In brief

The circuit between the parabrachial nucleus (PBN) and the lateral hypothalamus (green) control feeding motivation, whereas PBN neurons projecting to the central amygdala (red) suppress feeding in response to pain.

© Tan Yu Lin

Tracing the path between hunger and pain

9 May 2021

Researchers have identified a pain pathway that suppresses hunger, opening the door to understanding how pain quells other competing behaviors.

In life, our goals are often clouded by conflicting motives, where wanting to do something pleasurable may clash with the pain or difficulty of the task. Conflicts between pain and essential behaviors like feeding can have dire consequences, like the loss of appetite, anxiety and depression seen in many people with chronic pain.

In the brain, the pain pathway connecting the parabrachial nucleus (PBN) to the central amygdala (CeA) has long been thought to suppress feeding. However, the PBN-CeA circuit has never explicitly been studied for its role in suppressing motivational drive for feeding, noted Yu Fu, a Principal Investigator at A*STAR’s Singapore Bioimaging Consortium (SBIC). Apart from CeA, the PBN also relays pain signals to many other brain regions, but these circuits have not been rigorously studied because the pain-hunger connection was believed to have already been resolved, he added.

In a study published in Science Advances, Fu and his team report a new pathway important for regulating feeding: the PBN-lateral hypothalamus (LH) circuit. In contrast to the PBN-CeA circuit which seems to suppress feeding in response to the fear of pain, the PBN-LH circuit appears to suppress the motivation to feed in the first place.

To tease apart this key difference, Siew Cheng Phua, an A*STAR scholar and the lead author of the paper, refined the ‘approach-avoid’ experiment, a decades-old paradigm designed to see how mice resolve the conflict between the pain of a foot shock and the desire to eat. While previous versions of this experiment looked at how much food the mice consumed at different levels of pain, Fu and the team instead focused on how much time the mice spent deciding between avoiding pain and approaching food, a behavior known as vacillation.

“Although both mild and strong pain almost completely abolished food intake, the mice displayed vacillation behavior under mild shocks, showing a clear motivational conflict between trying to obtain food and avoiding mild pain,” Fu said. “However, animals facing strong shocks showed much less vacillation, probably due to intense fear driven by stronger pain.”

© A*STAR Research

Inactivating the PBN-LH circuit in mice suppressed their vacillation behavior under mild shock conditions and promoted food-seeking behavior, essentially resolving the motivational conflict between pain avoidance and reward approach. In contrast, disabling the PBN-CeA circuit did not have that effect and was instead linked to the escape behavior displayed in response to stronger shocks. “The PBN-CeA circuit is probably more involved in suppressing feeding by fear (strong shocks), which is qualitatively distinct from pain (mild shocks),” Fu explained.

Interestingly, the researchers also briefly looked at the effects of the common analgesic buprenorphine and found that it did not improve motivation to feed even under mild pain. “Better medicines should be developed to target neural circuits involved in motivation loss, such as the PBN-LH circuit, for rescuing chronic pain patients from depressive disorders,” Fu concluded.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium (SBIC).

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Phua, SC., Tan, YL., Kok, M.Y.A., Senol, E., Chiam, J.H.C., et al. A distinct parabrachial to lateral hypothalamus circuit for motivational suppression of feeding by nociception. Science Advances (2021) | article

About the Researcher

Yu Fu received his PhD in Neuroscience from Stony Brook University and did his postdoctoral training at the University of California San Francisco with Michael Stryker, where he pioneered a method to image genetically labeled GABAergic neurons in behaving mice, and elucidated the circuit mechanisms of behavioral state-dependent sensory modulation in mouse visual cortex. In 2014, he was awarded the prestigious A*STAR Investigatorship and started his lab in the Singapore Bioimaging Consortium in 2015. The main research interest of his lab is the neural mechanisms of metabolic regulation, currently with a focus on feeding behavior.

This article was made for A*STAR Research by Wildtype Media Group