Neurons in the primary visual cortex (V1) respond in well defined ways to stimuli within their classical receptive field, but these responses can be modified by stimuli overlying the surrounding area. For example patch-suppressed cells respond to gratings of a specific orientation within their classical receptive field, but the response diminishes if the grating is expanded to cover the surrounding area. We report here more complex effects in many such cells. When stimulated at their optimal orientation, introducing a surrounding field at a significantly different (for example, orthogonal) orientation enhanced their output by both a disinhibitory mechanism and an active facilitatory mechanism producing 'supra-optimal' responses. Importantly, some cells responded well if the orientations of centre and surround stimuli were swapped. The output reflected the discontinuity because neither stimulus component alone was effective. Under these stimulus conditions simultaneously recorded cells with orthogonally oriented receptive fields showed correlated firing consistent with neuronal binding to the configuration. We propose a mechanism integrating orientation-dependent information over adjacent areas of visual space to represent focal orientation discontinuities such as junctions or corners.

SUMMARY1. The iontophoretic application of the GABA antagonist bicuculline to simple and complex cells in the striate cortex of the cat produced extensive modifications of receptive field properties. These modifications appear to relate to a block or reduction of GABA-mediated intracortical inhibitory influences acting on the cells examined.2. For simple cells the effects of bicuculline on receptive field properties involved a loss of the subdivision of the receptive field into antagonistic ' on ' and 'off' regions, a reduction in orientation specificity and a reduction or elimination of directional specificity.3. The effect on the 'on' and 'off' subdivisions of the simple cell receptive field was such that all stationary flashing stimuli, whether covering the whole receptive field, or located within the receptive field over a previously determined 'on' or 'off' region, resulted in an 'on and off' response.4. The orientation specificity of complex cells was reduced during the application of bicuculline such that in many cases the original specificity of the cell was virtually lost with the response to the orientation at 900 to the optimal being of similar magnitude to the optimal. The directional specificity of complex cells was generally less affected than that of simple cells. Often when large changes in orientation specificity were observed the directional specificity was relatively unaffected.5. For some cells apparently showing to all visual stimuli only inhibitory responses, the application of bicuculline resulted in the appearance of excitatory responses.6. In all cases receptive field properties reverted to the original state after termination of the bicuculline application. It was not generally possible to duplicate the effects of bicuculline by raising neuronal excitability with iontophoretically applied glutamate. 306 A. M. SILLITO 7. On the basis of these results it is suggested that the normal subdivision of the simple cell receptive field into separate 'on' and 'off' regions and its directional specificity are dependent on intracortical inhibitory processes that are blocked by bicuculline. The orientational tuning of simple cells conversely appears to be largely determined by the excitatory input but normally enhanced by lateral type inhibitory processes acting in the orientation domain.8. It also appears that the excitatory input to some complex cells is not orientation specific. This suggests that for these cells it is extremely unlikely that they receive an orientation specific excitatory input from simple cells.

The function of the massive feedback projection from visual cortex to its thalamic relay nucleus has so far eluded any clear overview. This feedback exerts a range of effects, including an increase in the inhibition elicited by moving contours, but the functional logic of the direct connections to the thalamic cells that relay the retinal input to the cortex remains largely unknown. In contrast to its thalamic nucleus, the visual cortex is characterized by cells that are strongly sensitive to the orientation of moving contours. Here we report that when driven by moving oriented visual stimuli the cortical feedback induces correlated firing in relay cells. This cortically induced correlation of relay cell activity produces coherent firing in those groups of relay cells with receptive field alignments appropriate to signalling the particular orientation of the moving contour to the cortex. Synchronization of relay cell firing means that they will elicit temporally overlapping excitatory postsynaptic potentials in their cortical target cells, thus increasing the chance that the cortical cells will fire. Effectively this increases the gain of the input for feature-linked events detected by the cortex. We propose that this feedback loop serves to lock or focus the appropriate circuitry onto the stimulus feature.

