Your little brain loves to socialize

June 28th, 2022

Written by: Vanessa Sanchez

The cerebellum is a brain area that is well known for its involvement in motor-related behaviors, such as balance, coordination, and posture¹. Despite its well-known role in motor control, it is only within the past decade that the field of cerebellar neuroscience has begun to explore other functions of the cerebellum. Recently, scientists uncovered that the cerebellum can also contribute to cognitive functions and emotional control, yet little is known about whether the cerebellum can modulate our ability to socialize^1-4. One recent hypothesis is that a common neurotransmitter, dopamine, plays an important role.

Dopamine is a neurotransmitter (“feel good” chemical) that plays a role in the brain’s reward system. If you’d like to learn more about dopamine, check out this recent PNK article! In neurons, dopamine molecules bind to receptors on cell surfaces. There are two common types of dopamine receptors: D1 receptors (D1Rs) and D2 receptors (D2Rs)⁵. Scientists discovered that D1Rs in the cerebellum can contribute to several cognitive tasks, such as spatial navigation and working memory, but D2R had yet to be implicated in any other cerebellar functions^3,6,9. So, a team of scientists asked: are D2Rs implicated in the cerebellum’s contributions to social behavior?

First the scientists asked where D2Rs are found in the cerebellum. By using advanced imaging techniques to visualize where D2Rs are located within the cerebellum, scientists discovered that D2Rs are found predominantly on a certain type of cell found in the cerebellum called a Purkinje cell⁶. Cerebellar Purkinje cells are large neurons found throughout the cerebellar cortex and are known as “output neurons” because of their fundamental role in controlling motor movement. Having identified D2Rs on the Purkinje cells, the scientists next asked if these receptors were functional (i.e., do they work)?  To answer this question, scientists looked at what happens when the D2Rs are activated. To do this, they used the patch clamp method, which is a technique that allows scientists to measure the electrical currents flowing in and out of Purkinje cells – check out this PNK article for more background info! This allowed them to measure the way Purkinje cells responded when they activated their D2Rs. For example, when they exposed Purkinje cells to the D2R agonist quinpirole (a drug that can bind to D2R and activate it), scientists found that activation of D2Rs can alter Purkinje cell signaling. Put simply, not only are D2Rs on Purkinje cells functional (they work!), but they can also modulate if Purkinje cells are going to be excited (turned on), which can influence whether they will relay a signal or message to another cell or brain region.

Interestingly, loss or damage to Purkinje cells has been associated with cognitive and social deficits, including neurological and psychiatric disorders (e.g., autism spectrum disorder and Schizophrenia)^7-8. With this in mind, scientists wondered if there was a link between D2Rs on Purkinje cells and social behaviors. To explore this possibility, they took advantage of genetic approaches available in mice that allowed them to either deplete or overexpress (to generate a lot of) D2Rs, specifically from Purkinje cells. First, scientists found that mice that either lost or gained D2Rs in PCs did not display any disturbances in motor coordination or balance in comparison to mice who did not have changes to their D2Rs, suggesting that D2Rs are not playing an important role in the motor behaviors mediated by the cerebellum. Surprisingly, mice that were either lost or gained D2Rs in Purkinje cells exhibited changes in their social behaviors relative to mice with no changes to their D2Rs. What this suggests is that activation of D2Rs can inhibit social interaction. In other words, the more D2Rs that are activated, the less likely you are to socialize, similar to someone with autism, whereas the fewer D2Rs that are active, the more likely you are to want to socialize more likely to interact and socialize with someone familiar or a stranger whereas when you have more D2Rs in Purkinje cells , you are less likely to and might even be more reclusive – similar to that of someone with autism.

Taken together, these findings provide exciting new evidence that the cerebellum is important for social behavior and more than just motor control. D2Rs appear to play a fundamental role in modulating Purkinje cell signaling, which can lead to changes in social behavior.  When fewer D2Rs are active, Purkinje cells lose important modulation which might account for enhanced social behavior. On the other hand, if you have too much D2R activation, Purkinje cells synaptic excitation might be so tightly modulated that these neurons aren’t able to become excited and therefore relay a message to nearby neurons in different brain regions that ultimately results in impaired social behavior. These novel findings are exciting, and they have opened Pandora’s box of future questions about the enigmatic cerebellum’s role in social behavior. Perhaps one day, neuroscientists will have a better understanding of the cerebellum and uncover that it is more than just a tiny brain.

References

1. Reeber, S. L., Otis, T. S., & Sillitoe, R. V. (2013). New roles for the cerebellum in health and disease. Frontiers in systems neuroscience, 7, 83.
2. Carta, I., Chen, C. H., Schott, A. L., Dorizan, S., & Khodakhah, K. (2019). Cerebellar modulation of the reward circuitry and social behavior. Science, 363(6424), eaav0581.
3. Locke, T. M., Fujita, H., Hunker, A., Johanson, S. S., Darvas, M., Du Lac, S., … & Carlson, E. S. (2020). Purkinje cell-specific knockout of tyrosine hydroxylase impairs cognitive behaviors. Frontiers in Cellular Neuroscience, 14, 228.
4. INSERM (Institut national de la santé et de la recherche médicale). (2022, June 16). How the cerebellum modulates our ability to socialize. ScienceDaily. Retrieved June 20, 2022 from www.sciencedaily.com/releases/2022/06/220616121543.htm
5. Hasbi, A., O’Dowd, B. F., & George, S. R. (2011). Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance. Molecular brain, 4(1), 1-6.
6. Cutando, L., Puighermanal, E., Castell, L., Tarot, P., Belle, M., Bertaso, F., … & Valjent, E. (2022). Cerebellar dopamine D2 receptors regulate social behaviors. Nature Neuroscience, 1-12.
7. Cupolillo, D., Hoxha, E., Faralli, A., De Luca, A., Rossi, F., Tempia, F., & Carulli, D. (2016). Autistic-like traits and cerebellar dysfunction in Purkinje cell PTEN knock-out mice. Neuropsychopharmacology, 41(6), 1457-1466.
8. Peter, S., Ten Brinke, M. M., Stedehouder, J., Reinelt, C. M., Wu, B., Zhou, H., … & De Zeeuw, C. I. (2016). Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nature communications, 7(1), 1-14.
9. Locke, T. M., Soden, M. E., Miller, S. M., Hunker, A., Knakal, C., Licholai, J. A., … & Carlson, E. S. (2018). Dopamine D1 receptor–positive neurons in the lateral nucleus of the cerebellum contribute to cognitive behavior. Biological psychiatry, 84(6), 401-412.

Cover photo by Brooke Cagle on Unsplash