The recently announced BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative endeavors to ultimately map the brain neuronal activity. This presents challenges that are unique to the brain, as it comprises a complex set of neurons some of which exhibit varying degrees of plasticity, meaning that there is a constant change in the finer network of neurons and their interconnections (synapses). The brain could be imagined to be analogous to a computer-processing chip, with numerous multi-connections. However, unlike a computer-processing unit, in which one may turn on a single circuit or switch, the brain switches at the interface of neuronal connections cannot be individually turned on using electrical currents. The latter would resemble the act of walking into a hall with multiple light switches and using one's arm to flip all switches on at once, such that critical information of which switch turns on which light cannot be determined. The proposed work aims at developing molecular tools that enable the switching on of specific synapses using laser light in a rapid and focused manner, down to the scale of a single synapse, as in a single switch. There are only a handful of these types of molecular tools that have been used. However, not only are their preparation complex and rather elusive, but they also have lower sensitivities and efficiencies which necessitate their use in concentrations that are far too high for neurons, resulting in frequent inhibition of competing pathways. This proposal addresses means to develop improved molecular tools, with potentially higher photo efficiencies and lower interference, which can be used to stimulate a single synapse thus contributing to the ultimate goal of mapping out brain activity. Preliminary work has shown promise on improved methods of preparation of these molecular tools. The approach will take advantage of the PI's experience with light absorbing molecules combined with experience in catalysis and kinetics. The successful design of new efficient cages with four enhanced properties: 1. Improved quantum efficiency, 2. Enhanced photo cross-section, 3. Minimized interference with GABA receptors, and 4. Improved solubility will greatly advance the knowledge and available tools to understand brain functions and subsequently malfunctions. The preparation of effective photoactive molecular tools, caged neurotransmitters, will directly benefit the larger neuroscience community in studying the brain with the level of details that still remains a mystery. While there has been substantial advances in the medicinal research targeting various diseases of the body, the neurological diseases such as Alzheimer's, epilepsy, autism, bipolar, depression, to name a few, still remain elusive and a challenge. The proposed work will be critical in its contribution t help unravel these mysteries awaiting a solution. The ongoing work already developed in the Nesnas laboratory has already attracted a number of young scientists in as early as their junior high school. One such student, Margarita Cruz-Sanchez, is already making her first cage.
The Brain remains a mystery to science. Certain localized brain defects ultimately lead to familiar diseases such Autism, Alzheimer's, epilepsy; Huntington's, Lou Gehrig's, depression, and other neurological disorders, which to this day remain elusive to understand. The unimaginable complexity of nearly 100 billions neurons interconnected with as many as 10,000 connections (known as synapses) is partly a reason behind this mystery. One may imagine a humble comparison of the brain network to the vast road connections in a large country such as the US. It is therefore easily appreciated that having a map of these vast interconnected roads is of paramount importance for safe navigation. This proposal aims to develop the molecular tools that act like road intersection cameras, which are much needed by neuroscientists to effectively map out these brain connections down to the single synapse, i.e. road intersection.
| 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 |
