Function of mGlu1 receptors in the modulation of nociceptive processing in the thalamus.

As postsynaptic metabotropic subtype 1 (mGlu1) receptors are present in the thalamus, we have investigated the effect of potentiating and antagonising mGlu1 receptors on responses of thalamic neurones to noxious sensory stimulation. Extracellular recordings were made in vivo with multi-barrel iontophoretic electrodes from single neurones in the thalamus of urethane-anaesthetised rats. Responses to iontophoretic applications of the Group I mGlu agonist 3,5-dihydroxy-phenylglycine (DHPG) were selectively potentiated by co-application of the mGlu1 positive allosteric modulator Ro67-4853, whereas they were selectively reduced upon co-application of the mGlu1 receptor orthosteric antagonist LY367385. This indicates that thalamic DHPG responses are mediated primarily via mGlu1 receptors, consistent with the high postsynaptic levels of this receptor in the thalamus. Furthermore, potentiation of DHPG responses by Ro67-4853 were greater when the initial DHPG response was of a low magnitude. Ro67-4853 also potentiated responses of thalamic neurones to noxious thermal stimulation, whilst having little effect on the baseline activity of nociceptive neurones. By contrast, nociceptive responses were reduced by LY367385. In a further series of experiments we found that inactivation of somatosensory cortex by cooling resulted in a reduction of thalamic nociceptive responses. These results underline the importance of mGlu1 receptors in the processing of sensory information in the thalamus, particularly with respect to nociceptive responses. Furthermore, the involvement of mGlu1 receptors may reflect the activity of descending cortico-thalamic afferents.

Responses of primate LGN cells to moving stimuli involve a constant background modulation by feedback from area MT.

The feedback connections from the cortical middle temporal (MT) motion area, to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re-entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus.

Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator.

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes.

Imaging multiple phases of neurodegeneration: a novel approach to assessing cell death in vivo.

Nerve cell death is the key event in all neurodegenerative disorders, with apoptosis and necrosis being central to both acute and chronic degenerative processes. However, until now, it has not been possible to study these dynamically and in real time. In this study, we use spectrally distinct, well-recognised fluorescent cell death markers to enable the temporal resolution and quantification of the early and late phases of apoptosis and necrosis of single nerve cells in different disease models. The tracking of single-cell death profiles in the same living eye over hours, days, weeks and months is a significant advancement on currently available techniques. We identified a numerical preponderance of late-phase versus early-phase apoptotic cells in chronic models, reinforcing the commonalities between cellular mechanisms in different disease models. We showed that MK801 effectively inhibited both apoptosis and necrosis, but our findings support the use of our technique to investigate more specific anti-apoptotic and anti-necrotic strategies with well-defined targets, with potentially greater clinical application. The optical properties of the eye provide compelling opportunities for the quantitative monitoring of disease mechanisms and dynamics in experimental neurodegeneration. Our findings also help to directly observe retinal nerve cell death in patients as an adjunct to refining diagnosis, tracking disease status and assessing therapeutic intervention.

[The European Vision Institute. Opening up new frontiers?]. / Das "European Vision Institute". Aufbruch zu neuen Ufern?

The European Vision Institute EEIG (EVI) creates a new legal entity based on Community law to facilitate and encourage cross-border co-operation in vision research. Its major objectives are to conduct and support research, training, health information dissemination and other programmes with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight and the special health problems and requirements of the blind and visually disabled. EVI aims to foster centres in the EU in capacity building for innovative projects, to increase the flexibility, attractiveness and competitiveness of research careers, especially for young researchers. In addition, EVI will serve to co-ordinate activities with patient organisations and to build a pan-European platform for clinical trials.

Spatial organization and magnitude of orientation contrast interactions in primate V1.

