Photo credit: Florida Institute of Technology

The human brain has an average of 86 billion neurons. These nerve cells are connected to each other at junctions known as synapses, and some neurons have up to 10,000 such synapses. One key to understanding brain function is to better understand how this non-logical arrangement of complex neurons leads to certain behaviors and cognitive functions, including the storage of memory.

Recent advances that combined chemical applications with neurobiological techniques made it possible to use light as a trigger to turn on specific neurons by activating selected synapses. Chemical groups that effectively released active molecules like glutamate (a key molecule for learning and memory) helped control nerve signals by keeping them in a switched-off state. If necessary, targeted light can release the active molecules that lead to neurons being switched on and thus to paths of interest. The key to the success of this process depends heavily on the effectiveness of light in breaking molecular bonds.

Little was known about the exact mechanism by which light can induce the release of certain classes of molecules known as nitroindolinyl (NI), which are some of the most efficient photosensitive molecules.

Florida Tech’s Nasri Nesnas and Roberto Peverati research groups were now able to conduct detailed computational studies that revealed important details about how bonds break to release active molecules. This is extremely valuable in enabling future designs of other molecules that can modulate brain signals. This broader understanding of the ability of light to induce this type of chemical bond cleavage will lead to the creation of systems that are far more photosensitive, require lower amounts of such agents, and thereby minimize any interference with other neighboring neurons.

The collaborative study was recently published in Scientific Reports.

The study explains how light can activate neurons

Different proposed mechanisms for uncaging of MDNI-Glu (R = CH2CH2CH (NH2) COOH): Migration path (MP) – computational mechanism, reported by Pálfi et al.39; Cyclization Pathway (CP) – mechanism adopted by Ellis-Davies et al.34 and based on Morrison’s experimental data40. Credit: Scientific Reports (2021). DOI: 10.1038 / s41598-020-79701-4

Florida Tech’s Pierpaolo Morgante, first author of the paper, was thrilled to learn that there are two ways in which such a process can take place. “I was surprised to see that there was some confusion about this path in the previous literature, and I became interested in really understanding these mechanisms. I found something really unusual.”

Peverati, one of the developers of the reliable calculation method on which these new results are based, added: “Our method and the associated software can reliably predict the energies of the molecules that are involved in this pathway. We simulate the behavior of each one of them Electrons. Our program has allowed us to clarify a mechanism that has been widely debated in the literature. The predictions of our software are consistent with the results of Dr. Nesnas’ experiments which further validate the reliability of our approach. These results give trust us that we can use this computer software to predict new molecules that are more responsive to light and can be used to study neurons. “

Nesnas, whose group makes these connections, was pleased with the outcome of the study.

“Light has become a powerful tool in neuroscience in recent years,” he said. “We discovered that there is an unusual way that combines two known photochemical processes that until this study had never been observed to occur simultaneously. This is an exciting finding in the world of photochemistry.”

Understanding the complex brain network helps clarify possible causes of elusive brain disorders such as Alzheimer’s, epilepsy, depression and other brain disorders.

The new “molecular” tool helps to illuminate individual synapses in brain cells

More information:
Pierpaolo Morgante et al. Competition between cyclization and unusual Norrish type I and type II nitro-acyl migration pathways in photouncaging of 1-acyl-7-nitroindoline by calculations, Scientific Reports (2021). DOI: 10.1038 / s41598-020-79701-4 Provided by the Florida Institute of Technology

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