A distinguishing feature of the mammalian neocortex is its remarkable ability to change over a lifetime, especially during early development. Thus, the functional organization and connectivity of each individual's brain is tailored to the physical parameters of a specific environment, permitting behavior to be uniquely optimized for a given sensory milieu. Such plasticity plays an integral role in shaping the brains of normal humans as well those who suffer from severe visual impairments due to retinal abnormalities or cortical lesions that occur at various stages of development. This proposal will investigate the extent of cortical plasticity following experimentally induced manipulations to the visual system during development. Our first objective is to examine the alterations in sensory mediated behavior, as well as changes in the functional organization, connectivity and cellular composition of the neocortex that result from one of two induced neural insults: 1) loss of neocortex that would normally develop into visual cortex;2) loss of visual input normally provided by the retina. The second objective is to determine if early, pervasive sensory enhancement can be used to direct the functional reorganization of the neocortex and optimize sensory mediated behavior. Manipulations will be made at one of three developmental milestones: 1) Before retinal ganglion cell axons enter the diencephalon and before thalamocortical afferents have reached the cortex. 2) Before eye opening, after thalamocortical afferents have innervated the neocortex, but before axonal pruning and the completion of cortical development. 3) Just after the eyes have opened, when retinofugal and thalamocortical development is established and the subventricular zone and all six cortical layers are present. These animals will be exposed to either a normal or to a tactilely (for bilateral enucleates) or visually (for cortical lesions) enhanced environment. Our animal model, the short-tailed opossum (Monodelphis domestica) is born prematurely, allowing ex-utero manipulations to the nervous system at developmental time points that would be in-utero in other mammals. After the animals have reached maturity we will use behavioral testing combined with electrophysiological and neuroanatomical techniques to examine sensory discrimination, the functional organization and neural response properties of re-organized cortex, cortical and thalamic connectivity, and the cellular composition including neuronal number and density of re-organized cortex. These studies, which are novel in their scope, provide an opportunity to translate detailed knowledge gained at the cellular and systems level to produce significant therapeutic interventions designed to direct multisensory plasticity, and optimize sensory mediated behavior following loss of vision.

Public Health Relevance

The developing brain is particularly susceptible to neural insult. About 1 in 10,000 children are born blind, and 1.25 of every 1000 newborn infants suffer from some form of visual impairment, often due to problems associated with prematurity or complications during birth. In this investigation we will examine the effects of visual impairment due to central insult (lesions to visual cortex) or loss of input from the eyes (bilateral enucleation) at three important developmental stages. Animals will be reared in either a normal or enhanced sensory environment and the effects of both the loss of vision at different ages as well as the impact of rearing in enhanced environments will be examined at multiple levels of organization, from behavioral to cellular. This research will provide information about how and when environmental enhancements should be put in place for optimal therapeutic results.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022987-02
Application #
8600683
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Steinmetz, Michael A
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$367,522
Indirect Cost
$122,522
Name
University of California Davis
Department
Neurosciences
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Seelke, Adele M H; Dooley, James C; Krubitzer, Leah A (2014) The cellular composition of the marsupial neocortex. J Comp Neurol 522:2286-98
Seelke, A M H; Dooley, J C; Krubitzer, L A (2014) Photic preference of the short-tailed opossum (Monodelphis domestica). Neuroscience 269:273-80
Dooley, James C; Franca, João G; Seelke, Adele M H et al. (2013) A connection to the past: Monodelphis domestica provides insight into the organization and connectivity of the brains of early mammals. J Comp Neurol 521:3877-97
Hedges, James H; Adolph, Karen E; Amso, Dima et al. (2013) Play, attention, and learning: how do play and timing shape the development of attention and influence classroom learning? Ann N Y Acad Sci 1292:1-20
Krubitzer, Leah; Dooley, James C (2013) Cortical plasticity within and across lifetimes: how can development inform us about phenotypic transformations? Front Hum Neurosci 7:620