"Zombie neurons" play a major role in the learning process

Located at the back of our brain beneath the larger cerebrum, the cerebellum – often dubbed the “little brain” despite containing over half of the brain’s neurons – plays a vital role in coordinating our movements and learning from our experiences. 

While it is well known that the cerebellum refines our actions based on sensory feedback and past mistakes, the specific mechanics behind this learning have remained somewhat elusive. 

Discovery of zombie neurons 

Recently, a study by researchers at the Champalimaud Foundation has shed light on this mystery with the discovery of “zombie neurons.” 

These neurons, though alive, have undergone functional changes that significantly advance our understanding of the cerebellum‘s role in learning processes.

Sensory cues and motor actions

The cerebellum is crucial not just for enabling us to execute daily activities with precision, such as navigating crowded spaces or playing sports, but also for how we learn to associate sensory cues with motor actions. 

Every time we adjust our grip to prevent a drink from spilling, adjusting for the weight of the container and its contents, we’re experiencing the cerebellum’s capability to connect visual signals to motor responses.

Teaching signals in the brain 

Learning involves the cerebellum’s constant evaluation of external stimuli and the outcomes of our actions, using information about errors to fine-tune neural connections. This adjustment leads to changes in how we respond to specific cues over time. 

The nature of these “error” or “teaching signals” within the brain and their role in driving behavioral changes have already been subjects of extensive research. This latest study provides compelling evidence that activity in a particular class of cerebellar inputs, known as climbing fibers, is crucial for associative learning.

Study experiment with mice

To investigate the role of climbing fibers and their targets, cerebellar Purkinje cells, in learning, the researchers conducted 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 specific signal, such as a light, that precedes an event, usually a gentle puff of air directed at its eye. The animals then demonstrate associative learning, linking a sensory signal with an adaptive movement response, in this case, blinking.

Remote control for brain cells

“In our experiment, 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,” explained lead author Tatiana Silva, a research fellow in neurosciences at Champalimaud. 

“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 during the presentation of a visual cue, the mice learned to blink in response to that cue – even in the absence of stimulation. This proved that these fibers are sufficient to drive this type of associative learning.”

Climbing fibers are necessary for associative learning

The researchers managed to demonstrate that climbing fibers are also necessary for associative learning. “When we used optogenetics to selectively silence climbing fibers during the presentation of an actual air puff, the mice completely failed to learn to blink in response to the visual cue,” Silva said. 

The team manipulated various other types of brain cells within the cerebellum but found none could provide such reliable teaching signals for learning.

Adjusting specific activity patterns in targeted brain cells

Delving deeper into their data, the research team encountered an unexpected twist. To control climbing fiber activity via optogenetics, they introduced a light-sensitive protein known as Channelrhodopsin-2 (ChR2) into these specific neurons.

However, they observed that the mice engineered to express ChR2 failed to learn using the conventional air puff technique. 

“It turned out that introducing ChR2 into the climbing fibers altered their natural properties, preventing them from responding appropriately to standard sensory stimuli like air puffs. This, in turn, completely blocked the animals’ ability to learn,” said senior author Megan Carey, a group leader in the Neuroscience Program at Champalimaud.

“The remarkable thing was that these same mice learned perfectly well when we paired climbing fiber activation with a visual cue rather than an air puff,” added Silva.

This accidental discovery realized a long-sought goal within neuroscience: adjusting specific activity patterns in targeted neurons without completely halting their communication. 

Climbing fibers as zombie neurons 

This method offers a refined approach to probe their direct impact. Despite the climbing fibers being spontaneously active and ostensibly normal, their changed response to sensory input prevented the animals from learning the task, prompting Silva to term them zombie neurons: alive in function but detached from their usual role in brain circuits.

“These results serve as the most compelling evidence to date that climbing fiber signals are essential for cerebellar associative learning. Our next steps involve understanding why ChR2 expression leads to the ‘zombification’ of neurons and determining whether our findings extend to other forms of cerebellar learning,” Carey concluded. 

The study is published in the journal Nature Neuroscience.

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