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Human Brains and Mouse Brains: So Similar, So Different

Well, it’s inadvertently been sort of a Neuroscience Week here. This latest paper is a very interesting addition to the field indeed, just out from a very large team centered at the Allen Institute, where some rather large-scale work in the field has been done in the past. This one continues their tradition: it’s a look at single-cell-nucleus RNA sequencing in one brain region (the middle temporal gyrus), and seeing how much these standard classifications look when you get down to the gene expression level. And what’s more, they do the exact same in both human and mouse brain samples and compare across species. The MTG was chosen because it’s a region that’s often the subject of brain surgery for epilepsy, and there are thus frozen post-mortem samples available (as well as, in this study, a few that were provided immediately after such surgery itself). Isolating cell nuclei is also much easier then teasing apart individual neurons, and smaller single-cell studies have already shown that cell types can be distinguished from RNA in the nucleus.

There are a lot of results to think about. First off, it’s important to stipulate that the cellular architecture of the human and mouse brain tissues are “surprisingly well-conserved“, as the authors put it. This has been apparent from anatomical studies (at increasing levels of detail) for many decades. In other words, if you were handed a small brain tissue sample of this sort and some high-quality microscopes, you would have to bear down on them to say if you were looking at a human brain or a mouse one. They’re organized in very similar fashion with a similar apparent diversity of cell types. There are some distinct astrocyte types in human brain tissue as opposed to mouse and different distributions of other types (such as “rosehip neurons”), but these differences are not always easy to spot.

Now for the RNA sequencing. For the human side of the experiment, eight donor brains furnished 15,928 cell nuclei, which were taken layer by layer, and the general transcriptional profile sorted these into 10,708 excitatory neurons, 4,297 inhibitory neurons and 923 cells that weren’t neurons at all. Person-to-person variation didn’t seem to throw the results around too much, because the pooled samples still showed very robust clustering into transcriptional types. (They could, however, see some small but real differences between the post-mortem samples and the freshly derived ones, interestingly, although these still binned into the major clustering scheme just fine). Overall, there were about 75 transcriptionally distinct cell types in those >15,000 cells, and they fit (roughly) into the known developmental lineages. The upper-layer excitatory neurons had the most duplicates, but there was definitely a “long tail” distribution over the entire samples, with most of the types being rather rare.

Most of the neuron variations were quite spatially restricted. That said, they noticed particular excitatory types spanning several layers (while others showed up only in particular locations). The inhibitory neurons didn’t have as much layer-spanning, but definitely showed similar enhancements in different cluster types across the layers. The non-neuronal cells were more evenly distributed spatially (except for one particular astrocyte class), but the authors note that the clustering for these is more provisional since the sample size was so much smaller, and that a larger sample would surely reveal more distinct classes of (for example) astrocytes than we know about now. It’s worth noting that the broad features still match up very well:

“Despite differences across datasets, alignment based on expression covariation reveals a cellular architecture that is largely conserved between cortical areas and species, as anatomical studies have shown for the last century. . .Beyond similarities in overall diversity and hierarchical organization, most cell types mapped at the subclass level, seven cell types mapped one-to-one, and no major classes had missing homologous types despite the last common ancestor between humans and mice living at least 65 million years ago and despite the thousand-fold difference in brain size and number of cells. . .”

But even at this level, the differences are still daunting enough. It certainly fits the general neuroscience template of “the more you look, the more you see” – brain tissue seems to have a really terrifying level of differentiated detail no matter what technique you examine it by. But now the group compared the mouse and human cells more directly, focusing on the primary visual cortex and the anterior lateral motor cortex. The same genes tended to work as classifiers in both species, although less well in the non-neuronal types. There were three of the rare types in mouse that were not present in the human samples, although the authors note that these could well show up in larger samples. Overall, some particular classes were more diverse in the human samples, and some were more diverse in the mice.

Bearing down, the paper compares the expression of over 14,000 RNA transcripts across the two species, and they found that nearly 10,000 of them had divergent expression in at least one of 37 homologous cell types they identified. Moreover, many of these had such changes in only one of those types. The non-neuronal types had the greatest differences, suggesting that these have had the biggest evolutionary changes between mice and humans. Overall, though, the mice and human cells have very different expression patterns, even when you match down to particular cell types. While the overall organization holds quite well, levels of individual transcripts are quite different, and entire genes show up in one but not the other.

Most interestingly (and alarmingly?) the biggest divergences were seen in things like neurotransmitter receptors and ion channels, which of course have been extremely active areas in drug discovery. This is direct evidence for how poor mouse CNS models are, and why. That is not news in general to anyone who’s done that sort of work, since everyone knows that yeah, mice ain’t humans. But this shows that even down at deeply reductionist levels, mice really are not humans. Our serotonin receptors, our glutamate receptor subtypes – they’re expressed very differently and in different ratios to each other. If you’re making ligands for those sorts of things, they are going to do different things in mouse tissue and in live mice than they will in humans, and there appears to be no way to get around this. Our brains, mouse and human, are organized in very similar ways, but the tiniest gears and pulleys are hooked up in very different fashion. On a philosophical level, it’s quite interesting to see how such broadly similar architecture has been adapted to such different species, and also to see how that architecture can also contain and accommodate such varying mechanisms at the most fundamental levels. We now have a lot more for our own brains to work on!

