An instructive role for retinal waves in the development of retinogeniculate connectivity

A central hypothesis of neural development is that patterned activity drives the refinement of initially imprecise connections. We have examined this hypothesis directly by altering the frequency of spontaneous waves of activity that sweep across the mammalian retina prior to vision. Activity levels were increased in vivo using agents that elevate cAMP. When one eye is made more active, its layer within the LGN is larger despite the other eye having normal levels of activity. Remarkably, when the frequency of retinal waves is increased in both eyes, normally sized layers form. Because relative, rather than absolute, levels of activity between the eyes regulate the amount of LGN territory devoted to each eye, we conclude that activity acts instructively to guide binocular segregation during development.     

Competitive interactions between retinal ganglion cells during prenatal development

In the mammalian visual system, retinal ganglion cell axons terminate within the LGN in a series of alternating eye-specific layers. These layers are not present initially during development. In the cat they emerge secondarily following a prenatal period in which originally intermixed inputs from the two eyes gradually segregate from each other to give rise to the characteristic set of layers by birth. Many lines of evidence suggest that activity-dependent competitive interactions between ganglion cell axons from the two eyes for LGN neurons play an important role in the final patterning of retinogeniculate connections. Studies of the branching patterns of individual ganglion cell axons suggest that during the period when inputs from the two eyes are intermixed, axons from one eye send side branches into territory later occupied exclusively by axons from the other eye. Ultrastructural studies indicate that these branches in fact are sites of synaptic contacts, which are later eliminated since the side branches disappear as axons form their mature terminal arbors in appropriate territory. In vitro microelectrode recordings from LGN neurons indicate that they can receive convergent synaptic excitation from electrical stimulation of the optic nerves before but not after the eye-specific layers form, suggesting that at least some of the synaptic contacts seen at the ultrastructural level are functonal. Finally, experiments in which tetrodotoxin was infused intracranially during the two week period during which the eye-specific layers normally form demonstrate that it is possible to prevent, or at least delay, the formation of the layers. Accordingly, individual axons fail to develop their restricted terminal arbor branching pattern and instead branch widely throughout the LGN. These results indicate that all of the machinery necessary for synaptic function and competition is present during fetal life. Moreover, it is highly likely that neuronal activity is required for the formation of the eye-specific layers. If so, then activity would have to be present in the form of spontaneously generated action potentials, since vision is not possible at these early ages. Thus, the functioning of the retinogeniculate system many weeks before it is put to the use for which it is ultimately designed may contribute to the final patterning of connections present in the adult.     

Development of precise maps in visual cortex requires patterned spontaneous activity in the retina

The visual cortex is organized into retinotopic maps that preserve an orderly representation of the visual world, achieved by topographically precise inputs from the lateral geniculate nucleus. We show here that geniculocortical mapping is imprecise when the waves of spontaneous activity in the retina during the first postnatal week are disrupted genetically. This anatomical mapping defect is present by postnatal day 8 and has functional consequences, as revealed by optical imaging and microelectrode recording in adults. Pharmacological disruption of these retinal waves during the first week phenocopies the mapping defect, confirming both the site and the timing of the disruption in neural activity responsible for the defect. Analysis shows that the geniculocortical miswiring is not a trivial or necessary consequence of the retinogeniculate defect. Our findings demonstrate that disrupting early spontaneous activity in the eye alters thalamic connections to the cortex.     

A Burst-Based “Hebbian” Learning Rule at Retinogeniculate Synapses Links Retinal Waves to Activity-Dependent Refinement

Patterned spontaneous activity in the developing retina is necessary to drive synaptic refinement in the lateral geniculate nucleus (LGN). Using perforated patch recordings from neurons in LGN slices during the period of eye segregation, we examine how such burst-based activity can instruct this refinement. Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with “Hebbian” development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.     

