The role of intrinsic cortical connections in processing sensory input and in generating behavioral output is poorly understood. We have examined this issue in the context of the tuning of neuronal responses in cortex to the orientation of a visual stimulus. We analytically study a simple network model that incorporates both orientationselective input from the lateral geniculate nucleus and orientation-specific cortical interactions. Depending on the model parameters, the network exhibits orientation selectivity that originates from within the cortex, by a symmetrybreaking mechanism. In this case, the width of the orientation tuning can be sharp even if the lateral geniculate nucleus inputs are only weakly anisotropic. By using our model, several experimental consequences of this cortical mechanism of orientation tuning are derived. The tuning width is relatively independent of the contrast and angular anisotropy of the visual stimulus. The transient population response to changing of the stimulus orientation exhibits a slow "virtual rotation." Neuronal cross-correlations exhibit long time tails, the sign of which depends on the preferred orientations of the cells and the stimulus orientation.Neurons in the primary visual cortex respond preferentially to edges with a particular orientation. The input to the cortex is provided by neurons in the lateral geniculate nucleus (LGN), which respond independently of the stimulus orientation. The mechanism for the generation of orientation selectivity in the cortex is not fully known (1-8). According to the classical model of Hubel and Wiesel (1), the preferred orientation (PO) of a cortical cell originates from the geometrical alignment of the circular receptive fields of the LGN neurons that are afferent to it. The experimental evidence of this model is ambiguous. The alignment of the receptive fields of the LGN inputs to a cortical cell apparently parallels the cell's PO (2). However, suppression of cortical inhibition tends to considerably degrade orientation tuning (3, 4), suggesting that cortical circuitry plays an important role in shaping the relatively sharp orientation tuning in the cortex. Furthermore, estimates based on intracellular measurements indicate that most of the orientation-selective excitatory input to cortical cells comes from cortical feedback (6). Several models implicating cortical inhibition have been proposed (for reviews, see refs. 7 and 8). Their analysis, however, is hindered by the need to resort to massive numerical simulations of the different models. Computational complexity also precluded a detailed study of the role of the cortical excitatory connections. An important constraint on modeling orientation selectivity, which has not yet been fully addressed, is the experimental finding that the tuning width is relatively insensitive to the contrast of the stimulus (9). Most experimental and theoretical studies of orientation selectivity focus on the response properties of single neurons. However, valuable insight into the cooperat...

The intracellular activity of the p53 tumor suppressor protein is regulated through a feedback loop involving its transcriptional target, mdm2. We present a simple mathematical model suggesting that, under certain circumstances, oscillations in p53 and Mdm2 protein levels can emerge in response to a stress signal. A delay in p53-dependent induction of Mdm2 is predicted to be required, albeit not sufficient, for this oscillatory behavior. In line with the predictions of the model, oscillations of both p53 and Mdm2 indeed occur on exposure of various cell types to ionizing radiation. Such oscillations may allow cells to repair their DNA without risking the irreversible consequences of continuous excessive p53 activation.

Mutations in the p53 tumor-suppressor gene promote increased genomic instability and cancer. Mutations in the WRN gene, encoding a DNA helicase, underlie the segmental progeroid Werner syndrome (WS). WS is also associated with increased genomic instability and elevated cancer risk. The p53 and WRN proteins can engage in direct protein-protein interactions. We report that excess WRN elicits increased cellular p53 levels and potentiates p53-mediated apoptosis. Importantly, cells derived from WS patients exhibit an attenuated and delayed induction of p53 by UV or by the topoisomerase I inhibitor camptothecin. These results suggest that WRN may participate in the activation of p53 in response to certain types of DNA damage. Furthermore, the failure to induce p53 effectively may contribute to enhanced genomic instability and elevated cancer risk in WS patients.