The job descriptions of thousands of types of neurons in the brain typically involve a common function: releasing chemicals called neurotransmitters to communicate across circuit connections called synapses. In a new study funded by the National Institutes of Health, Professor Troy Littleton’s MIT laboratory will seek to understand how neurons build different strengths, a variety that may be key to the diversity of neural connectivity.
The findings could increase scientists’ understanding of how neural circuits evolve and change to reflect learning and experience – a phenomenon called plasticity – and he might also suggest ways to fine-tune the strength of neural circuits. Synaptism when it is atypical in disorders such as autism or intellectual disability.
Using neurons that control Drosophila muscles, the study will focus on “active regions” (AZs), which are delicate neurotransmitters that enable the release of neurotransmitters across each synapse. Littleton said flies provide a simple model that could help elucidate many of the fundamental factors affecting A to Z strength that also play a role in the neurons of other animals, including mammals.
“Understanding the rules in a simple model like Drosophila that help determine when a synapse is strong or weak allows us to look at these principles as fundamental elements of how neurons control synaptic growth and development,” he said. “Depending on which of these factors the neurons modulate or manipulate them, they are likely to be able to make synapses stronger or weaker in completely different patterns.”
As the larvae develop, the nerve cells build hundreds of larvae. In a 2018 study, Littleton’s lab found that AZs vary greatly in potency: about 10% release 50 times more neurotransmitters than the majority of weaker synapses. The researchers also found that the strongest AZs were usually the ones that had the most time to develop and assemble many of the protein building blocks.
In the new study, which will save nearly $ 1.9 million over five years, the team will learn how to build these active regions step-by-step from more than a dozen different proteins that reach different stages of development. Because some residential areas from the ground up look bigger and stronger than others, Littleton is like the process by building a variety of homes in the neighborhood – from large four-bedroom homes to tiny homes. The new study, including the team’s initial work with support from the Picower Institute’s Innovation Fund, will help explain how each type of structure appears, in relative abundance, in the same cell.
In one set of experiments, for example, his team will study whether the provision of building materials – the various proteins – is a limitation on the number of AZs that can mature to full strength before development is halted (that is, perhaps not all of them get enough wood) Or nails to completely frame the house at the right time). Scientists will test this, for example, with genetic manipulation that alters the amount of key proteins produced. By imaging proteins as they accumulate and looking at the same AZs day in and day out, a technique the lab uses called “intraorbital imaging,” they can see how the availability of the altered protein alters the formation of AZs in neurons.
In another set of experiments, the team will test whether some AZs are better than others at obtaining and using the supply of available materials (for example, some may have more joiners than others to make the best use of nails and wood available). To better understand how the building process works in longer-lived animals such as mammals, where protein materials not only need to be collected but also need to be maintained and replaced, they will artificially extend the larval stage of the flies.
In a third set of tests, they will check the status of two types of neurons that each communicate with the same fly muscles but exert control in different ways. Although each type works by releasing the same neurotransmitter, called glutamate, “activator” neurons are characterized by a small but steady release of glutamate, while “metaphase” cells release stronger, but occasionally bursts. The study will examine how the development of AZ varies, for example, due to differences in gene expression to enhance the different function of these similar cells.
In general, their goal will be to determine how neurons build their various capacities, communication and communication patterns.
In addition to Littleton, the research team includes researchers Yulia Akberginova and Suresh Getty, and graduate students Karen Leopold Cunningham and Andres Crane.