A burst-based "Hebbian" learning rule at retinogeniculate synapses links retinal waves to activity-dependent refinement

Patterned spontaneous activity in the developing retina is necessary to drive synaptic refinement in the lateral geniculate nucleus (LGN). Using perforated patch recordings from neurons in LGN slices during the period of eye segregation, we examine how such burst-based activity can instruct this refinement. Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with “Hebbian” development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.     

Rapid plasticity of visual responses in the adult lateral geniculate nucleus

Compared to the developing visual system, where neuronal plasticity has been well characterized at multiple levels, little is known about plasticity in the adult, particularly within subcortical structures. We made intraocular injections of 2-amino-4-phosphonobutyric acid (APB) in adult cats to block visual responses in On-center retinal ganglion cells and examined the consequences on visual responses in the lateral geniculate nucleus (LGN) of the thalamus. In contrast to current views of retinogeniculate organization, which hold that On-center LGN neurons should become silent with APB, we find that ～50% of On-center neurons rapidly develop Off-center responses. The time course of these emergent responses and the actions of APB in the retina indicate the plasticity occurs within the LGN. These results suggest there is greater divergence of retinogeniculate connections than previously recognized and that functionally silent, nonspecific retinal inputs can serve as a substrate for rapid plasticity in the adult.     

Nob mice wave goodbye to eye-specific segregation

Spontaneous retinal activity is necessary to establish and maintain eye-specific projections to the LGN, but whether the spatial and temporal structure of this activity is important remains unclear. A new study by Demas et al. in the current issue of Neuron shows that when the frequency of spontaneous retinal waves is increased and waves abnormally persist past eye opening, eye-specific projections to the LGN desegregate. These results provide important new insight into the mechanisms that drive eye-specific refinement and stabilization.     

Abnormal functional organization in the dorsal lateral geniculate nucleus of mice lacking the beta 2 subunit of the nicotinic acetylcholine receptor

Spontaneous activity patterns in the developing retina appear important for the functional organization of the visual system. We show here that an absence of early retinal waves in mice lacking the beta2 subunit of the nicotinic acetylcholine receptor (nAChR) is associated with both gain and loss of functional organization in the dorsal lateral geniculate nucleus (dLGN). Anatomical studies show normal gross retinotopy in the beta2(-/-) dLGN but suggest reduced topographic precision in the retinogeniculate projection. Physiological recordings reveal normal topography in the dorsoventral visual axis but a lack of fine-scale mapping in the nasotemporal visual plane. In contrast, unlike wild-type mice, on- and off-center cells in the beta2(-/-) dLGN are spatially segregated. The presence of the beta2 subunit of the nAChR in the CNS is therefore important for normal functional organization in the retinogeniculate projection.     

The development of the retinogeniculate pathways in normal and albino ferrets

The retinogeniculate pathways of normal and albino ferrets have been studied with horseradish peroxidase and tritiated proline used as axonal markers. The uncrossed retinogeniculate projection of adult albino ferrets is abnormally small and occupies only a fraction of the geniculate area normally occupied by uncrossed afferents. The crossed pathway is correspondingly expanded, occupying almost the entire nucleus. The geniculate laminae in the albino ferret are abnormal, showing abnormal fusions between layers receiving crossed input and abnormal discontinuities next to the small cell islands receiving uncrossed afferents. In early development, retinofugal fibres can be labelled within the optic tracts on the 28th intrauterine day and a few crossed fibres can be traced into the lateral geniculate nucleus. At this stage, the uncrossed component is extremely small in normal and albino animals and cannot be traced beyond the tract. By day 32 retinal fibres are invading the lateral geniculate nucleus bilaterally, the invasion by the crossed component being significantly more advanced than that by the uncrossed component. The uncrossed pathway of the albinos is already abnormal in terms of its size, in terms of the position it occupies in the optic tract, and in terms of its limited invasion of the lateral geniculate nucleus. The abnormally reduced size of the uncrossed component appears earlier than the abnormal segregation of the retinogeniculate terminals, suggesting that the primary action of the albino gene upon central visual pathways is prechiasmatic. At postnatal stages (41 days after conception and older) the normal, gradual withdrawal of the uncrossed fibres from the monocular segment, and the separation of crossed from uncrossed retinogeniculate terminal arbors is significantly delayed in the albinos. The uncrossed retinogeniculate terminals are abnormally sparse initially and become distributed in an abnormal, interrupted pattern as development proceeds. The abnormal pattern of geniculate lamination appears to be secondary to the abnormal distribution of retinogeniculate afferents.     

