stereotaxic coordinates derived from our previous work w29,30,32–34x. Briefly, for the study of striatal projections, small deposits of 3 H leucine–proline ŽNew England Nuclear or ICN. or 10% fluororuby ŽMolecular Probes. were made using pressure injections through micropipettes. For the simultaneous examination of thalamic afferents and efferents, fluororuby or a mixture of fluorogold ŽFluorochrome. and 3 H leucine–proline was injected into AGm. For each brain, serial coronal sections were cut at 40 mm on a freezing microtome and collected in six parallel rostrocaudal series; thus, adjacent sections in each series were spaced at 240 mm intervals. One series was stained with cresyl violet and used for cytoarchitectural orienta-
3.1.1. Rostrocaudal topography The three cases presented in Fig. 1 illustrate the rostrocaudal topography exhibited as injections of fluororuby are located at successively more caudal levels in AGm. In case 98-1, the fluororuby injection was located in rostral AGm and resulted in labeling that was dense and widespread in the rostral caudatoputamen ŽCP. ŽFig. 1A–B., becoming confined to dorsocentral CP by the level of the crossing of the anterior commissure ŽFig. 1C.. The more caudally located injection of case 98-2 resulted in a diminution in the extent and density of rostral CP labeling ŽFig. 1D. and extension of labeling into caudal CP, where it was largely confined to the lateral border of CP adjacent to the external capsule ŽFig. 1F.. Injections in far caudal AGm produced a continuation of this pattern, with light labeling in rostral CP ŽFig. 1G., a sharp reduction in dorsocentral labeling around the level of the crossing of the anterior commissure ŽFig. 1H., and moderate labeling along the border of the external capsule ŽFig. 1I.. Cases AGm 29, 30
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Fig. 1. Anterograde striatal labeling resulting from injections of fluororuby at three different rostrocaudal levels of AGm. In this and subsequent figures, insets show the centers of injection sites, and arrowheads denote boundaries of AGm. Panels A–C represent labeling in case 98-1; D–F are from case 98-2; G–I are from case 98-3. Lines represent labeled axons, dots represent terminal profiles. ŽGP — globus pallidus, ic — internal capsule..
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Fig. 2. Mediolateral topography of corticostriatal projections. Results from three cases with injections of 3 H leucine–proline in rostral AGm have been combined in this schematic representation. The medial injection of case 83077 was located at the border of rostral AGm and anterior cingulate cortex; resultant striatal labeling is indicated by darker shading. In case 83058, the injection was centrally located; striatal labeling is represented by dots. The injection of case 84003 affected lateral agranular cortex and the far lateral portion of rostral AGm; striatal labeling is shown by lighter shading.
and 43 Žnot illustrated., had injections of 3 H leucine–proline located at locations virtually identical to those above, and produced similar patterns of labeling. In the rostral case AGm 29, terminal field labeling extends from the head of the CP to the level of the postcommisural fornix, and is densest in dorsocentral CP from the level of the genu to the septal nuclei. In case AGm 30, the injection is located in post-genual AGm and the dense focus of labeling in dorsocentral CP seen with rostral injections is replaced by more diffuse labeling located closer to the external capsule. The far caudal injection of case AGm 43 also produced less dense labeling than in case AGm 29, as well as a further shift of labeling caudally and dorsally.
3.1.2. Mediolateral topography Cases 83077, 83058 and 84003 ŽFig. 2. illustrate the mediolateral topography and bilaterality seen in the projections of AGm and neighboring cortical areas to the CP, as assessed after injections of 3 H leucine–proline. These cortical injections are located at comparable levels of rAGm but at different mediolateral positions. In all three cases, heavy to moderate terminal field labeling extends from the head of the CP caudally to the level of the crossing of the anterior commissure, and is much less dense caudal to this level. There is substantial overlap among these terminal fields in rostral CP ŽFig. 2A., but a distinct mediolateral topography emerges more caudally ŽFig. 2B–C.. Case
Fig. 3. Anterograde and retrograde labeling in the thalamus in resulting from injections of 3 H leucine–proline at three different rostrocaudal levels of AGm. Large dots denote neuron somata retrogradely labeled with fluorogold; small dots represent terminal field labeling associated with autoradiographic silver grains. Other conventions as in Fig. 1. ŽCL — central lateral nucleus, CM — central medial nucleus, fr — fasciculus retroflexus, LD — laterodorsal nucleus, LHb — lateral habenular nucleus, LP — lateral posterior nucleus, MD — mediodorsal nucleus, mt — mammillothalamic tract, PC — paracentral nucleus, PF — parafascicular nucleus, Po — posterior nucleus, PV — paraventricular nucleus, Rh — rhomboid nucleus, Sm — submedial nucleus, sm — stria medullaris, VL — ventrolateral nucleus, VM — ventromedial nucleus, VPL–VPM — ventral posterolateralq posteromedial nuclei..
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83058, in which the injection was centrally located within AGm, resulted in labeling concentrated in the dorsocentral CP. The medial injection of case 83077 produced axonal
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labeling and terminal field labeling focused in the dorsomedial CP, whereas the lateral injection of case 84003 resulted in dense labeling focused more laterally and ven-
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Fig. 4. Anterograde and retrograde thalamic labeling resulting from injections of fluororuby at three rostrocaudal levels of AGm. Injection sites are the same as those illustrated in Fig. 1. Conventions as in Fig. 1.
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Fig. 5. Rostrocaudal topography of thalamic connections with area AGm, summarized schematically. Shading represents qualitative variations in extent and density of cells of origin and terminal fields. Note the changes in pattern which occur at the levels of the genu and the crossing of the anterior commissure.
trally in the CP. Although there is some overlap in the distribution of labeling among these three cases, particularly rostrally, the densest zones of labeling appear to be topographically distinct. In each of these cases, labeling in contralateral CP is identical in location, but less dense than, ipsilateral labeling. 3.2. Topography of thalamic connections Cases AGm 44, 42 and 43 ŽFig. 3. represent combined injections of fluorogold and 3 H leucine–proline which were made at three different rostrocaudal levels of AGm. In each case, the distributions of retrograde and anterograde labeling are largely overlapping, indicating that thalamic afferents and efferents involve the same nuclei. Three regions of the thalamus were labeled in all cases. For rostral injections like that of case AGm 44 ŽFig. 3A–C., labeling was heavy in the first region, which includes the lateral segment of the mediodorsal nucleus ŽMDl. and the adjacent central lateral ŽCL. and paracentral ŽPC. nuclei. As this patch of labeling is followed caudally, it also includes the medial portion of the lateral posterior nucleus ŽLP.. The second region of labeling involves a strip in the central region of the ventral lateral nucleus ŽVL. which continues medially into the central medial and rhomboid nuclei. The third region of labeling is seen in the rostral portion of the ventromedial nucleus ŽVM.. Injections centered in mid-AGm Žbetween the level of the genu and the crossing of the anterior commissure., like that of case AGm 42, result in much less labeling in MDl ŽFig. 3D–F.. The second region of labeling in VL continues caudally into a dense patch in the posterior nucleus ŽPo.. There is only sparse labeling in VM. Injections in caudal AGm, like that of case AGm 43, produce labeling shifted even farther laterally and caudally. There is an emphasis on far lateral VL, LP, Po, and the lateral dorsal nucleus ŽLD., and no involvement of VM ŽFig. 3G–I..
