What Makes Us Human? Dopamine and the Cerebellum Hold Clues
Differences in the cerebellum and dopamine production make human brains unique.
Posted November 24, 2017
Yale-led researchers recently conducted a massive and detailed comparative analysis of human, chimpanzee and macaque brains. Their paper, "Molecular and Cellular Reorganization of Neural Circuits in the Human Lineage," was published November 24, 2017, in the journal Science. This groundbreaking project unearths small but distinct evolutionary differences related to dopamine production in the neocortex and gene expression in the cerebellum (Latin for "little brain") that appear to make the human brain unique.
To pinpoint differences between human and nonhuman primate brains, André M. M. Sousa of Yale University—along with co-lead author Ying Zhu and dozens of collaborators from around the globe—evaluated brain tissue samples from six humans, five chimpanzees, and five macaque monkeys. During their analysis, the researchers generated transcriptional profiles of 247 tissue samples from 16 different brain regions including the amygdala, cerebellar cortex, cerebral neocortex, hippocampus, striatum, and others.
One of the most striking discoveries of this analysis appears to be that humans have an abundance of cortical circuits in the neocortex and striatum (a brain region most commonly associated with movement) that facilitate the production of dopamine.
As a neurotransmitter, dopamine plays a fundamental role in many aspects of human cognition, fluid movement, reward-motivated behavior, and drives pleasure centers. Dopamine pathways are also linked to working memory, wise reasoning, reflective exploratory behavior, and overall human intelligence.
Sousa et al. found that human brains exhibited significant up-regulation of a gene (TH) that is involved in dopamine production. Notably, TH was highly expressed in the human neocortex and striatum but absent from the neocortex of chimpanzees. “The neocortical expression of this gene was most likely lost in a common ancestor and reappeared in the human lineage,” Sousa said in a statement to Yale News.
Another surprising discovery of this study involves the cerebellum. Evolutionarily, the cerebellum is one of the most ancient regions of the human brain. Historically, the cerebellum was considered by most experts to be a "non-thinking" primordial part of Homo sapiens' brains responsible for things such as fine-tuning muscle coordination, balance, and smooth/synchronized saccades during eye tracking movements (vestibulo-ocular reflex).
However, in recent years neuroscientists have discovered that the cerebellum also plays a mysterious but significant role in human cognition, emotion regulation, and overall psychological well-being. Additionally, countless human and animal studies have found a correlation between atypical structure/functional connectivity of Purkinje neurons in the cerebellum and autism spectrum disorders (ASD).
Prior to publication of this comparative analysis of human and nonhuman primate brains in Science, I emailed the senior and corresponding author, Nenad Sestan, with two questions about his team's findings. Sestan is a professor of neuroscience, comparative medicine, genetics, and psychiatry. He is also an investigator for the Kavli Institute of Neuroscience and director of the Seston Lab at Yale University.
First, Christopher Bergland inquired: "The cerebellar cortex was one of several different brain regions the Yale-led research team took tissue samples of for their comparison between human and nonhuman primate brains. For the past decade, I've kept my antennae up for any fresh insights about the cerebellum. Therefore, I was curious to learn: Did your analysis reveal anything surprising or noteworthy when comparing differences between cerebellar cortex tissue samples of humans, chimpanzees, and macaques?" André Sousa responded via email:
"Yes, we found several interesting differences in gene expression in the adult human cerebellar cortex. The one that caught most of our attention was the geneZP2. This gene encodes a protein that mediates sperm-egg recognition. It has been widely studied for its role in reproduction. However, we found that this gene is highly expressed in the human cerebellum (but not in other regions of the human brain) and it is not expressed in any brain region of both chimpanzee and macaque. We mapped its expression to the granule cells but still do not know what its function is in the brain."
Second, I asked the Yale team, "Regarding the notable difference between dopaminergic interneurons in humans and nonhuman primates: Can you articulate why unique cortical circuits underlying dopamine production in the human brain might provide a significant new hint as to "what makes us human" for Psychology Today readers?" Sousa responded in an email:
"This is a very good question but also one that is very hard to answer. All the analyzed species have dopamine, which is mainly produced in cells present in the midbrain. These cells project into several regions of the brain and release dopamine. What we found was that humans, but not chimpanzees, bonobos, or gorillas, have a rare population of interneurons in the neocortex that is also capable of producing dopamine. Interneurons are one type of neurons that form connections with other neurons that are close to them. They do not project to other brain regions. It is possible that these interneurons are capable of producing dopamine locally and therefore are able to modulate the local circuitry in a more precise way. We know that dopamine is involved, among other things, in working-memory and learning and this finding is indicating that our dopaminergic system might be different from the ones in chimpanzee and gorillas, our closest living relatives."
In conclusion, the authors wrote in the study abstract, "Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease." Stay tuned for more insights gained from this pioneering comparison between human and nonhuman primate brains. Fascinating stuff!
Sousa, André M. M., Ying Zhu, Mary Ann Raghanti, Robert R. Kitchen, Marco Onorati, Andrew T. N. Tebbenkamp, Bernardo Stutz, Kyle A. Meyer, Mingfeng Li, Yuka Imamura Kawasawa, Fuchen Liu, Raquel Garcia Perez, Marta Mele, Tiago Carvalho, Mario Skarica, Forrest O. Gulden, Mihovil Pletikos, Akemi Shibata, Alexa R. Stephenson, Melissa K. Edler, John J. Ely, John D. Elsworth, Tamas L. Horvath, Patrick R. Hof, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, Mark Reimers, Richard P. Lifton, Shrikant M. Mane, James P. Noonan, Matthew W. State, Ed S. Lein, James A. Knowles, Tomas Marques-Bonet, Chet C. Sherwood, Mark B. Gerstein, Nenad Sestan. "Molecular and Cellular Reorganization of Neural Circuits in the Human Lineage" Science (Published November 24, 2017) DOI: 10.1126/science.aan3456