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Introduction: Immune paralysis with massive T-cell apoptosis is a central pathogenic event during sepsis and correlates with septic patient mortality. Previous observations implied a crucial role of peroxisome proliferator-activated receptor gamma (PPARγ) during T-cell apoptosis.
Methods: To elucidate mechanisms of PPARγ-induced T-cell depletion, we used an endotoxin model as well as the caecal ligation and puncture sepsis model to imitate septic conditions in wild-type versus conditional PPARγ knockout (KO) mice.
Results: PPARγ KO mice showed a marked survival advantage compared with control mice. Their T cells were substantially protected against sepsis-induced death and showed a significantly higher expression of the pro-survival factor IL-2. Since PPARγ is described to repress nuclear factor of activated T cells (NFAT) transactivation and concomitant IL-2 expression, we propose inhibition of NFAT as the underlying mechanism allowing T-cell apoptosis. Corroborating our hypothesis, we observed up-regulation of the pro-apoptotic protein BIM and downregulation of the anti-apoptotic protein Bcl-2 in control mice, which are downstream effector proteins of IL-2 receptor signaling. Application of a neutralizing anti-IL-2 antibody reversed the pro-survival effect of PPARγ-deficient T cells and confirmed IL-2-dependent apoptosis during sepsis.
Conclusion: Apparently antagonizing PPARγ in T cells might improve their survival during sepsis, which concomitantly enhances defence mechanisms and possibly provokes an increased survival of septic patients.
‘The whole is more than the sum of its parts.’ This idea has been brought forward by psychologists such as Max Wertheimer who formulated Gestalt laws that describe our perception. One law is that of collinearity: elements that correspond in their local orientation to their global axis of alignment form a collinear line, compared to a noncollinear line where local and global orientations are orthogonal. Psychophysical studies revealed a perceptual advantage for collinear over non-collinear stimulus context. It was suggested that this behavioral finding could be related to underlying neuronal mechanisms already in the primary visual cortex (V1). Studies have shown that neurons in V1 are linked according to a common fate: cells responding to collinearly aligned contours are predominantly interconnected by anisotropic long-range lateral connections. In the cat, the same holds true for visual interhemispheric connections. In the present study we aimed to test how the perceptual advantage of a collinear line is reflected in the anatomical properties within or between the two primary visual cortices. We applied two neurophysiological methods, electrode and optical recording, and reversibly deactivated the topographically corresponding contralateral region by cooling in eight anesthetized cats. In electrophysiology experiments our results revealed that influences by stimulus context significantly depend on a unit’s orientation preference. Vertical preferring units had on average a higher spike rate for collinear over non-collinear context. Horizontal preferring units showed the opposite result. Optical imaging experiments confirmed these findings for cortical areas assigned to vertical orientation preference. Further, when deactivating the contralateral region the spike rate for horizontal preferring units in the intact hemisphere significantly decreased in response to a collinear stimulus context. Most of the optical imaging experiments revealed a decrease in cortical activity in response to either stimulus context crossing the vertical midline. In conclusion, our results support the notion that modulating influences from stimulus context can be quite variable. We suggest that the kind of influence may depend on a cell’s orientation preference. The perceptual advantage of a collinear line as one of the Gestalt laws proposes is not uniformly represented in the activity of individual cells in V1. However, it is likely that the combined activity of many V1 neurons serves to activate neurons further up the processing stream which eventually leads to the perceptual phenomenon.
"The whole is more than the sum of its parts." This idea has been brought forward by psychologists such as Max Wertheimer who formulated Gestalt laws that describe our perception. One law is that of collinearity: elements that correspond in their local orientation to their global axis of alignment form a collinear line, compared to a noncollinear line where local and global orientations are orthogonal. Psychophysical studies revealed a perceptual advantage for collinear over non-collinear stimulus context. It was suggested that this behavioral finding could be related to underlying neuronal mechanisms already in the primary visual cortex (V1). Studies have shown that neurons in V1 are linked according to a common fate: cells responding to collinearly aligned contours are predominantly interconnected by anisotropic long-range lateral connections. In the cat, the same holds true for visual interhemispheric connections. In the present study we aimed to test how the perceptual advantage of a collinear line is reflected in the anatomical properties within or between the two primary visual cortices. We applied two neurophysiological methods, electrode and optical recording, and reversibly deactivated the topographically corresponding contralateral region by cooling in eight anesthetized cats. In electrophysiology experiments our results revealed that influences by stimulus context significantly depend on a unit’s orientation preference. Vertical preferring units had on average a higher spike rate for collinear over non-collinear context. Horizontal preferring units showed the opposite result. Optical imaging experiments confirmed these findings for cortical areas assigned to vertical orientation preference. Further, when deactivating the contralateral region the spike rate for horizontal preferring units in the intact hemisphere significantly decreased in response to a collinear stimulus context. Most of the optical imaging experiments revealed a decrease in cortical activity in response to either stimulus context crossing the vertical midline. In conclusion, our results support the notion that modulating influences from stimulus context can be quite variable. We suggest that the kind of influence may depend on a cell’s orientation preference. The perceptual advantage of a collinear line as one of the Gestalt laws proposes is not uniformly represented in the activity of individual cells in V1. However, it is likely that the combined activity of many V1 neurons serves to activate neurons further up the processing stream which eventually leads to the perceptual phenomenon.