The results obtained with injections of fluororuby produced patterns similar to those described above. In case 98-1, the injection site was located in rostral AGm at a level comparable to that of case AGm 44, and produced a nearly identical pattern of thalamic labeling involving the regions of MDl, PC and CL; VL, CM and Rh; and VM ŽFig. 4A–C.. Cases 98-2 and 98-3 illustrate the progressive emphasis on more caudal and lateral thalamic labeling as injection sites are located more caudally within AGm. Case 98-2 exhibits more labeling in MDl ŽFig. 4D–F. than does case AGm 42, but this is likely due to its more rostrally located injection site. Case 98-3 produced thalamic labeling comparable to that of case AGm 43 ŽFig. 4G–I.. Fig. 5 summarizes the overall pattern of thalamic connections.
4. Discussion The present study has delineated the topographic pattern of striatal and thalamic connections of AGm. This new information can be used to more precisely guide experimental behavioral and pharmacological studies aimed at understanding its functional role, particularly with regard to the dorsocentral striatum. 4.1. Corticostriatal topography We found that striatal projections from AGm are arranged along rostrocaudal and mediolateral gradients, which correspond to the positions of the cell bodies of origin within AGm and adjacent cortical areas. Furthermore, striatal projections from rostral AGm are denser and more widespread than projections from caudal AGm. Several previous studies also bear on the issue of topographic organization in the corticostriatal projections of rats. Using
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autoradiographic analysis of anterograde axonal transport, Beckstead w2x confirmed the suggestion of earlier axon degeneration studies that frontal cortical areas project to separate longitudinal sectors of the striatum, and that the organization follows dorsoventral and mediolateral gradients. He also found that more ventrally located frontal cortical areas project to the ventral striatum in addition to the caudatoputamen. However, Beckstead did not present cases having injections in AGm. More recently, Berendse et al. w5x used anterograde transport of Phaseolus Õulgaris to map in detail the topography of the striatal projections of nine contiguous prefrontal areas, including the medial agranular cortex. They described the organization as consisting of largely separate but partially overlapping longitudinal terminal fields, with medial cortical areas projecting to rostral and medial portions of the striatum and lateral cortical areas projecting to more caudal and lateral striatal territories. For both the medial and lateral prefrontal fields, they found that a ventral to dorsal cortical gradient corresponded to a ventromedial to dorsolateral gradient in the striatum. Our results for the corticostriatal projections from AGm support the longitudinal organization described in earlier studies, but indicate a second level of topographical organization. This is manifested within the longitudinal striatal territory to which AGm projects as a continuous gradient whereby successively more caudal portions of AGm project most densely to successively more caudal portions of this striatal territory. Our finding of a mediolateral gradient associated with the corticostriatal projections of AGm is consistent with the results of earlier reports. The dorsocentral portion of the head of the caudatoputamen, the location of the densest striatal projections from AGm, is flanked medially and laterally by corticostriatal projections from the anterior cingulate and lateral agranular cortices, which lie medially and laterally adjacent to AGm, respectively. Anterior cingulate cortex projects to the far medial portion of the head of the caudatoputamen w2,5x, whereas cortex at the boundary of AGm and cingulate cortex projects slightly more laterally ŽSesack et al. w37x; their case P391.. Striatal projections from the lateral agranular cortex are located in the lateral half of the striatum, as found in the present study and in earlier reports w11,13,25x. Furthermore, they are topographically arranged in accordance with the representation of the body in motor cortex Žw13x; McGeorge and Faull w25x; their cases CP 184 and CP 173.. Corticostriatal projections from AGm appear to overlap those of posterior parietal cortex in the portion of the dorsocentral caudatoputamen around the level of the anterior commissure Žw30x, see their Fig. 2B–D.. Because the posterior parietal area is also involved in directed attention and spatial processing w7x, this raises the possibility that the dorsocentral caudatoputamen represents a nodal point for cortical circuitry related to these functions, analogous to the proposal made by Selemon and Goldman-Rakic w38x for primates. However, the extent of convergence in rats
needs to be examined more closely using double anterograde tracing in single brains. 4.2. Thalamic topography We found that the thalamic connections of AGm are organized in a continuous gradient whereby more caudal portions of AGm have connections with progressively more lateral and caudal regions of the thalamus. At all rostrocaudal locations within AGm, the distribution of cells of origin for the thalamocortical projections to AGm is largely coextensive with the terminal fields of corticothalamic projections from AGm. The continuous rostrocaudal topography we have described for the thalamic connections of AGm is supported by the collective findings of earlier studies. Reciprocal connections of rAGm with lateral MD, CM, CL, PC, VL, VM and Po were reported by Reep et al. w31,32x. Sukekawa w41x found that caudal AGm has reciprocal thalamic connections with lateral MD, CL, LD, LP and Po, and Takahashi w42x had earlier reported labeling in LD and LP following injections of anterograde tracer in far caudal AGm and PPC. Hicks and Huerta w18x noted a difference in the thalamic connections of rAGm and cAGm, but described it as a pattern of common thalamic inputs featuring lateral MD, CL, VL, VM and Po, with cAGm having additional input from LD and LP, rather than as a continuous gradient. The progressive change we have noted throughout AGm continues into the caudally adjacent posterior parietal area, which has thalamic connections with LD, LP and Po, but not with VL w30x. Specific cortical areas, basal ganglia regions and thalamic nuclei are interconnected, forming a set of segregated, parallel circuits w1,15x. A dorsal anterior cingulate circuit related to the lateral segment of the mediodorsal nucleus and its associated cortical–striatal–pallidal interconnections was identified by Groenewegen et al. w15x, and this may be considered to include AGm as well. In agreement with Berendse and Groenewegen w4x, we have found that the thalamic connections of AGm heavily involve the central lateral and paracentral intralaminar nuclei. These nuclei also project densely to the dorsocentral portion of the striatum where corticostriatal projections from AGm terminate w3,46x. 4.3. Functional considerations Studies of recovery from neglect induced by lesions of AGm indicate that the dorsolateral quadrant of striatum, including much of the region we have referred to as the dorsocentral striatum, undergoes dynamic changes that are correlated with behavioral recovery. Following unilateral lesions of the entire AGm, Vargo and Marshall w44x found that severe neglect was correlated with a 40% decrease in dopamine agonist-induced immediate early gene expression Žc-fos . in the ipsilesional vs. contralesional dorsolat-
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eral striatum. A return to symmetrical levels of c-fos expression was correlated with spontaneous behavioral recovery from neglect over the course of 3 weeks. In addition, widespread striatal glutamatergic blockade produces severe multimodal neglect w36x, and animals with severe neglect exhibit significant decreases in NMDA and kainate receptors in ipsilesional dorsolateral quadrant of the ipsilesional striatum w45x. In recovered animals, there is a 10% increase in NMDA receptors, and a return to normal levels of kainate receptors in the dorsolateral quadrant w45x. These findings suggest that the dorsocentral striatum is a focus for interactions among glutamatergic and dopaminergic systems involved in neglect and recovery associated with unilateral lesions of AGm. The present study has identified specific striatal and thalamic regions associated with rAGm and cAGm, and it provides an anatomical basis upon which to test functional hypotheses and interpret data concerning the functional roles of these cortical, striatal and thalamic regions in directed attention, lesion-induced neglect, and behavioral recovery from neglect.
