Helen E. Jones

Always returning: feedback and sensory processing in visual cortex and thalamus

Feedback projections are an integral part of the mammalian visual system. Although it is tempting to relegate them to a subsidiary role in visual processing, because their supposed latency and lag might appear to be unfavourable for an involvement in fast processing, this is a dangerous simplification. Certainly for the world in motion, feedback from higher motion areas can influence the transfer of ascending input when, or even before, the input arrives. Here, we consider the circuit formed by layer 6 feedback cells in the visual cortex and how this straddles the retinothalamic and thalamocortical transfer of visual input. We discuss its links to feedback from the cortical motion area MT (V5), and suggest that motion perception involves a dynamic interplay between MT, V1 and the thalamus. This review is part of the TINS special issue on The Neural Substrates of Cognition.

Functional alignment of feedback effects from visual cortex to thalamus.

Following from the classical work of Hubel and Wiesel, it has been recognized that the orientation and the on- and off-zones of receptive fields of layer 4 simple cells in the visual cortex are linked to the spatial alignment and properties of the cells in the visual thalamus that relay the retinal input. Here we present evidence showing that the orientation and the on- and off-zones of receptive fields of layer 6 simple cells in cat visual cortex that provide feedback to the thalamus are similarly linked to the alignment and properties of the receptive fields of the thalamic cells they contact. However, the pattern of influence linked to on- and off-zones is phase-reversed. This has important functional implications.

Corticothalamic feedback enhances stimulus response precision in the visual system

There is a tightly coupled bidirectional interaction between visual cortex and visual thalamus [lateral geniculate nucleus (LGN)]. Using drifting sinusoidal grating stimuli, we compared the response of cells in the LGN with and without feedback from the visual cortex. Raster plots revealed a striking difference in the response pattern of cells with and without feedback. This difference was reflected in the results from computing vector sum plots and the ratio of zero harmonic to the fundamental harmonic of the fast Fourier transform (FFT) for these responses. The variability of responses assessed by using the Fano factor was also different for the two groups, with the cells without feedback showing higher variability. We examined the covariance of these measures between pairs of simultaneously recorded cells with and without feedback, and they were much more strongly positively correlated with feedback. We constructed orientation tuning curves from the central 5 ms in the raw cross-correlograms of the outputs of pairs of LGN cells, and these curves revealed much sharper tuning with feedback. We discuss the significance of these data for cortical function and suggest that the precision in stimulus-linked firing in the LGN appears as an emergent factor from the corticothalamic interaction.

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°) was much smaller than that of cortical cells (3.58°). 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.

Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro

Summary Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for &agr;SMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGF&bgr;, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of &agr;-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.

Effects of cortical feedback on the spatial properties of relay cells in the lateral geniculate nucleus

Feedback connections to early-level sensory neurons have been shown to affect many characteristics of their neural response. Because selectivity for stimulus size is a fundamental property of visual neurons, we examined the summation tuning and discretely mapped receptive field (RF) properties of cells in the lateral geniculate nucleus (LGN) both with and without feedback from visual cortex. Using extracellular recording in halothane-anesthetized cats, we used small luminance probes displaced in Cartesian coordinates to measure discrete response area, and optimal sinusoidal gratings of varying diameter to estimate preferred optimal summation size and level of center-surround antagonism. In conditions where most cortical feedback was pharmacologically removed, discretely mapped RF response areas showed an overall significant enlargement for the population compared with control conditions. A switch to increased levels of burst firing, spatially displaced from the RF center, suggested this was mediated by changes in excitatory-inhibitory balance across visual space. With the use of coextensive stimulation, there were overall highly significant increases in the optimal summation size and reduction of surround antagonism with removal of cortical feedback in the LGN. When fitted with a difference-of-Gaussian (DOG) model, changes in the center size, center amplitude, and surround amplitude parameters were most significantly related to the removal of cortical feedback. In summary, corticothalamic innervation of the visual thalamus can modify spatial summation properties in LGN relay cells, an effect most parsimoniously explained by changes in the excitatory-inhibitory balance.

