Technical Description and Intellectual Merit: Optic nerve injuries due to diseases (e.g. glaucoma) or trauma often result in lifelong disabilities, and at present most are incurable. Retrograde degeneration of ganglion cells following optic nerve injuries is believed to result primarily from a reduction in the transport of neurotrophic materials these neurons obtain from their target neurons in the visual thalamus. Current neurotrophic factor-based treatments are inadequate to provide long-term neuroprotection and can produce abnormal dendritic morphology in both transduced and non-transduced nerve cells. The objective of this proposed research is to investigate an innovative strategy for treatment of optic nerve injuries, combining neurotrophic therapy of the eye with optical stimulation of the visual cortex to promote endogenous neuroprotection and preservation of retinal ganglion cells (RGC) and retinal function. It is hypothesized that combined treatment of both the eye and visual cortex provides a more significant and sustained level of neuroprotection as compared to treating the eye alone. Specifically, optical stimulation of cortical neurons across different layers will be achieved via a novel three-dimensional (3-D) Opto-µECoG (electrocorticography) interface, which consists of multiple micro light emitting diode (µ-LED) light sources, out-of-plane microscale polymer waveguides, and transparent µECoG electrodes on a single flexible polymer platform. Integration of individually addressable µ-LED chips with waveguides will help minimize the LED light scattering within brain tissue to achieve high-spatial resolution and precise light delivery to the target neurons. The transparent epidural ECoG electrodes will permit real-time monitoring of light-induced neural activity in visual cortex. The functionality and reliability of the engineered Opto-µECoG interface will be evaluated using both in-vitro primary cortical slices and in vivo rat models. Light-induced activation of the visual thalamus will be assessed, as indicated by enhanced electrical activity of neurons in the visual thalamus as well as up-regulated levels of BDN Fandits associated anti-apoptotic proteins (ERK 1,2, PI3K/Akt, and CREB).Enhanced neuroprotection and preservation of vision following the combined treatment will also be investigated ina rat model with optic nerve trauma, by comparing electroretinographic responses from animal eyes and vision-evoked potentials from visual cortex. The ultimate goal is the development of optogenetics-based treatment strategies not only for optic neuropathies, but also for other brain injuries in general. The PIs have established collaborations and complementary research expertise in the areas of biomedical microelectrome chanical systems (BioMEMS), neural engineering, and neurophysiology, which make this project viable in its execution.
Broader Impacts: The scientific impacts of this research include: 1) investigation of a transformative treatment strategy for neural protection and restoration in eyes with glaucoma, 2) development of optogenetics-based engineering tools for seamless communication with neurons, and 3) in-depth understanding of the mechanisms of trauma-induced cellular degeneration and neuroprotection. While it is specifically tailored for glaucoma treatment, the proposed treatment strategy can also be used to treat trauma-induced optic nerve injuries and other brain injuries such as sensory deficits, Parkinson's disease, and depression. The most pronounced long-term benefits of this work to society include a reduction of healthcare cost and quality of life improvement for a sizeable, and growing, population affected by the above conditions. In addition to its scientific impacts, this work will offer unique research experiences for undergraduate and graduate students to understand technical details of different disciplines and develop multiple, translational, biomedical skills. To reach larger audiences, the results will be shared with students through science fairs, with scientific communities through conference presentations and journal publications, and with the public through exhibits. The integrated outreach program will be very effective due to the visually appealing nature of microscale devices and systems. The curriculum development and improvement will provide tremendous opportunities to introduce interdisciplinary topics and hands-on experimental experiences to students at multiple levels. The results of the educational programs will be assessed through internal and external evaluators and disseminated through conferences (e.g. ASEE, FIE and MEMS) and in-house programs, such as Frontiers in Science, at MSU. These efforts will encourage more students to pursue careers in research and ultimately produce skilled and knowledgeable workforces for biomedical, neural science, and engineering.
