In the mature mammalian visual system, information from the two eyes is anatomically segregated into layers in the lateral geniculate nucleus, and into ocular dominance columns in primary visual cortex. During the past half century, the development of this segregation has served as a premier model for the development of specific connections in the brain. Groundbreaking work in the 1960s showed that neuronal activity is important for the normal development of ocular dominance columns. If poor vision or no vision is experienced by one eye early in life, then that eye loses anatomical and functional connections to the brain. This results in blindness through the affected eye later in life, even if the cause of the poor vision is fixed so that the eye itself functions normally. Many studies over the ensuing years have looked at the effects of altering or abolishing neuronal activity on the development of eye-specific segregation. Findings from these studies lead to the following conclusions: 1) During development, specific connections in the visual system emerge over time from initially diffuse connections, 2) abolishing retinal activity during development maintains the initial imprecise connections, and 3) temporal correlation in the firing patterns of neurons within each eye, and lack of correlation between eyes is responsible for the development of eye-specific connections. These conclusions formed the dogma of the field of development of sensory systems, and significantly influenced related fields such as neurodevelopmental disorders, adult plasticity in the brain, and learning and memory. However, new experiments over the past decade have questioned each of these conclusions. This proposal will address the controversies by performing the following specific aims. 1) What is the normal pattern of development of ocular dominance columns? Anatomical tracing methods will be used to determine whether afferents serving the two eyes are initially overlapping or segregated in primary visual cortex. 2) What is the effect of complete retinal activity blockade on the development of eye-specific segregation in the LGN and cortex? Pharmacological agents will be used to silence retinal ganglion cell action potentials during development, and the effects on segregation will be examined. 3) What aspects of retinal ganglion cell activity are important for normal development of eye-specificity in the LGN? Manipulations that alter patterns of activity in the retina will be compared in order to determine which aspects of activity patterns are associated with normal segregation versus lack of segregation. 4) What is the role of correlated activity in the development of segregation? Light activatable molecules will be used to control activity patterns to determine whether increased correlation of firing of neighboring cells between the two eyes leads to lack of eye-specific segregation. These experiments will not only help to resolve important basic science controversies, but will also have clinical implications. Understanding the initial state of connections in the brain, the effects of absent or altered activity, and the key aspects of activity patterns that are needed for normal development, will all aid in the understanding and eventual treatment of neurodevelopmental disorders.
Neurodevelopmental disorders, including autism, schizophrenia, fetal alcohol syndrome, seizure disorders, attention deficit / hyperactivity disorder, etc. are devastating to families and costly to society. In order to understand and eventually treat these disorders, it is necessary to understand how the brain develops. The current proposal will answer questions about normal development of connections in the brain, and how connections are altered when neuronal activity is affected. The understanding of basic developmental neurobiology gained from these experiments may someday help in the treatment of neurodevelopmental disorders.
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