For the longest time the cerebellum, a dense, fist-size formation located at the base of the brain, never got much respect from neuroscientists.
For about two centuries the scientific community believed the cerebellum (Latin for “little brain”), which contains approximately half of the brain’s neurons, was dedicated solely to the control of movement. In recent decades, however, the tide has started to turn, as researchers have revealed details of the structure’s role in cognition, emotional processing and social behavior.
The longstanding interest in the cerebellum can be seen in the work of French physiologist Marie Jean Pierre Flourens—(1794–1867). Flourens removed the cerebella of pigeons and found the birds became unbalanced, although they could still move. Based on these observations, he concluded the cerebellum was responsible for coordinating movements. “[This] set the dogma that the cerebellum was involved in motor coordination,” says Kamran Khodakhah, a neuroscientist at Albert Einstein College of Medicine, adding: “For many years, we ignored the signs that suggested it was involved in other things.”
One of the strongest pieces of evidence for the cerebellum’s broader repertoire emerged around two decades ago, when Jeremy Schmahmann, a neurologist at Massachusetts General Hospital, described cerebellar cognitive affective syndrome after discovering behavioral changes such as impairments in abstract reasoning and regulating emotion in individuals whose cerebella had been damaged. Since then this line of study has expanded. There has been human neuroimaging work showing the cerebellum is involved in cognitive processing and emotional control—and investigations in animals have revealed, among other things, that the structure is important for the normal development of social and cognitive capacities. Researchers have also linked altered cerebellar function to addiction, autism and schizophrenia.
Although many of these findings suggested the cerebellum played an important part both in reward-related and social behavior, a clear neural mechanism to explain this link was lacking. New research, published this week in Science, demonstrates that a pathway directly tying the cerebellum to the ventral tegmental area (VTA)—one of the brain’s key pleasure centers—can control these two processes. “This work helps lay out the circuitry connecting the cerebellum to social and reward processing,” says Julie Fiez, a cognitive neuroscientist at the University of Pittsburgh who was not involved in this study. “I think it’s really exciting.”
Khodakhah, one of the study’s authors, had focused his work on the cerebellum’s role in motor coordination until he stumbled across the literature on the structure’s nonmotor functions while reviewing grants. Intrigued by the cerebellum’s links to conditions such as autism and addiction, he set out to investigate whether it may directly communicate with the VTA, an area of the brain previously linked to these disorders.
Earlier investigations in his lab had hinted there might be unexpected connections between the cerebellum and other parts of the brain. Specifically, while examining the brain circuits underlying dystonia—a movement disorder that causes uncontrollable muscle contractions—in mice, Khodakhah’s team discovered the cerebellum directly communicated with the basal ganglia (involved in movement, motivation and reward functions) to control complex movements. It was previously thought that to coordinate such actions, the two brain areas communicated via the cortex, the region responsible for higher-order tasks such as planning and decision-making. “That really fueled us to start looking at the direct cerebellar manipulation of other brain structures,” Khodakhah says.
To investigate the link between the cerebellum and the VTA, Khodakhah’s team first injected the cerebellar cells of mice with herpes viruses, which act as mobile sentinels as they jump through synapses—the tiny gaps between brain cells—while carrying fluorescent tags. This experiment revealed several neurons in the VTA lit up with the glowing markers, indicating that cells in this brain region were, indeed, receiving direct connections from the cerebellum. Then, using optogenetics (a method that allows scientists to switch on or off specific cells in a neural pathway with flashes of light), the researchers demonstrated that stimulating the cerebellar neurons could activate cells in the VTA.
Next, the team tested whether this circuit could influence both reward-related and social behaviors. They found that stimulating this pathway with optogenetics while mice explored one quadrant of a square enclosure caused them to develop a strong preference for the spot. By activating this pathway, the scientists were also able to condition the rodents—which are nocturnal—to favor exploring a bright compartment, despite their natural preference for dark places. “These findings suggest that this pathway could be involved in addictive behavior,” Khodakhah says. He notes the latter experiment has been extensively used to study drug addiction in animals, and his group plans further studies. A future experiment might supply cocaine to rodents to see whether inhibiting the pathway between the cerebellum and the VTA can manipulate addictive behaviors.
When the researchers conducted similar mouse experiments using three interconnected chambers, they made an interesting discovery. The mice encountered a familiar animal that had been placed in one compartment (the “social chamber”). Adjoining it was an empty compartment (the “object chamber”). Mice typically spent more time in the social compartment. But after deactivating the cerebellum–VTA pathway using optogenetics, that preference disappeared, mirroring the behavior typically observed when scientists conduct the same test with animal models of autism.
Interestingly, the team found stimulating this circuit did not increase the rodents’ interactions with an unfamiliar animal. According to the authors, this observation suggests the pathway does not necessarily increase pro-social behaviors but instead makes inanimate objects, for example, just as rewarding as interacting with others. “This [study] is one of the most clear and interesting demonstrations that the cerebellum is indeed involved in the control of high-level, nonmotor functions,” says Egidio D’Angelo, a neurophysiologist at the University of Pavia in Italy who was not part of the work but penned a commentary accompanying the paper. “But this work is done in mice—now we have to see whether this happens in humans.”
Schmahmann, who also did not take part in the study, notes these findings confirm the existence of a pathway first proposed by scientists several decades ago. “I was delighted to see [this research],” he adds. “They provide another really important building block in our ongoing attempt to [understand] the cerebellar contribution to cognition and emotion.”
Further probing the cerebellum–VTA circuit could one day help scientists treat various disorders, Khodakhah says. This circuit might be manipulated—using techniques such as transcranial magnetic stimulation or deep-brain stimulation—in individuals with addiction or autism. But more research is necessary before such interventions become reality—and for now, Khodakhah’s team plans to test some of these methods in mice.
“This is a really exciting time for cerebellar research,” Khodakhah says. “I think over the next few years we’ll see that the cerebellum plays a more and more prominent role in nonmotor functions, [such as] cognitive and emotional processing.”