Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography

Primates are unique among mammals in possessing a region of dorsolateral prefrontal cortex with a well-developed internal granular layer. This region is commonly implicated in higher cognitive functions. Despite the histological distinctiveness of primate dorsolateral prefrontal cortex, the work of Rose, Woolsey, and Akert produced a broad consensus among neuroscientists that homologues of primate granular frontal cortex exist in nonprimates and can be recognized by their dense innervation from the mediodorsal thalamic nucleus (MD). Additional characteristics have come to be identified with dorsolateral prefrontal cortex, including rich dopaminergic innervation and involvement in spatial delayed-reaction tasks. However, recent studies reveal that these characteristics are not distinctive of the dorsolateral prefrontal region in primates: MD and dopaminergic projections are widespread in the frontal lobe, and medial and orbital frontal areas may play a role in delay tasks. A reevaluation of rat frontal cortex suggests that the medial frontal cortex, usually considered to be homologous to the dorsolateral prefrontal cortex of primates, actually consists of cortex homologous to primate premotor and anterior cin-date cortex. The lateral MD-projection cortex of rats resembles portions of primate orbital cortex. If prefrontal cortex is construed broadly enough to include orbital and cingulate cortex, rats can be said to have prefrontal cortex. However, they evidently lack homologues of the dorsolateral prefrontal areas of primates. This assessment suggests that rats probably do not provide useful models of human dorsolateral frontal lobe function and dysfunction, although they might prove valuable for understanding other regions of frontal cortex.

Do rats have prefrontal cortex? the rose-woolsey-akert program reconsidered

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

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

This study analyzed the topographic organization of the associational fibers within the olfactory cortex of the rat, by using the autoradiographic method. Small injections of 3H-leucine were placed in all of the subdivisions of the olfactory cortex, to label selectively the fibers arising in each area. Intracortical fibers were identified from all of the olfactory cortical areas except the olfactory tubercle and were classified into two major systems (the layer Ib system and the layer II-deep Ib system) on the basis of their laminar pattern of termination (see Luskin and Price, '83). The layer Ib fiber system arises in the anterior olfactory nucleus, piriform cortex, and lateral entorhinal area, and is broadly organized in relation to the lateral olfactory tract. Cortical areas deep to or near the lateral olfactory tract are preferentially interconnected with areas near the tract, while parts of the cortex lateral and caudal to the lateral olfactory tract are most heavily interconnected with areas lateral, caudal, and medial to the tract. Commissural projections from the anterior olfactory nucleus and the anterior piriform cortex match some (but not all) components of the ipsilateral layer Ib fiber system. The layer II-deep Ib fiber system arises in three small areas--the ventral tenia tecta, the dorsal peduncular cortex, and the periamygdaloid cortex. The fibers from the ventral tenia tecta terminate in layer II of the anterior olfactory nucleus and are topographically organized. The fibers from the dorsal peduncular cortex and the periamygdaloid cortex are more widely distributed, especially in the lateral and caudal parts of the cortex. Two other intracortical projections do not fit into either of these fiber systems. The nucleus of the lateral olfactory tract projects bilaterally to the islands of Calleja and the medial edge of the anterior piriform cortex. The anterior cortical nucleus projects to many parts of the olfactory cortex, but the fibers end in both superficial and deep parts of layer I (layer Ia and Ib). There are projections from several of the olfactory cortical areas to the cortical areas surrounding the olfactory cortex. Virtually all of the olfactory areas also project to the ventral and dorsal endopiriform nuclei deep to the piriform cortex and/or to the polymorph zone deep to the olfactory tubercle. In addition, projections have been demonstrated to the deep amygdaloid nuclei, especially from the more ventromedial and caudal parts of the olfactory cortex.

The topographic organization of associational fibers of the olfactory system in the rat, including centrifugal fibers to the olfactory bulb

The cytoarchitecture and thalamic afferents of cingulate cortex were evaluated in the rhesus monkey (Macaca mulatto). Area 24 has three divisions of which area 24a is adjacent to the callosal sulcus and has the least laminar differentiation. Area 24b has more clearly defined layers II, III, and Va, and area 24c, which forms the lower bank of the anterior cingulate sulcus, has a particularly dense layer III. Area 23 also has three divisions, each of which has a distinct layer IV. Area 23a is adjacent to the callosal sulcus and has the thinnest layers II–IV, which have the same cell density as layers V and VI. Area 23b has the largest pyramids in layers IIIc and Va, and area 23c, in the depths of the posterior cingulate sulcus, has the broadest external and thinnest internal pyramidal layers. Finally, areas 29 and 30 are located in the posterior depths of the callosal sulcus. Two divisions of area 29 are apparent: one with a granular layer directly adjacent to layer I (area 29a–c) and another with differentiation of layers III and IV (area 29d). Area 30 has a dysgranular layer IV.