We have explored the spatial organization of orientation contrast effects in primate V1. Our stimuli were either concentric patches of drifting grating of varying orientation and diameter or grating patches displaced in x-y coordinates around a central patch overlying the classical receptive field (CRF). All cells in the sample exhibited response suppression to iso-oriented stimuli exceeding the CRF. Changing the outer stimulus orientation revealed five response patterns: 1) orientation alignment suppression (17% of cells)-a suppressive component tuned to the same orientation as the cell's optimal, 2) orientation contrast facilitation (63%)-responses to orientation contrast stimuli exceeded those to the center stimulus alone, 3) nonorientation specific suppression (3%), 4) mixed general suppression and alignment suppression (14%), and 5) orientation contrast suppression (14%)-cross-oriented stimuli evoked stronger suppression than iso-oriented stimuli. Thus most cells (94%) showed larger responses to orientation contrast stimuli than to iso-oriented stimuli, and over one-half showed orientation contrast facilitation. There appeared to be a spatially structured organization of the zones driving the different response patterns with respect to the CRF. Nonorientation-specific suppression and orientation contrast suppression were predominantly evoked by orientation contrast borders located within the CRF, and orientation contrast facilitation was mainly driven by surround stimuli lying outside the CRF. This led to different response patterns according to border location. Zones driving orientation contrast facilitation were not necessarily contiguous to, nor uniformly distributed around, the CRF. Our data support two processes underlying orientation contrast enhancement effects: a simple variation in the strength of surround suppression drawing on the fact that surround suppression is tuned to the same orientation as the CRF and a second process driven by orientation contrast that enhanced cells' responses to CRF stimulation by either dis-inhibition or orientation contrast facilitation. We suggest these processes may serve to enhance response levels to salient image features such as junctions and corners and may contribute to orientation pop-out.

Surround suppression in primate V1.

We investigated the spatial organization of surround suppression in primate primary visual cortex (V1). We utilized drifting stimuli, configured to extend either from within the classical receptive field (CRF) to surrounding visual space, or from surrounding visual space into the CRF or subdivided to generate direction contrast, to make a detailed examination of the strength, spatial organization, direction dependence, mechanisms, and laminar distribution of surround suppression. Most cells (99/105, 94%) through all cortical layers, exhibited suppression (mean reduction 67%) to uniform stimuli exceeding the CRF, and 43% exhibited a more than 70% reduction. Testing with an annulus revealed two different patterns of surround influence. Some cells (37% of cells), classical surround suppression (CSS) cells exhibited responses to an annulus encroaching on the CRF that were less than the plateau in the spatial summation curve. The majority (63%), center-gated surround suppression (CGSS) cells, showed responses to annuli that equaled or exceeded the plateau in the spatial summation curve. Analysis suggested the CSS mechanism was implemented in all cells while the CGSS mechanism was implemented in varying strength across the sample with the extreme reflected in cells that gave larger responses to annuli than to a center stimulus. Reversing the direction of motion of the portion of the stimulus surrounding the CRF revealed four different patterns of effect: no reduction in the degree of suppression (22% of cells), a reduction in surround suppression (41%), a facilitation of the response above the level to the inner stimulus alone (37%), and a facilitation of the response above that to the inner stimulus alone that also exceeded the values associated with an optimal inner stimulus. The facilitatory effects were only seen for reverse direction interfaces between the central and surrounding stimulus at diameters equal to or more than the CRF size. The zones driving the suppressive influences and the direction contrast facilitation were often spatially heterogeneous and for a number of cells bore strong comparison with the class of behavior reported for surround mechanisms in MT. This suggests a potential role, for example, in extracting information about motion contrast in the representation of the three dimensional structure of moving objects.

Spatial summation in lateral geniculate nucleus and visual cortex.

We have compared the spatial summation characteristics of cells in the primary visual cortex with those of cells in the dorsal lateral geniculate nucleus (LGN) that provide the input to the cortex. We explored the influence of varying the diameter of a patch of grating centred over the receptive field and quantitatively determined the optimal summation diameter and the degree of surround suppression for cells at both levels of the visual system using the same stimulus parameters. The mean optimal summation size for LGN cells (0.90 degrees) was much smaller than that of cortical cells (3.58 degrees). Virtually all LGN cells exhibited strong surround suppression with a mean value of 74%+/-1.61% SEM for the population as a whole. This potent surround suppression in the cells providing the input to the cortex suggests that cortical cells must integrate their much larger summation fields from the low firing rates associated with the suppression plateau of the LGN cell responses. Our data suggest that the strongest input to cortical cells will arise from geniculate cells representing areas of visual space located at the borders of a visual stimulus. We suggest that analysis of response properties by patterns centred over the receptive fields of cells may give a misleading impression of the process of the representation. Analysis of pattern terminations or salient borders over the receptive field may provide much more insight into the processing algorithms involved in stimulus representation.

Oscillations and long-lasting correlations in a model of the lateral geniculate nucleus and visual cortex.

