Development of Light Triggered Molecular Tools Critical for Understanding the Brain's Network PI: Nasri Nesnas, PhD PROJECT SUMMARY Brain disorders, such as dementia, epilepsy, and depression, continue to be a major challenge in medicine. This is not surprising considering the enormous complexity of the brain's network of neurons. An average human brain incorporates nearly 86 billion neurons intertwined with as many as 10,000 synaptic connections. Such complexity is far more colossal than any computer processor or even the entire worlds' road maps. Therefore, brain-mapping efforts have become of apparent urgency to enable a better understanding of this complex maze. Making substantial advances in this area certainly requires collaboration of multiple disciplines. Light responsive molecular tools have become indispensible to neuroscientists as they provide means to manipulate specific neuronal connections with precise timing. We established collaborations with several neuroscientists, including Attila Losonczy of Columbia University and James Schummers of Florida International University (FIU), to design and use these critical tools. Recent advances in neuroscience led to the development of genetically engineered GPCR and LGIC receptors (DREADD and PSAM, respectively), which can be introduced into a select population of neurons. These receptors can be controlled with high specificity by loyal (inactive to other receptors) synthetic drugs to enable studying animal behavior in vivo. However, there are currently no means to precisely control the timing of delivery of these drugs as they are injected or administered orally. Photocleavable protecting groups, also known as cages, enable the release of active agonists with light. The principal advantage of this technique is the unparalleled precision of activation in location as well as timing, otherwise referred to as spatio-temporal control. We have prepared several of these cages, and we aim to design more efficient ones that can also respond in visible and near IR wavelengths to avoid photo toxicities associated with UV light traditionally used. We also aim to use these longer wavelength chromophores to cage DREADD and PSAM molecules to enable their activation with precise timing. This would present a technique that incorporates advantages of both optogenetics as well as chemogenetics. Preparation of effective photoactive molecular tools will directly benefit the larger neuroscience community in studying the brain with the level of detail essential to treating elusive brain disorders. I will continue to actively engage undergraduate students in these endeavors, and particularly emphasize the diversity of educational and cultural backgrounds of the members in my research lab. I have been successful at maintaining a larger percentage of female students than our university's average and I will continue to do so as well as encouraging minority students to engage in research.
(Relevance) Brain conditions such Autism, Alzheimer's, epilepsy, Huntington's, Lou Gehrig's, depression, and many other neurological disorders continue to be elusive to understand and treat. The unimaginable brain complexity of nearly 100 billions neurons interconnected with as many as 10,000 connections is partly a reason behind the challenging task of brain mapping. This proposal aims to develop light controlled molecular tools that act like neuron switches to effectively aid in mapping out these brain connections.
| Guruge, Charitha; Ouedraogo, Yannick P; Comitz, Richard L et al. (2018) Improved Synthesis of Caged Glutamate and Caging Each Functional Group. ACS Chem Neurosci 9:2713-2721 |
