HALT! Scientists decode brain mechanisms of stopping

Ever wish you could stop that fruit fly on your kitchen counter in its tracks? Scientists at Max Planck Florida Institute for Neuroscience have created flies that halt under red light. In doing so, they discovered the precise neural mechanisms involved in stopping. Their findings, published this week in Nature, have implications far beyond controlling fly behavior. They demonstrate how the brain engages different neural mechanisms depending on environmental context. 

The power of Drosophila to understand complex behaviors 

Halting is a critical action essential for almost all animal behaviors. When foraging, an animal must stop when it detects food to eat; when dirty, it must stop to groom itself. The ability to stop, while seemingly simple, has not been well understood as it involves complex interactions with competing behaviors like walking. 

Max Planck Florida scientist Dr. Salil Bidaye is an expert in using the powerful research model Drosophila Melanogaster (aka the fruit fly) to understand how neural circuit activity leads to precise and complex behaviors such as navigating through an environment. Having previously identified neurons critical for forward, backward, and turning locomotion, Dr. Bidaye and his team turned to stopping. 

“Purposeful movement through the world relies on halting at the correct time as much as walking. It is central to important behaviors like eating, mating, and avoiding harm. We were interested in understanding how the brain controls halting and  where halting signals override signals for walking,” said Bidaye.  

Taking advantage of the fruit fly's power as a research model, including the animal’s simplified nervous system, short lifespan, and large offspring numbers, Bidaye and his team used a genetic screen to identify neurons that initiate stopping. Using optogenetics to activate specific neurons by shining a red light, the researchers turned on small groups of neurons to see which caused freely walking flies to stop. 

Two mechanisms for stopping 

Three unique neuron types, named Foxglove, Bluebell, and Brake, caused the flies to stop when activated. Through careful and precise analysis, the scientists determined that the flies' stopping mechanisms differed depending on which neuron was active. Foxglove and Bluebell neurons inhibited forward walking and turning, respectively, while Brake neurons overrode all walking commands and enhanced leg-joint resistance. 

“Our research team’s diverse expertise was critical in analyzing precise stopping mechanisms. Each team member contributed to our understanding by approaching the question through different methods, including leg movement analysis, imaging of neural activity, and computational modeling,” credits Bidaye. “Further, large research collaborations spanning multiple labs and countries have recently mapped the connections between all the neurons in the fly brain and nerve cord. These wiring diagrams guided our experiments and understanding of the neural circuitry and mechanisms of halting.” 

The research team, consisting of scientists from Max Planck Florida, Florida Atlantic University, University of Cambridge, University of California, Berkeley and the MRC Laboratory of Molecular Biology, combined the data from the wiring diagrams and these multiple approaches to gain a holistic understanding of the behavioral, muscular, and neuronal mechanisms that induced the fly's halting. They found that activating these different neurons did not stop the flies in the same way but used unique mechanisms, which they named ‘Walk-OFF’ and ‘Brake’. 

As the name implies, the “Walk-OFF” mechanism works by turning off neurons that drive walking, similar to removing your foot from the gas pedal of a car. This mechanism, used by the Foxglove and Bluebell neurons, relies on the inhibitory neurotransmitter GABA to suppress neurons in the brain that induce walking.  

The “Brake” mechanism, on the other hand, employed by the excitatory cholinergic Brake neurons in nerve cord, actively prevents stepping by increasing the resistance at the leg joints and providing postural stability. This mechanism is similar to stepping on the brake in your car to actively stop the wheels from turning. And just as you would remove your foot from the gas to step on the brake, the “Brake” mechanism also inhibits walking-promotion neurons in addition to preventing stepping. 

Lead researcher on the project Neha Sapkal, describes the team’s excitement in discovering the “Brake” mechanism. “Whereas the ‘Walk-Off’ mechanism was similar to stopping mechanisms identified in other animal models, the ‘Brake’ mechanism was completely new and caused such robust stopping in the fly. We were immediately interested in understanding how and when the fly would use these different mechanisms.”  

Context-specific activation of halt mechanisms  

To determine when the fly might use the “Walk-OFF" and “Brake” mechanisms, the team again took multiple approaches, including predictive modeling based on the wiring diagram of the fly nervous system, recording the activity of halting neurons in the fly, and disrupting the mechanisms in different behavioral scenarios.  

Their findings suggested that the two mechanisms were used mutually exclusively in different behavioral contexts and were activated by relevant environmental cues. The “Walk-OFF” mechanism is engaged in the context of feeding and activated by sugar-sensing neurons. On the other hand, the “Brake” mechanism is used during grooming and is predicted to be activated by the sensory information coming from the bristles of the fly.  

During grooming the fly must lift several legs and maintain balance.  The Brake mechanism provides this stability through the active resistance at joints and increased postural stability of the standing legs. Indeed, when the scientists disrupted the ‘Brake’ mechanism, flies often tipped over during grooming attempts. 

“The fly brain has provided insight into how contextual information engages specific mechanisms of behaviors such as stopping.” Bidaye says, “We hope understanding these mechanisms will allow us to identify similar context-specific processes in other animals. In humans, when we stop and lift our foot to adjust our shoe or remove a stone from our tread, we are likely taking advantage of a stabilizing mechanism similar to the Brake mechanism. Understanding context-specific neural circuits and how they work together with other sensory and motor circuits is the key to understanding complex behaviors.”  

Paper: https://www.nature.com/articles/s41586-024-07854-7 

About the Max Planck Florida Institute for Neuroscience 

The Max Planck Florida Institute for Neuroscience, a not-for-profit research organization, is part of the world-renowned Max Planck Society, Germany’s most successful research organization with more than 80 institutes worldwide. Since its establishment, 31 Nobel laureates have emerged from the ranks of its scientists including six in the last four years alone. 

As its first U.S. institution, MPFI provides exceptional neuroscientists from around the world with the resources and technology to answer fundamental questions about brain development and function. MPFI researchers employ a curiosity-driven approach to science to develop new technologies that make groundbreaking scientific discoveries possible. For more information, visit mpfi.org. 

This research was supported by DFG- German Research Foundation, the Carl Angus DeSantis Foundation, the Wellcome foundation and the Max Planck Florida Institute for Neuroscience. This content is solely the authors' responsibility and does not necessarily represent the official views of the funders.