Many complicated neurological disorders appear to have a gender bias. Women, for example, are more likely to develop Alzheimer’s disease, while men are at greater risk for Parkinson’s disease. Understanding some of the molecular mechanisms that may account for this gender-specific neuronal bias is the aim of a research program at Worcester Polytechnic Institute (WPI) funded by a new five-year, $1.6 million award from the National Institutes of Health (NIH).
The project is led by Jagan Srinivasan, PhD, assistant professor of biology and biotechnology at WPI, and principal investigator for the new grant. “If we can understand the differences in the basic neurobiology of males and females, then perhaps that knowledge will help us devise better treatment strategies for neurological disorders that have a gender bias,” he said.
The research will be conducted using the small, soil-dwelling worms known as Caenorhabditis elegans (C. elegans). An adult C. elegans is about 1 millimeter long and has approximately 1,000 cells, about a third of which are dedicated to its nervous system. Despite its small size, the worm is a complex organism capable of carrying out all of the processes required for animal survival, including foraging for food and seeking out mates, making it one of the most powerful research models in molecular biology.
Most C. elegans worms are self-fertilizing hermaphrodites, carrying both egg and sperm cells. But a very small percentage of the C. elegans population is fully male (there are no fully female C. elegans worms). Srinivasan will use that gender differentiation to explore varying neural activity, focusing on a cluster of neurons that allow the worms to “smell” cues from their environment.
“It is known that in human cases of Alzheimer’s, a diminished sense of smell is one of the early symptoms of the disease,” said Srinivasan, whose earlier research analyzed the electrical activity of sensory neurons located near the male worm’s head that detect and process olfactory cues and allow them to navigate their environment and find a mate. “So, focusing on understanding the circuit mechanisms that show gender differences in the worm’s olfactory system may give us new information that is relevant for what is seen in human neuropathology.”
In previous studies, Srinivasan discovered a novel sensory circuit with feedback loops involving four worm neurons that process environmental cues. In the newly funded project, Srinivasan and colleagues will dig deeper into the molecular mechanisms that actuate the olfactory nerve circuitry in the male worms, seeking to identify the specific neurotransmitters and neuropeptides involved. The project will also study how signals propagate through the worms’ neural circuits following an olfactory cue to affect behavior. The male-specific findings will then be compared to the activity in hermaphrodite worms.
Dirk Albrecht, PhD, assistant professor of biomedical engineering at WPI, a co-investigator of the grant, also studies how neuronal signals govern behavior using the worm model. He has developed several imaging technologies and data processing algorithms that allow for visualizing specific neuronal activity in free moving worms. “The new project seeks to image multiple neurons, in multiple worms, responding to multiple stimuli in real time. And we know the responses will be different in each animal,” Albrecht said. “That means we need to develop new technologies to push the existing boundaries of imaging throughput and analysis to handle the experimental load. That makes this an exciting and important challenge.”
The Srinivasan and Albrecht labs are part of the growing “worm community” at WPI, and the imaging and bioinformatics technologies developed through their work will become enhanced platforms promoting further interdisciplinary research programs across the WPI Life Sciences and Bioengineering Center.
“We are very fortunate to have Dirk and his team right down the hall to collaborate with,” Srinivasan said. “It’s a great example of the interdisciplinary research work, blending science and engineering, that is possible here at WPI.”