Mapping by waves. Patterned spontaneous activity regulates retinotopic map refinement

A role for spontaneous spiking activity in shaping neuronal circuits has frequently been debated. Analyses of retinotopy in mutant mice with reduced correlated firing among neighboring retinal cells by Grubb et al. and McLaughlin et al. in this issue of Neuron indicate the importance of patterned spontaneous activity for retinotopic map refinement in subcortical visual targets.     

From retinal waves to activity-dependent retinogeniculate map development

A neural model is described of how spontaneous retinal waves are formed in infant mammals, and how these waves organize activity-dependent development of a topographic map in the lateral geniculate nucleus, with connections from each eye segregated into separate anatomical layers. The model simulates the spontaneous behavior of starburst amacrine cells and retinal ganglion cells during the production of retinal waves during the first few weeks of mammalian postnatal development. It proposes how excitatory and inhibitory mechanisms within individual cells, such as Ca(2+)-activated K(+) channels, and cAMP currents and signaling cascades, can modulate the spatiotemporal dynamics of waves, notably by controlling the after-hyperpolarization currents of starburst amacrine cells. Given the critical role of the geniculate map in the development of visual cortex, these results provide a foundation for analyzing the temporal dynamics whereby the visual cortex itself develops.     

An instructive role for patterned spontaneous retinal activity in mouse visual map development

Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of β2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye-specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity.     

The refinement of invertebrate synapses during development

Evidence is provided that during invertebrate development synapses undergo a period of refinement during which there are changes in synaptic connectivity and specific synaptic properties. It appears that extrinsic cues such as competition and neural activity are involved in guiding these synaptic changes in invertebrates. Comparisons are made with findings in the vertebrate literature.     

Control of spontaneous activity during development

Electrical activity participates in the development of the nervous system and comes in two general forms. Use-dependent or experience-driven activity occurs relatively late in development, and is important in events of terminal nervous system differentiation, such as stabilization of synaptic connections. Earlier in development, activity is spontaneous, occurring independently of normal sensory input and motor output. Spontaneous activity participates in many of the initial events of axon outgrowth, pruning of synaptic connections, and maturation of neuronal signaling properties. Despite its importance, the genesis of spontaneous activity is poorly understood. What is clear is that spontaneous activity must be regulated by the patterns with which voltage- and ligand-gated ion channels develop in individual neurons. This review explores how that regulation most likely occurs. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 97–109, 1998     

The role of nAChR-mediated spontaneous retinal activity in visual system development

In the developing vertebrate retina, nAChR synapses are among the first to appear. This early cholinergic circuitry plays a key role in generating "retinal waves," spontaneously generated waves of action potentials that sweep across the ganglion cell layer. These retinal waves exist for a short period of time during development when several circuits within the visual system are being established. Here I review the cholinergic circuitry of the developing retina and the role these early circuits play in the development of the retina itself and of retinal projections to the lateral geniculate nucleus of the thalamus.     

The role of retinal waves and synaptic normalization in retinogeniculate development

The prenatal development of the cat retinogeniculate pathway is thought to involve activity-dependent mechanisms driven by spontaneous waves of retinal activity. The role of these waves upon the segregation of the dorsal lateral geniculate nucleus (LGN) into two eye-specific layers and the development of retinotopic mappings have previously been investigated in a computer model. Using this model, we examine three aspects of retinogeniculate development. First, the mapping of visual space across the whole network into projection columns is shown to be similar to the mapping found in the cat. Second, the simplicity of the model allows us to explore how different forms of synaptic normalization affect development. In comparison to most previous models of ocular dominance, we find that subtractive postsynaptic normalization is redundant and divisive presynaptic normalization is sufficient for normal development. Third, the model predicts that the more often one eye generates waves relative to the other eye, the more LGN units will monocularly respond to the more active eye. In the limit when one eye does not generate any waves, that eye totally disconnects from the LGN allowing the non-deprived eye to innervate all of the LGN. Thus, as well as accounting for normal retinogeniculate development, the model also predicts development under abnormal conditions which can be experimentally tested.     

Expression of angiogenesis-related genes during retinal development

We assessed expression patterns of angiogenesis-related genes in mouse retina during perinatal vascularization and in adulthood. Vascular endothelial growth factor (vegf) and its receptors flk, flt1, and neuropilins 1 and 2 are expressed in both vascularized and avascular areas. Within the expression domain for vegf, appearance of these receptors is spatially and temporally non-overlapping. Expression of flk, flt1, the matrix metalloproteinase mt1-mmp, and the tissue inhibitor of metalloproteinase timp2, but not of mmp2, mmp9, timp1, or timp3, correlates with inner retinal vascularization. In particular, expression of flk, flt1 and mt1-mmp in the inner retina begins adjacent to the optic nerve head and extends anteriorly during the first week of life, roughly concordant with the growth of retinal vessels. Several genes (vegf, flk, flt1, timp2, possibly mmp9) appear to be expressed by retinal glia.     

