The role of NMDA receptors and nitric oxide in retinogeniculate development.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M Sur
Publications and source records attributed to M Sur.
Layer-specific programs of development in neocortical projection neurons.
How are long-range axonal projections from the cerebral cortex orchestrated during development? By using both passively and actively transported axonal tracers in fetal and postnatal ferrets, we have analyzed the development of projections from the cortex to a number of thalamic nuclei. We report that the projections of a cortical area to its corresponding thalamic nuclei follow highly cell-specific programs of development. Axons from cells in the deepest layers of the cerebral cortex (layer 6 and superficial subplate neurons) appear to grow very slowly and be delayed for several weeks in the cerebral white matter, reaching the thalamus over a protracted period. Neurons of layer 5, on the other hand, develop their projections much faster; despite being born after the neurons of deeper layers, layer 5 neurons are the first to extend their axons out of the cortical hemisphere and innervate the thalamus. Layer 5 projections are massive in the first postnatal weeks but may become partly eliminated later in development, being overtaken in number by layer 6 cells that constitute the major corticothalamic projection by adulthood. Layer 5 projections are area-specific from the outset and arise as collateral branches of axons directed to the brainstem and spinal cord. Our findings show that the early development of corticofugal connections is determined not by the sequence of cortical neurogenesis but by developmental programs specific for each type of projection neuron. In addition, they demonstrate that in most thalamic nuclei, layer 5 neurons (and not subplate or layer 6 neurons) establish the first descending projections from the cerebral cortex.
Animals↗
Somatosensory cortex. Maps of time and space.
Explore the source record for details and available documents.
Animals↗
Rapid acquisition of dendritic spines by visual thalamic neurons after blockade of N-methyl-D-aspartate receptors.
N-Methyl-D-aspartate (NMDA) receptors play an important role in the development of retinal axon arbors in the mammalian lateral geniculate nucleus (LGN). We investigated whether blockade of NMDA receptors in vivo or in vitro affects the dendritic development of LGN neurons during the period that retinogeniculate axons segregate into on-center and off-center sublaminae. Osmotic minipumps containing either the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV) or saline were implanted in ferret kits at postnatal day 14. After 1 week, LGN neurons were intracellularly injected with Lucifer yellow. Infusion of D-APV in vivo led to an increase in the number of branch points and in the density of dendritic spines compared with age-matched normal or saline-treated animals. To examine the time course of spine formation, crystals of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate were placed in the LGN in brain slices from 14- to 18-day-old ferrets. Labeled LGN cell dendrites were imaged on-line in living slices by confocal microscopy, with slices maintained either in normal perfusion medium or with the addition of D-APV or NMDA to the medium. Addition of D-APV in vitro at doses specific for blocking NMDA receptors led to a > 6-fold net increase in spine density compared with control or NMDA-treated slices. Spines appeared within a few hours of NMDA receptor blockade, indicating a rapid local response by LGN cells in the absence of NMDA receptor activation. Thus, activity-dependent structural changes in postsynaptic cells act together with changes in presynaptic arbors to shape projection patterns and specific retinogeniculate connections.
2-Amino-5-phosphonovalerate↗
Transient expression of NADPH-diaphorase in the lateral geniculate nucleus of the ferret during early postnatal development.
Retinogeniculate projections in the ferret are refined during postnatal development so that inputs from the two eyes become segregated into eye-specific laminae, and each eye-specific lamina is further divided into sublaminae containing inputs from on-center or off-center afferents. Segregation into eye-specific laminae and on/off sublaminae is dependent on neuronal activity; sublamination depends on activation of N-methyl-d-aspartate (NMDA) receptors. By analogy with the suggested role of nitric oxide in NMDA-mediated long-term potentiation in the hippocampus, we investigated a possible role for nitric oxide in ferret retinogeniculate development. The expression of NADPH-diaphorase, a nitric oxide synthase, was examined histologically in the lateral geniculate nucleus of ferrets at several postnatal ages. At birth, neuropil is labeled in the nucleus, although no cell bodies are visible. After the first postnatal week, some labeled cells appear, predominantly in the C laminae. By three postnatal weeks, cell bodies are clearly labeled in all geniculate laminae. Staining reaches a peak in density at about four postnatal weeks, then declines such that by six postnatal weeks labeled cells are no longer visible. This transient expression of NADPH-diaphorase activity is consistent with a role for nitric oxide in the development of mature connections within the ferret lateral geniculate nucleus.