A reaction-diffusion model to capture disparity selectivity in primary visual cortex

Decades of experimental studies are available on disparity selective cells in visual cortex of macaque and cat. Recently, local disparity map for iso-orientation sites for near-vertical edge preference is reported in area 18 of cat visual cortex. No experiment is yet reported on complete disparity map in V1. Disparity map for layer IV in V1 can provide insight into how disparity selective complex cell receptive field is organized from simple cell subunits. Though substantial amounts of experimental data on disparity selective cells is available, no model on receptive field development of such cells or disparity map development exists in literature. We model disparity selectivity in layer IV of cat V1 using a reaction-diffusion two-eye paradigm. In this model, the wiring between LGN and cortical layer IV is determined by resource an LGN cell has for supporting connections to cortical cells and competition for target space in layer IV. While competing for target space, the same type of LGN cells, irrespective of whether it belongs to left-eye-specific or right-eye-specific LGN layer, cooperate with each other while trying to push off the other type. Our model captures realistic 2D disparity selective simple cell receptive fields, their response properties and disparity map along with orientation and ocular dominance maps. There is lack of correlation between ocular dominance and disparity selectivity at the cell population level. At the map level, disparity selectivity topography is not random but weakly clustered for similar preferred disparities. This is similar to the experimental result reported for macaque. The details of weakly clustered disparity selectivity map in V1 indicate two types of complex cell receptive field organization.     

Fractal features of dark, maintained, and driven neural discharges in the cat visual system

We employ a number of statistical measures to characterize neural discharge activity in cat retinal ganglion cells (RGCs) and in their target lateral geniculate nucleus (LGN) neurons under various stimulus conditions, and we develop a new measure to examine correlations in fractal activity between spike-train pairs. In the absence of stimulation (i.e., in the dark), RGC and LGN discharges exhibit similar properties. The presentation of a constant, uniform luminance to the eye reduces the fractal fluctuations in the RGC maintained discharge but enhances them in the target LGN discharge, so that neural activities in the pair cease to be mirror images of each other. A drifting-grating stimulus yields RGC and LGN driven spike trains similar in character to those observed in the maintained discharge, with two notable distinctions: action potentials are reorganized along the time axis so that they occur only during certain phases of the stimulus waveform, and fractal activity is suppressed. Under both uniform-luminance and drifting-grating stimulus conditions (but not in the dark), the discharges of pairs of LGN cells are highly correlated over long time scales; in contrast discharges of RGCs are nearly uncorrelated with each other. This indicates that action-potential activity at the LGN is subject to a common fractal modulation to which the RGCs are not subjected.     

Kinetics of low threshold calcium channels of relay cells in cat lateral geniculate nucleus

Kinetics of the low threshold T-type Ca2+ channel is studied with single electrode voltage damp technique on brain slices of the cat lateral geniculate nucleus (LGN). Space damp is dramatically improved by blocking various K+ and Na+ channels, decreasing Ca2+ current and selecting proper holding potentials. Results from this study are similar to those obtained from acutely dissociated LGN neurons of the rat, indicating that the kinetics of T-Ca2+ channels of the cat LGN neurons is the same as that of the rat LGN. The result reported previously on the cat LGN may result from a defect in space damp.     