The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-␤ (A␤) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that A␤ colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose-and time-dependent manner. We demonstrate that targeting different components of the A␤ formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the A␤ pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the A␤ pathway may be the most effective strategy in A␤-related diseases.combination therapy ͉ neuroprotection ͉ retinal ganglion cell apoptosis A lthough glaucoma, a major cause of blindness worldwide (1), is commonly linked to raised intraocular pressure (IOP) (2), the precise means by which IOP may lead to the irreversible destruction of retinal ganglion cells (RGCs, which are the nerve cells that transfer visual information from the eye to the brain) is far from clear. Indeed, interpretation of the mechanism is further complicated by the fact that damage can also occur at low IOP. Thus, for example, recent evidence indicates progressive visual-field loss in patients despite normalization of IOP with pressure-lowering treatment strategies (3, 4), which means that an alternative approach to the treatment of glaucoma is urgently needed. The principal step leading to irreversible loss of vision in glaucoma is RGC apoptosis, and the question is what mechanisms precede this cell death. Raised IOP in experimental glaucoma models can clearly precipitate RGC apoptosis (5-7) whatever the actual intervening steps. However, the presence of progressive glaucomatous damage in patients with normalized IOP has focused a growing body of work on alternative strategies to those regulating IOP and especially approaches targeting the cellular mechanisms leading to apoptosis.Amyloid-␤ (A␤) is the major constituent of senile plaques in Alzheimer's disease (AD), the formation of which, caused by abnormal processing of amyloid precursor protein (APP), has been involved in AD neuropathology, although the proximate cause of the neurodegeneration responsible for cognitive impairment is not clear (8). A␤ has recently been reported to be implicated in the development of RGC apoptosis in glaucoma, with evidence of caspase-3-mediated abnormal APP processing and increased expression of A␤ in RGCs in experimental glaucoma (9) and decreased vitreous A␤ levels (consistent with retinal A␤ deposition) in patients with glaucoma (10). Further evidenc...

Apoptotic nerve cell death is implicated in the pathogenesis of several devastating neurodegenerative conditions, including glaucoma and Alzheimer's and Parkinson's diseases. We have devised a noninvasive real-time imaging technique using confocal laserscanning ophthalmoscopy to visualize single nerve cell apoptosis in vivo, which allows longitudinal study of disease processes that has not previously been possible. Our method utilizes the unique optical properties of the eye, which allow direct microscopic observation of nerve cells in the retina. We have been able to image changes occurring in nerve cell apoptosis over hours, days, and months and show that effects depend on the magnitude of the initial apoptotic inducer in several models of neurodegenerative disease in rat and primate. This technology enables the direct observation of single nerve cell apoptosis in experimental neurodegeneration, providing the opportunity for detailed investigation of fundamental disease mechanisms and the evaluation of interventions with potential clinical applications, together with the possibility of taking this method through to patients.A poptosis is an orchestrated form of cell ''death by suicide.'' It is essential in both the development and normal maintenance of tissue function. It is also implicated in the pathology of a number of severe neurodegenerative disorders such as glaucoma, motor neuron, and Alzheimer's, Parkinson's, and Huntington's diseases (1). There is evidence that a similar pathogenesis may contribute to neurodegenerative processes in these conditions (2), and that the extent of nerve cell loss is correlated with functional deficit (3-6). If we could directly visualize this process, it would facilitate a much more precise diagnosis and critically enable accurate tracking of the disease state and the action of therapy. However, until now, it has not been possible to detect nerve cell apoptosis in vivo (1, 7-10).Annexin 5 is a protein that, in the presence of Ca 2ϩ , has a high affinity for phosphatidylserine (PS), an anionic phospholipid that is enriched in the inner leaflet of plasma membranes. The externalization of PS from the inner leaflet to the outer layer of the cell membrane is an invariant early feature in the apoptotic process that occurs before DNA fragmentation and nuclear condensation. Because of its properties, FITC-annexin 5 has become widely used in the cytological detection of cells undergoing apoptosis (11). More recently, annexin 5 has been shown to be effective in the identification of apoptosis in vivo by using radiological and macroscopic fluorescent techniques (7,8,10,12,13).However, existing in vivo techniques using annexin 5 either have been unable to resolve the process to a single cellular level (7-9) or require an invasive method performed under terminal anesthesia (10). Imaging the eye, compared with the rest of the body, offers a unique opportunity because of the presence of clear optical media allowing direct visualization of labeled disease processes as they occur. This mea...