Acknowledgements We appreciate the technical assistance of Maggie Stoll, and commentary by Karen Burcham and Tom Van Vleet on earlier drafts of the manuscript. Supported by the University of Florida College of Veterinary Medicine and the Maxwell Fund. College of Veterinary Medicine Journal Series Number 540.
References w1x G.E. Alexander, M.D. Crutcher, M.R. DeLong, Basal ganglia– thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions, in: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner, M.G.P. Feenstra ŽEds.., The Prefrontal Cortex: Its Structure, Function, and Pathology, Elsevier, Amsterdam, 1990, pp. 119–146 ŽProg. Brain Res. 85, 119–146.. w2x R.M. Beckstead, An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection Žprefrontal. cortex in the rat, J. Comp. Neurol. 184 Ž1979. 43–62. w3x H.W. Berendse, H.J. Groenewegen, Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum, J. Comp. Neurol. 299 Ž1990. 187–228. w4x H.W. Berendse, H.J. Groenewegen, Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat, Neuroscience 42 Ž1991. 73–102. w5x H.W. Berendse, Y. Galis-DeGraaf, H.J. Groenewegen, Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat, J. Comp. Neurol. 316 Ž1992. 314–347. w6x K. Burcham, J.V. Corwin, M. Stoll, R.L. Reep, Disconnection of medial agranular and posterior parietal cortex produces multimodal neglect in rats, Behav. Brain Res. 86 Ž1997. 41–47. w7x J.V. Corwin, R.L. Reep, Rodent posterior parietal cortex as a component of a cortical network mediating directed spatial attention, Psychobiology 26 Ž1998. 87–102.
51
w8x J.V. Corwin, S. Kanter, R.T. Watson, K.M. Heilman, E. Valenstein, A. Hashimoto, Apomorphine has a therapeutic effect on neglect produced by unilateral dorsomedial prefrontal cortex lesions in rats, Exp. Neurol. 94 Ž1986. 683–698. w9x J.V. Corwin, K.J. Burcham, G.I. Hix, Apomorphine produces an acute dose-dependent therapeutic effect on neglect produced by unilateral destruction of the posterior parietal cortex in rats, Behav. Brain Res. 79 Ž1996. 41–49. w10x D.P. Crowne, M.N. Pathria, Some attentional effects of unilateral frontal lesions in the rat, Behav. Brain Res. 6 Ž1982. 25–39. w11x J.P. Donoghue, M. Herkenham, Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat, Brain Res. 365 Ž1986. 397–403. w12x J.P. Donoghue, S.P. Wise, The motor cortex of the rat: cytoarchitecture and microstimulation mapping, J. Comp. Neurol. 212 Ž1982. 76–88. w13x R.L.M. Faull, The organization of corticostriate projections from the motor cortex in the rat, Neurosci. Lett. Suppl. 8 Ž1982. S47. w14x Y. Gioanni, M. Lamarche, A reappraisal of rat motor cortex organization by intracortical microstimulation, Brain Res. 344 Ž1985. 49–61. w15x H.J. Groenewegen, H.W. Berendse, J.G. Wolters, A.H.M. Lohman, The anatomical relationship of prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization, in: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner, M.G.P. Feenstra ŽEds.., The Prefrontal Cortex: Its Structure, Function, and Pathology Elsevier, Amsterdam, 1990, pp. 95–118 ŽProg. Brain Res. 85, 95–118.. w16x R.D. Hall, E.P. Lindholm, Organization of motor and somatosensory neocortex in the albino rat, Brain Res. 66 Ž1974. 23–38. w17x K.M. Heilman, R.T. Watson, E. Valenstein, Neglect and related disorders, in: K.M. Heilman, E. Valenstein ŽEds.., Clinical Neuropsychology, 3rd edn., Oxford Univ. Press, New York, 1993, pp. 279–336. w18x R.R. Hicks, M.F. Huerta, Differential thalamic connectivity of rostral and caudal parts of area Fr2 in rats, Brain Res. 568 Ž1991. 325–329. w19x E.G. Jones, The Thalamus, Plenum, New York, 1985, 935 pp. w20x R.P. Kesner, G. Farnsworth, B.V. DiMattia, Double dissociation of egocentric and allocentric space following prefrontal and parietal cortex lesions in the rat, Behav. Neurosci. 103 Ž1989. 956–961. w21x V. King, J.V. Corwin, Neglect following unilateral ablation of the caudal but not the rostral portion of medial agranular cortex of the rat and the therapeutic effect of apomorphine, Behav. Brain Res. 37 Ž1990. 169–184. w22x V. King, J.V. Corwin, Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex, Behav. Brain Res. 143 Ž1992. 237–242. w23x G.R. Leichnetz, A. Gonzalo-Ruiz, Collateralization of frontal eye field Žmedial precentralranterior cingulate. neurons projecting to the paraoculomotor region, superior colliculus, and medial pontine reticular formation in the rat: a fluorescent double-labeling study, Exp. Brain Res. 68 Ž1987. 355–364. w24x G.R. Leichnetz, S.G.P. Hardy, M.K. Carruth, Frontal projections to the region of the oculomotor complex in the rat: a retrograde and anterograde HRP study, J. Comp. Neurol. 263 Ž1987. 387–399. w25x A.J. McGeorge, R.L.M. Faull, The organization of the projection from the cerebral cortex to the striatum in the rat, Neurosci. 29 Ž1989. 503–537. w26x M.W. Miller, The origin of corticospinal projection neurons in rat, Exp. Brain Res. 67 Ž1987. 339–351. w27x E.J. Neafsey, E.L. Bold, G. Haas, K.M. Hurley-Guis, G. Quirk, C.R. Sievert, R.R. Terreberry, The organization of the rat motor cortex: a microstimulation mapping study, Brain Res. Rev. 11 Ž1986. 77–96. w28x G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, 2nd edn., Academic Press, Sydney, 1986, 263 pp.