We have previously developed a model of the corticogeniculate system to explore cortically induced synchronization of lateral geniculate nucleus (LGN) neurons. Our model was based on the experiments of Sillito et al. Recently Brody discovered that the LGN events found by Sillito et al. correlate over a much longer period of time than expected from the stimulus-driven responses and proposed a cortically induced slow covariation in LGN cell membrane potentials to account for this phenomenon. We have examined the data from our model, and we found, to our surprise, that the model shows the same long-term correlation. The model's behavior was the result of a previously unsuspected oscillatory effect, not a slow covariation. The oscillations were in the same frequency range as the well-known spindle oscillations of the thalamocortical system. In the model, the strength of feedback inhibition from the cortex and the presence of low-threshold calcium channels in LGN cells were important. We also found that by making the oscillations more pronounced, we could get a better fit to the experimental data.

Comparison of the laminar distribution of input from areas 17 and 18 of the visual cortex to the lateral geniculate nucleus of the cat.

The feedback from area 18 of the cat visual cortex to the lateral geniculate nucleus has been investigated by labeling and reconstructing seventeen axons of known receptive field position and eye preference. The distribution of boutons from each axon was quantified with respect to the compartments of the geniculate complex, and the results were compared with an equivalent analysis of fourteen area 17 axons. Area 18 axons form large, sparse arborizations that extend up to 1.9 mm laterally (1170 +/- 85 microm; mean +/- SEM), with a core of relatively dense innervation spanning on average 600 +/- 70 microm (mean +/- SEM). Thus, they have the potential to influence the transmission of visual information from well beyond their own classical receptive fields. In this respect, they are surprisingly similar to the axons from area 17, despite the fact that the two cortical areas have very different retinotopy. However, there are important differences between the pathways. Area 18 axons project more heavily to the C layers and medial interlaminar nucleus. Whereas the input from both areas to the A layers is biased toward the layer appropriate to the eye preference of each axon, the area 18 input to magnocellular layer C is not. The distribution of area 18 boutons favors the bottom of their preferred A layer, and the area 17 boutons favor the top. These differences mirror those seen in the afferent pathways, suggesting that each cortical area preferentially targets the cells from which it receives input. Finally, their greater diameter suggests that area 18 axons provide the earliest feedback signal in the corticogeniculate loop.

Feedback connections to the lateral geniculate nucleus and cortical response properties.

The cerebral cortex receives sensory input from the periphery by means of thalamic relay nuclei, but the flow of information goes both ways. Each cortical area sends a reciprocal projection back to the thalamus. In the visual system, the synaptic relations that govern the influence of thalamic afferents on orientation selectivity in the cortex have been studied extensively. It now appears that the connectivity of the corticofugal feedback pathway is also fundamentally linked to the orientation preference of the cortical cells involved.

Functional morphology of the feedback pathway from area 17 of the cat visual cortex to the lateral geniculate nucleus.

Two approaches were adopted to study the pattern of connectivity between the cat visual cortex and lateral geniculate nucleus. Fourteen individual cortico-geniculate axons were labeled and reconstructed after intracellular or extracellular injection of biocytin into regions of known receptive-field position and ocular dominance preference, and the distribution of boutons from multi-axon clusters was mapped in three dimensions and compared with the locations of strategically placed geniculate recordings made in the same tissue. The results show that the feedback has an accurate retinotopic component but that individual axons are both more extensive and more selective than described previously. Area 17 feedback axons terminate primarily in layers A and A1, but the distribution of terminal boutons is strongly biased (3:1 ratio) toward the layer that matches their eye preference. Thus, those driven by the contralateral eye preferentially target layer A, and those driven by the ipsilateral eye target layer A1. Each axon also innervates the perigeniculate nucleus (PGN), but the pattern is otherwise variable, suggesting that there are different axonal classes. The terminal fields of individual axons are much larger than described previously, with a maximum spread of 500-1500 microns. Nevertheless, the projection from a given location in area 17 has a center of maximum terminal density 400-500 microns across, which is in retinotopic correspondence with the aggregate receptive field of the cortical cells of origin. The surrounding zone of relatively sparse boutons, however, must permit corticofugal cells to influence visual processing well beyond the regions over which their own responses summate. It follows that any geniculate cell receives corticofugal input covering an equally extensive area of visual space.

Spatial frequency tuning of orientation-discontinuity-sensitive corticofugal feedback to the cat lateral geniculate nucleus.