20 comments on “Human Brains and Mouse Brains: So Similar, So Different”

  1. John Wayne says:

    My brain hurts.

    1. Nick K says:

      Neuroscience has the same effect on me too.

  2. Lane Simonian says:

    I wonder how the different glutamate subtypes are differentially expressed in mice than in humans. More or less of certain types (apparently)? Found in different parts of the brain at different levels?

    Of perhaps equal importance laboratory mice are not generally exposed to the same level of brain stressors as human beings: pesticides, air pollutants, mercury and other heavy metals, a diet high in sugar and other carbohydrates, salt, and high fructose corn syrup, various infections, heavy smoking and drinking, and so forth. For both internal and external reasons, altering genes may produce less neurological damage in mice, and mimicked diseases may be easier to “cure” in mice than in humans.

  3. Anonymous says:

    “Are you pondering what I’m pondering?”

    1. biotechinvestmentparadigm says:

      “Umm, I think so, Brain, but what if the chicken won’t wear the nylons?”

    2. Scott says:

      “I think so, Brain, but where are we going to find a circus clown at this time of noight?”

      1. Wavefunction says:

        “Uh… yeah, Brain, but where are we going to find rubber pants our size?”

    3. Crossover episode says:

      Uhrm yeah, but how are we gonna find Halloween costumes in January?

  4. Isidore says:

    “Trouble with mice is you always kill ’em. ” – John Steinbeck, “Of Mice and Men”

    1. loupgarous says:

      Unfortunately, Lennie branched out to other species.

    2. John Beckstein says:

      Mice cleverer than you might think. As Tom and Jerry animators Hanna and Barbera knew all along. Every winter Jerry and mates break and enter local houses uninvited. Fields all round, grass, hedges, trees. You’d prefer a dry warm house to cold wet grass or the base of a damp hedge wouldn’t you? Clever little chap Jerry. Can help himself to cheese and peanut butter without springing the mouse trap. When thirsty can gnaw through washing machine inlet pipe. When seeking a cheap thrill can have fun with electrical wiring. When fancies a good read can eat through that cardboard box in the loft where you keep that copy of East of Eden first read 50 years ago. Then digest Steinbeck in one sitting.

      It’s war. A war of attrition set to last a lifetime. Lest you be squeamish, what would you do on waking to sound of hissing water and kitchen awash and sparking at dawn? Them or us. Cold steel and chemical warfare. Jerry’s less clever mates fall for the cheese and peanut butter. The man himself sneaks across the kitchen floor in a blur but you get his less clever mate with the coal shovel you’ve left in readiness on top of the kitchen wall units. Hand to mouse combat. Afterwards you feel like a gladiator. You’ve fought a lion and won.

      Chemical warfare. Anticoagulation. No idea where the bodies end up. Maybe in a mausoleum under the floorboards. Active ingredient Difenacoum. A hydroxychromenone with a greasy biphenyl tetralin dangling off the middle of the embedded hydroxyenone. Looks like a greasier version of Warfarin. Merci Jean Treilles and Jean-Claude Lechevin for inventing. Could however be a crisis looming. Attritional balance could shift the wrong way. Sorexa no longer available in Europe. Meant to rule out poisoning next predators up food chain. So that leaves Roban and the last half tub of Sorexa you’ve got left. Jerry and mates scoff Sorexa overnight but pick at Roban for weeks on end…

      Yet labelling says Sorexa and Roban contain each contain Difenacoum as active entity. Looks like main difference is formulation. Canary seed coating for Sorexa, wheat chaff for Roban. Enteric coating vs primitive tablet. Clearly Jerry loves canary seed but not keen on wheat chaff. Perfectly understandable – shiny canary seed looks more appetising to me too! But why ban Sorexa and not Roban? Maybe concern is predators such as owls and sparrow hawks eating poison direct in places like farmyards rather than ingesting via a rodent corpse? Canary seed must look more appetising to owls and sparrow hawks too.

      Anyway with only Roban on offer suspect Jerry will either turn up nose as usual or perversely gobble, pump up biceps and come back for more. Better fit a steel inlet on the washing machine. So there we have it. Of mice and man. And no, cat never an option. Lived in a shared house with Tom 40 odd years ago and had to barricade the bedroom door at night to stop Tom getting in and clawing me to death. Give me Jerry any day…

      And re the paper from the Allen Institute, maybe issue in part semantic. English language (like most other languages?) has only one word for brain. Therefore linguistic predisposition that brains “alike” across species. Word neuroscience could also be predispositive. Cloaks reductio ad absurdum in respectability. Who knows, brain biophysics might turn out to have parallels with quantum physics – a century of trying and still no grand unifying theory of everything (unless of course a handful of geniuses have at last worked it all out and are now working out how to clear away the fog for the rest of us without rocking apple carts political, social and historical – it might take a while…).

