Search

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.

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.

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.

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.

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.

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.

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.