Gene expression patterns in visual cortex during the critical period: synaptic stabilization and reversal by visual deprivation.

The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.

Ephrin-A2 and -A5 influence patterning of normal and novel retinal projections to the thalamus: conserved mapping mechanisms in visual and auditory thalamic targets.

Sensory axons are targeted to modality-specific nuclei in the thalamus. Retinal ganglion cell axons project retinotopically to their principal thalamic target, the dorsal lateral geniculate nucleus (LGd), in a pattern likely dictated by the expression of molecular gradients in the LGd. Deafferenting the auditory thalamus induces retinal axons to innervate the medial geniculate nucleus (MGN). These retino-MGN projections also show retinotopic organization. Here we show that ephrin-A2 and -A5, which are expressed in similar gradients in the MGN and LGd, can be used to pattern novel retinal projections in the MGN. As in the LGd, retinal axons from each eye terminate in discrete eye-specific zones in the MGN of rewired wild-type and ephrin-A2/A5 knockout mice. However, ipsilateral eye axons, which arise from retinal regions of high EphA5 receptor expression and represent central visual field, terminate in markedly different ways in the two mice. In rewired wild-type mice, ipsilateral axons specifically avoid areas of high ephrin expression in the MGN. In rewired ephrin knockout mice, ipsilateral projections shift in location and spread more broadly, leading to an expanded representation of the ipsilateral eye in the MGN. Similarly, ipsilateral projections to the LGd in ephrin knockout mice are shifted and are more widespread than in the LGd of wild-type mice. In the MGN, as in the LGd, terminations from the two eyes show little overlap even in the knockout mice, suggesting that local interocular segregation occurs regardless of other patterning determinants. Our data demonstrate that graded topographic labels, such as the ephrins, can serve to shape multiple related aspects of afferent patterning, including topographic mapping and the extent and spread of eye-specific projections. Furthermore, when mapping labels and other cues are expressed in multiple target zones, novel projections are patterned according to rules that operate in their canonical targets.

Normal eye-specific patterning of retinal inputs to murine subcortical visual nuclei in the absence of brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) is a preferred ligand for a member of the tropomyosin-related receptor family, trkB. Activation of trkB is implicated in various activity-independent as well as activity-dependent growth processes in many developing and mature neural systems. In the subcortical visual system, where electrical activity has been implicated in normal development, both differential survival, as well as remodeling of axonal arbors, have been suggested to contribute to eye-specific segregation of retinal ganglion cell inputs. Here, we tested whether BDNF is required for eye-specific segregation of visual inputs to the lateral geniculate nucleus and the superior colliculus, and two other major subcortical target fields in mice. We report that eye-specific patterning is normal in two mutants that lack BDNF expression during the segregation period: a germ-line knockout for BDNF, and a conditional mutant in which BDNF expression is absent or greatly reduced in the central nervous system. We conclude that the availability of BDNF is not necessary for eye-specific segregation in subcortical visual nuclei.

Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics.

Finding a conductive substrate that promotes neural interactions is an essential step for advancing neural interfaces. The biocompatibility and conductive properties of polypyrrole (PPy) make it an attractive substrate for neural scaffolds, electrodes, and devices. Stand-alone polymer implants also provide the additional advantages of flexibility and biodegradability. To examine PPy biocompatibility, dissociated primary cerebral cortical cells were cultured on PPy samples that had been doped with polystyrene-sulfonate (PSS) or sodium dodecylbenzenesulfonate (NaDBS). Various conditions were used for electrodeposition to produce different surface properties. Neural networks grew on all of the PPy surfaces. PPy implants, consisting of the same dopants and conditions, were surgically implanted in the cerebral cortex of the rat. The results were compared to stab wounds and Teflon implants of the same size. Quantification of the intensity and extent of gliosis at 3- and 6-week time points demonstrated that all versions of PPy were at least as biocompatible as Teflon and in fact performed better in most cases. In all of the PPy implant cases, neurons and glial cells enveloped the implant. In several cases, neural tissue was present in the lumen of the implants, allowing contact of the brain parenchyma through the implants.

Role of afferent activity in the development of cortical specification.

The surgical cross-modal rewiring paradigm is an experimental method for examining the physiological and anatomical consequences of exposing developing cortical subregions to specific types of patterned sensory inputs. Data from these experiments provide strong inferences about the role of extrinsic (subcortical) cortical inputs in shaping the local cortical networks that organize and process sensory information. Behavioral results from this work also suggest that such activity (and activity in general) is a profound organizer of cerebral connectivity. We discuss one future direction of these studies: the implication that extrinsic inputs regulate developmental genes that are responsible for refining the connectivity within local circuits, and a strategy to discover and characterize such genes.