353 7567.Garc -Cabezas and BarbasPagelayer IV of sensory and association cortices. This interpretation implies that the neurons in layer IV of area 4 are bigger than in the sensory areas situated behind it. The closest sensory neighbor of area 4 is the somatosensory cortex. Further front are the premotor areas, which are also regarded by most as agranular, and in front of them is the prefrontal cortex. In many accounts the prefrontal cortex has been called the `granular’ frontal cortex to distinguish it from its premotor neighbors [e.g., (Akert Warren, 1964; Dihexa chemical information Preuss Goldman-Rakic, 1991)]. The significance of the issue of whether area 4 has layer IV is based on core organizational features of the cerebral cortex. First, it pertains to the centrality of layer IV as the recipient of pathways from the thalamus. If area 4 has no layer IV, where do thalamic pathways terminate? Second, the term `agranular’ groups area 4 with the agranular limbic areas. The phylogenetically ancient limbic cortices differ markedly in architecture from area 4. They either lack, or have a rudimentary layer IV and their superficial layers (II II) and deep layers (V I) are not distinct and cannot be subdivided into individual layers. Third, if area 4 lacks layer IV, what is its connectional relationship with surrounding areas? The latter poses a particular dilemma in view of the known laminar patterns of origin and termination of corticocortical connections seen in other cortical systems, such as the visual [for discussion see (Shipp, 2005)]. Here we approach the issue of the status of layer IV in area 4 from a historical perspective and employ experimental analyses to help conclude that area 4 indeed has a layer IV. We discuss the significance of this issue in the context of thalamocortical connections, and from the perspective of the organization of cortical architecture, the patterns of corticocortical connections and cortical evolution.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptThe status of layer IV in area 4: historical perspectiveThe father of brain histology, Santiago Ram y Cajal, was the first to provide a detailed cytoarchitectonic description of the human primary motor cortex using the Nissl technique that stains the bodies of neurons and glia. Cajal also summarized earlier studies on the physiology of the motor cortex and clarified the apparent confusion of the primary motor area with the more caudally situated somatosensory area (Ram y Cajal, 1899). Cajal used a seven layer system for the primary motor cortex. In Table 1 we provide the equivalent layers to the six layer system proposed by Bevan Lewis (1880) for the isocortex, which was used later by Monocrotaline chemical information Brodmann (1909/1999) and is still used today. For Cajal, the granule zone (layer 5 in his terminology) of the human primary motor cortex was rudimentary, discontinuous and hard to discern. But Cajal stressed that the granule zone is invaded by large neurons of the `deep pyramidal formation’ composed of layers 4, 5, and 6. Accordingly, the transition from the primary somatosensory to the primary motor cortex is accompanied by loss of a compact central (inner) granular layer that is characteristic of sensory cortices. Using the Golgi method, Cajal described several types of neurons with short axons in the inner granular zone of the motor cortex, some of which have the morphological features of granule neurons found in the primary somatosensory and the primary visual cortex.353 7567.Garc -Cabezas and BarbasPagelayer IV of sensory and association cortices. This interpretation implies that the neurons in layer IV of area 4 are bigger than in the sensory areas situated behind it. The closest sensory neighbor of area 4 is the somatosensory cortex. Further front are the premotor areas, which are also regarded by most as agranular, and in front of them is the prefrontal cortex. In many accounts the prefrontal cortex has been called the `granular’ frontal cortex to distinguish it from its premotor neighbors [e.g., (Akert Warren, 1964; Preuss Goldman-Rakic, 1991)]. The significance of the issue of whether area 4 has layer IV is based on core organizational features of the cerebral cortex. First, it pertains to the centrality of layer IV as the recipient of pathways from the thalamus. If area 4 has no layer IV, where do thalamic pathways terminate? Second, the term `agranular’ groups area 4 with the agranular limbic areas. The phylogenetically ancient limbic cortices differ markedly in architecture from area 4. They either lack, or have a rudimentary layer IV and their superficial layers (II II) and deep layers (V I) are not distinct and cannot be subdivided into individual layers. Third, if area 4 lacks layer IV, what is its connectional relationship with surrounding areas? The latter poses a particular dilemma in view of the known laminar patterns of origin and termination of corticocortical connections seen in other cortical systems, such as the visual [for discussion see (Shipp, 2005)]. Here we approach the issue of the status of layer IV in area 4 from a historical perspective and employ experimental analyses to help conclude that area 4 indeed has a layer IV. We discuss the significance of this issue in the context of thalamocortical connections, and from the perspective of the organization of cortical architecture, the patterns of corticocortical connections and cortical evolution.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptThe status of layer IV in area 4: historical perspectiveThe father of brain histology, Santiago Ram y Cajal, was the first to provide a detailed cytoarchitectonic description of the human primary motor cortex using the Nissl technique that stains the bodies of neurons and glia. Cajal also summarized earlier studies on the physiology of the motor cortex and clarified the apparent confusion of the primary motor area with the more caudally situated somatosensory area (Ram y Cajal, 1899). Cajal used a seven layer system for the primary motor cortex. In Table 1 we provide the equivalent layers to the six layer system proposed by Bevan Lewis (1880) for the isocortex, which was used later by Brodmann (1909/1999) and is still used today. For Cajal, the granule zone (layer 5 in his terminology) of the human primary motor cortex was rudimentary, discontinuous and hard to discern. But Cajal stressed that the granule zone is invaded by large neurons of the `deep pyramidal formation’ composed of layers 4, 5, and 6. Accordingly, the transition from the primary somatosensory to the primary motor cortex is accompanied by loss of a compact central (inner) granular layer that is characteristic of sensory cortices. Using the Golgi method, Cajal described several types of neurons with short axons in the inner granular zone of the motor cortex, some of which have the morphological features of granule neurons found in the primary somatosensory and the primary visual cortex.