Injections of the retrograde tracer horseradish peroxidase (HRP) were made into subdivisions of cingulate cortex in the monkey. Area 25 received thalamic input mainly from the midline parataenial (Pt), central densocellular (Cdc), and reuniens nuclei as well as from the dorsal parvicellular division of the mediodorsal nucleus (MDpc). A less dense projection also originated in the intralaminar parafascicular (Pf), central superior, and limitans (Li) nuclei as well as the medial division of the anterior nuclei (AM).



Areas 24a and 24b received most thalamic afferents from fusiform and multipolar cells in the Cdc and Pf nuclei with fewer from the ventral anterior (VA) and MDpc and MD densocellular (MDdc) nuclei and only minor input from AM. Most input to premotor cingulate area 24c appeared to originate in VA, MDdc, and Li.



Area 29 received the most dense input from nuclei traditionally associated with limbic cortex including the anteroventral (AV), anterodorsal (AD), and laterodorsal (LD) nuclei. Areas 23a and 23b, in contrast, did not receive AV, AD, or LD input, but the greatest proportion of their thalamic afferents arose in AM. Less-pronounced input also came from the lateroposterior (LP), medial pulvinar, and MDdc nuclei. This latter nucleus projected more to area 23b than to areas 30 or 23a.



Anterior medial nucleus efferents to cingulate cortex were of particular note for two reasons. First, AM projected primarily to posterior cingulate areas with area 23 receiving its principal thalamic input from AM. Second, projections to areas 30, 23a, and 23b were topographically organized with ventral areas 30 and 23a receiving from the central core of AM. While the more dorsally located area 23b received input from peripheral and medial.



In light of the extensive projections of Cds, Csl, and Pf to anterior cingulate cortex, it is proposed that the midline and intralaminar thalamic nuclie be classified as part of limbic thalamus along with the anterior, LD, and MD nuclei. Furthermore, although AM projects mainly to posterior cingulate cortex, it also has light projections to area 25 and minor input to area 24. As suhc, AM is the only limbic thalamic nucleus that has such widespread projections to cingulate cortex. Finally, visually evoked activity in area 23 may be the result of projections from the LP and medial pulvinar.

Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents

Cortical projections of the thalamic mediodorsal nucleus in the rabbit.

Some sources of olfactory input to the opossum mediodorsal thalamic nucleus (MD) were identified by retrograde horseradish peroxidase and anterograde autoradiographic methods. One major source originated from the olfactory tubercle and a narrow strip of piriform cortex bordering the tubercle. The tubercle-MD projection exhibited a definite spatial organization and included all except the most medial part of MD. The fact that the projection reached the most lateral and ventral extent of MD abutting the intralaminar complex suggests that the entire opossum MD may correspond to only the medial, magnocellular division in the primate and that the equivalents of both the parvocellular and paralamellar divisions may be absent.

Sources of olfactory inputs to opossum mediodorsal nucleus identified by horseradish peroxidase and autoradiographic methods.

Summary: Homotaurine and taurine are two powerful inhibitory aminoacids with anticonvulsant properties against various experimental models of focal epilepsy. This study reports on their effects in the feline model of corticoreticular epilepsy induced by parenteral administration of large amounts of penicillin. Both aminoacids, but particularly homotaurine, remarkably potentiate epileptiform discharges in cats. Brainstem transection at the precollicular level does not modify the activation, thus ruling out the intervention of mesoromboencephalic structures in the observed effect. The opposing action of these two amino acids on focal epilepsy as compared to corticoreticular epilepsy suggests that the two types of epileptiform activity stem from very different pathophysiological mechanisms. Homotaurine is a powerful GABA agonist that exerts a central action upon parenteral administration. Other GABA analogs such as muscimol, imidazole acetic acid, and γ-hydroxy-butyrate have been reported to potentiate experimental models of spike and wave epilepsy. Thus, the activating effects of homotaurine in this epilepsy model are in keeping with the demonstrated GABAmimetic properties of the compound.



RESUME

L'homotaurine et la taurine sont deux puissants aminoacides inhibiteurs ayant des proprietes anticon-vulsivantes a l'egard de divers modeles experimataux d'epilepsie partielle. Ce travail fait etat de leureffet sur la modele felin d'epilepsie cortico-reticulaire induite par l'administration parenterale de grandes quantites de penicilline. Les deux acides amines, mais particulierement l'homotaurine, augmentent remarqu-ablement les decharges epileptiformes chez les chats. La section du tronc cerebral au niveau precolliculaire ne modifie pas cette activation, ecartant ainsi la possibilite d'une intervention de structures mesorhom-bencephaliques sur l'effet observe. L'action opposee de ces deux aminoacides sur l'epilepsie focale par rapport a l'epilepsie “cortico-reticulaire” suggere que ces deux types d'acitiviteepileptiforme dependant de mecanismes physiopathologiques tres differents. L'homotaurine est un puissant agoniste du GABA qui exerce une action centrale apres administration parenteral. II a ete rapporte que d'autres agonistes du GABA comme le muscimol, l'acide acetique imidazole et le γ-hydroxybutyrate potentialisent des modeles experimentaux d'epilepsie avec pointe-ondes? Ainsi les effets activateurs de l'homotaurine dans ce modele d'epilepsie sont en accord avec la notion, deja demon-tree, de proprietes GABA mimetiques de ce produit.



