In a new study, University of Illinois scientists have shown how a specific group of neurons respond to information about an animal’s energy state and external challenges to regulate anxiety, fear, and similar behavior. The findings, published in the Journal of Neuroscience, suggest these neurons could be a potential target for better understanding the neurobiology of anorexia nervosa and other disorders related to metabolism and psychiatry.
Patrick Sweeney, a professor of molecular and integrative physiology in the School of Molecular & Cellular Biology, investigates how the brain regulates feeding and body weight and how the complex circuits and pathways within our brain are affected in pathological conditions such as eating disorders and dietary obesity. His lab studies the central melanocortin system, a neuronal pathway essential to regulating body weight in humans as well as rodents and even fish. Mutations in these pathways lead to body weight changes across species.
Among the many questions he and members of his lab have posed: How do changes in energy state, e.g. hunger, affect behavior? “When we are hungry, we become more motivated to seek food, food smells become heightened, and we may become irritable. But in patients with anorexia nervosa this typical behavioral response to hunger is impaired,” Sweeney explained.
In the recent study, led by first-year neuroscience PhD student Dajin Cho and MCB undergraduate student Kyle O’Berry (BS, 2023), the lab focused on two types of melanocortin neurons: AgRP neurons, which are activated when you are hungry and signal that it’s time to eat; and POMC neurons, which are activated when you’re full and tell you to stop eating. One of the places where these neurons communicate is with cells in the paraventricular thalamus (PVT), a brain region important for diverse behavioral states such as arousal, motivation, and anxiety-related behaviors. Here, the authors characterized the role of the melanocortin 3 receptor (MC3R), a receptor that directly responds to the melanocortin neurons, in the PVT. When there are mutations in the pathway producing melanocortin ligands (i.e. the natural compounds that stimulate or inhibit melanocortin receptors), both people and rodents develop insatiable hunger and obesity.
Sweeney and his research team applied a variety of strategies to turn on and off the MC3R neurons in male and female mice to see how behavior was affected.
“What we found was [MC3R neurons] bidirectionally regulate anxiety-related behavior in rodents. When you turn up the activity, the mice act more anxious. When you turn down the activity, they act less anxious. That’s very interesting because these are cells that are directly linked to fasting via their connection to the melanocortin neurons, they’re directly linked to the energy state of the animal, and they regulate anxiety-related behavior in accordance with the energy state of the animal,” Sweeney said.
Researchers also observed that turning the cells on and off also affected how motivated the animal was to seek food, particularly palatable food. Ongoing and future experiments in the Sweeney lab will further explore those observations.
“We will be interested in seeing the link back to obesity and eating disorders. It’s well known when you’re fasted, you’re more motivated to seek food. We think this pathway is involved in that,” he said.
Sweeney said much of his lab’s work is related to basic biology research with the aim of understanding how the brain normally responds to hunger, and what circuits are engaged when an animal is hungry. Only then will scientists have a fuller picture of which pathways and circuits they can further target to develop treatments for disorders.
The research article, “Paraventricular Thalamic MC3R Circuits Link Energy Homeostasis with Anxiety-Related Behavior,” can be accessed via https://pubmed.ncbi.nlm.nih.gov/37591737/
This work was supported by the National Institutes of Health–National Institute of Diabetes and Digestive and Kidney Diseases, the Foundation for Prader Willi Research, and the Brain and Behavior Research Foundation.
Photo: The paper's authors included, from left, back row: Jared Butts, PhD student in neuroscience and MCB graduate (BS, '22); Professor Patrick Sweeney; Ingrid Possa Paranhos, PhD student in molecular and integrative physiology; and Dajin Cho, PhD student in neuroscience. Authors not pictured include MCB graduate Kyle O'Berry (BS, '23) and Naraen Palanikumar.