Animals↗
Cerebral cortex: function and development.
Explore the source record for details and available documents.
Animals↗
Activity-dependent remodeling of connections in the mammalian visual system.
The development of precise connections in the mammalian central nervous system requires neural activity. Synchronous patterns of afferent activity, and coincident afferent and target activity are required for specifying the neuronal connectivity that characterizes the adult visual pathway in mammals. During development, postsynaptic target neurons communicate with presynaptic afferents. Recent evidence suggests that the mechanisms that underlie activity-dependent development of connections in the visual system may share significant similarities with the mechanisms responsible for synaptic plasticity in the adult brain.
Afferent Pathways↗
An emergent model of orientation selectivity in cat visual cortical simple cells.
It is well known that visual cortical neurons respond vigorously to a limited range of stimulus orientations, while their primary afferent inputs, neurons in the lateral geniculate nucleus (LGN), respond well to all orientations. Mechanisms based on intracortical inhibition and/or converging thalamocortical afferents have previously been suggested to underlie the generation of cortical orientation selectivity; however, these models conflict with experimental data. Here, a 1:4 scale model of a 1700 microns by 200 microms region of layer IV of cat primary visual cortex (area 17) is presented to demonstrate that local intracortical excitation may provide the dominant source of orientation-selective input. In agreement with experiment, model cortical cells exhibit sharp orientation selectivity despite receiving strong iso-orientation inhibition, weak cross-orientation inhibition, no shunting inhibition, and weakly tuned thalamocortical excitation. Sharp tuning is provided by recurrent cortical excitation. As this tuning signal arises from the same pool of neurons that it excites, orientation selectivity in the model is shown to be an emergent property of the cortical feedback circuitry. In the model, as in experiment, sharpness of orientation tuning is independent of stimulus contrast and persists with silencing of ON-type subfields. The model also provides a unified account of intracellular and extracellular inhibitory blockade experiments that had previously appeared to conflict over the role of inhibition. It is suggested that intracortical inhibition acts nonspecifically and indirectly to maintain the selectivity of individual neurons by balancing strong intracortical excitation at the columnar level.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Morphology of retinal axons induced to arborize in a novel target, the medial geniculate nucleus. I. Comparison with arbors in normal targets.
Ferret retinal axons can be induced to innervate the medial geniculate nucleus (MGN) by a combination of brain lesions early in development. Our previous work suggests that the retinal ganglion cells responsible for this plasticity are W cells. The present study continues this work with a morphological investigation of normal retinal ganglion-cell axons and retinal ganglion-cell axons induced to arborize in the MGN. Retinal axons were bulk filled with horseradish peroxidase placed in the optic tract, and individual axons were serially reconstructed from sagittal sections. The control population consisted of fine-caliber axons arborizing in the superior colliculus (SC) and in the ventral C laminae of the lateral geniculate nucleus (LGN) of normal ferrets. We also compared the axons in the MGN of lesioned ferrets to intracellularly filled X and Y axons from normal ferrets as reported by Roe et al. ([1989] J. Comp. Neurol. 288:208). We have found that the retino-MGN axons in the lesioned ferrets do not resemble X or Y axons in normal ferrets in axon diameter, arbor volume, bouton number, or bouton density. However, they do resemble the fine-caliber, presumed W axons arborizing in the C laminae of the LGN and in the SC of normal ferrets. Thus, this study, in combination with previous studies, suggests strongly that W retinal ganglion cells are responsible for the retinal input to the MGN in lesioned animals. In addition, we find that the retino-MGN axons are of two types, branched and unbranched, which may correspond to different subtypes of retinal W cells.
Animals↗
Morphology of retinal axon arbors induced to arborize in a novel target, the medial geniculate nucleus. II. Comparison with axons from the inferior colliculus.