A simple model of retina-LGN transmission

To gain a deeper understanding of the transmission of visual signals from retina through the lateral geniculate nucleus (LGN), we have used a simple leaky integrate and-fire model to simulate a relay cell in the LGN. The simplicity of the model was motivated by two questions: (1) Can an LGN model that is driven by a retinal spike train recorded as synaptic (‘S’) potentials, but does not include a diverse array of ion channels, nor feedback inputs from the cortex, brainstem, and thalamic reticular nucleus, accurately simulate the LGN discharge on a spike-for-spike basis? (2) Are any special synaptic mechanisms, beyond simple summation of currents, necessary to model experimental recordings? We recorded cat relay cell responses to spatially homogeneous small or large spots, with luminance that was rapidly modulated in a pseudo-random fashion. Model parameters for each cell were optimized with a Simplex algorithm using a short segment of the recording. The model was then tested on a much longer, distinct data set consisting of responses to numerous repetitions of the noisy stimulus. For LGN cells that spiked in response to a sufficiently large fraction of retinal inputs, we found that this simplified model accurately predicted the firing times of LGN discharges. This suggests that modulations of the efficacy of the retino-geniculate synapse by pre-synaptic facilitation or depression are not necessary in order to account for the LGN responses generated by our stimuli, and that post-synaptic summation is sufficient.     

Predictive Feedback Can Account for Biphasic Responses in the Lateral Geniculate Nucleus

Biphasic neural response properties, where the optimal stimulus for driving a neural response changes from one stimulus pattern to the opposite stimulus pattern over short periods of time, have been described in several visual areas, including lateral geniculate nucleus (LGN), primary visual cortex (V1), and middle temporal area (MT). We describe a hierarchical model of predictive coding and simulations that capture these temporal variations in neuronal response properties. We focus on the LGN-V1 circuit and find that after training on natural images the model exhibits the brain's LGN-V1 connectivity structure, in which the structure of V1 receptive fields is linked to the spatial alignment and properties of center-surround cells in the LGN. In addition, the spatio-temporal response profile of LGN model neurons is biphasic in structure, resembling the biphasic response structure of neurons in cat LGN. Moreover, the model displays a specific pattern of influence of feedback, where LGN receptive fields that are aligned over a simple cell receptive field zone of the same polarity decrease their responses while neurons of opposite polarity increase their responses with feedback. This phase-reversed pattern of influence was recently observed in neurophysiology. These results corroborate the idea that predictive feedback is a general coding strategy in the brain.     

A minimal mechanistic model for temporal signal processing in the lateral geniculate nucleus

The receptive fields of cells in the lateral geniculate nucleus (LGN) are shaped by their diverse set of impinging inputs: feedforward synaptic inputs stemming from retina, and feedback inputs stemming from the visual cortex and the thalamic reticular nucleus. To probe the possible roles of these feedforward and feedback inputs in shaping the temporal receptive-field structure of LGN relay cells, we here present and investigate a minimal mechanistic firing-rate model tailored to elucidate their disparate features. The model for LGN relay ON cells includes feedforward excitation and inhibition (via interneurons) from retinal ON cells and excitatory and inhibitory (via thalamic reticular nucleus cells and interneurons) feedback from cortical ON and OFF cells. From a general firing-rate model formulated in terms of Volterra integral equations, we derive a single delay differential equation with absolute delay governing the dynamics of the system. A freely available and easy-to-use GUI-based MATLAB version of this minimal mechanistic LGN circuit model is provided. We particularly investigate the LGN relay-cell impulse response and find through thorough explorations of the model’s parameter space that both purely feedforward models and feedback models with feedforward excitation only, can account quantitatively for previously reported experimental results. We find, however, that the purely feedforward model predicts two impulse response measures, the time to first peak and the biphasic index (measuring the relative weight of the rebound phase) to be anticorrelated. In contrast, the models with feedback predict different correlations between these two measures. This suggests an experimental test assessing the relative importance of feedforward and feedback connections in shaping the impulse response of LGN relay cells.     