Black bear movements and habitat use during a critical period for moose calves

In sub-Arctic and north-temperate ecosystems, opportunistic carnivores, such as black bears (Ursus americanus) and brown bears (Ursus arctos), are active on the landscape for a shorter period annually than sympatric gray wolves (Canis lupus). Therefore, bear movement patterns and habitat use might be expected to be more deliberate and of greater consequence, in terms of energy acquisition, than those of predators not undergoing hibernation. Habitat choices concerning feeding, bedding, and denning grounds made by black bears therefore should reflect seasonal abundance and distribution of vegetation and key prey items as these are sites where bears remain and forage for prolonged periods of time. We recorded the movement patterns of 6 GPS-collared black bears from den emergence to onset of moose (Alces alces) parturition in 2003. Over approximately 3 weeks prior to parturition, results from average distance calculations suggest that black bears moved closer to probable moose calving-site habitat. Additionally, the seasonal habitat use by black bears surrounding dens reflected the same trend for areas where cow moose gave birth in spring 2003, with a propensity to use needleleaf forest more than any other habitat.     

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.     

Uncoupling of neurogenesis and differentiation during retinal development

Conventionally, neuronal development is regarded to follow a stereotypic sequence of neurogenesis, migration, and differentiation. We demonstrate that this notion is not a general principle of neuronal development by documenting the timing of mitosis in relation to multiple differentiation events for bipolar cells (BCs) in the zebrafish retina using in vivo imaging. We found that BC progenitors undergo terminal neurogenic divisions while in markedly disparate stages of neuronal differentiation. Remarkably, the differentiation state of individual BC progenitors at mitosis is not arbitrary but matches the differentiation state of post-mitotic BCs in their surround. By experimentally shifting the relative timing of progenitor division and differentiation, we provide evidence that neurogenesis and differentiation can occur independently of each other. We propose that the uncoupling of neurogenesis and differentiation could provide neurogenic programs with flexibility, while allowing for synchronous neuronal development within a continuously expanding cell pool.     

Epithelial tube morphogenesis during Drosophila tracheal development requires Piopio,a luminal ZP protein

The formation of branched epithelial networks is fundamental to the development of many organs, such as the lung, the kidney or the vasculature. Little is known about the mechanisms that control cell rearrangements during tubulogenesis and regulate the size of individual tubes. Recent studies indicate that whereas the basal surface of tube cells interacts with the surrounding tissues and helps to shape the ramification pattern of tubular organs, the apical surface has an important role in the regulation of tube diameter and tube growth. Here we report that two proteins, Piopio (Pio) and Dumpy (Dp), containing a zona pellucida (ZP) domain are essential for the generation of the interconnected tracheal network in Drosophila melanogaster. Pio is secreted apically, accumulates in the tracheal lumen and possibly interacts with Dp through the ZP domains. In the absence of Pio and Dp, multicellular tubes do not rearrange through cell elongation and cell intercalation to form narrow tubes with autocellular junctions; instead they are transformed into multicellular cysts, which leads to a severe disruption of the branched pattern. We propose that an extracellular matrix containing Pio and Dp provides a structural network in the luminal space, around which cell rearrangements can take place in an ordered fashion without losing interconnections. Our results suggest that a similar structural role might be attributed to other ZP-domain proteins in the formation of different branched organs.     

A precisely timed asynchronous pattern of ON and OFF retinal ganglion cell activity during propagation of retinal waves

Patterns of coordinated spontaneous activity have been proposed to guide circuit refinement in many parts of the developing nervous system. It is unclear, however, how such patterns, which are thought to indiscriminately synchronize nearby cells, could provide the cues necessary to segregate functionally distinct circuits within overlapping cell populations. Here, we report that glutamatergic retinal waves possess a substructure in the bursting of neighboring retinal ganglion cells with opposite light responses (ON or OFF). Within a wave, cells fire repetitive nonoverlapping bursts in a fixed order: ON before OFF. This pattern is absent from cholinergic waves, which precede glutamate-dependent activity, providing a developmental sequence of distinct activity-encoded cues. Asynchronous bursting of ON and OFF retinal ganglion cells depends on inhibition between these parallel pathways. Similar asynchronous activity patterns could arise throughout the nervous system, as inhibition matures and might help to separate connections of functionally distinct subnetworks.     

Transient expression of adheron molecules during chick retinal development

Neuritogenesis and synapse formation are transient phenomena mediated in part by filopodial attachments (Tsui, Lankford, and Klein, Proc. Natl. Acad. Sci. 82:8256–8260 1985). These attachments can be labeled by antisera against adherons, adhesive microparticles isolated from cell culture media (Tsui, Schubert, and Klein, J. Cell Biol. 106:2095–2108 1988). Here, two monoclonal antibodies raised against adherons have been found to recognize transiently expressed membrane antigens of developing avian retina. Early in development, monoclonal antibody (mAb) AD1 stained antigens that spanned the entire tissue. With time, immunoreactivity became restricted to optic fiber, ganglion cell, and inner plexiform layers. Immunoblots of embryonic day (E) 13 retina showed a broad band at 66–72 kD for particulate fractions and a fine band at 70 kD for suluble fractions. The particulate forms disappeared as retinas matured, but the soluble form did not. mAb AD2 initially labeled retina antigens of optic fiber, ganglion cell, and inner plexiform layers (IPL). Labeling in the plexiform layer showed discrete lamina. Immunoreactivity first appeared at E9, peaked at E15, and then disappeared shortly after hatching. In isolated cells, AD2 labeled small cell surface aggregates. Cytoarchitectural studies, using whole mount transmission electron microscopy, showed AD2 antigen in cell surface microfilaments, including some that joined filopodia together. The adheron antigens recognized by mAbs AD1 and AD2 thus were (1) topographically restricted; (2) associated with cell surfaces; and (3) developmentally down-regulated. This pattern suggests a role in developmentally transient cell surface phenomena, such as neurite extension or junction biogenesis. © 1992 John Wiley & Sons, Inc.