Specific neonatal lesions in ferrets can induce retinal axons to project into the medial geniculate nucleus (MGN). In the accompanying paper (Pallas et al., this issue), we described the morphology of these retinal ganglion cell axons. Those results and others (Roe et al. [1993] J. Comp. Neurol. 334:263) suggest that these axons belong to the W class of retinal axons. In this paper, the retino-MGN axons are compared with the normal inputs to the MGN from the brachium of the inferior colliculus (BIC). We first sought to determine further the extent to which a novel target might influence retinal axon arbor morphology. The second issue concerns retinal topography. Ferrets with retinal projections to the MGN have a two-dimensional retinotopic map in the MGN and the primary auditory cortex rather than the one-dimensional tonotopic map normally present (Roe et al. [1990] Science 250:818). To investigate whether there might be an anatomical substrate for a two-dimensional retinotopic map in the MGN, we compared the space-filling characteristics of the retino-MGN axons with the IC-MGN axons. Our results show that the branched retino-MGN axons resemble normal retinal W axons much more closely than they resemble the normal inputs to MGN. In addition, most of the axon arbors from the BIC are elongated along the rostrocaudal (isofrequency) axis, whereas the branched retino-MGN axons are more spatially restricted, suggesting an anatomical substrate for a retinotopic map in the MGN of the rewired ferrets.
Animals↗
An N-methyl-D-aspartate receptor antagonist does not prevent eye-specific segregation in the ferret retinogeniculate pathway.
Recent studies have shown that electrical activity, particularly that mediated by NMDA receptors, has a profound effect on the development of specific neuronal connections. Blocking NMDA receptors in the ferret's lateral geniculate nucleus prevents the segregation of retinal afferents into ON and OFF sublaminae. We have now examined the involvement of NMDA receptors in the separation of afferents from the two eyes that occurs in the lateral geniculate nucleus several weeks earlier in development. Blockade of NMDA receptor activity does not appear to interfere with this eye-specific segregation.
Animals↗
Orientation selectivity of cortical neurons during intracellular blockade of inhibition.
Neurons in the primary visual cortex of the cat are selectively activated by stimuli with particular orientations. This selectivity can be disrupted by the application of antagonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to a local region of the cortex. In order to determine whether inhibitory inputs are necessary for a single cortical neuron to show orientation selectivity, GABA receptors were blocked intracellularly during whole cell recording. Although the membrane potential, spontaneous activity, subfield antagonism, and directional selectivity of neurons were altered after they were perfused internally with the blocking solution, 18 out of 18 neurons remained selective for stimulus orientation. These results indicate that excitatory inputs are sufficient to generate orientation selectivity.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Early discordant binocular vision disrupts signal transfer in the lateral geniculate nucleus.
The mammalian lateral geniculate nucleus (LGN) is known to regulate signal transfer from the retina to the brain neocortex in a highly complex manner. Besides inputs from the brainstem, extraretinal inputs via corticogeniculate projections and local inhibitory neurons modulate signal transfer in the LGN. However, very little is known about whether the postnatal development of LGN signal-transfer mechanisms is influenced by early discordant binocular vision. By intraunit comparisons of responses between individual X-LGN cells and their direct retinal inputs, the efficiency of signal transfer was found permanently reduced due to an early interocular misalignment (strabismus). The contrast sensitivity and spatial resolution of cat LGN cells were significantly lower relative to their retinal inputs, and there was substantial decrease in signal-transfer speed. The observed physiological deficits were associated with immature X-retinogeniculate axon arbors. Thus, contrary to previous ideas, conflicting binocular inputs can produce neural deficits in subcortical visual structures.
Action Potentials↗
Abnormal development of retinogeniculate X axons in strabismic cats: a possible substrate for visual dysfunction.
Rearing cats with surgically induced esotropia results in a number of structural and functional abnormalities in the visual system. In the present experiments, we have studied the morphology of individual retinogeniculate X axons in esotropic cats using intracellular recording and staining techniques. After serially reconstructing stained axonal arbors, we find that some X axon terminations in A-laminae of the lateral geniculate nucleus (LGN) have larger volumes and lower bouton densities than normal. This is true for X axons projecting from both the deviated and the non-deviated eye. It is possible that these abnormalities in morphological development contribute to the disruptions in signal transfer that has been observed in X-cells in the LGN of esotropic cats.
Animals↗
Visual projections induced into the auditory pathway of ferrets: II. Corticocortical connections of primary auditory cortex.
