Plasticity of Neural Connections

Dynamic alterations of adult brain function, or Neural Plasticity, can occur at the level of metabolites, protein chemistry, synaptic morphology, systems-level activation or anatomical rearrangement. Frank Anatomical Plasticity in the adult mammalian CNS is minimal in comparison to the developing and adolescent brain. Classically, one of the last stages in neural development is the "critical period" during which activity has a pronounced effect on connectivity, prior to entering the anantomically static adult stage. We are exploring the molecular basis for restriction of Anatomical Plasticity in the adult brain and spinal cord.

Nogo Receptor in Plasticity

Monocular deprivation normally alters ocular dominance in the visual cortex
only during a postnatal critical period (20 to 32 days postnatal in mice). This is a period when intracortical myelination is reaching adult levels. Therefore, we focused on the role of the myelin inhibitor pathway in plasticity. Mutations in the Nogo-66 receptor (NgR1) affect cessation of ocular dominance plasticity. In NgR1-/- mice, plasticity during the critical period is normal, but it continues abnormally such that ocular dominance at 45 or 120 days postnatal is subject to the same plasticity as at juvenile ages. Thus, physiological NgR signaling from myelin-derived Nogo, MAG, and OMgp consolidates the neural circuitry established during experience-dependent plasticity.

Our current work explores the anatomical basis of NgR1-regulated plasticity. We hypothesize that alterations in Anatomical Plasticity underlie the electrophysiological evidence of increased cortical plasticity. We are using in vivo imaging and conditional NgR1 alleles to test the ability of this pathway to titrate adult Anatomical Plasticity in the mouse cerebral cortex. Such regulation may underlie the genetic linkage of NgR1 mutations we have described in human Schizophrenia (dysfunction of one Schizophrenia derived human NgR1 mutation shown below).
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Chronic In Vivo Imaging

Progress in defining the extent and control of Anatomical Plasticity in the adult brain requires high resolution imaging of axons and dendrites over weeks. Fortunately, recent advances in two-photon microscopy and transgenic expression of fluorescent proteins allow repeated imaging of anatomy over weeks in the adult cerebral cortex (as shown below). These methods have revealed that turnover of axonal varicosities and dendritic spines is most pronounced in the developing and adolescent brain, and decreases in the adult. Specific changes in activity and experience are reported to enhance adult Anatomical Plasticity. We are now testing the role of NgR1 in cortical Anatomical Plasticity using constitutive and conditional gene targeting.
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Anatomical Plasticity after Injury

From our studies of stroke and of surgical cuts of the corticospinal tract in the medulla, it is clear that uninjured tracts can beinduced to rearrange anatomically after injury to adult CNS. Furthermore, NgR1 limits the extent of this plasticity. Thus studies of Anatomical Plasticity have relevance for Translational Neurology.