How Endocannabinoids and Runner’s High Prime the Cerebellum

Self-produced cannabinoids promote cerebellum-dependent learning via exercise.

Posted Oct 21, 2020

 CLIPAREA l Custom media/Shutterstock
The cerebellum (Latin for "little brain") is the seat of implicit muscle memory and coordinates "non-thinking" physical movements that we learn to do automatically, such as riding a bicycle or touch typing without looking at the keyboard. Cerebellar means "relating to the cerebellum."
Source: CLIPAREA l Custom media/Shutterstock

For the past two decades, I've kept my antennae up for new research that would give athletes and coaches more science-based knowledge about specific ways to optimize how the "little brain" encodes cerebellum-dependent implicit learning. Improving cerebellar muscle memory reduces cerebral overthinking and promotes the fluidity of automatic, well-coordinated muscle movements in sports and everyday life.

In 2004, when I put together a book proposal for The Athlete's Way: Sweat and the Biology of Bliss, I knew from anecdotal and empirical evidence that exercise-induced endocannabinoids facilitated a state of so-called runner's high—which makes some humans (and most mice) want to run more regularly—by docking with the CB1 cannabinoid receptors. I also knew that aerobic exercise increases neuroplasticity and promotes the birth of new neurons via neurogenesis. (See "Motivation to Run (or Not to Run) Is Linked to Cannabinoids.") 

 Photo and illustration by Christopher Bergland (circa 2005)
This page of "The Athlete's Way" (p. 81) illustrates an early version of the Bergland split-brain model and describes a theoretical paradigm within the two-tiered, cerebellar-cerebral cortex learning and memory system.
Source: Photo and illustration by Christopher Bergland (circa 2005)

A quick review of The Athlete's Way, published in 2007, shows constant mentions of the cerebellum, cerebellar functions, Purkinje cells, implicit vs. explicit learning, neuroplasticity, neurogenesis, BDNF, the "bliss molecule" known as anandamide, reward-seeking behaviors, and the link between endocannabinoids and runner's high. That said, in the early 2000s, when I was writing the book, it was impossible to know how all of these novel concepts were interconnected. This research was still in its infancy.

 Illustration by Rita Félix, Ph.D., labeled for reuse with proper credit.
Fluorescent image of a mouse brain with the cerebellum highlighted in the shape of a marijuana leaf.
Source: Illustration by Rita Félix, Ph.D., labeled for reuse with proper credit.

This morning, I was thrilled to learn about a new study (Albergaria et al., 2020) that helps to connect the dots and shed light on how self-produced endocannabinoids may reduce hypoactivity by motivating mice to spend more time running on a treadmill, which appears to improve cerebellum-dependent (i.e., implicit) learning. This paper, "Cannabinoids Modulate Associative Cerebellar Learning via Alterations in Behavioral State," was published on October 20 in the peer-reviewed journal eLife.

In recent years, numerous studies have shown that CB1KO knockout mice, which are genetically engineered with a mutation that blocks CB1 cannabinoid receptors, tend to exhibit reduced activity levels and opt to run less if they are given access to a running wheel in their laboratory habitat. CB1KO hypoactive mice also tend to display less robust cerebellum-dependent learning and memory functions.

However, the million-dollar question remains: How do cannabinoids and CB1 receptors influence cerebellum-dependent learning?

A few years ago, Megan Carey of the Champalimaud Center for the Unknown in Portugal and Catarina Albergaria, a postdoctoral researcher in Carey's lab, decided to investigate this question by studying how locomotor activity modulates associative learning in the mouse cerebellum by studying eyeblink conditioning using CB1KO mice and regular mice who ran at varying speeds on a treadmill. Delay eyeblink conditioning is a cerebellum-dependent learning paradigm that is widely used to study implicit learning in mammalian animals and humans. 

This study (Albergaria et al., 2018) demonstrated that mice who regularly engaged in high levels of locomotor activity (e.g., treadmill running) also had more robust cerebellar learning capacity indexed by delay eyeblink conditioning results. (See "Why Does Running Faster Speed Up Learning in the Cerebellum?")

This 2018 study raised the question of whether hypoactivity and a lack of physical exercise might indirectly contribute to cerebellar learning impairments in CB1KO mice. The recently published (2020) follow-up study by Albergaria et al. finds that "decreased locomotor activity fully accounts for the effects of CB1 deletion on eyeblink conditioning." As the authors explain: 

"We conclude that the previously described effects of CB1 receptor deletion on cerebellar learning arise as a secondary consequence of hypoactivity in CB1KOs, and not from direct effects on cerebellar plasticity. These findings highlight the modulation of behavioral state, including locomotor activity, as a powerful mechanism through which individual genes contribute to cognition and behavior. In conclusion, CB1 receptors modulate cerebellum-dependent associative learning via indirect effects on the behavioral state, and not via CB1-mediated parallel fiber plasticity."

"Many studies support the idea that cannabinoids mediate neural plasticity or experience-dependent changes in the connections between neurons," Carey explained in an October 20 news release. "In a study [2018] we published two years ago, we found that the more mice ran, the better they learned. We wondered whether the mutant mice weren't learning as well simply because they weren't active enough."

Remarkably, when the researchers created a lab environment with a motorized treadmill that ensured the CB1KO mice (who can't experience runner's high and tend to avoid running) ran as much as typical mice, their cerebellum-dependent learning abilities were completely restored.

"These experiments further supported our hypothesis that disrupted cannabinoid signaling was impairing learning by altering behavioral state, and not through direct effects on neural plasticity in the cerebellum," Carey said. "We were able to overcome a learning deficit associated with a genetic mutation with a purely behavioral intervention." Although more research is needed, these mouse study findings suggest that cardio workouts may also enhance cerebellum-dependent learning in the human brain.

Illustration by Rita Félix via EurekAlert

References

Catarina Albergaria, N. Tatiana Silva, Dana M. Darmohray, and Megan R. Carey. "Cannabinoids Modulate Associative Cerebellar Learning via Alterations in Behavioral State." eLife (First published: October 20, 2020) DOI: 10.7554/eLife.61821

Catarina Albergaria, N. Tatiana Silva, Dominique L. Pritchett, and Megan R. Carey. "Locomotor Activity Modulates Associative Learning in Mouse Cerebellum." Nature Neuroscience (First published: April 16, 2018) DOI: 10.1038/s41593-018-0129-x