1. The influence of spatial frequency on the inhibitory component of the effects mediated by feedback from the visual cortex has been examined in X and Y cells in the A laminae of the feline dorsal lateral geniculate nucleus (dLGN). Experiments utilized a concentric, bipartite visual stimulus centered over the receptive fields of the cells studied. The responses of dLGN cells to selective stimulation of receptive field centre (with the inner window) were compared with those to stimulation of centre and surround mechanisms (both inner and outer window), with the stimuli either in or out of orientation alignment. 2. With these same stimuli, layer VI cells in the visual cortex showed a marked increase in response magnitude when the inner and outer components of the stimulus were in orientation alignment, and presented at the preferred orientation. In the case of dLGN X and Y cells we observed an enhancement of the surround antagonism of the centre response when the inner and outer sections of the stimulus were in orientation alignment. 3. The effects of varying spatial frequency on these responses were examined in dLGN cells in the presence of corticofugal feedback. With the stimulus sections in orientation alignment, surround stimulation produced a powerful and significant reduction in the response to stimulation of centre mechanism alone with the most marked effects for stimuli in the range 0.1-0.85 cycles per degree (c.p.d.). The reduction produced by surround stimulation in the range 0.1-0.5 c.p.d. was notably more potent in X cells than in Y cells. 4. The responses to the same stimuli were examined in dLGN cells with the corticofugal feedback inactivated. Comparison of data from cells studied with and without feedback revealed a significant decrease in surround-mediated attenuation of the centre response in Y cells for spatial frequencies in the range 0.1-0.85 c.p.d. For X cells the decrease in strength of the surround antagonism was also clear and significant but only seen in the range 0.1-0.5 c.p.d. 5. The influence of the orientation alignment of inner and outer stimulus sections revealed a marked difference between cells studied with and without feedback. In the presence of feedback fully aligned stimuli enhanced surround antagonism of centre responses for spatial frequencies in the range 0.1-0.5 c.p.d., in X and Y cells. In the absence of corticofugal feedback this alignment effect was essentially eliminated. 6. These data show that surround antagonism of the centre response is influenced by orientation alignment of the stimulus sections at low spatial frequencies and in the presence of corticofugal feedback. They support a cortically driven enhancement of the inhibitory mechanisms reinforcing surround mechanisms in the dLGN. We propose that feedback enhances a low spatial frequency cut-off in the dLGN, that this effect is maximal for a continuous iso-orientated contour, but diminished whenever there is an orientation discontinuity. The hyperpolarizing influence underlying this effect may contribute to the recently described synchronizing influence of the direct corticofugal contacts onto relay cells. We suggest feedback of the cortical level of analysis refines the transfer of the visual input at geniculate level in a stimulus-context-dependent fashion.

Context-dependent interactions and visual processing in V1.

We examined the influence of stimulus context on the response of cells in primate V1 utilising both concentric and spatially discrete stimuli. The majority of cells (63/71) showed marked patch suppression, including non-oriented cells. This suppression was reduced or lost if there was an orientation discontinuity in the stimulus overlying the receptive field. Cross-oriented stimuli could exert strong facilitatory effects so that a cell's response to an optimally oriented stimulus over its receptive field was increased by the presence of an adjacent cross-oriented stimulus. This increase appeared to involve both disinhibition as well as a direct facilitation. The strength of the cross-orientation effects was such that for some cells it seemed appropriate to define a cross-oriented stimulus configuration as the 'optimal' stimulus. Effects following from orientation context could be strongly influenced by stimulus direction. Subcortical as well as cortical interactions may contribute to these observations. It is suggested that the properties of the network as a whole define the responses of individual cells and that the representation of discontinuities is an important component of network function in V1.

Visual cortical mechanisms detecting focal orientation discontinuities.

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.

Differential properties of cells in the feline primary visual cortex providing the corticofugal feedback to the lateral geniculate nucleus and visual claustrum.

We have examined the responses of 141 layer VI cells in the feline visual cortex. Within this group we compared the responses of a subpopulation of cells checked for connectivity by electrical stimulation in the dLGN and the visual claustrum. The antidromically identified corticogeniculate projecting cells had relatively short receptive fields, as judged from length response curves, measured quantitatively, and were located at the "short" end of the receptive field length spectrum seen in the general population. Of the 17 corticogeniculate projecting cells, 71% were S type cells, which were typically monocular and directionally selective, with relatively long latencies following electrical stimulation. The remaining 29% were C type cells, also directionally selective, but with a wider spread of ocular dominance preferences and shorter latencies following electrical stimulation. S and C type subpopulations did not differ in their receptive field lengths. The mean receptive field length for this subpopulation was 2.2 degrees +/- 0.27, the shortest field being 1 degrees and the longest 5 degrees. The five layer VI cells activated by electrical stimulation from electrodes within the dorsocaudal (visual) claustrum all had much longer receptive field lengths than the corticogeniculate population, often 10 degrees or longer and were monocular and directionally selective S type cells. These data indicate that the information carried in the corticogeniculate stream (and that from layer VI directly to layer IV carried by axon collaterals) is relatively tightly focused in spatial terms whilst the less spatially focused, long receptive field output from layer VI projects to the claustrum.