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w29x R.L. Reep, M.J. Baccala, M.P. Booth, G.S. Goodwin, Combined retrograde and anterograde tracing of neuronal connections: fluorogold and autoradiography, J. Neurosci. Methods 23 Ž1988. 1–5. w30x R.L. Reep, H.C. Chandler, V. King, J.V. Corwin, Rat posterior parietal ortex: topography of corticocortical and thalamic connections, Exp. Brain Res. 100 Ž1994. 67–84. w31x R.L. Reep, J.V. Corwin, A. Hashimoto, R.T. Watson, Afferent connections of medial precentral cortex in the rat, Neurosci. Lett. 44 Ž1984. 247–252. w32x R.L. Reep, J.V. Corwin, A. Hashimoto, R.T. Watson, Efferent connections of the rostral portion of medial agranular cortex in rats, Brain Res. Bull. 19 Ž1987. 203–221. w33x R.L. Reep, J.V. Corwin, V. King, Neuronal connections of orbital cortex in rats: topography of cortical and thalamic afferents, Exp. Brain Res. 111 Ž1996. 215–232. w34x R.L. Reep, G.S. Goodwin, J.V. Corwin, Topographic organization in the corticocortical connections of medial agranular cortex in rats, J. Comp. Neurol. 294 Ž1990. 262–280. w35x K.J. Sanderson, W. Welker, G.M. Shambes, Reevaluation of motor cortex and of sensorimotor overlap in cerebral cortex of albino rats, Brain Res. 292 Ž1984. 251–260. w36x J.J. Schuller, D.D.Q. Tran, J.F. Marshall, Striatal glutamate antagonism induces contralateral neglect, Brain Res. 788 Ž1998. 315–319. w37x S.R. Sesack, A.Y. Deutch, R.H. Roth, B.S. Bunney, Topographical organization of the efferent projections of medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus Õulgaris leucoagglutinin, J. Comp. Neurol. 290 Ž1989. 213–242. w38x L.D. Selemon, P.S. Goldman-Rakic, Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network
w39x
w40x
w41x
w42x w43x
w44x
w45x
w46x
w47x
subserving spatially guided behavior, J. Neurosci. 8 Ž1988. 4049– 4068. H.M. Sinnamon, B.S. Galer, Head movements elicited by electrical stimulation of the anteromedial cortex of the rat, Physiol. Behav. 33 Ž1984. 185–190. S.L. Stuesse, D.B. Newman, Projections from the medial agranular cortex to brain stem visuomotor centers in rats, Exp. Brain Res. 80 Ž1990. 532–544. K. Sukekawa, Reciprocal connections between medial prefrontal cortex and lateral posterior nucleus in rats, Brain Behav. Evol. 32 Ž1988. 246–251. T. Takahashi, The organization of the lateral thalamus of the hooded rat, J. Comp. Neurol. 231 Ž1985. 281–309. T.M. Van Vleet, J.V. Corwin, K.J. Burcham, R.L. Reep, Unilateral lesions of dorsal central striatum produce multimodal neglect in rats, Soc. Neurosci. Abstr. 23 Ž1997. 1839. J.M. Vargo, J.F. Marshall, Time-dependent changes in dopamine agonist-induced striatal fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefrontal cortex injury, Synapse 20 Ž1995. 305–315. J.M. Vargo, J.F. Marshall, Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors, Behav. Brain Res. 77 Ž1996. 189–199. J.G. Veening, F.M. Cornelissen, P.A.J.M. Lieven, The topical organization of the afferents to the caudatoputamen of the rat: a horseradish peroxidase study, Neuroscience 5 Ž1980. 1253–1268. K. Zilles, A. Wree, Cortex: areal and laminar structure, in: G. Paxinos ŽEd.., The Rat Nervous System: Forebrain and Midbrain, Vol. 1, Academic Press, Sydney, 1985, pp. 375–415.
Research report
Topographic organization of the striatal and thalamic connections of rat medial agranular cortex R.L. Reep a
a, )
, J.V. Corwin
b
Department of Physiological Sciences and Brain Institute, UniÕersity of Florida, GainesÕille, FL 32610, USA b Department of Psychology, Northern Illinois UniÕersity, De Kalb, IL, USA Accepted 22 June 1999
Abstract The rostral and caudal portions of rat medial agranular cortex ŽAGm. play different functional roles. To refine the anatomical framework for understanding these differences, axonal tracers were used to map the topography of the connections of AGm with the striatum and thalamus. The striatal projections follow mediolateral and rostrocaudal gradients that correspond to the locations of the neurons of origin within AGm. Projections from rostral AGm are widespread and dense rostrally, then coalesce into a circumscribed dorsocentral region at the level of the pre-commissural septal nuclei. Projections from mid and caudal AGm are less widespread and less dense, and are focused more caudally. Striatal projections from the adjacent anterior cingulate and lateral agranular areas overlap those of AGm but are concentrated more medially and laterally, respectively. Thalamic connections of AGm are organized so that more caudal portions of AGm have connections with progressively more lateral and caudal regions of the thalamus, and the full extent of AGm is connected with the ventrolateral ŽVL. nucleus. Rostral AGm is interconnected with the lateral portion of the mediodorsal nucleus ŽMDl., VL, and the central lateral ŽCL., paracentral ŽPC., central medial, rhomboid and ventromedial nuclei. Caudal AGm has robust connections with VL, the posterior, lateral posterior and lateral dorsal nuclei, but little or none with MDl, CLrPC and VM. These differences in the subcortical connections of rostral and caudal AGm parallel their known differences in corticocortical connections, and represent another basis for experimental explorations of the functional roles of these cortical territories. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Cerebral cortex; Striatum; Thalamus; Connection; Medial agranular
1. Introduction Recent studies have pointed to medial agranular cortex ŽAGm. as one component of a cortical–subcortical network subserving directed spatial attention in rats, and have shown that the rostral ŽrAGm. and caudal ŽcAGm. portions of AGm play differing functional roles w6,7x. Anatomical and microstimulation findings w12,14,16,27,31,32, 34,35x suggest that AGm may represent the homolog of primate area 8, which also plays a pivotal role in spatial processing and directed attention w17x. Unilateral lesions of AGm result in severe multimodal neglect of visual, auditory, and tactile stimuli that is qualitatively similar to
) Corresponding author. Department of Physiological Sciences, Box 100144, HSC, University of Florida, Gainsville, FL 32610, USA. Fax: q1-352-392-5145; E-mail: [email protected]
neglect in primates w8,10x. Whereas small unilateral lesions of cAGm result in severe multimodal neglect, larger rAGm lesions produce allesthesiarallokinesia in which the animal demonstrates inappropriate contralateral orientations to stimulation w21x. Bilateral lesions of AGm produce deficits in egocentric spatial processing w20,22x. The functional distinctions between rAGm and cAGm are reflected in their distinct but partially overlapping patterns of connections with cortex w34x, thalamus w18x, brainstem w23,24,40x and spinal cord w12,26x. In addition, rAGm is selectively involved in head orientation movements w39x. The dorsocentral striatum, the major site of corticostriatal projections from rAGm w32x, appears to play a pivotal role in directed attention and recovery of function from lesion-induced attentional disorders. Axon-sparing lesions of the dorsocentral striatum produce severe multimodal neglect of stimuli presented contralesionally, whereas lesions placed more laterally and ventrally do not w43x. The dopamine agonist apomorphine, which induces acute re-
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 7 7 9 - 5
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covery in animals with severe neglect produced by cortical lesions w8,9,21x, does not result in recovery when administered to animals with lesions of the dorsocentral striatum w43x. This finding suggests that the dorsocentral striatum may be the site of action for drug-induced recovery from neglect. In view of the crucial role of the striatum in the dynamics of directed attention, neglect, and behavioral recovery from neglect, and the different functional roles of rAGm and cAGm, it is important to understand the topography of the projections from AGm to the striatum. In an earlier anatomical study, we found that rostral Žpregenual. AGm projects to the dorsocentral region of the caudatoputamen w32x. However, the striatal projections of more caudal portions of AGm have not been described sytematically. Berendse et al. w5x confirmed the dorsocentral location of projections from AGm to the caudatoputamen, and noted that caudal Žsupragenual. AGm projected more dorsally and caudally to the striatum than rostral AGm. However, this topography was not presented in any detail. Thalamic afferents to AGm were reported to be topographically organized w18x but no information has been available concerning corticothalamic projections. Therefore, in the present study, we examined the topography of the striatal and thalamic connections of AGm throughout its mediolateral and rostrocaudal extent. Because AGm is narrow in the mediolateral dimension and elongated in the rostrocaudal dimension, we hypothesized that there was rostrocaudal topography in these subcortical connections, as had been found for its corticocortical connections w34x. This seemed particularly likely because of the functional heterogeneity of AGm along the rostrocaudal dimension, as outlined above.
