The structural and functional heterogeneity of the human cerebral cortex was demonstrated at the beginning of the last century. The cortex was parcellated into numerous cortical areas (Brodmann, 1909; Vogt and Vogt, 1919; von Economo and Koskinas, 1925). The resulting cortical maps are based on local differences in the regional and laminar distribution of cell bodies (i.e., cytoarchitecture) or myelinated fibers (i.e., myeloarchitecture). The pioneering map of Brodmann (1909) is the reference system, if a precise anatomical localization has to be assigned to functional imaging data (e.g., functional magnetic resonance imaging (fMRI)). Such attempts, however, reveal a mismatch between the Brodmann map and the functional imaging data. The reason for this mismatch is manifold. Beside technical and methodological problems of classical cytoarchitectonic approaches, the restriction to cell bodies or myelinated nerve fibers as markers of cortical organization is apparently not sufficient to analyze the enormous functional and structural complexity of the cerebral cortex. Since transmitter receptors play a key role in neurotransmission, and are molecular markers of the cortical organization, we explored the regional and laminar distributions of receptors by using quantitative in vitro receptor autoradiography and image analysis procedures. The regional and laminar distribution patterns of 15 different receptor types and subtypes representing all classical transmitter systems (glutamate, GABA, acetylcholine, dopamine, noradrenaline, serotonin) were analyzed by labelling the receptors with highly specific, tritiated ligands in 20 micrometer thin, serial cryostat sections through complete human hemispheres. These distribution patterns were correlated with cyto- and myeloarchitectonic data in immediately adjacent sections. In some cases, a perfect match between the cytoor myeloarchitectonic definition of cortical borders on one hand and local changes in receptor patterns on the other hand were found. However, the receptor-based parcellation of the cerebral cortex leads in many cases to more detailed cortical maps than previously described indicating the segregation of the cortex into molecular-based units. E.g., the muscarinic M2, serotoninergic 5-HT2, and noradrenergic alpha2 as well as to some degree also the GABAergic GABAA receptors show exceptionally high densities in the primary sensory areas as opposed to other cortical areas. This clearly demonstrates a molecular diversity of the cortex, and suggests that, e.g., pharmacotherapy with receptor ligands may cause different effects in the different cortical regions. Since receptors interact with each other, the balance between different receptors in each cortical region seems to be even more important than the local density of a single receptor type. To visualize this complex multimodal aspect, the “receptor fingerprint” was recently introduced as a molecular marker of cortical organization. In the present talk, a receptor fingerprint is the polar coordinate plot of the mean (averaged over all cortical layers) receptor densities of 15 receptor types and subtypes in each of the different cortical fields. The fingerprint is a graphical representation of a multidimensional feature vector representing the contribution of each receptor to the balance between all receptors in a cortical area. The analysis of the fingerprints using multidimensional scaling and cluster algorithms reveals a novel and highly segregated regional and laminar organization of the human cerebral cortex, which is the molecular basis of its diverse functions. Supported by DFG, EU, and NIH.
KeywordsManifold Dopamine Cortisol Serotonin Noradrenaline
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