Thomas E Krahe, Ph.D. - US grants

DESCRIPTION (adapted from applicant's abstract): Degradation of the visual characterized by a decrease of visual acuity that cannot be improved by corrective lenses. Amblyopia is relatively common in the general population and constitutes a major cause of visual disability. In this condition, connections relaying information from the deprived eye to the visual cortex withdraw and connections relaying information from the experienced eye expand, with most cortical neurons responding only to stimulation of the experienced eye. As a consequence, visual function mediated by the deprived eye can be completely and irreversibly lost. Recovery of binocular function can be obtained, however, if normal visual stimulation to the deprived eye is restored promptly after deprivation has been initiated. In view of the substantial scientific and clinical relevance of these types of neural plasticity, there is an urgent need to elucidate the underlying cellular and molecular mechanisms. Neurophysiological activity involving the N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be required for the loss of connections from the deprived eye. The prevailing hypothesis is that the voltage-dependent magnesium blockade of the NMDA receptor enables it to act as a correlation detector. Inputs from the non-deprived eye that can drive correlated pre-and post-synaptic activity are strengthened, while synaptic inputs from the deprived eye that exhibit uncorrelated firing with the post-synaptic cell are lost. In addition, calcium influx through the NMDA receptor associated channel regulates intracellular kinases that activate the transcription factor cAMP/Calcium-dependent response element binding protein (CREB). Although this cascade of events has provided a framework for understanding the mechanisms of cortical plasticity, several important questions have remained unanswered concerning the role of NMDA receptors and CREB in ocular dominance plasticity: I) do NMDA receptors function as correlation detectors in ocular dominance plasticity? ii) is activation of CREB required for the loss of cortical binocularity during monocular deprivation?, iii) do NMDA receptors have a function in recovery of cortical binocularity following re-establishment of visual stimulation to the deprived eye?, and iv) what function does CREB have in recovery of cortical binocularity? The proposed studies will use molecular-genetic manipulations to answer these important questions. Antisense reagents will be used to reduce expression of individual genes, and viral mediated gene transfer will be used to induce overexpression of individual genes or expression of mutated genes in the visual cortex. Use of these complementary techniques will provide a new and exciting opportunity to examine the molecular mechanisms of loss and recovery of visual cortical function. Collectively the results of the proposed studies will place us in a position to start tracing the sequence of molecular events leading to loss and recovery of cortical function in monocular deprivation amblyopia. A better understanding of these mechanisms should provide specific targets to develop novel therapeutic approaches in the treatment of amblyopia.

DESCRIPTION (provided by applicant): Much is known about how inputs from sources other than the retina affect the thalamic relay of retinal signals in route to the visual cortex. They arse from a variety of subcortical and cortical sources, comprise the bulk of synapses onto thalamic relay cells and act as modulators to affect the gain of retinogeniculate signal transmission. The superior collliculus (SC), a primary retino-recipient structure, also sends a prominent projection to the dorsal lateral geniculate nucleus (dLGN), the first order nucleus that conveys retinal signals to visual cortex. However, whether SC input acts as a driver to help shape the receptive field structure of dLGN relay neurons or as a modulator to dampen or amplify the flow of thalamic information remains untested. To understand how information arising from the SC influences dLGN function and how particular SC cell types contribute to this, we shall make use of mouse transgenics to visualize or target cell types and projections of the tectogeniculate pathway, optogenetics to photo-activate SC inputs to evoke postsynaptic activity in dLGN cells, and in vitro and in vivo recording techniques to assess whether SC inputs behave as drivers or modulators of dLGN activity. These combined approaches will allow us to selectively control the neuronal activity of the tecto-geniculate pathway and shed light on how interactions between two retino- recipient subcortical structures affect the processing and transfer of visual information. PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how first-order sensory nuclei of the thalamus receive and process information from peripheral sense organs. They shall also reveal how afferent input from central structures can modulate the flow of thalamic information in route to sensory cortical areas. Understanding the functional and structural organization of thalamic circuitry with optogenetic tools may offer further insight into the study and treatment of neurological disorders that result from the formation of abnormal patterns of connectivity.

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a national health care problem, impacting upon both our civilian and military populations. With severe TBI, focal and diffuse changes are seen in the brain while mild to moderate TBI is typically associated with scattered changes, with diffuse axonal injury (DAI) being a major determinant of the subsequent morbidity and recovery. Because of the importance of DAI, our lab and many others have focused on achieving a better understanding of its pathogenesis and its potential therapeutic management. Despite progress in this area, there has been virtually no consideration of DAI's downstream/deafferentation- mediated morphological, physiological, and functional consequences or the brain's ability to adapt to DAI. The failure of the basic scientific community to address this issue is related to the complexity of DAI and the difficulties in following diffusely/scattered damaged axons and their terminal projections in a diffusely injured brain. Recently, we have explored mild TBI in multiple strains of YFP-expressing mice. Using the YFP-16 variant expressing YFP throughout the visual axis, we recognized DAI scattered throughout the prechiasmatic segment of the optic nerve and the subcortical white matter within the visual cortex, allowing us to follow, for the first time, the consequences of DAI for its downstream sites in the lateral geniculate body and the associated primary visual cortex. Using advanced bioimaging and electrophysiological studies conducted in vivo and in vitro, we now seek to determine if DAI translates into diffuse deafferentation within the lateral geniculate nucleus and visual cortex, while also assessing its implications for long-term synaptic function and rearrangement. These studies will be interfaced with a critical evaluation of the natural history o recovery of visual function post DAI while also seeking to determine if DAI compromises visual cortical plasticity, reflected in the ability of the visual axis to respond to manipulations in visal experience. Lastly, with this information in hand, we will utilize multiple therapeutic approaches previously reported by our lab to exert axonal protection to determine if significant reductions in the burden of axonal damage within the visual axis translate into either temporally altered or significantly improved visual function and plasticity. We believe these studies are important in that they represent a comprehensive attempt to understand the consequences of DAI for its downstream target sites. Moreover, in that the organization of the mouse visual system has many structural and functional homologies with the visual system of higher order animals and provides an excellent model system for understanding basic cortical synaptic plasticity and regenerative failure, we believe the proposed studies take on even more importance. Lastly, because disturbances of visual function have been reported in a large cohort of brain-injured soldiers returning from Iraq and Afghanistan, the importance of these studies is further highlighted.