Control of thalamocortical afferent rearrangement by postsynaptic activity in developing visual cortex.

The formation of specific connections in the developing central nervous system is thought to result from mechanisms that increase the strengths of synapses at which pre- and postsynaptic activity are correlated and decrease it otherwise. In the visual cortex, initially widespread inputs normally sort out into eye-specific patches during early life. If only one eye can see during this period, its patches are much larger than normal, and patches from the occluded eye become much smaller. Anatomical experiments here show that closed-eye inputs expand within a region of cortex that is silenced, establishing that inhibition of common target cells gives less active inputs a competitive advantage.

Rapid remodeling of axonal arbors in the visual cortex.

If vision in one eye is blurred or occluded during a critical period in postnatal development, neurons in the visual cortex lose their responses to stimulation through that eye within a few days. Anatomical changes in the nerve terminals that provide input to the visual cortex have previously been observed only after weeks of deprivation, suggesting that synapses become physiologically ineffective before the branches on which they sit are withdrawn. Reconstruction of single geniculocortical axonal arbors in the cat after either brief or prolonged monocular occlusion revealed striking axonal rearrangements in both instances. Rapid withdrawal of the branches of deprived-eye arbors suggests that axonal branches bearing synapses respond quickly to changing patterns of neuronal activity.

Modification of cortical orientation selectivity in the cat by restricted visual experience: a reexamination.

Recent reports have stated that the orientation selectivity of cells in the cat's visual cortex can be biased by limiting the early visual environment to stripes of one orientation. Data obtained from seven kittens using systematic and quantitative sampling of preferred orientation, together with a blind procedure, do not show a bias toward the orientation presented in one type of restricted rearing environment.

Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents.

In the adult mammalian visual system, ganglion cell axons from the two eyes are segregated from each other into separate layers within their principal target, the lateral geniculate nucleus. The involvement of spontaneously generated action potential activity in the process of segregation was investigated during the fetal period in which segregation normally occurs in the cat, between embryonic day 45 (E45) and birth (E65). Tetrodotoxin, which blocks the voltage-sensitive sodium channel, was used to prevent action potentials. Fetuses received continuous intracranial infusions of tetrodotoxin from osmotic minipumps implanted in utero on E42. After a 2-week infusion, intraocular injections of anterograde tracers revealed that tetrodotoxin prevented segregation. The contralateral projection filled the lateral geniculate nucleus uniformly, and the ipsilateral projection expanded to occupy most of what would normally be contralaterally innervated layer A. Thus, in the fetus, long before the onset of vision, spontaneous action potential activity is likely to be present in the visual system and to contribute to the segregation of the retinogeniculate pathway.

Rapid extragranular plasticity in the absence of thalamocortical plasticity in the developing primary visual cortex.

Monocular deprivation during early postnatal development remodels the circuitry of the primary visual cortex so that most neurons respond poorly to stimuli presented to the deprived eye. This rapid physiological change is ultimately accompanied by a matching anatomical loss of input from the deprived eye. This remodeling is thought to be initiated at the thalamocortical synapse. Ocular dominance plasticity after brief (24 hours) monocular deprivation was analyzed by intrinsic signal optical imaging and by targeted extracellular unit recordings. Deprived-eye responsiveness was lost in the extragranular layers, whereas normal binocularity in layer IV was preserved. This finding supports the hypothesis that thalamocortical organization is guided by earlier changes at higher stages.

Ocular dominance plasticity under metabotropic glutamate receptor blockade.

Occluding vision through one eye during a critical period in early life nearly abolishes responses to that eye in visual cortex. This phenomenon is mimicked by long-term depression of synaptic transmission in vitro, which may require metabotropic glutamate receptors (mGluRs) and is age-dependent. Peaks in mGluR expression and glutamate-stimulated phosphoinositide turnover during visual cortical development have been proposed as biochemical bases for the critical period. Pharmacological blockade of mGluRs specifically prevented synapse weakening in mouse visual cortical slices but did not alter kitten ocular dominance plasticity in vivo. Thus, a heightened mGluR response does not account for the critical period in development.

Ocular dominance column development: analysis and simulation.

The visual cortex of many adult mammals has patches of cells that receive inputs driven by the right eye alternating with patches that receive inputs driven by the left eye. These ocular dominance patches (or "columns") form during early life as a consequence of competition between the activity patterns of the two eyes. A mathematical model of several biological mechanisms that can account for this development is presented. Analysis of this model reveals the conditions under which ocular dominance segregation will occur and determines the resulting patch width. Simulations of the model also exhibit other phenomena associated with early visual development, such as topographic refinement of cortical receptive fields, the confinement of input cell connections to patches, monocular deprivation plasticity including a critical period, and the effect of artificially induced strabismus. The model can be used to predict the results of proposed experiments and to discriminate among various mechanisms of plasticity.

