Machines Comparing Circuitry (or, Understanding Our Uniquely Human Brain)

I became fascinated by the brain because I was – and continue to be – fascinated by humans. Why are we so obsessed with other people’s lives, including (sometimes especially) those whom we’ve never met? How are we able to communicate such complex emotions with a raise of an eyebrow or even just a glance? How are we capable of such profound cognitive dissonance that we would often go against our own self-interest rather than change our beliefs? How has the human mind managed to take us to outer space, back in time to understand our earliest ancestors, and into its own machinery to understand itself at the microscopic level?

While understanding humans is a common impetus for wide-eyed students such as myself to enter the field of neuroscience, I, like many others, have turned to non-humans (in my case, rodents) to begin trying to understand ourselves. Although there are many reasons for this (most of which come back to the unfortunate truth that most humans are not willing to let us open up their skulls to peak inside), evaluating the relevance and potential impact of our research inevitably comes back to a simple question: just how unique is the human brain?

On one hand, much of the brain’s underlying organization is remarkably conserved across animal species; this is essentially what justifies the use of animal models to understand, say, how the brain processes visual information or how motor signals are transformed to produce coordinated movements. These sorts of questions fall within the realm of understanding neural circuits: how different neurons and the connections among them are organized to perform a particular function (much like electronic circuits). The field of “systems neuroscience” has exploded in the last 15 years and has made tremendous progress in understanding how neural circuits are organized for behavior. This progress is largely owed to the rodent and primate models that have allowed a greater level of precision and detailed analysis than is possible with humans. Nonetheless, our brains are undeniably capable of much, much more than are those of these other animal models, and so systems neuroscientists are often stuck at the edge of a giant gulf separating non-human mammals from bonafide Homo sapiens. What lies in between? How have neural circuits changed through the course of human evolution?

 

A glimpse at the cogs in three different machines: comparing humans, chimpanzees, and macaques

 

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From top to bottom: a human, a chimpanzee, and a macaque

A huge international team of researchers recently tackled that daunting question [1], and this revealed some fascinating and sometimes surprising results. To do this, they utilized a popular genetic analysis technique known as RNA-sequencing (RNAseq for short). You might remember RNA from high school biology – it’s essentially the translated version of your cells’ DNA that acts as the recipe for making proteins. While every cell in the body (with very few exceptions) possesses the same genetic code or “genome”, the RNA recipes that are made from the DNA can vary significantly between cells. This is what allows for the difference between liver cells and neurons, and for the differences among distinct types of neurons. RNA-sequencing allows us to look at how genes are differently expressed in various parts of the brain and/or in individual cells; i.e., it lets us look at all of the different recipes.

 

 

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Primate phylogeny tree. Humans and chimpanzees diverged 4.5-6 million years ago, whereas humans and macaque (an Old World monkey) diverged more than 22 million years ago! (image courtesy of UCSD Center for Academic Research and Training in Anthropogeny (CARTA)

First, the researchers wanted to understand the variability in recipes found across the brain – in the hippocampus, cerebellum, different areas of cortex, etc. – and how much those region-specific recipes vary among humans, chimpanzees (one of our closest living relatives), and macaque monkeys (a commonly studied primate in biomedical research). While humans and chimps share about 99% of their genes and humans and macaques share 93%, their region-specific RNA varied quite a bit more. In fact, between 25 and 40% of RNA (depending on the type of RNA) exhibited species differences in one or more brain areas, and about 12% of RNA showed human-specific differences [1]. So while humans, chimps and macaques’ cookbooks are remarkably similar on the whole, their individual recipes for making the same dishes are far from identical.

 

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A comparison of different primate brains (including human, chimpanzee and macaque) highlighting the prefrontal cortex (see below).

The mammalian neocortex – the outer sheath of the brain – is generally believed to be the structure in the brain that has changed most drastically in the evolution of the human lineage and might thereby contribute most strongly to our unique intellectual attributes [2]. However, one of the study’s most surprising findings was that cortex ranked behind a lesser-known subcortical structure in terms of amount of human-specific gene expression. By a significant margin, the structure with the most uniquely-human RNA was the striatum. The striatum is perhaps best known for its involvement in dopamine signaling (important for reward among other things) and is also important for motor function. Meanwhile, the prefrontal cortex, which is involved in language, short-term memory, decision-making, and other quintessential human cognitive abilities ranked only 4th [1]. This may call into question the general dogma that the prefrontal cortex is the most uniquely human part of the brain (or this may merely be due to the fact that they separately analyzed different portions of the prefrontal cortex).