tion, and the two neighboring series were processed for autoradiography or fluorescence. From the cresyl violet stained sections, drawings were traced using a macroprojector. Cortical, striatal and thalamic boundaries were identified, as were landmarks such as blood vessels. The locations of cortical injection sites were determined in each brain by mapping the boundaries of area AGm and surrounding cortical areas, using the Nissl stained series of sections and according to cytoarchitectural criteria previously reported w30,34x. The terms AGm and AGl are synonymous with areas Fr2 and Fr1 w47x, respectively. Thalamic nuclei were identified and demarcated according to the criteria and maps of Jones w19x and Paxinos and Watson w28x. An Olympus BH-2 microscope was used in darkfield mode for viewing autoradiographic silver grain labeling, and in epifluorescence mode for visualizing fluorescent labeled somata, axons and terminal fields. The distributions of labeled profiles of interest were plotted on drawings made from the corresponding adjacent Nissl stained sections. Within the caudatoputamen, labeling associated with axon bundles was distinguished in autoradiographic material as tightly packed groups of silver grains overlying white matter bundles, the latter visible when viewing the cresyl violet stained sections with brightfield illumination. Terminal field labeling appeared as more uniformly scattered grains overlying gray matter zones rather than bundles of white matter. In fluororuby material, axonal and terminal field labeling were readily distinguished by the threadlike appearance of the former and the fine granular appearance of the latter.
3. Results 2. Materials and methods
3.1. Projections from AGm to the caudatoputamen
A total of 21 albino and hooded rats was used for analysis in this study. All animal procedures were done according to institutional protocols that meet or exceed NIH and Society for Neuroscience guidelines. Each rat received one injection of an axonal tracer into the cerebral cortex, using procedures and stereotaxic coordinates derived from our previous work w29,30,32–34x. Briefly, for the study of striatal projections, small deposits of 3 H leucine–proline ŽNew England Nuclear or ICN. or 10% fluororuby ŽMolecular Probes. were made using pressure injections through micropipettes. For the simultaneous examination of thalamic afferents and efferents, fluororuby or a mixture of fluorogold ŽFluorochrome. and 3 H leucine–proline was injected into AGm. For each brain, serial coronal sections were cut at 40 mm on a freezing microtome and collected in six parallel rostrocaudal series; thus, adjacent sections in each series were spaced at 240 mm intervals. One series was stained with cresyl violet and used for cytoarchitectural orienta-
3.1.1. Rostrocaudal topography The three cases presented in Fig. 1 illustrate the rostrocaudal topography exhibited as injections of fluororuby are located at successively more caudal levels in AGm. In case 98-1, the fluororuby injection was located in rostral AGm and resulted in labeling that was dense and widespread in the rostral caudatoputamen ŽCP. ŽFig. 1A–B., becoming confined to dorsocentral CP by the level of the crossing of the anterior commissure ŽFig. 1C.. The more caudally located injection of case 98-2 resulted in a diminution in the extent and density of rostral CP labeling ŽFig. 1D. and extension of labeling into caudal CP, where it was largely confined to the lateral border of CP adjacent to the external capsule ŽFig. 1F.. Injections in far caudal AGm produced a continuation of this pattern, with light labeling in rostral CP ŽFig. 1G., a sharp reduction in dorsocentral labeling around the level of the crossing of the anterior commissure ŽFig. 1H., and moderate labeling along the border of the external capsule ŽFig. 1I.. Cases AGm 29, 30
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Fig. 1. Anterograde striatal labeling resulting from injections of fluororuby at three different rostrocaudal levels of AGm. In this and subsequent figures, insets show the centers of injection sites, and arrowheads denote boundaries of AGm. Panels A–C represent labeling in case 98-1; D–F are from case 98-2; G–I are from case 98-3. Lines represent labeled axons, dots represent terminal profiles. ŽGP — globus pallidus, ic — internal capsule..
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Fig. 2. Mediolateral topography of corticostriatal projections. Results from three cases with injections of 3 H leucine–proline in rostral AGm have been combined in this schematic representation. The medial injection of case 83077 was located at the border of rostral AGm and anterior cingulate cortex; resultant striatal labeling is indicated by darker shading. In case 83058, the injection was centrally located; striatal labeling is represented by dots. The injection of case 84003 affected lateral agranular cortex and the far lateral portion of rostral AGm; striatal labeling is shown by lighter shading.
and 43 Žnot illustrated., had injections of 3 H leucine–proline located at locations virtually identical to those above, and produced similar patterns of labeling. In the rostral case AGm 29, terminal field labeling extends from the head of the CP to the level of the postcommisural fornix, and is densest in dorsocentral CP from the level of the genu to the septal nuclei. In case AGm 30, the injection is located in post-genual AGm and the dense focus of labeling in dorsocentral CP seen with rostral injections is replaced by more diffuse labeling located closer to the external capsule. The far caudal injection of case AGm 43 also produced less dense labeling than in case AGm 29, as well as a further shift of labeling caudally and dorsally.
