Why Mapping Cerebellum–Prefrontal Cortex Circuitry Matters

Autism-like behaviors are modulated by brain circuitry rooted in the cerebellum.

Posted Jul 31, 2020

Wikimedia Commons
Cerebellum (Latin for "little brain") in red. Cerebellar means "related to the cerebellum."
Source: Wikimedia Commons

Last week, I wrote a blog post that recapped how my neuroscientist father, Richard Bergland (1932-2007), and I created a split-brain model in the early 2000s we called "up brain-down brain." Based on this model, the key to avoiding "paralysis by analysis" in sports is to "unclamp" the intellectual machinery of the prefrontal cortex and to let the cerebellum take the reins. I included a full-page diagram of this split-brain model in The Athlete's Way, which was published on June 12, 2007.

Tragically, my father died of a heart attack soon after the book's pub date. After his death, I made a vow that I'd continue trying to figure out what the mysterious "little brain" does in honor of my dad who always said: "We don't know exactly what the cerebellum is doing; but whatever it's doing, it's doing a lot of it."

Wikimedia Commons
The prefrontal cortex (PFC) in red.
Source: Wikimedia Commons

Around 2009, I began to realize that the key to understanding the interplay between the "thinking brain" (cerebrum) and "non-thinking brain" (cerebellum) was less about the location of these brain regions and more about the inter-hemispheric functional connectivity between both cerebral hemispheres and both cerebellar hemispheres as well as the intra-hemispheric connectivity between microzones within each hemisphere.

As you can see in the rudimentary brain map (below) that I drew in 2009, the left cerebral hemisphere works with the right cerebellar hemisphere to control the right side of the body and vice versa.

 Photo and illustration by Christopher Bergland (circa 2009)
This brain map illustrates how both cerebral hemispheres and both cerebellar hemspheres work together to optimize whole-brain functions via cerebro-cerebellar circuitry.
Source: Photo and illustration by Christopher Bergland (circa 2009)

Ever since I drew this "Super 8" brain map over a decade ago, I've kept my antennae up for scientific advances that would help to explain why "bridging the gaps" between all four brain hemispheres matters. In 2018, I reported on a breakthrough in cerebellar brain mapping by Xavier Guell, John Gabrieli, and Jeremy Schmahmann of the McGovern Institute for Brain Research at MIT and Harvard Medical School's Massachusetts General Hospital. (See "Mapping the Human Cerebellum Reframes Whole-Brain Functions") 

Cerebellar Cerebro-Cortical Circuits Regulate ASD-Relevant Behaviors

This month, another groundbreaking study provides fresh insights and new detailed maps that illustrate how a microzone in the right cerebellar hemisphere called the "Rcrus1" and the cerebellar vermis (which is sandwiched between the left and right hemispheres of the cerebellum) work in conjunction with the medial prefrontal cortex (mPFC). This paper (Kelly, Meng, Fujita, et al., 2020) was published on July 13 in Nature Neuroscience.

 Image credited to UT Southwestern Medical Center
The illustration shows cerebellar cerebro-cortical circuits mediating autism spectrum disorder-relevant behaviors; specifically, modulation of Rcrus1 influences social behavior while modulation of the posterior vermis impacts repetitive behaviors and behavioral flexibility. UTSW researchers reported these findings in a recent study in Nature Neuroscience.
Source: Image credited to UT Southwestern Medical Center

As you can see in their brain map above, the UT Southwestern Medical Center researchers found that this cerebro-cerebellar circuitry appears to play a vital role in social behaviors, repetitive behaviors, and behavioral flexibility in mice. These autism-relevant behaviors in mice mirror ASD behaviors in humans. As the authors explain, "Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown." (See "Cerebro-Cerebellar Circuits Remind Us: To Know Is Not Enough")

"In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors," the authors write. "We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC."

Previous research by senior author Peter Tsai and colleagues demonstrated that inhibiting Purkinje cell activity in the Rcrus1 region of the cerebellum altered social, repetitive, and inflexible behaviors in mice. Conversely, they also found that stimulating this area rescued typical social behaviors in the ASD-relevant mouse model.

For their latest study (2020), Tsai and co-authors used mice who had been genetically engineered to knock-out Purkinje cell activity. Interestingly, the researchers found that when Purkinje cell activity in the cerebellum was reduced, neural activity in the prefrontal cortex increased. More specifically, they discovered that decreased Rcrus1 activity was associated with increased mPFC activity.

Notably, when the researchers inhibited (i.e., "unclamped") prefrontal cortex activity in these genetically engineered mice, their social impairments and repetitive/inflexible behaviors improved.

By tracking autism-relevant behaviors associated with cerebellar–prefrontal cortical circuits, the researchers also found that neural circuits from the posterior vermis and the rCrus1 region of the cerebellum converge in the prefrontal cortex. "Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice," the authors write in the paper's abstract.

"Each of these regions could play a key role in potential future therapies for ASD," Tsai said in a news release. "Just as an electrician can repair a home's wiring once he or she understands the wiring diagram, these findings give us potential hope for improving dysfunctional activity in the circuits involved in ASD."

This pioneering mouse research raises the possibility that someday, therapies designed to target the cerebro-cerebellar circuitry that connects the rCrus1 and vermis region of the cerebellum with the prefrontal cortex could improve ASD-related behavior in humans.

References

Elyza Kelly, Fantao Meng, Hirofumi Fujita, Felipe Morgado, Yasaman Kazemi, Laura C. Rice, Chongyu Ren, Christine Ochoa Escamilla, Jennifer M. Gibson, Sanaz Sajadi, Robert J. Pendry, Tommy Tan, Jacob Ellegood, M. Albert Basson, Randy D. Blakely, Scott V. Dindot, Christelle Golzio, Maureen K. Hahn, Nicholas Katsanis, Diane M. Robins, Jill L. Silverman, Karun K. Singh, Rachel Wevrick, Margot J. Taylor, Christopher Hammill, Evdokia Anagnostou, Brad E. Pfeiffer, Catherine J. Stoodley, Jason P. Lerch, Sascha du Lac, Peter T. Tsai. "Regulation of Autism-Relevant Behaviors by Cerebellar–Prefrontal Cortical Circuits." Nature Neuroscience (First published: July 13, 2020) DOI: 10.1038/s41593-020-0665-z