Although the development of corticocortical projections has been well studied, less is known about the role of sensory inputs in the specification of these connections. As part of an ongoing series of studies in our laboratory, we have examined the role of thalamic input modality in the development of corticocortical connections. These studies involve making unilateral lesions and inducing retinal inputs into the auditory thalamus (MGN) during early development in ferrets, thereby conferring visual responsiveness on primary auditory cortex (AI). In this way we can examine the role of input identity in cortical specification in general, and connectivity patterns specifically. A previous paper (Pallas et al. [1990] J. Comp. Neurol. 298:50-68) described the pattern of thalamocortical and corticothalamic connections of auditory cortex in normal and lesioned animals. This study compares the pattern of auditory corticocortical connections in normal and lesioned animals. We injected neuroanatomical tracers into AI and mapped out the distribution of retrogradely labelled cells in the cortex. We report that the cortical inputs to ferret AI resembled those in cats, and that the pattern of ipsi- and contralateral corticocortical connections of ferret AI with visual input was similar to the normal pattern. Auditory cortex with visual input did not make ectopic connections with visual cortex, but maintained its connections with other auditory cortical areas. These results suggest that the overall corticocortical connections of an area are not influenced by the modality or activity pattern of its inputs. In particular, altering the input activity to a cortical area does not seem to promote the formation of entirely new connections, although small changes in the strength of existing connections are possible (Sur et al. [1990] Trends Neurosci. 13:227-233).
Animals↗
Experimentally induced visual projections to the auditory thalamus in ferrets: evidence for a W cell pathway.
We have previously reported that following specific neonatal brain lesions in ferrets, a retinal projection is induced into the auditory thalamus (Sur et al., Science 242:1437, '88). In these "rewired" ferrets, a novel visual pathway is established through auditory thalamus [the medial geniculate nucleus (MGN)] and primary auditory cortex (A1); cells in both MGN and A1 are visually responsive and exhibit properties similar to those of visual cells in the normal visual pathway. In this paper, we use three approaches--physiological, anatomical, and developmental--to examine which of the retinal ganglion cells project to the MGN in these rewired ferrets. We find that: 1) physiological response properties of postsynaptic visual cells in the MGN are W-like; 2) retinal ganglion cells back-filled from the MGN are small and similar to soma sizes of subsets of the normal retinal W cell population; and 3) subpopulations of these small cells can be preferentially rerouted to the MGN in response to different surgical manipulations at birth, consistent with differential W cell projection patterns in normal animals. These data suggest that retinal W cells come to project to the MGN in rewired animals. These findings not only provide a basis on which to interpret functional properties of this novel visual pathway, but also provide important information about the developmental capabilities of specific retinal ganglion cell classes and the regulation of their projections by target structures in the brain during development.
Animals↗
Spike trains and signaling modes of neurons in the ferret lateral geniculate nucleus.
Intracellular recordings were used to examine the action potential firing modes of cells in the ferret lateral geniculate nucleus (LGN) in vitro. We compared the effects of altered membrane voltage on patterns of action potential trains evoked by direct current injection and by retinal afferent (synaptic) stimulation. The results confirm that LGN cells in the ferret can fire action potentials in the "burst" and "tonic" modes that have been described previously for other species. At depolarized membrane potentials, LGN neurons respond to sustained depolarization with short-latency trains of action potentials whose frequency is directly proportional to the amount of current injected. At hyperpolarized membrane potentials, LGN cells enter burst mode, in which depolarizing inputs are differentiated into brief high-frequency discharges whose latency varies with membrane potential. We also observed a "mixed" mode, in which LGN cell responses to synaptic or injected currents within a narrow range of membrane potentials reflect aspects of both burst and tonic firing simultaneously. Thus a striking consequence of the interplay among voltage-dependent membrane conductances in thalamic cells is wide variability in length, duration, and latency of spike discharges elicited by identical stimuli. These results also suggest that the concept that LGN cells display only two active response modes must be expanded to include varying amounts of delay and the possibility of mixed discharges.
Action Potentials↗
Competitive interactions influencing the development of retinal axonal arbors in cat lateral geniculate nucleus.
Explore the source record for details and available documents.
Animals↗