3.1.2. Mediolateral topography Cases 83077, 83058 and 84003 ŽFig. 2. illustrate the mediolateral topography and bilaterality seen in the projections of AGm and neighboring cortical areas to the CP, as assessed after injections of 3 H leucine–proline. These cortical injections are located at comparable levels of rAGm but at different mediolateral positions. In all three cases, heavy to moderate terminal field labeling extends from the head of the CP caudally to the level of the crossing of the anterior commissure, and is much less dense caudal to this level. There is substantial overlap among these terminal fields in rostral CP ŽFig. 2A., but a distinct mediolateral topography emerges more caudally ŽFig. 2B–C.. Case
Fig. 3. Anterograde and retrograde labeling in the thalamus in resulting from injections of 3 H leucine–proline at three different rostrocaudal levels of AGm. Large dots denote neuron somata retrogradely labeled with fluorogold; small dots represent terminal field labeling associated with autoradiographic silver grains. Other conventions as in Fig. 1. ŽCL — central lateral nucleus, CM — central medial nucleus, fr — fasciculus retroflexus, LD — laterodorsal nucleus, LHb — lateral habenular nucleus, LP — lateral posterior nucleus, MD — mediodorsal nucleus, mt — mammillothalamic tract, PC — paracentral nucleus, PF — parafascicular nucleus, Po — posterior nucleus, PV — paraventricular nucleus, Rh — rhomboid nucleus, Sm — submedial nucleus, sm — stria medullaris, VL — ventrolateral nucleus, VM — ventromedial nucleus, VPL–VPM — ventral posterolateralq posteromedial nuclei..
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83058, in which the injection was centrally located within AGm, resulted in labeling concentrated in the dorsocentral CP. The medial injection of case 83077 produced axonal
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labeling and terminal field labeling focused in the dorsomedial CP, whereas the lateral injection of case 84003 resulted in dense labeling focused more laterally and ven-
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Fig. 4. Anterograde and retrograde thalamic labeling resulting from injections of fluororuby at three rostrocaudal levels of AGm. Injection sites are the same as those illustrated in Fig. 1. Conventions as in Fig. 1.
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Fig. 5. Rostrocaudal topography of thalamic connections with area AGm, summarized schematically. Shading represents qualitative variations in extent and density of cells of origin and terminal fields. Note the changes in pattern which occur at the levels of the genu and the crossing of the anterior commissure.
trally in the CP. Although there is some overlap in the distribution of labeling among these three cases, particularly rostrally, the densest zones of labeling appear to be topographically distinct. In each of these cases, labeling in contralateral CP is identical in location, but less dense than, ipsilateral labeling. 3.2. Topography of thalamic connections Cases AGm 44, 42 and 43 ŽFig. 3. represent combined injections of fluorogold and 3 H leucine–proline which were made at three different rostrocaudal levels of AGm. In each case, the distributions of retrograde and anterograde labeling are largely overlapping, indicating that thalamic afferents and efferents involve the same nuclei. Three regions of the thalamus were labeled in all cases. For rostral injections like that of case AGm 44 ŽFig. 3A–C., labeling was heavy in the first region, which includes the lateral segment of the mediodorsal nucleus ŽMDl. and the adjacent central lateral ŽCL. and paracentral ŽPC. nuclei. As this patch of labeling is followed caudally, it also includes the medial portion of the lateral posterior nucleus ŽLP.. The second region of labeling involves a strip in the central region of the ventral lateral nucleus ŽVL. which continues medially into the central medial and rhomboid nuclei. The third region of labeling is seen in the rostral portion of the ventromedial nucleus ŽVM.. Injections centered in mid-AGm Žbetween the level of the genu and the crossing of the anterior commissure., like that of case AGm 42, result in much less labeling in MDl ŽFig. 3D–F.. The second region of labeling in VL continues caudally into a dense patch in the posterior nucleus ŽPo.. There is only sparse labeling in VM. Injections in caudal AGm, like that of case AGm 43, produce labeling shifted even farther laterally and caudally. There is an emphasis on far lateral VL, LP, Po, and the lateral dorsal nucleus ŽLD., and no involvement of VM ŽFig. 3G–I..
The results obtained with injections of fluororuby produced patterns similar to those described above. In case 98-1, the injection site was located in rostral AGm at a level comparable to that of case AGm 44, and produced a nearly identical pattern of thalamic labeling involving the regions of MDl, PC and CL; VL, CM and Rh; and VM ŽFig. 4A–C.. Cases 98-2 and 98-3 illustrate the progressive emphasis on more caudal and lateral thalamic labeling as injection sites are located more caudally within AGm. Case 98-2 exhibits more labeling in MDl ŽFig. 4D–F. than does case AGm 42, but this is likely due to its more rostrally located injection site. Case 98-3 produced thalamic labeling comparable to that of case AGm 43 ŽFig. 4G–I.. Fig. 5 summarizes the overall pattern of thalamic connections.
4. Discussion The present study has delineated the topographic pattern of striatal and thalamic connections of AGm. This new information can be used to more precisely guide experimental behavioral and pharmacological studies aimed at understanding its functional role, particularly with regard to the dorsocentral striatum. 4.1. Corticostriatal topography We found that striatal projections from AGm are arranged along rostrocaudal and mediolateral gradients, which correspond to the positions of the cell bodies of origin within AGm and adjacent cortical areas. Furthermore, striatal projections from rostral AGm are denser and more widespread than projections from caudal AGm. Several previous studies also bear on the issue of topographic organization in the corticostriatal projections of rats. Using
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autoradiographic analysis of anterograde axonal transport, Beckstead w2x confirmed the suggestion of earlier axon degeneration studies that frontal cortical areas project to separate longitudinal sectors of the striatum, and that the organization follows dorsoventral and mediolateral gradients. He also found that more ventrally located frontal cortical areas project to the ventral striatum in addition to the caudatoputamen. However, Beckstead did not present cases having injections in AGm. More recently, Berendse et al. w5x used anterograde transport of Phaseolus Õulgaris to map in detail the topography of the striatal projections of nine contiguous prefrontal areas, including the medial agranular cortex. They described the organization as consisting of largely separate but partially overlapping longitudinal terminal fields, with medial cortical areas projecting to rostral and medial portions of the striatum and lateral cortical areas projecting to more caudal and lateral striatal territories. For both the medial and lateral prefrontal fields, they found that a ventral to dorsal cortical gradient corresponded to a ventromedial to dorsolateral gradient in the striatum. Our results for the corticostriatal