Do cortical areas emerge from a protocottex? Dennis D. M. O'Leary Dennis D. M. O'Leary is at the Departments of Neurology and Neurological Surgery and of Anatomy and Neurobiolo~/ and The McDonnell Center for Studies of Higher Brain Function, Washington Univer~ity School of Medicine, 5t Louis, M063110, USA. The adult mammalian neocortex consists of numerous 'areas' distinguished from one another largely on the basis of distinctions in cytoarchitecture and connec- tions. The developing neocortex, though, lacks many of these area-specific distinctions, and is more uniform across its extent. This less differentiated structure, here termed the 'protocortex', undergoes considerable modi- fication after neurogenesis which results in the emergence of well-defined neocortical areas. To what extent, then, are neocortical areas predetermined? This issue is considered in the context of recent findings on the generation of the neocortex and its subsequent parcellation into distinct areas. The neocortex is unique to mammals. Although it differs greatly in complexity between mammalian species, in all mammals it can be divided on both morphological and functional grounds into a sizeable number of 'areas 'L2. There are phylogenetic differ- ences in neocortical parcellation which reflect the addition of higher order 'associational' areas and an increase in the specialization of regions of neocortex to perform specific functions 3. Much attention has been directed toward understanding the organization and operation of the neocortex. Recently, though, an increased amount of effort has been focused on determining how areas of the neocortex acquire their unique characteristics 4. Although this question relates to an understanding of the mechanisms underlying the phylogenetic expansion of the neocortex in terms of the size and the number of definable areas, studies of neocortical development provide the best opportunity for answers. One can imagine two extreme positions of how distinct areas are developed: the neuro- epithelium which gives rise to the neocortex may be regionally specified to generate area-unique lineages of neurons that reflect the area-specific features of the adult neocortex, or alternatively, the neocortical neuroepithelium may generate uniform lineages across its extent and rely on subsequent interactions to bring about the differentiation of areas. I will consider here an increasing body of evidence which suggests that many prominent features distinctive of the differentiation of areas of the neocortex are not determined at the time of neurogenesis, but rather are established through subsequent epigenetic interactions involving a variety of mechanisms. Some distinctions and similarities between cortical areas in the adult Areas of the adult neocortex are clearly dissimilar. Neocortical areas can be distinguished from one another by differences in connections, both outputs and inputs, as well as by distinctions in architecture, from different distributions of receptors for neuro- transmitters to variations in cell sizes and densities. These area-specific characteristics contribute to the unique functional properties of the various neocortical areas. But, in spite of the many striking differences between areas, certain features are shared. The most obvious common feature is that by convention all neocortical areas have six primary layers. Although the appearance of individual layers changes at the borders between areas, the chief characteristics of each layer are retained. For example, the same basic scheme of laminar organization of sources of cortical outputs applies to all: neurons in layer 6 project to the thalamus and claustnun, neurons in layer 5 send their axons to all other subcortical targets, and layers 2 and 3 are the principal source of projections to other neocortical areas, ipsilaterally and contralaterally 5'6. Even the basic cellular constituents seem to be consistent from one area to another. Although cortical thickness varies considerably, the number of neurons found in a 'radial traverse' through the six layers is surprisingly constant between diverse cortical areas within a species, as well as across species 7'8. A notable exception is that the number of neurons found in a radial traverse in primary visual cortex (area 17) is higher than in other areas 7-9. The proportion of cells classified by shape as pyramidal or non-pyramidal is also constant between two very different areas, the primary motor and visual areas 1°. Similarly, the predominant cortical inhibitory cell, the GABAergic neuron, is present in roughly equivalent proportions in all areas examined 8. Cortical neurons that might use other neurotransmitters or modulators, for example those immunoreactive for choline acetyltransferase (the synthesizing enzyme for the neurotransmitter acetylcholine) n, as well as interneurons of various peptide phenotypes 12-15, are also found in all neocorti- cal areas. In short, all of the basic morphological and chemically defined types of cortical neurons identified to date are widely distributed within the adult neocortex. Based on these and other structural and functional consistencies between areas of the adult neocortex, it has been proposed by both neuroanatomists and neurophysiologists, especially Lorente de No TM, Creutzfeld 17, Mountcastle TM, Powel119 and Eccles 2°, that different primary cortical areas share a common organizational scheme. This suggestion has been addressed experimentally in two independent sets of experiments in which somatosensory or auditory cortex was induced to process visual information by misrouting, during development, retinal axons to somatosensory thalamus 2~ or to auditory thalamus 22 (Fig. 1). In these animals, the receptive field and response properties of cells in somatosensory or auditory cortex to visual stimuli resemble those normally seen in visual cortex. The most straightfor- ward explanation for these findings is that the primary sensory areas of the neocortex normally process sensory information relayed through the thalamus in a fundamentally similar way, implying that the basic organization of cells and