Dennis Mathew is an associate professor in the Department of Biology at the 鶹ӳ, and studies insect olfaction at the cellular and molecular levels. He is also a co-director of the Integrative Neuroscience Graduate Program at the University and a director of the National Institutes of Health-funded 鶹ӳ ENDURE program. Mathew recently applied for a grant from the National Science Foundation’s (NSF) Modulation program within the Division of Integrative Organismal Systems. The NSF awarded the Mathew lab $750,000 to study how hunger shapes smell-related decision-making in insects.
Mathew and his lab study the larvae of Drosophila melanogaster, commonly known as the fruit fly. The fruit fly is a useful and well-studied research model with a simple nervous system, which allows detailed analyses of smell neurons and their functions. Over the last few years, the Mathew lab has innovated or optimized lab-based behavior, molecular, and imaging methods to gather and analyze data using the Drosophila larvae.
Neurons are cells that communicate with one another via neurotransmitters. Neuronal functions are further shaped by hormones such as insulin. Mathew is particularly interested in how the larvae’s hunger state and insulin signaling shape the functions of a particular neuron in the olfaction part of the larvae’s brain to affect the larva’s navigational decisions.
Fruit flies, they’re just like us
As fly larvae navigate in search of food, they engage in head-sweeping behavior akin to sniffing in humans. Their smell sensory neurons, similar to the ones located inside human nostrils, are located at the tips of their heads. Moving their heads back and forth can help the larvae sense and assess the location of an odor that could be coming from food. The head sweeping motion is associated with decision-making during larval navigation.
Previous research in the Mathew lab found that navigational decisions are influenced by the larvae’s hunger state. For instance, when the larvae are hungry, they tend to decrease the angle of head sweeping by approximately ten degrees, which seems counterintuitive. However, an undergraduate student in the Mathew lab did a literature survey and found that this decrease in head-sweeping when hungry was consistent across many species of insect larvae, and when the larvae reduce their head-sweeping behavior, they tend to move in straighter paths. Traveling in straighter paths likely allows them to escape quickly away from an area with no food and find food elsewhere.
Subsequently, the Mathew lab found that larval head-sweeping behaviors depend on the activity of a pair of inhibitory neurons in their smell circuit known as Keystone neurons. They found that the Keystone neuron’s ability to induce head-sweep behavior is affected by the larva’s hunger state and that the Keystone neuron is sensitive to insulin (yes, fruit flies have insulin, too!). When Mathew and his colleagues decreased insulin signaling in Keystone neurons to simulate a hunger state, they found that the larvae had significantly smaller head sweeps and traveled in straighter paths. Overall, their research suggested that insulin (low levels during the hunger state and high levels during the fed state) might convey information about the animal’s satiety state to the Keystone neuron to influence the larvae’s head-sweep behavior and, ultimately, the larva’s navigational decision-making.
Inhibitory neurons play important roles in the neural circuits of animals, including the circuits that control motor behavior in humans.
“However, from a basic neuroscience point of view, we don't really understand how inhibitory neurons are modulated,” Mathew said. “Here, we have an excellent opportunity to study how Keystone neuron, an inhibitory neuron controlling larval head movements, is modulated by hunger and insulin.”
Mathew lab researchers will use the grant funding to study how insulin mediates the satiety-dependent changes in Keystone neuron functions. They will investigate the underlying mechanisms using state-of-the-art behavior, imaging, and molecular approaches.
Small brains, big possibilities
By studying the brains of fruit flies, which are barely visible to the naked eye, Mathew hopes to explore exciting neuroscience frontiers.
“We think we have the ability to understand the neuroscience of decision-making,” Mathew said.
A better understanding of how insects make decisions about smells could prove incredibly useful in public health and agriculture. Insects that cause harm to humans, like mosquitoes, and insects that consume plants, like locusts, primarily navigate to their human or plant hosts through their sense of smell.
“The exciting thing about the project is if we better understand the neuroscience underlying this navigational decision-making, perhaps we can develop more effective and strategic tools to target these harmful insect pests rather than flooding the environment with toxic and harmful insecticides,” Mathew said.
But there are other potential implications for the research, too. It is believed that the improper modulation of inhibitory neurons in the human basal ganglia by dopamine leads to motor disorders such as Parkinson’s Disease. Poor regulation of inhibitory neurons could explain why Parkinson’s patients have trouble initiating movements and, once initiated, have trouble stopping movements, which is observed as tremor symptoms in these patients.
Mathew isn’t claiming that the two systems—larval Keystone inhibitory neuron being modulated by insulin and the human basal ganglia inhibitory neurons being modulated by dopamine—are exactly the same, but having a greater understanding of the molecular and cellular processes underlying inhibitory neuron modulation could lead to new insights for research into human motor disorders.
“Because it's a Drosophila system, we have the opportunity to study these questions at a level of granular detail, which would be very difficult to do in the basal ganglia of mice or humans,” Mathew said.
The research is already underway, and Mathew hopes to have research findings within four years. In addition to this research, this NSF grant includes funding for outreach programs. Mathew plans to use this funding to bring K-12 students from rural parts of 鶹ӳ to the University campus for summer workshops. Starting next summer, Mathew will collaborate with the Museum of Natural History and explain to students the important roles that insects play in our day-to-day lives and how basic science research using insect models can have far-reaching implications for human health. The outreach efforts aim to inspire more 鶹ӳ K-12 students to consider STEM-related careers.
