Mark Alkema, PhD, and colleagues are the first to show that it’s possible to reverse the behavior of an animal by flipping a switch in neuronal communication.

UMass Medical School scientists are the first to show that it’s possible to reverse the behavior of an animal by flipping a switch in neuronal communication. The research, published in PLOS Biology, provides a new approach for studying the neural circuits that govern behavior. It also has important implications for how scientists think about the neural roadmap.

New technologies have fueled the quest to map all the neural connections in the brain to understand how these networks process information and control behavior. The human brain consists of 100 billion neurons that make a quadrillion connections. The total length of neuronal processes in the human brain is approximately 4 million miles long, similar in length to the total number of roads in the U.S. Along these networks, neurons communicate with each other through excitatory and inhibitory synapses that turn neurons on or off, respectively.

The neuronal roadmap, or connectome, however, doesn’t include information about the activity of neurons or the signals they transmit. The complexity of the human brain makes it almost impossible to address questions such as how stable are neural circuits in the brain and does their wiring constrain the flow of information or the behaviors they control.

Mark Alkema, PhD, associate professor of neurobiology, turned to the nematode C. elegans to find answers. A tiny worm with only 302 neurons, it is the only animal whose neural roadmap has been completely defined.

In this study, Dr. Alkema and colleagues sought to determine if flipping the sign of a synapse from inhibitory to excitatory in the worm’s brain was enough to reverse a behavior. To do this, they analyzed nematode touch response that C. elegans employ to escape from carnivorous fungi that use threadlike nooses to catch nematodes. During this escape response, neurotransmitters in C. elegans are released that activate an inhibitory ion channel. This causes the worm to relax its head and quickly reverse direction away from the predator.

Jenn Pirri, a doctoral student in the Alkema lab, and Diego Rayes, PhD, a former post-doctoral fellow now at the Instituto de Investigaciones Bioquímicas de Bahía Blanca in Argentina, replaced the inhibitory ion channel with an excitatory version of the channel in a live nematode.

“Surprisingly, the engineered channel does not affect development of and is properly incorporated into the neural circuits of the worm brain,” said Alkema. “Cells that are normally inhibited in the brain now get activated.”

“What was most striking is that we were able to completely reverse behavior by simply switching the sign of a synapse in the neural network,” explained Alkema. “Now the animal contracts its head and tends to move forward in response to touch. This suggests that the neural wiring diagram is remarkably stable and allows these types of changes.”

“Our studies indicate that switching the sign of a synapse not only provides a novel synthetic mechanism to flip behavioral output but could even be an evolutionary mechanism to change behavior,” said Alkema. “As we start to unravel the complexity and design of the neural network, it holds great promise as a novel mechanism to test circuit function or even design new neural circuits in vivo.”