projections from AGm support the longitudinal organization described in earlier studies, but indicate a second level of topographical organization. This is manifested within the longitudinal striatal territory to which AGm projects as a continuous gradient whereby successively more caudal portions of AGm project most densely to successively more caudal portions of this striatal territory. Our finding of a mediolateral gradient associated with the corticostriatal projections of AGm is consistent with the results of earlier reports. The dorsocentral portion of the head of the caudatoputamen, the location of the densest striatal projections from AGm, is flanked medially and laterally by corticostriatal projections from the anterior cingulate and lateral agranular cortices, which lie medially and laterally adjacent to AGm, respectively. Anterior cingulate cortex projects to the far medial portion of the head of the caudatoputamen w2,5x, whereas cortex at the boundary of AGm and cingulate cortex projects slightly more laterally ŽSesack et al. w37x; their case P391.. Striatal projections from the lateral agranular cortex are located in the lateral half of the striatum, as found in the present study and in earlier reports w11,13,25x. Furthermore, they are topographically arranged in accordance with the representation of the body in motor cortex Žw13x; McGeorge and Faull w25x; their cases CP 184 and CP 173.. Corticostriatal projections from AGm appear to overlap those of posterior parietal cortex in the portion of the dorsocentral caudatoputamen around the level of the anterior commissure Žw30x, see their Fig. 2B–D.. Because the posterior parietal area is also involved in directed attention and spatial processing w7x, this raises the possibility that the dorsocentral caudatoputamen represents a nodal point for cortical circuitry related to these functions, analogous to the proposal made by Selemon and Goldman-Rakic w38x for primates. However, the extent of convergence in rats
needs to be examined more closely using double anterograde tracing in single brains. 4.2. Thalamic topography We found that the thalamic connections of AGm are organized in a continuous gradient whereby more caudal portions of AGm have connections with progressively more lateral and caudal regions of the thalamus. At all rostrocaudal locations within AGm, the distribution of cells of origin for the thalamocortical projections to AGm is largely coextensive with the terminal fields of corticothalamic projections from AGm. The continuous rostrocaudal topography we have described for the thalamic connections of AGm is supported by the collective findings of earlier studies. Reciprocal connections of rAGm with lateral MD, CM, CL, PC, VL, VM and Po were reported by Reep et al. w31,32x. Sukekawa w41x found that caudal AGm has reciprocal thalamic connections with lateral MD, CL, LD, LP and Po, and Takahashi w42x had earlier reported labeling in LD and LP following injections of anterograde tracer in far caudal AGm and PPC. Hicks and Huerta w18x noted a difference in the thalamic connections of rAGm and cAGm, but described it as a pattern of common thalamic inputs featuring lateral MD, CL, VL, VM and Po, with cAGm having additional input from LD and LP, rather than as a continuous gradient. The progressive change we have noted throughout AGm continues into the caudally adjacent posterior parietal area, which has thalamic connections with LD, LP and Po, but not with VL w30x. Specific cortical areas, basal ganglia regions and thalamic nuclei are interconnected, forming a set of segregated, parallel circuits w1,15x. A dorsal anterior cingulate circuit related to the lateral segment of the mediodorsal nucleus and its associated cortical–striatal–pallidal interconnections was identified by Groenewegen et al. w15x, and this may be considered to include AGm as well. In agreement with Berendse and Groenewegen w4x, we have found that the thalamic connections of AGm heavily involve the central lateral and paracentral intralaminar nuclei. These nuclei also project densely to the dorsocentral portion of the striatum where corticostriatal projections from AGm terminate w3,46x. 4.3. Functional considerations Studies of recovery from neglect induced by lesions of AGm indicate that the dorsolateral quadrant of striatum, including much of the region we have referred to as the dorsocentral striatum, undergoes dynamic changes that are correlated with behavioral recovery. Following unilateral lesions of the entire AGm, Vargo and Marshall w44x found that severe neglect was correlated with a 40% decrease in dopamine agonist-induced immediate early gene expression Žc-fos . in the ipsilesional vs. contralesional dorsolat-
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eral striatum. A return to symmetrical levels of c-fos expression was correlated with spontaneous behavioral recovery from neglect over the course of 3 weeks. In addition, widespread striatal glutamatergic blockade produces severe multimodal neglect w36x, and animals with severe neglect exhibit significant decreases in NMDA and kainate receptors in ipsilesional dorsolateral quadrant of the ipsilesional striatum w45x. In recovered animals, there is a 10% increase in NMDA receptors, and a return to normal levels of kainate receptors in the dorsolateral quadrant w45x. These findings suggest that the dorsocentral striatum is a focus for interactions among glutamatergic and dopaminergic systems involved in neglect and recovery associated with unilateral lesions of AGm. The present study has identified specific striatal and thalamic regions associated with rAGm and cAGm, and it provides an anatomical basis upon which to test functional hypotheses and interpret data concerning the functional roles of these cortical, striatal and thalamic regions in directed attention, lesion-induced neglect, and behavioral recovery from neglect.
Acknowledgements We appreciate the technical assistance of Maggie Stoll, and commentary by Karen Burcham and Tom Van Vleet on earlier drafts of the manuscript. Supported by the University of Florida College of Veterinary Medicine and the Maxwell Fund. College of Veterinary Medicine Journal Series Number 540.
References w1x G.E. Alexander, M.D. Crutcher, M.R. DeLong, Basal ganglia– thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions, in: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner, M.G.P. Feenstra ŽEds.., The Prefrontal Cortex: Its Structure, Function, and Pathology, Elsevier, Amsterdam, 1990, pp. 119–146 ŽProg. Brain Res. 85, 119–146.. w2x R.M. Beckstead, An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection Žprefrontal. cortex in the rat, J. Comp. Neurol. 184 Ž1979. 43–62. w3x H.W. Berendse, H.J. Groenewegen, Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum, J. Comp. Neurol. 299 Ž1990. 187–228. w4x H.W. Berendse, H.J. Groenewegen, Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat, Neuroscience 42 Ž1991. 73–102. w5x H.W. Berendse, Y. Galis-DeGraaf, H.J. Groenewegen, Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat, J. Comp. Neurol. 316 Ž1992. 314–347. w6x K. Burcham, J.V. Corwin, M. Stoll, R.L. Reep, Disconnection of medial agranular and posterior parietal cortex produces multimodal neglect in rats, Behav. Brain Res. 86 Ž1997. 41–47. w7x J.V. Corwin, R.L. Reep, Rodent posterior parietal cortex as a component of a cortical network mediating directed spatial attention, Psychobiology 26 Ž1998. 87–102.