The role of visual experience in the development of columns in cat visual cortex.

The role of experience in the development of the cerebral cortex has long been controversial. Patterned visual experience in the cat begins when the eyes open about a week after birth. Cortical maps for orientation and ocular dominance in the primary visual cortex of cats were found to be present by 2 weeks. Early pattern vision appeared unimportant because these cortical maps developed identically until nearly 3 weeks of age, whether or not the eyes were open. The naïve maps were powerfully dominated by the contralateral eye, and experience was needed for responses to the other eye to become strong, a process unlikely to be strictly Hebbian. With continued visual deprivation, responses to both eyes deteriorated, with a time course parallel to the well-known critical period of cortical plasticity. The basic structure of cortical maps is therefore innate, but experience is essential for specific features of these maps, as well as for maintaining the responsiveness and selectivity of cortical neurons.

Local GABA circuit control of experience-dependent plasticity in developing visual cortex.

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

Selective pruning of more active afferents when cat visual cortex is pharmacologically inhibited.

Activity-dependent competition is thought to guide the normal development of specific patterns of neural connections. Such competition generally favors more active inputs, making them larger and stronger, while less active inputs become smaller and weaker. We pharmacologically inhibited the activity of visual cortical cells and measured the three-dimensional structure of inputs serving the two eyes when one eye was occluded. The more active inputs serving the open eye actually became smaller than the deprived inputs from the occluded eye, which were similar to those in normal animals. These findings demonstrate in vivo that it is not the amount of afferent activity but the correlation between cortical and afferent activity that regulates the growth or retraction of these inputs.

Sleep enhances plasticity in the developing visual cortex.

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.

Relationship between the ocular dominance and orientation maps in visual cortex of monocularly deprived cats.

The significance of functional maps for cortical plasticity was investigated by imaging of intrinsic optical signals together with single-unit recording in kittens. After even a brief period of monocular deprivation during the height of the critical period, only isolated patches of visual cortex continued to respond strongly to the closed eye. These deprived-eye patches were located on the pinwheel center singularities of the orientation map and consisted of neurons that were poorly selective for stimulus orientation. Neurons in regions surrounding the deprived-eye patches responded only weakly to the deprived eye but were well tuned for the same stimulus orientation that optimally excited them when presented to the open, nondeprived eye. The coincidence of deprived-eye patches with pinwheel center singularities, and the selective loss of orientation tuning within the deprived-eye patches, indicate that the orientation and ocular dominance maps are functionally linked and provide compelling evidence that pinwheel center singularities are important for cortical plasticity.

Deficient plasticity in the primary visual cortex of alpha-calcium/calmodulin-dependent protein kinase II mutant mice.

The recent characterization of plasticity in the mouse visual cortex permits the use of mutant mice to investigate the cellular mechanisms underlying activity-dependent development. As calcium-dependent signaling pathways have been implicated in neuronal plasticity, we examined visual cortical plasticity in mice lacking the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha CaMKII). In wild-type mice, brief occlusion of vision in one eye during a critical period reduces responses in the visual cortex. In half of the alpha CaMKII-deficient mice, visual cortical responses developed normally, but visual cortical plasticity was greatly diminished. After intensive training, spatial learning in the Morris water maze was severely impaired in a similar fraction of mutant animals. These data indicate that loss of alpha CaMKII results in a severe but variable defect in neuronal plasticity.

CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period.

Neuronal activity-dependent processes are believed to mediate the formation of synaptic connections during neocortical development, but the underlying intracellular mechanisms are not known. In the visual system, altering the pattern of visually driven neuronal activity by monocular deprivation induces cortical synaptic rearrangement during a postnatal developmental window, the critical period. Here, using transgenic mice carrying a CRE-lacZ reporter, we demonstrate that a calcium- and cAMP-regulated signaling pathway is activated following monocular deprivation. We find that monocular deprivation leads to an induction of CRE-mediated lacZ expression in the visual cortex preceding the onset of physiologic plasticity, and this induction is dramatically downregulated following the end of the critical period. These results suggest that CRE-dependent coordinate regulation of a network of genes may control physiologic plasticity during postnatal neocortical development.

Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB.

To examine functions of TrkB in the adult CNS, TrkB has been removed from neurons expressing CaMKII, primarily pyramidal neurons, using Cre-mediated recombination. A floxed trkB allele was designed so that neurons lacking TrkB express tau-beta-galactosidase. Following trkB deletion in pyramidal cells, their dendritic arbors are altered, and cortical layers II/III and V are compressed, after which there is an apparent loss of mutant neurons expressing the transcription factor SCIP but not of those expressing Otx-1. Loss of neurons expressing SCIP requires deletion of trkB within affected neurons; reduction of neuronal ER81 expression does not, suggesting both direct and indirect effects of TrkB loss. Thus, TrkB is required for the maintenance of specific populations of cells in the adult neocortex.

