Considering the amount and diversity of computational tasks performed by the neocortex, it is a remarkably homogenous structure. Whereas other brain structures are immediately recognizable both on the microscopic (cellular) and macroscopic (network) level, a degree of expertise is required to distinguish differences between neocortical regions. This is despite the fact that the neocortex deals with widely different modalities and computational tasks in relatively defined regions. An engineer designing such a system would surely feel compelled to design each area with the specific task in mind. Nature on the other hand, apparently chose a one-size-fits-all solution.This homogeneity naturally leads to the suggestion that there are organizing principles of cortical architecture however there is still no consensus about what the organizing principle of the cortex might be. Two histological features stand out in all regions: 1) a laminar structure defined by the relative density of particular cell types and the terminations of distinct classes of axonal projections, and 2) an abundance of pyramidal shaped neurons with an apical dendrite projecting towards the cortical surface. In fact, the pyramidal neuron cell type constitutes 60-70% of all the neurons of the cortex and yet is completely absent in mid-brain structures and the peripheral nervous system. This project funded by the Swiss National Science Foundation examines the role of the pyramidal neuron in relationship to the laminar cortical network and offers a hypothesis about its function based on its morphology and cellular properties.Layer 5 pyramidal neurons constitute the principal output neurons and therefore have the role of encapsulating the information of any given column. Their stereotypical morphology, with a tuft dendrite in upper layers and basal dendrites in lower layers, coupled with the presence of a second spike initiation zone situated within the distal dendritic arborization, provides an ideal biophysical and anatomical locus for long-range cortical associations. In this project we are investigating the integrative properties of pyramidal neurons and their role in cortical associative behavior. We focus on dendritic calcium spikes because we hypothesize that they are most likely to occur during the conjunction of top-down and bottom-up inputs. Electrophysiological experiments are carried out with patch pipettes directly from the dendrites and somata of pyramidal neurons in cortical slices and in vivo in the whole brain. Calcium imaging is used to focus on dendritic Ca2+ spikes and we have developed an optical fiber system attached to the skull of a rat to record dendritic Ca2+ spikes in the behaving rat.The mechanisms that we examine with this research program address how the brain interprets the constant flow of sensory information. The major underlying hypothesis is that bottom-up input (sensory information) meets top-down input (internal representation) in the dendrites of neocortical pyramidal neurons. When this occurs, these neurons fire more APs and change their mode of firing to burst firing.