RESUMEN

La homotaurina y la taurina son dos aminoacidos con potente accion inhibitoria y con propiedades anticonvulsivas demostradas en varios modelos experimentales de epilepsyia focal. Este estudio expone sus efectos en el modelo felino de epilepsyia cortico-reticular inducida mediante la administracion parenteral de grandes dosis de penicilina. Ambos aminoacidos, y particularmente la homotaurina, potencian las descargas epileptiformes en gatos, de modo considerable. La transeccion del tronco cerebral a nivel precolicular no modifico esta activacion eliminando, de este modo, la intervencion de estructuras meso-romboencefalicas en el efecto observado. La opuesta accion de estos dos aminoacidos sobre la epilepsia focal compareandola con la epilepsia “cortico-reticular” sugiere que estos dos tipos de actividad epileptiforme surge de diversos mecanismos fisiopatologicos. La homotaurina es un potente agonista del GABA que ejerce una accion central tras su administracion parenteral. Otros GABA-agonistas como el muscimol, el acido imidazolacetico y el gammahidroxibutirato han sido considerados como potenciadores de los modeles experimentales de la epilepsia de punta-onda. Asi pues, los efectos activadores de la homotaurina en este modelo de epilepsia estan de acuerdo con las demostradas propiedades gabomimeticas de este compuesto.



ZUSAMMENFASSUNG

Homotaurin und Taurin sind zwei wirkungsvolle inhibitorische Aminosauren mit antikonvulsiven Einges-chaften gegenuber verschiedenen experimentellen Modeller! der fokalen Epilepsie. Diese Untersuchung berichtet uber die Wirkung auf das Katzenmodell der cortico-retikularen Epilepsie nach parenteraler Gabe von grosen Mengen von Penicillin. Beide Aminosauren, aber besonders Homotaurin verstarken wesentlich die epileptiformen Entladungen bei Kat-zen. Hirnstammschnitte in Hone des prakollikularen Niveaus modifizierten diese Aktivierung nicht. Damit schliesen sie die Bedeutung mesorhombocephaler Strukturen auf die beobachtete Wirkung aus. Die gegensatzliche Wirkung dieser zwei Aminosauren auf die fokale Epilepsie verglichen mit der kortikoretikularen Epilepsie last vermuten, das die beiden Typen epilepiformer Aktivitat sehr verschiedenen patho-physiologischen Mechanismen entsprechen. Homotaurin ist ein wirkungsvoller Gabaagonist, der bei parenteraler Anwendung zentrale Wirkung besitzt. Von anderen Gabaagonisten wie Muszimol, Im-idazolessigsaure und Gammahydroxybutyrat wurde berichtet, das sie die experimentellen Modelle der spike wave Epilepsie potenzieren. Damit steht der ak-tivierende Effekt von Homotaurin bei diesem Epilep-siemodell in Ubereinstimmung mit den demonstrierten gabamimetischen Eigenschaften des Stoffes.

Activating effects of homotaurine and taurine on corticoreticular epilepsy.

Prefrontal cortex is commonly defined as cortex which receives afferents from the thalamic mediodorsal nucleus (MD). The extent of opossum prefrontal cortex was mapped with anterograde and retrograde axonal transport methods. The prefrontal field was found to include not only cortex on the lateral convexity of the frontal lobe as reported in earlier studies, but, in addition, cortex within the rhinal fissure and cortex on the rostral medial wall of the hemisphere. The organization of the thalamic input to the medial wall was analyzed in some detail and compared with that of the rat. The reason for this emphasis stemmed from earlier observations which suggested that a lateral, nonolfactory segment of MD, prominent in the rat and other species, may not be present in opossum MD. In the rat, the lateral segment, which constitutes approximately one-third of MD, projects to a relatively large expanse of rostral medial cortex which is also projected upon by the anteromedial nucleus. The main projection field of the lateral one-third of opossum MD is to cortex on the lateral convexity of the frontal lobe which has no input from the anteromedial nucleus and has no counterpart in the rat. Only the most lateral edge of opossum MD projects to medial cortex, to a very small field, which is also projected upon by the anteromedial nucleus. In other respects, the organization of the rostral medial cortex is similar in rat and opossum. These results suggest that, rather than being absent, an equivalent of a nonolfactory segment may be present in opossum MD but is markedly reduced in size, compared to that in rat and other species.

Gregory T. Golden

Papers

Cortical projections of the thalamic mediodorsal nucleus in the rabbit.

Sources of olfactory inputs to opossum mediodorsal nucleus identified by horseradish peroxidase and autoradiographic methods.

Activating effects of homotaurine and taurine on corticoreticular epilepsy.

Extent and organization of opossum prefrontal cortex defined by anterograde and retrograde transport methods.

The distribution of olfactory input in the opossum mediodorsal nucleus.