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Human-specific gene expression in two parts of the prefrontal cortex – dorsolateral (pink) and orbitofrontal (blue) prefrontal cortex – and the striatum (STR). Right: number of genes with increased (tan) and decreased (black) expression in humans compared to both chimpanzees and macaques in different brain regions (prefrontal cortex and striatum are highlighted). Figure modified from [1].

Next, the researchers were interested in particular genes that were over- or under-expressed in humans relative to non-human primates and whether any of these genes were expressed in particular types of neurons. One such gene, PKD2L1, was comparatively enriched in human cortical areas (excluding the motor cortex) compared to in non-human primate cortex and was highly expressed in neurons responsible for sending information to other parts of the brain. This suggests that human brains could have evolved an expanded and/or enhanced arsenal of information transmitters to accommodate human brains’ increased processing power.

Interestingly, another gene that they found was differently expressed in humans and in particular types of cells ties back to the striatum. The TH gene, when expressed, provides the recipe for tyrosine hydroxylase (TH), a protein involved in the synthesis of dopamine. TH is commonly expressed in the striatum (remember how I said the striatum is involved in dopamine signaling?) and was even more strongly expressed in human striatum compared to in chimpanzees or macaques. However, remarkably, the researchers also found that TH was additionally expressed in a unique type of cortical neuron found in macaques and humans, but not in chimpanzees or any other great apes (like bonobos and gorillas). Since these great apes are our closest primate relatives, how is it that our TH recipe would be more similar to much more distantly related primates like macaques? The authors speculate that some genetic event may have occurred in our last common ancestor with the great apes that disrupted the expression of TH in the cortex, but was subsequently reversed in the evolutionary lineage of humans.

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In situ hybridization images showing cortical neurons expressing PKD2L1 in human but not chimpanzee or macaque (left) and cortical neurons expressing TH in human and macaque, but not chimpanzee (right). Figure from [1].

So, why does it matter that TH is upregulated in humans and that humans have a specific type of TH-expressing cortical neuron that chimpanzees do not? Remember once again that TH is important for the synthesis of dopamine, which in turn is important for attention, memory, motivation, reward, and many other cognitive processes that are critical for humans navigating through their everyday lives. In fact, the numbers of TH cortical neurons have been found to be diminished in Parkinson’s [3] and dementia patients [4], suggesting that these neurons might be very important for the cognitive functions that are negatively affected by those disorders.

However, this study is far from concluding that TH neurons in the cortex are solely responsible for the gulf of cognitive abilities separating humans from our closest living relatives. Rather, this tour-de-force study reveals previously unknown differences between humans and other primates on the level of neural circuits. As neuroscientists studying non-human animal models, we must not forget the important caveat that our models may well be even more different from humans than we currently appreciate. And as our techniques for understanding neural circuits become more and more sophisticated, we should take every opportunity to relate our findings in non-human models to humans whenever possible. Lucky for us, this movement is already in motion; the Allen Brain Institute in Seattle very recently released their first atlas of human cell types, characterized by their physiology, morphology, and gene expression and reported findings of another human-specific cortical neuron type. All in all, I am optimistic that we are beginning to bridge the gap in our understanding of cortical circuits in the uniquely human brain. With a more complete grasp of which cell types and circuits are common among mammals and which are not, I am hopeful that using a combination of non-human and human samples (when possible) with the ever-increasing neuroscience toolkit, we may be able to make some headway in understanding what makes us so uniquely, bizarrely human.

 

References:

[1] Sousa, A. M. M., Zhu, Y., Raghanti, M. A., Kitchen, R. R., Onorati, M., Tebbenkamp, A. T. N., … Sestan, N. (2017). Molecular and cellular reorganization of neural circuits in the human lineage. Science, 358(6366), 1027. https://doi.org/10.1126/science.aan3456

[2] Preuss, T. M. (2011). The human brain: rewired and running hot. Annals of the New York Academy of Sciences, 1225(Suppl 1), E182–E191. http://doi.org/10.1111/j.1749-6632.2011.06001.x

[3] Fukuda, T., Takahashi, J. and Tanaka, J. (1999), Tyrosine hydroxylase-immunoreactive neurons are decreased in number in the cerebral cortex of Parkinson’s disease. Neuropathology, 19: 10–13. doi:10.1046/j.1440-1789.1999.00196.x

[4] Marui, W., Iseki, E., Kato, M., & Kosaka, K. (2003). Degeneration of tyrosine hydroxylase-immunoreactive neurons in the cerebral cortex and hippocampus of patients with dementia with Lewy bodies. Neuroscience Letters, 340(3), 185–188. https://doi.org/10.1016/S0304-3940(03)00101-0
Title image: https://listverse.com/wp-content/uploads/2012/02/200990121.jpg

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