In the same order of idea, or along the same lines, you know in a similar vein, it's around that idea...
What Makes Us Human? Dopamine and the Cerebellum Hold Clues
Differences in the cerebellum and dopamine production make human brains unique.
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, i
n 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!
André Sousa:
Discovering the basis for the unique properties of the human brain is a major goal of modern science. Yet, many fundamental gaps remain in our knowledge of the human brain development and evolution.
In this study we analyzed the transcriptome from sixteen human brain regions, comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and eleven areas of the neocortex, throughout the entire prenatal development and postnatal life. Approximately 86% of genes were found to be expressed, and over 90% of these were differentially expressed across regions and/or time. Genes were organized into functionally distinct co-expression networks. Furthermore, sex differences were present in both gene expression and exon usage. We also demonstrate that these results can be used to profile trajectories of genes associated with several neurobiological themes, such as developmental processes, cell types, neurotransmitter systems, autism, and schizophrenia.
In the second part of this study, we analyzed the temporal dynamics and laterality of gene expression across the eleven neocortical areas. We found that inter-areal transcriptional differences exhibit a temporal hourglass pattern, characterized by more expression differences prenatally and from adolescence onward, and almost no differences in infancy and childhood. Further analyses revealed distinct gradients and areal-restricted expression. We also found that global gene expression trajectories of each area become increasingly synchronized, especially after birth. Furthermore, analyses of gene expression between corresponding left and right areas revealed global symmetry throughout the fetal development and postnatal lifespan.
Finally, we analyzed the gene expression from human, chimpanzee, and rhesus macaque adult brains, using the aforementioned sixteen regions. We found 6,389 genes were differentially expressed among species, with 3,154 specifically up- or downregulated in humans. Furthermore, a multi-regional approach allowed us to examine intra-species differentially expressed genes among all regions. In addition, we found region-specific gene co-expression modules that are conserved across all three species, as well as species-specific transcription modules. We also found several genes involved in the dopamine synthesis pathway were upregulated in humans, especially in the striatum. Lastly, we analyzed the co-expression patterns of neurotransmitter receptors systems and found that the glutamatergic and GABAergic systems receptors were the most conserved among species, while serotoninergic and cholinergic systems were the least conserved.
This study provides a comprehensive dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment, as well as new insights into species-specific gene expression patterns
-http://gabba.up.pt/student/index.php?idStudent=120
Small but distinct differences among species mark evolution of human brain
Summary:
The most dramatic divergence between humans and other primates can be found in the brain, the primary organ that gives our species its identity. However, all regions of the human brain have molecular signatures very similar to those of our primate relatives, yet some regions contain distinctly human patterns of gene activity that mark the brain's evolution and may contribute to our cognitive abilities, a new study has found.
The most dramatic divergence between humans and other primates can be found in the brain, the primary organ that gives our species its identity.
However, all regions of the human brain have molecular signatures very similar to those of our primate relatives, yet some regions contain distinctly human patterns of gene activity that mark the brain's evolution and may contribute to our cognitive abilities, a new Yale-led study has found.
The massive analysis of human, chimpanzee, and monkey tissue published Nov. 23 in the journal Science shows that the human brain is not only a larger version of the ancestral primate brain but also one filled with distinct and surprising differences.
"Our brains are three times larger, have many more cells and therefore more processing power than chimpanzee or monkey," said Andre M.M. Sousa, a postdoctoral researcher in the lab of neuroscientist Nenad Sestan and co-lead author of the study. "Yet there are also distinct small differences between the species in how individual cells function and form connections."
Despite differences in brain size, the researchers found striking similarities between primate species of gene expression in 16 regions of the brain -- even in the prefrontal cortex, the seat of higher order learning that most distinguishes humans from other apes. However, the study showed the one area of the brain with the most human-specific gene expression is the striatum, a region most commonly associated with movement.
Distinct differences were also found within regions of the brain, even in the cerebellum, one of the evolutionarily most ancient regions of the brain, and therefore most likely to share similarities across species. Researchers found one gene, ZP2, was active in only human cerebellum -- a surprise, said the researchers, because the same gene had been linked to sperm selection by human ova.
"We have no idea what it is doing there," said Ying Zhu, a postdoctoral researcher in Sestan's lab and co-lead author of the paper.
Zhu and Sousa also focused on one gene, TH, which is involved in the production of dopamine, a neurotransmitter crucial to higher-order function and depleted in people living with Parkinson's disease. They found that TH was highly expressed in 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.
Researchers also found higher levels of expression of the gene MET, which is linked to autism spectrum disorder, in the human prefrontal cortex compared to the other primates tested.
TH:
A deficiency of tyrosine hydroxylase leads to impaired synthesis of dopamine as well as epinephrine and norepinephrine. It is represented by a progressive encephalopathy and poor prognosis. Clinical features include dystonia that is minimally or nonresponsive to levodopa, extrapyramidal symptoms, ptosis, miosis, and postural hypotension. This is a progressive and often lethal disorder, which can be improved but not cured by levodopa.Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).Additionally alterations in the tyrosine hydroxylase enzyme activity may be involved in disorders such as Segawa's dystonia, Parkinson's disease and schizophrenia.Tyrosine hydroxylase is activated by phosphorylation dependent binding to 14-3-3 proteins.Since the 14-3-3 proteins also are likely to be associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, it makes an indirect link between tyrosine hydroxylase and these diseases.[42] The activity of tyrosine hydroxylase in the brains of patients with Alzheimer’s disease has been shown to be significantly reduced compared to healthy individuals.Tyrosine hydroxylase is also an autoantigen in Autoimmune Polyendocrine Syndrome (APS) type I.
A consistent abnormality in Parkinson's disease is degeneration of dopaminergic neurons in the substantia nigra, leading to a reduction of stratial dopamine levels. As tyrosine hydroxylase catalyzes the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine, tyrosine hydroxylase-deficiency does not cause Parkinson's disease, but typically gives rise to infantile parkinsonism, although the spectrum extends to a condition resembling dopamine-responsive dystonia. A direct pathogenetic role of tyrosine hydroxylase has also been suggested, as the enzyme is a source of H2O2 and other reactive oxygen species (ROS), and a target for radical-mediated injury. It has been demonstrated that L-DOPA is effectively oxidized by mammalian tyrosine hydroxylase, possibly contributing to the cytotoxic effects of L-DOPA.Like other cellular proteins, tyrosine hydroxylase is also a possible target for damaging alterations induced by ROS. This suggests that some of the oxidative damage to tyrosine hydroxylase could be generated by the tyrosine hydroxylase system itself.
Tyrosine hydroxylase can be inhibited by the drug α-methyl-para-tyrosine (metirosine). This inhibition can lead to a depletion of dopamine and norepinepherine in the brain due to the lack of the precursor L-Dopa (L-3,4-dyhydroxyphenylalanine) which is synthesized by tyrosine hydroxylase. This drug is rarely used and can cause depression, but it is useful in treating pheochromocytoma and also resistant hypertension. Older examples of inhibitors mentioned in the literature include oudenone and aquayamycin.
https://en.wikipedia.org/wiki/Tyrosine_hydroxylase
