The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.

Despite the lack of direct evidence, it is generally believed that top-down signals are mediated by the abundant feedback connections from higher-to lower-order sensory areas. Here we provide direct evidence for a top-down mechanism. We stained the visual cortex of the ferret with a voltage-sensitive dye and presented a short-duration contrast square. This elicited an initial feedforward and lateral spreading depolarization at the square representation in areas 17 and 18. After a delay, a broad feedback wave (FBW) of neuron peak depolarization traveled from areas 21 and 19 toward areas 18 and 17. In areas 18 and 17, the FBW contributed the peak depolarization of dendrites of the neurons representing the square, after which the neurons decreased their depolarization and firing. Thereafter, the peak depolarization surrounded the figure representation over most of areas 17 and 18 representing the background. Thus, the FBW is an example of a well behaved long-range communication from higher-order visual areas to areas 18 and 17, collectively addressing very large populations of neurons representing the visual scene. Through local interaction with feedforward and lateral spreading depolarization, the FBW differentially activates neurons representing the object and neurons representing the background.T he current view of perception and cognition is that they rely on three main brain mechanisms, each supported by the existence of particular anatomical connections: bottom up, i.e., processing by early sensory areas, which is conveyed to higherorder areas; lateral processing through horizontal connections within an area; and top-down modulatory influences exerted by the rather extensive anatomical connections from higher-order sensory areas to the cortex in early sensory areas. Despite the fact that these top-down connections have been known for Ͼ25 years (1), and despite an overwhelming number of reports in which one could interpret the observations as presumed effects of top-down modulations, there is still no direct physiological evidence revealing the mechanism(s) by which higher-order sensory areas alter the computations of neurons in early sensory areas (2). That is, there is no evidence how, when, and where the top-down inputs alter the computation of neurons in early sensory areas. Further, the relative importance and timing of local lateral computations and top-down effects in previous studies of object perception are not obvious (3-5).Here, we define top-down modulation as a mechanism by which higher-order sensory areas through their connections influence computations of neurons in early sensory areas. These connections typically target neurons in upper (supragranular) layers or in lower (infragranular) layers within these early areas. Theoretically, it has been proposed that lateral interactions and the eventual feedback from higher-order visual areas would be finely timed to engage a large population of supragranular neurons in areas 17 and 18 in a cooperative computation of the visual stimulus and its surrou...

The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) [1], this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2-4]. Here, we employed optogenetic and electrophysiological techniques to systematically analyze the functional role of five key subareas of the rat medial PFC (mPFC) and orbitofrontal cortex (OFC) in action control [5-9]. Inactivation of mPFC subareas induced drastic changes in performance, namely an increase (prelimbic cortex, PL) or decrease (infralimbic cortex, IL) of premature responses. Additionally, electrophysiology revealed a significant decrease in neuronal activity of a PL subpopulation prior to premature responses. In contrast, inhibition of OFC subareas (mainly the ventral OFC, i.e., VO) significantly impaired the ability to respond rapidly after external cues. Consistent with these findings, mPFC activity during response preparation predicted trial outcomes and reaction times significantly better than OFC activity. These data support the concept of opposing roles of IL and PL in directing proactive behavior and argue for an involvement of OFC in predominantly reactive movement control. By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders [10-12].

Motion can be perceived when static images are successively presented with a spatial shift. This type of motion is an illusion and is termed apparent motion (AM). Here we show, with a voltage sensitive dye applied to the visual cortex of the ferret, that presentation of a sequence of stationary, short duration, stimuli which are perceived to produce AM are, initially, mapped in areas 17 and 18 as separate stationary representations. But time locked to the offset of the 1st stimulus, a sequence of signals are elicited. First, an activation traverses cortical areas 19 and 21 in the direction of AM. Simultaneously, a motion dependent feedback signal from these areas activates neurons between areas 19/21 and areas 17/18. Finally, an activation is recorded, traveling always from the representation of the 1st to the representation of the next or succeeding stimuli. This activation elicits spikes from neurons situated between these stimulus representations in areas 17/18. This sequence forms a physiological mechanism of motion computation which could bind populations of neurons in the visual areas to interpret motion out of stationary stimuli.

Purpose: Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. Methods: Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining was used to detect apoptosis. Results: A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with α-tubulin and γ-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6 ± 6.6% to 67 ± 5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8 ± 1.3% to 17.6 ± 2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining 5 to 7 days after irradiation. Conclusion: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.