Differential Feedback Modulation of Center and Surround Mechanisms in Parvocellular Cells in the Visual Thalamus

Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input. However, local thalamic inhibitory interneurons also play a role, and as we examine here, feedback from the visual cortex too. Here, we show in the primate (macaque) that spatially organized cortical feedback provides a clear and differential influence serving to enhance both responses to stimulation within the center of the receptive field and the ability of the nonclassical surround mechanism to attenuate this. In short, both center and surround mechanisms are influenced by the feedback. This dynamically sharpens the spatial focus of the receptive field and introduces nonlinearities from the cortical mechanism into the LGN.

Figure-ground modulation in awake primate thalamus

Significance Perceptually, the visual cortical areas are considered to reconstruct objects from the diverse components of early distributed processing by grouping image elements and segregating them from the background as a figure. An assumption here is that raw, essentially unchanged information from the visual thalamus provides the basic pattern essential for the operation of these higher-level abstractions. However, here we demonstrate strong enhancement of neuronal firing to the figure component of a figure-ground stimulus in recordings from the visual thalamus of behaving primates. This suggests the signature of a higher-order percept is introduced into the thalamus in a reentrant manner via the corticofugal feedback connections and causes our visual input to confirm what we think we are seeing. Figure-ground discrimination refers to the perception of an object, the figure, against a nondescript background. Neural mechanisms of figure-ground detection have been associated with feedback interactions between higher centers and primary visual cortex and have been held to index the effect of global analysis on local feature encoding. Here, in recordings from visual thalamus of alert primates, we demonstrate a robust enhancement of neuronal firing when the figure, as opposed to the ground, component of a motion-defined figure-ground stimulus is located over the receptive field. In this paradigm, visual stimulation of the receptive field and its near environs is identical across both conditions, suggesting the response enhancement reflects higher integrative mechanisms. It thus appears that cortical activity generating the higher-order percept of the figure is simultaneously reentered into the lowest level that is anatomically possible (the thalamus), so that the signature of the evolving representation of the figure is imprinted on the input driving it in an iterative process.

Focal Gain Control of Thalamic Visual Receptive Fields by Layer 6 Corticothalamic Feedback

The projections between the thalamus and primary visual cortex (V1) are a key reciprocal neural circuit, relaying retinal signals to cortical layers 4 & 6 while being simultaneously regulated by massive layer 6 corticothalamic feedback. Effectively dissecting the influence of this corticothalamic feedback circuit in higher mammals remains a challenge for vision research. By pharmacologically increasing the focal gain of visually driven layer 6 responses of cat V1 in a controlled fashion, we examined the effects of such focal cortical changes on the response amplitudes and spatial structure of the receptive fields (RFs) of individual dorsal lateral geniculate nucleus (dLGN) cells. We found that enhancing visually driven cortical feedback could facilitate or suppress the overall responses of dLGN cells, and such an effect was linked to the orientation preference of the cortical neuron. Related to these selective retinotopic gain changes, enhanced feedback induced the RFs of dLGN cells to expand, contract or shift their spatial focus. Our results provide further evidence for a functional mechanism through which the cortex can selectively gate visual information flow from the thalamus back to the visual cortex.

The role of the thalamic reticular nucleus in visual processing

The thalamic reticular nucleus (TRN) is an integral part of the thalamic circuitry that mediates the transfer of information to the cortex in the major sensory pathways. Here, we consider its role in visual processing. The TRN provides an inhibitory, GABA-mediated input to relay cells in the thalamus. A key feature of TRN cells is that, because of the extent of their dendritic arborization, they have the capacity to collate visual information from the ascending relay cells and feedback axons from the cortex over a wide retinotopic area, but they feed it back to the thalamus in a narrowly focused retinotopic projection. The corticofugal input to TRN cells is mediated by a higher proportion of AMPA receptors than that to thalamic relay cells and produces sharp EPSCs. We suggest that this might bias the TRN cells to precisely timed, feature-driven feedback from the visual cortex. TRN cells are particularly well driven by either phasic or moving stimuli, so the influence on relay cells provides a strong, transient, inhibitory modulation of relay-cell activity. This might aid image segmentation and highlight responses to moving contours. Although the role of the TRN has been especially linked to selective attention, we suggest that, for vision, its function is linked more closely to the operation of the thalamocortico-thalamic loop as a whole, and that retinotopically selective attentional effects draw on the interaction with the cortical mechanism that influences TRN and relay-cell circuitry equally.