Uncovering the Role of “Zombie Neurons” in Cerebellar Learning

Saturday - April 6 2024, 15:52 UTC - 7 months ago

A team at the Champalimaud Foundation has discovered the role of “zombie neurons” in the cerebellum's critical teaching signals. These neurons, alive but functionally altered, have helped to advance our understanding of the cerebellum's role in associative learning. By manipulating them in mice, the researchers were able to induce changes in behavior, shedding light on the intricate mechanisms involved in learning. This could have implications for rehabilitation strategies and further our understanding of psychiatric disorders linked to the cerebellum.

Nestled at the back of your head, the cerebellum is a brain structure that plays a pivotal role in how we learn, adapting our actions based on past experiences. Yet the precise ways in which this learning happens are still being defined. A study led by a team at the Champalimaud Foundation brings new clarity to this debate, with a serendipitous finding of so-called “zombie neurons.” These neurons, alive but functionally altered, have helped to advance our understanding of the cerebellum’s critical teaching signals.

The word “cerebellum” means “little brain,” despite the fact that it holds more than half the brain’s neurons. It is essential for coordinating movements and balance, helping you perform everyday tasks smoothly, like walking down a crowded street, or playing sports. It is also crucial for the learning process that allows you to associate sensory cues with specific actions. Every time you pick up a cup without spilling its contents, effortlessly adjusting the amount of force you apply based on the weight of the container and how full it is, you’re experiencing the consequences of the cerebellum’s ability to link visual signals with corresponding movement responses. For learning to take place, the cerebellum continuously monitors the outside world and the outcome of movements that we make within it. When we make a mistake, information about our errors can be used to adjust the strength of brain connections, leading over time to changes in our behavioral responses to specific cues. However, it is not known exactly how such “error” or “teaching signals” are represented within the brain to drive learned changes in behavior.

The latest research from the Champalimaud Foundation’s Carey Lab, published in Nature Neuroscience, provides compelling evidence that activity in a specific class of cerebellar inputs, called climbing fibers, are absolutely essential for associative learning to occur. To examine the role of climbing fibers and their targets, cerebellar Purkinje cells, in learning, the researchers designed an experiment involving mice. They used a common learning task known as eyeblink conditioning. In this task, a mouse learns to blink in response to a certain signal, such as a light, which precedes an event, typically a gentle puff of air aimed at its eye. The animals then display associative learning, learning to link a sensory signal with an adaptive movement response, in this case, blinking.

“In our experiment,” explains Dr. Tatiana Silva, the study’s first author, “we used a technique called optogenetics. This method functions like a highly precise remote control for brain cells, using light to turn on or off certain cells of interest at extremely specific times.” Silva continues, “Climbing fibers normally respond to sensory stimuli like a puff of air to the eye. By precisely activating these fibers with optogenetics, we were able to trick the mouse into thinking it had received an air puff, when in fact it had not. After we consistently stimulated climbing fibers 30 milliseconds after the light cue, the mice learned the wrong association.” .

This discovery sheds light on the intricate mechanisms underlying learning in the cerebellum. By manipulating the climbing fibers in mice, the researchers were able to induce changes in behavior, demonstrating the crucial role these neurons play in associative learning. This could have implications for rehabilitation strategies for patients with motor or cognitive impairments, as well as furthering our understanding of the cerebellum's role in a range of psychiatric disorders. The findings of this study also emphasize the importance of serendipitous discoveries in scientific research, leading to new insights and advancements in our knowledge of the brain.