Non-length-tuned cells in layers II/III and IV of the visual cortex: the effect of blockade of layer VI on responses to stimuli of different lengths.

We have previously shown, using a local inactivation technique, that layer VI provides a facilitatory input to the majority of hypercomplex cells located in layer IV above, and hence to layers II/III, which in many cases enhances length selectivity. However, many cells in these layers are not tuned for stimulus length, being equally responsive to long and short stimuli. Thus it is important to known whether layer VI can influence the responses of these cells. We have now used a similar paradigm of iontophoretic application of GABA to examine the effect of blockade of layer VI on the length tuning profiles of these cells in layers II-IV. During the blockade of layer VI, the most common effect, seen in 41% of the cells, was inhibition of visual responses, (i.e. commensurate with loss of a facilitatory input). An increase in response magnitude was found in 21% of the population, and responses were unaffected in 36% of cells tested. This suggests that the predominant influence of local regions of layer VI on this cell type, located in layers II/III and IV, is facilitatory, with a smaller proportion of cells receiving an inhibitory input. Such effects were seen even with the shortest lengths tested, suggesting once more that elements of layer VI are responsive to stimuli much shorter than was previously accepted. Thus these data suggest that layer VI plays a role in the generation of the response dynamics of non-length-tuned cells in overlying layers II/III and IV.

Directional asymmetries in the length-response profiles of cells in the feline dorsal lateral geniculate nucleus.

1. The visual cortex provides a major synaptic input to the dorsal lateral geniculate nucleus (dLGN). Cortical layer VI cells giving rise to this projection are strongly influenced by stimulus orientation, length and direction of motion. In the dLGN, a significant component of the strong length tuning exhibited by most cells follows from the corticofugal influence. We have now checked whether there are directional biases in geniculate cell responses, and whether such biases are influenced by stimulus length. 2. The responses of A-laminae dLGN cells were assessed by single-unit extracellular recording. Length preference was examined by plotting multihistogram length-tuning curves to moving bars of light of various length. 3. Over half of the cells tested (100/183) exhibited directional bias and in many cases, this bias was highly dependent on bar length, resulting in radically different length response profiles for the two directions of motion. These asymmetries are similar to those documented for cortical hypercomplex cells, but do not equate to any known facet of the centre-surround organization of dLGN cell receptive fields. 4. We suspected the directional biases followed from the influence of the corticofugal projection. To test this, we recorded from preparations where areas 17 and 18 of the visual cortex had been removed. Surprisingly, a similar proportion of cells exhibited directional biases after removal of the corticofugal input, suggesting that the biases are generated subcortically. 5. The widespread presence of systematic biases in the response profiles of dLGN cells further underlines the possibility that geniculate mechanisms may make a far greater contribution to visual processing than hitherto suspected.

The length-response properties of cells in the feline perigeniculate nucleus.

Perigeniculate cells receive visual input from the dorsal lateral geniculate nucleus (dLGN) and from the visual cortex. In contrast to the extensive literature documenting dLGN and cortical cell responses, comparatively little quantitative data exists for perigeniculate nucleus cells, and very little is known about the role of the corticofugal input to the perigeniculate nucleus. We have previously shown that dLGN relay cells have sharply length-tuned receptive fields and that a significant component of this is dependent on the corticofugal system. In this report, we have explored the length-response properties of perigeniculate nucleus cells in the presence and absence of corticofugal feedback. The response profiles of most perigeniculate nucleus cells contrasted markedly with the sharply length-tuned fields of dLGN cells, but exhibited a notable resemblance to those exhibited by VI cells with short summation lengths, which have recently been shown to constitute a considerable proportion of the layer VI cell population. This might suggest that the responses of perigeniculate nucleus cells to long bars derive from their cortical input. However, our data failed to reveal a discernible change in their profiles after removal of the corticofugal drive. This surprising observation implies that their length-tuning profiles follow from subcortical circuitry. The ways in which this might occur are discussed.