ERC-Witter-The entorhinal connectome: a way to read the cortex

One important challenge of modern neuroscience is to causally relate the complex architecture of cortical networks to functional outcomes of cortical processing. Experimentally based rules on why and to what extent architecture causes function, with time, will i) be necessary to efficiently implement biologically inspired computer architectures and ii) significantly enhance the potential to predict the detrimental functional effects of architectural alterations that occur in a number of brain diseases, including dementia, promising a breakthrough in research into targeted treatment of these devastating diseases. We used the entorhinal cortex as an optimal model network to address this challenge since it is essentially a twin structure where the siblings, called lateral and medial, have comparable architectures, but show strikingly different functions. The central hypothesis of the project was that variations in the architecture, particularly in i) intrinsic wiring and ii) input connectivity, result in striking differences in function, represented by the presence or absence of spatially modulated cells. Our current results show that the initial hypothesis that neurons in the most superficial layer II of the two entorhinal subdivisions form differently organized neural networks is not true for the two main excitatory celltypes in this layer. A similar conclusion holds for the organization of excitatory neurons in layer V. Regarding inhibitory interneuron connectivity, we conclude that there are subtle differences between the two entorhinal parts, reflecting the established differences in cortical connectivity. We finally have data indicating the presence of dense intrinsic connections with a very complex and different organization in the two entorhinal parts.

One important challenge of modern neuroscience is to causally relate the complex architecture of cortical networks to functional outcomes of cortical processing. Experimentally based rules on why and to what extent architecture causes function, with time, will i) be necessary to efficiently implement biologically inspired computer architectures and ii) significantly enhance the potential to predict the detrimental functional effects of architectural alterations that occur in a number of brain diseases, in cluding dementia, promising a breakthrough in research into targeted treatment of these devastating diseases. My current research suggests that the entorhinal cortex provides an optimal cortical network to address this challenge since it is essentially a ?twin structure? where the siblings, called lateral and medial, have comparable architectures with variations in layer II, but show strikingly different functions. The central hypothesis of the research is that variations in the architecture, particularl y in i) intrinsic wiring and ii) input connectivity, result in striking differences in function, represented by the presence or absence of spatially modulated cells. The results will first provide qualitative and quantitative descriptions of interlaminar and intralaminar connections of principal neurons and interneurons of the lateral and medial entorhinal cortex, second identify commonalities and differences in postsynaptic targets of characteristic inputs to lateral and medial entorhinal cortex, and thi rd determine the effects of changes in wiring of layer II on functional properties of the two entorhinal networks. The unique opportunity offered by the?twin approach? will allow establishing causal relationships between the architectures of multi-layered cortices and their functions and eventually lead to a theoretical framework (a set of rules) necessary to make reliable functional inferences on the basis of normal or diseased-altered network architectures.