It was found that the cerebellum of the brain influences the addictive and social behavior



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Credit: Wikimedia Commons

In a study published online today in the magazine. ScienceResearchers at the Albert Einstein College of Medicine, part of Montefiore, prove for the first time that the cerebellum of the brain, which for a long time is thought to be primarily involved in the coordination of movement, helps control the reward circuits of the brain. The surprising finding indicates that the cerebellum plays an important role in the processing of rewards and social behaviors and could lead to new strategies to treat addiction.

Previous studies had suggested that the talents of the cerebellum, a fist-sized structure just above the brainstem, were underestimated. For example, several functional studies of MRI (which measure the changes in blood flow that occur with brain activity) evaluated the brain activity of people who are recovering from an addiction to which they were shown images badociated with their addiction, like a syringe. Unexpectedly, the cerebellum of these individuals shone in the magnetic resonance images, indicating greater activity; In addition, the brightness intensity correlated with the risk of relapse of a person. This and other evidence suggests that the cerebellum is involved in some way in the release of the neurotransmitter dopamine to feel good in areas of the brain that receive gratifying stimuli.

"The idea that the cerebellum did much more than control movement was met with much skepticism, and no one had real clues about how the cerebellum could affect dopamine release," said study leader Kamran Khodakhah, Ph.D. professor and President of the Department of Neuroscience Dominick P. Purpura and President of Neuroscience Florence and Irving Rubinstein. Letter Ilaria, Ph.D. The students of Einstein and Christopher Chen, Ph.D., are co-first authors in the study.




Kamran Khodakhah, Ph.D., and his team in his laboratory at Albert Einstein College of Medicine. Credit: Albert Einstein College of Medicine



Kamran Khodakhah, Ph.D., of the Albert Einstein School of Medicine, discusses his research in which the cerebellum of the brain is found to influence addictive and social behavior. Credit: Albert Einstein College of Medicine

Dr. Khodakhah, who is also a professor of psychiatry and behavioral sciences and a professor in the Department of Neurology at Saul R. Korey, suspected that the cerebellum was directly connected to the ventral tegmental area (VTA), a nearby structure that is known that plays a role. in addition. (VTA neurons synthesize and release dopamine in the mesolimbic pathway, which mediates pleasure and reward). In studies designed to test this hypothesis, his laboratory showed that stimulating cerebellar neurons activate VTA and lead to "addictive" behaviors in mice.

Opting for optogenetics

To perform these studies, Dr. Khodakhah used optogenetics, which involves inserting genes that produce light-sensitive proteins in selected neurons. Then, researchers can selectively activate or deactivate the treated neurons by exposing them to light.




Kamran Khodakhah, Ph.D., of the Albert Einstein School of Medicine, discusses his research in which the cerebellum of the brain is found to influence addictive and social behavior. Credit: Albert Einstein College of Medicine



Kamran Khodakhah, Ph.D., of the Albert Einstein School of Medicine, discusses his research in which the cerebellum of the brain is found to influence addictive and social behavior. Credit: Albert Einstein College of Medicine

In an initial experiment, Dr. Khodakhah's team inserted the genes into the cerebellar neurons, some of which connected to the VTA through long fibers called axons. When the cerebellar axons that extended into the VTA were selectively stimulated with light, approximately one third of the VTA neurons increased their firing. Since only cerebellar axons contained light-sensitive proteins that could be activated by light, this experiment demonstrated for the first time that cerebellar neurons form working synapses (connections) with VTA neurons.

Activating the Reward Center

Do those connections have any influence on behavior? To answer that question, Dr. Khodakhah performed a so-called open field camera test, in which the mice were free to explore any corner of a square enclosure. Each time a mouse reached a particular corner (chosen at random for each mouse), the cerebellar neurons linked to the VTA were stimulated optogenetically. If this stimulation was pleasing to the mice, they would be expected to return to this corner (to obtain another gratifying flash of light) instead of the other corners, and they did, much more often than with the control animals.

Could stimulate cerebellar projections to VTA trigger "addiction" in mice? To find out, Dr. Khodakhah and his colleagues placed mice in a chamber that was half dark and half-lit. As the mice prefer the dark areas, to avoid becoming the next meal of a predator, they spent more time exploring the dark part of the chamber. Then, the researchers repeated the experiment, except that this time, every two days for six days, the mice were limited to the bright side for 30 minutes, while the cerebellar axons with connections to the VTA were stimulated optogenetically. After that initial conditioning period, the mice were allowed to freely explore the entire chamber.

"Although mice normally avoid bright areas, they now preferentially run towards the light, because that's where they remembered receiving a reward," said Dr. Khodakhah. "This suggests that the cerebellum plays a role in addictive behaviors." He notes that the results were "very similar" to the findings in other studies in which mice confined to the bright part of the cameras received addictive drugs such as cocaine instead of stimulation of the cerebellum.

A role in social behavior

Cerebellar anomalies have been implicated in autism spectrum disorder (ASD), although it is not clear how the cerebellum contributes to ASD. Because VTA is necessary for social behavior, Dr. Khodakhah and his colleagues evaluated whether the VTA-cerebellum pathway could be involved. They placed the mice in a three-chamber box in which they could travel freely to an inanimate object, another mouse or an empty chamber. The activity of the cerebellar axons was monitored within its VTA.

The mice studied normally spent most of their time socializing with another mouse, and when they did, the cerebellar axons in their VTA were more active, which is consistent with the idea that the cerebellum transmits relevant information to the social behavior of the VTA. Interestingly, when the researchers silenced optogenetically the cerebellar axons that were projected in the VTA, the mice no longer preferred to interact with other mice. This finding suggests that social behavior requires a functional pathway of cerebellum-VTA and that interference with this pathway may be a failure through which cerebellar dysfunction contributes to ASD.

Next steps

In future studies, Dr. Khodakhah will test whether the VTA-cerebellum pathway can be manipulated, using drugs or optogenetics, to treat addiction and prevent relapse after treatment. It will also investigate whether cerebellar neurons affect the prefrontal cortex and nucleus accumbens, two other brain regions that are attacked by VTA and are intimately badociated with addictive behavior and mental disorders. "Cerebellar anomalies are also linked to a number of other mental disorders such as schizophrenia," said Dr. Khodakhah, "so we want to find out if this pathway also plays a role in those disorders."


Autism therapy: brain stimulation restores social behavior in mice


More information:
I. Letter al., "Cerebellar modulation of reward circuits and social behavior" Science (2019). science.sciencemag.org/cgi/doi… 1126 / science.aav0581

"The cerebellum becomes social" Science (2019). science.sciencemag.org/cgi/doi… 1126 / science.aaw2571

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