The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons.

The development of precise connections in the mammalian brain proceeds through refinement of initially diffuse patterns, a process that occurs largely within critical developmental windows. To elucidate the molecular pathways that orchestrate these early periods of circuit remodeling, we have examined the role of a calcium- and cAMP-regulated transcriptional pathway. We show that there is a window of CRE/CREB-mediated gene expression in the developing thalamus, which precedes neocortical expression. In the LGN, this wave of gene expression occurs prior to visual experience, but requires retinal function. Mutant mice with reduced CREB expression show loss of refinement of retinogeniculate projections. These results suggest an important role of the CRE/CREB transcriptional pathway in the coordination of experience-independent circuit remodeling during forebrain development.

Origin of orientation tuning in the visual cortex.

The results of recent experiments have thrown new light on the neuronal connections underlying orientation-selective responses in the primary visual cortex of adult animals. The pattern of afferent input from the lateral geniculate nucleus to the cortex appears to be specific for orientation, while intracortical inhibitory connections appear to be non-specific in this respect. Experimental and theoretical studies have suggested that the development of cortical cell orientation tuning is an activity-dependent process.

Sleep does not enhance the recovery of deprived eye responses in developing visual cortex.

Monocular deprivation (MD) during a critical period of visual development triggers a rapid remodeling of cortical responses in favor of the open eye. We have previously shown that this process is enhanced by sleep and is inhibited when the sleeping cortex is reversibly inactivated. A related but distinct form of cortical plasticity is evoked when the originally deprived eye (ODE) is reopened, and the non-deprived eye is closed during the critical period (reverse monocular deprivation (RMD)). Recent studies suggest that different mechanisms regulate the initial loss of deprived eye responses following MD and the recovery of deprived eye responses following RMD. In this study we investigated whether sleep also enhances RMD plasticity in critical period cats. Using polysomnography combined with microelectrode recordings and intrinsic signal optical imaging in visual cortex we show that sleep does not enhance the recovery of ODE responses following RMD. These findings add to the growing evidence that different forms of plasticity in vivo are regulated by distinct mechanisms and that sleep has divergent roles upon different types of experience-dependent cortical plasticity.

Rapid anatomical plasticity of horizontal connections in the developing visual cortex.

Experience can dramatically alter the responses of cortical neurons. During a critical period in the development of visual cortex, these changes are extremely rapid, taking place in 2 d or less. Anatomical substrates of these changes have long been sought, primarily in alterations in the principal visual input from the thalamus, but the significant changes that have been found take 1 week. Recent results indicate that the initial physiological changes in the cortical circuit take place outside of the primary input layer. We now find that rapid plasticity of binocular responses in the upper layers of cortex is mirrored by similarly rapid anatomical changes in the horizontal connections between ocular dominance columns in the upper layers, which reorganize within 2 d.

Synaptic density in geniculocortical afferents remains constant after monocular deprivation in the cat.

Monocular eyelid closure in cats during a critical period in development produces both physiological plasticity, as indicated by a loss of responsiveness of primary visual cortical neurons to deprived eye stimulation, and morphological plasticity, as demonstrated by a decrease in the total length of individual geniculocortical arbors representing the deprived eye. Although the physiological plasticity appears maximal after 2 d of monocular deprivation (MD), the shrinkage of deprived-eye geniculocortical arbors is less than half-maximal at 4 d and is not maximal until 7 d of deprivation, at which time the deprived arbors are approximately half their previous size. To study this form of plasticity at the level of individual thalamocortical synapses rather than arbors, we developed a new double-label colocalization technique. First, geniculocortical afferent arbors serving either the deprived or nondeprived eye were labeled by injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin into lamina A of the lateral geniculate nucleus. Then, using antibodies to synaptic vesicle proteins, we identified presynaptic terminals within the labeled arbors in layer IV of the primary visual cortex. Analysis of serial optical sections obtained using confocal microscopy allowed measurement of the numerical density of presynaptic sites and the relative amounts of synaptic vesicle protein in geniculocortical afferents after both 2 and 7 d of MD. We found that the density of synapses in geniculocortical axons was similar for deprived and nondeprived afferents, suggesting that this feature of the afferents is conserved even during periods in which synapse number is reduced by half in deprived-eye arbors. These results are not consistent with the hypothesis that a rapid loss of deprived-eye geniculocortical presynaptic sites is responsible for the prompt physiological effects of MD.