  5. loupgarous says:

    More intellectual food for belief in a Watchmaker (as the less thorough similarities between the “camera eye” structures of vertebrates and cephalopods were). It is striking that going back 65 million years, Nature selected for middle temporal gyruses to be so similar between mice and humans.

    I wonder if that “conserved structure” is conserved in the MTG branch-wise from the ancestor mice and humans shared 65 mya, so you see, say, the same MTG structure in chimps?

    1. Matthew K says:

      “Nature selected for middle temporal gyruses to be so similar between mice and humans” – here’s your fallacy. In fact the basic architecture of the cerebral cortex is selected for flexibility – it doesn’t deal with the sensory receptors or the motor outputs, just abstractions of those things. It’s all just information that cortex absorbs, compares and emits as streams of action potentials. If you genetically knock in a third colour receptor in the mouse retina, cortex adapts to processing trichromatic vision without any “selection” required (Jacobs et al PNAS 2007). Re-route auditory pathways to visual cortex, it becomes auditory cortex, and vice versa (Mriganka Sur’s group in the early 2000s). Transplant visual cortex primordium into the region for whisker somatosensory, it develops barrels (Schlaggar and O’Leary in the 1990s).
      There is no selection pressure to change because cortex processes whatever information it’s handed. The only major difference across the mammals is how many neurons, how much dendrite and axon each grows, and how developed layers 2 and 3 are, corresponding to how much information is shared between regions.

      1. loupgarous says:

        Thanks for the enlightenment. I hadn’t realized cortical tissue was so flexible.

        And it means I have to change my comment on a Long Bet someone made, ““By 2027, humanity will have learned how to create new colors,feelings,qualias.”

        Of course, the colors of the visible light spectrum are what they are, but let’s say someone modifies the retina to have new receptors uniquely sensitive to IR or UV, then you’d have whole ranges of “new colors”, and (if I understand you correctly), the visual cortex would perceive those new colors automatically.

        ( have no idea what the bettor meant by ‘qualias’.)

        1. Matthew K says:

          That’s an interesting one – definitely mice with a knocked-in third cone pigment are able to behave as if they are seeing in trichrome colour rather than their usual red/green dichromat. Other species use more than 3 wavelengths to make colour discriminations (I think lampreys use 7 and mantis shrimp use 7-8 plus different polarisations) but I don’t know of a mammal with tetrachrome vision. Now that I look at Wikipedia I see that there are a few and that we even use rod responses for a fourth channel in some circumstances. So yeah, if we knocked in a UV sensitive cone or even one with a wavelength between the R/G/B trio, we would see tetrachrome colour. I have no idea what that would feel like, but to the cortex it would just be four channels of information coming through the same pathway, and it would set itself up to compare / contrast between the channels for maximum efficiency. Amazing stuff really – cortex is just a general-purpose analyser / comparator which extracts higher level information out of multiple sets of input activity.
          It’s not too much of a stretch to see the cortex as an abstraction machine, whose activity is coupled to sensory inputs and motor outputs by nuclei / systems which act as adapters between the language of the cortex and the nitty-gritty of which neuron moves which muscle fibre, etc.
          Re the bet around new colours – I’d say it would be a certainty if the humans were genetically engineered / transfected early enough in development. It wouldn’t have to be modifying the genome in the zygote, but you’d need to have the receptors in place before birth, ideally, or soon after.

  6. re-patenter says:

    entresto flops
    it’s just a rework of diovan
    and people wonder why drug prices are so high

  7. Barry says:

    The pitfalls of mice a models of human psychiatry are legion; it’s huge to have them laid out like this. But this study permits us to look for intra-species variation, too. E.g. do serontonin receptors co-express w/ the same actuators in all humans? Can we segregate thrill-seekers from monks?

    1. loupgarous says:

      The nucleus accumbens might be a good place to find structures associated with thrill-seeking (plenty of inputs from the limbic system) and the experience of pleasure in general.

  8. Curious in MA says:

    I apologize for my ignorance… but wonder: this study was done comparing mouse and human cortices.
    Just thinking here… given the brain regions studied (at the border of the tissue) perhaps one could understand why both species share some characteristics?
    I recall having seen reports where the human brain has other areas, which are totally missing in rodent brain…

    I don’t mean to put down the paper or its conclusions… I think it is very exciting to see this work. Just a thought, before getting too excited.
    Any others?

  9. matt says:

    If the human tissue was excised from epileptic brains, isn’t it likely it has been “rode hard and put up wet” so to speak? It has been over-stimulated constantly by signaling cascades, no? So did they compare to human brain tissue from non-epileptic brains as a control? I would expect there would be interesting and important differences between tissue so near a seizure focal point and tissue involved in more typical signaling.

    What would you think if you were comparing human heart tissue from someone who died of a heart attack to healthy cardiac tissue in mice? Or liver tissue from someone who died of cirrhosis to healthy mice liver tissue? I would expect, even for homologous cell types, RNA expression differences perhaps in cellular distress? perhaps signs of the cellular equivalent of working its tail off, doing extraordinarily more of whatever it normally does? And, for a neuron, wouldn’t that involve ion channels and neurotransmitters?

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