51
w8x J.V. Corwin, S. Kanter, R.T. Watson, K.M. Heilman, E. Valenstein, A. Hashimoto, Apomorphine has a therapeutic effect on neglect produced by unilateral dorsomedial prefrontal cortex lesions in rats, Exp. Neurol. 94 Ž1986. 683–698. w9x J.V. Corwin, K.J. Burcham, G.I. Hix, Apomorphine produces an acute dose-dependent therapeutic effect on neglect produced by unilateral destruction of the posterior parietal cortex in rats, Behav. Brain Res. 79 Ž1996. 41–49. w10x D.P. Crowne, M.N. Pathria, Some attentional effects of unilateral frontal lesions in the rat, Behav. Brain Res. 6 Ž1982. 25–39. w11x J.P. Donoghue, M. Herkenham, Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat, Brain Res. 365 Ž1986. 397–403. w12x J.P. Donoghue, S.P. Wise, The motor cortex of the rat: cytoarchitecture and microstimulation mapping, J. Comp. Neurol. 212 Ž1982. 76–88. w13x R.L.M. Faull, The organization of corticostriate projections from the motor cortex in the rat, Neurosci. Lett. Suppl. 8 Ž1982. S47. w14x Y. Gioanni, M. Lamarche, A reappraisal of rat motor cortex organization by intracortical microstimulation, Brain Res. 344 Ž1985. 49–61. w15x H.J. Groenewegen, H.W. Berendse, J.G. Wolters, A.H.M. Lohman, The anatomical relationship of prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization, in: H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.A. Corner, M.G.P. Feenstra ŽEds.., The Prefrontal Cortex: Its Structure, Function, and Pathology Elsevier, Amsterdam, 1990, pp. 95–118 ŽProg. Brain Res. 85, 95–118.. w16x R.D. Hall, E.P. Lindholm, Organization of motor and somatosensory neocortex in the albino rat, Brain Res. 66 Ž1974. 23–38. w17x K.M. Heilman, R.T. Watson, E. Valenstein, Neglect and related disorders, in: K.M. Heilman, E. Valenstein ŽEds.., Clinical Neuropsychology, 3rd edn., Oxford Univ. Press, New York, 1993, pp. 279–336. w18x R.R. Hicks, M.F. Huerta, Differential thalamic connectivity of rostral and caudal parts of area Fr2 in rats, Brain Res. 568 Ž1991. 325–329. w19x E.G. Jones, The Thalamus, Plenum, New York, 1985, 935 pp. w20x R.P. Kesner, G. Farnsworth, B.V. DiMattia, Double dissociation of egocentric and allocentric space following prefrontal and parietal cortex lesions in the rat, Behav. Neurosci. 103 Ž1989. 956–961. w21x V. King, J.V. Corwin, Neglect following unilateral ablation of the caudal but not the rostral portion of medial agranular cortex of the rat and the therapeutic effect of apomorphine, Behav. Brain Res. 37 Ž1990. 169–184. w22x V. King, J.V. Corwin, Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex, Behav. Brain Res. 143 Ž1992. 237–242. w23x G.R. Leichnetz, A. Gonzalo-Ruiz, Collateralization of frontal eye field Žmedial precentralranterior cingulate. neurons projecting to the paraoculomotor region, superior colliculus, and medial pontine reticular formation in the rat: a fluorescent double-labeling study, Exp. Brain Res. 68 Ž1987. 355–364. w24x G.R. Leichnetz, S.G.P. Hardy, M.K. Carruth, Frontal projections to the region of the oculomotor complex in the rat: a retrograde and anterograde HRP study, J. Comp. Neurol. 263 Ž1987. 387–399. w25x A.J. McGeorge, R.L.M. Faull, The organization of the projection from the cerebral cortex to the striatum in the rat, Neurosci. 29 Ž1989. 503–537. w26x M.W. Miller, The origin of corticospinal projection neurons in rat, Exp. Brain Res. 67 Ž1987. 339–351. w27x E.J. Neafsey, E.L. Bold, G. Haas, K.M. Hurley-Guis, G. Quirk, C.R. Sievert, R.R. Terreberry, The organization of the rat motor cortex: a microstimulation mapping study, Brain Res. Rev. 11 Ž1986. 77–96. w28x G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates, 2nd edn., Academic Press, Sydney, 1986, 263 pp.
52
R.L. Reep, J.V. Corwinr Brain Research 841 (1999) 43–52
w29x R.L. Reep, M.J. Baccala, M.P. Booth, G.S. Goodwin, Combined retrograde and anterograde tracing of neuronal connections: fluorogold and autoradiography, J. Neurosci. Methods 23 Ž1988. 1–5. w30x R.L. Reep, H.C. Chandler, V. King, J.V. Corwin, Rat posterior parietal ortex: topography of corticocortical and thalamic connections, Exp. Brain Res. 100 Ž1994. 67–84. w31x R.L. Reep, J.V. Corwin, A. Hashimoto, R.T. Watson, Afferent connections of medial precentral cortex in the rat, Neurosci. Lett. 44 Ž1984. 247–252. w32x R.L. Reep, J.V. Corwin, A. Hashimoto, R.T. Watson, Efferent connections of the rostral portion of medial agranular cortex in rats, Brain Res. Bull. 19 Ž1987. 203–221. w33x R.L. Reep, J.V. Corwin, V. King, Neuronal connections of orbital cortex in rats: topography of cortical and thalamic afferents, Exp. Brain Res. 111 Ž1996. 215–232. w34x R.L. Reep, G.S. Goodwin, J.V. Corwin, Topographic organization in the corticocortical connections of medial agranular cortex in rats, J. Comp. Neurol. 294 Ž1990. 262–280. w35x K.J. Sanderson, W. Welker, G.M. Shambes, Reevaluation of motor cortex and of sensorimotor overlap in cerebral cortex of albino rats, Brain Res. 292 Ž1984. 251–260. w36x J.J. Schuller, D.D.Q. Tran, J.F. Marshall, Striatal glutamate antagonism induces contralateral neglect, Brain Res. 788 Ž1998. 315–319. w37x S.R. Sesack, A.Y. Deutch, R.H. Roth, B.S. Bunney, Topographical organization of the efferent projections of medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus Õulgaris leucoagglutinin, J. Comp. Neurol. 290 Ž1989. 213–242. w38x L.D. Selemon, P.S. Goldman-Rakic, Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network
w39x
w40x
w41x
w42x w43x
w44x
w45x
w46x
w47x
subserving spatially guided behavior, J. Neurosci. 8 Ž1988. 4049– 4068. H.M. Sinnamon, B.S. Galer, Head movements elicited by electrical stimulation of the anteromedial cortex of the rat, Physiol. Behav. 33 Ž1984. 185–190. S.L. Stuesse, D.B. Newman, Projections from the medial agranular cortex to brain stem visuomotor centers in rats, Exp. Brain Res. 80 Ž1990. 532–544. K. Sukekawa, Reciprocal connections between medial prefrontal cortex and lateral posterior nucleus in rats, Brain Behav. Evol. 32 Ž1988. 246–251. T. Takahashi, The organization of the lateral thalamus of the hooded rat, J. Comp. Neurol. 231 Ž1985. 281–309. T.M. Van Vleet, J.V. Corwin, K.J. Burcham, R.L. Reep, Unilateral lesions of dorsal central striatum produce multimodal neglect in rats, Soc. Neurosci. Abstr. 23 Ž1997. 1839. J.M. Vargo, J.F. Marshall, Time-dependent changes in dopamine agonist-induced striatal fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefrontal cortex injury, Synapse 20 Ž1995. 305–315. J.M. Vargo, J.F. Marshall, Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors, Behav. Brain Res. 77 Ž1996. 189–199. J.G. Veening, F.M. Cornelissen, P.A.J.M. Lieven, The topical organization of the afferents to the caudatoputamen of the rat: a horseradish peroxidase study, Neuroscience 5 Ž1980. 1253–1268. K. Zilles, A. Wree, Cortex: areal and laminar structure, in: G. Paxinos ŽEd.., The Rat Nervous System: Forebrain and Midbrain, Vol. 1, Academic Press, Sydney, 1985, pp. 375–415.