Integrate-and-fire vs Poisson models of LGN input to V1 cortex: noisier inputs reduce orientation selectivity

One of the reasons the visual cortex has attracted the interest of computational neuroscience is that it has well-defined inputs. The lateral geniculate nucleus (LGN) of the thalamus is the source of visual signals to the primary visual cortex (V1). Most large-scale cortical network models approximate the spike trains of LGN neurons as simple Poisson point processes. However, many studies have shown that neurons in the early visual pathway are capable of spiking with high temporal precision and their discharges are not Poisson-like. To gain an understanding of how response variability in the LGN influences the behavior of V1, we study response properties of model V1 neurons that receive purely feedforward inputs from LGN cells modeled either as noisy leaky integrate-and-fire (NLIF) neurons or as inhomogeneous Poisson processes. We first demonstrate that the NLIF model is capable of reproducing many experimentally observed statistical properties of LGN neurons. Then we show that a V1 model in which the LGN input to a V1 neuron is modeled as a group of NLIF neurons produces higher orientation selectivity than the one with Poisson LGN input. The second result implies that statistical characteristics of LGN spike trains are important for V1’s function. We conclude that physiologically motivated models of V1 need to include more realistic LGN spike trains that are less noisy than inhomogeneous Poisson processes.     

Rearrangement of Retinogeniculate Projection Patterns after Eye-Specific Segregation in Mice

It has been of interest whether and when the rearrangement of neuronal circuits can be induced after projection patterns are formed during development. Earlier studies using cats reported that the rearrangement of retinogeniculate projections could be induced even after eye-specific segregation has occurred, but detailed and quantitative characterization of this rearrangement has been lacking. Here we delineate the structural changes of retinogeniculate projections in the C57BL/6 mouse in response to monocular enucleation (ME) after eye-specific segregation. When ME was performed after eye-specific segregation, rearrangement of retinogeniculate axons in the dorsal lateral geniculate nucleus (dLGN) was observed within 5 days. Although this rearrangement was observed both along the dorsomedial-ventrolateral and outer-inner axes in the dLGN, it occurred more rapidly along the outer-inner axis. We also examined the critical period for this rearrangement and found that the rearrangement became almost absent by the beginning of the critical period for ocular dominance plasticity in the primary visual cortex. Taken together, our findings serve as a framework for the assessment of phenotypes of genetically altered mouse strains as well as provide insights into the mechanisms underlying the rearrangement of retinogeniculate projections.     

A function of the corpus callosum in the Siamese cat

Recordings were made from 180 single cells, or cell clusters, in the Clare-Bishop area of two Siamese cats. In one cat, the corpus callosum had been sectioned prior to recording and all cells were driven by the contralateral eye exclusively. In the other recordings were made before and after callosal section. Before callosal section, most cells were binocularly driven but dominated by the contralateral eye. There were striking examples of binocular interaction and some cells could only be activated by simultaneous binocular stimulation. After callosal section, cells were driven by the contralateral eye only. The same experiment performed in a normal cat revealed no change in binocularity following section of the corpus callosum. We conclude that one of the functions of the corpus callosum in the Siamese cat is to generate binocular neurons.     

Serendipity and the Siamese cat: the discovery that genes for coat and eye pigment affect the brain

One day in the late 1960s, Ray Guillery was examining brain sections through the visual thalamus of cats, and he recognized that the arrangement of layers in the lateral geniculate nucleus (LGN) of one cat was strangely abnormal. The cat was identified as a Siamese cat, one of a breed selected for its unusual coat color, with reduced pigment over much of the body and eyes. This chance observation and the recognition of its significance led to a broad-ranging series of investigations. These experiments showed that the lack of normal levels of pigment in the retina in Siamese cats (and other hypopigmented mammals) was the critical factor in the misdirection of many of the projections of the retina to the brain, the nature of the projection error, and the developmental consequences of the relay of the misdirected retinal inputs to visual cortex. As a result, we have a better understanding of how the brain forms proper connections and of the neural basis of visual problems in albino humans.