Regulation of Plasticity in the Developing Visual System

The development of sensory systems is initiated through an innate process that creates rudimentary neural circuits subsequently refined postnatally by experience. The important synergy that exists between experience and brain development is exemplified in the visual system where the refinement of neural circuits that support normal perception requires unobstructed vision early in postnatal life - during the so-called critical period. It is during this stage that neural circuits exhibit their highest capacity for plasticity, and is when high plasticity levels enable cascading patterns of sensory neural impulses to direct development of brain circuits to their mature form. With increasing age beyond the critical period there is a natural decline in plasticity capacity that acts to stabilize neural connections preserving them for a lifetime. Recent studies from my lab suggest that the timing of the critical period is governed by a developmentally-regulated balance of plasticity facilitating and inhibiting molecules. Plasticity facilitators dominate early in development, whereas at older ages inhibitors accumulate to stabilize neural circuits and reduce plasticity potential. We currently have only a surface understanding of the molecules and processes that regulate neural plasticity, and almost nothing is known in higher mammals. Recent failed attempts to manipulate plasticity levels in animal models and in humans have revealed a significant gap in our understanding of the factors that govern plasticity throughout development. The focus of my research program is to investigate these knowledge gaps to understand characteristics that govern neural plasticity with the ultimate goal of elucidating principles that will enable manipulation of brain malleability. My trainees and I propose three projects that form the basis of this proposal. (Project 1): We will examine a collection of putative plasticity inhibitors whose characteristics we believe are suited to consolidate neural circuitry during development. (Project 2): We will investigate a new and intriguing hypothesis that post-translational modification of proteins is a natural developmental process that confers neural stability and therefore acts to inhibit plasticity. (Project 3): Our final project will employ an experimental manipulation aimed to reduce levels of plasticity inhibitors and elevate plasticity capacity at ages when it would normally be low. Our proposal aims to contribute fundamental insight into the mechanisms that govern brain plasticity and development. How these mechanisms can be manipulated and what benefits arise from their manipulation are principal questions that guide our long-term vision. Results from these projects will be transformative in the field of systems neuroscience by revealing a realistic path to alter plasticity capacity throughout life, an objective that is at the forefront of neuroscience, and is a research area in which my lab has played a leading role.