The FIRSTS: Adult neurogenesis (1962)

New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).
New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).

I am starting a new category today: the Firsts. It will feature articles that showed something really interesting for the first time. Yes, all articles show something for the first time, that’s why they are published. But I have noticed either a lack of acknowledgment (“it is known that x”) or a disregard for the old papers (“doesn’t count if it’s before, say, 2001”), particularly among the new generation of scientists. So I will feature both the really big ones (e.g., first proof of adult neurogenesis) or the more obscure, but nonetheless, first in their field (e.g., first synthesis of morphine).

Today, first proof of adult neurogenesis. Altman (1962) wanted to see the kinetics of glial proliferation after brain injury. Glial cells are the other type of cells in the brain and they outnumber the neurons 10 to 1. Altman lesioned the rat lateral geniculate nucleus (a portion of the thalamus that deals primarily with vision) and then injected the rats with thymidine-H3, a dye that labels the newly formed cells. In addition to the expected glial proliferation, he also observed (by microscope and careful histology) that some neurons were also stained with the dye, which means that they were born after the injection. The new neurons were in many regions of the brain (so not only those associated with the lesioned area), including the cortical areas.

Altman followed up and three years later published the first comprehensive study of postnatal (not adult) neurogenesis in dendate gyrus of the hippocampus.

References:

  1. Altman, J. (30 March 1962). Are New Neurons Formed in the Brains of Adult Mammals?. Science, 135 (3509): 1127-1128. DOI: 10.1126/science.135.3509.1127. Article | PDF
  2. Altman, J, & Das, G. D. (June 1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. The Journal of Comparative Neurology, 124 (3): 319 –335. DOI: 10.1002/cne.901240303. Article | PDF

by Neuronicus, 30 September 2015

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Viruses are as alive as crystals

Crystal of ultrapure bismuth. Photo credit: Intangir (public domain)
Crystal of ultrapure bismuth. Credit: Intangir. License: PD

The biology hype of the week is the notion that viruses are alive. Well, the true answer to that is… maybe. But that’s not catchy enough for headlines, is it?

Let’s start, as usual, with the source. Nasir & Caetano-Anollés (2015) published a paper where they did a lot of computer sniffing in existing proteomics databases to find out that viruses express a few dozen unique protein folds and they share several hundred more with cells. In other words, some of the viral proteins are unique. Using this information and some neat math they managed to calculate an evolutionary tree, that is, they classified the viruses via genetic relatedness to themselves and living organisms. That’s the strictu sensu of the term “tree of life”. From this taxonomy exercise, the authors speculate about when and how viruses might have appeared. They concluded that viruses appeared as RNA chunks spat out of cells. To give you a little background, there are two main hypotheses about the origin of viruses: appeared before cells as free floating RNA, or they were pieces of RNA that have been kicked out of a living cell, so after the evolution of cells. All well and good, I’m not going to open that can of worms, which hypothesis is more supported from data and so on.

Now, and this is the contentious part, verbatim: “Here, we put forth the bold conjecture of a universal tree of life (uToL) that describes the evolution of cellular and viral proteomes. […]. Thus, viruses should be considered “living” organisms that simply survive by means of an atypical reproduction method that requires infecting a cell ” (p.18.). It’s their opinion. Not a fact. Not – and this is important – a direct consequence of their awesome taxonomy exercise. For a formal definition, a conjecture is an opinion or conclusion formed on the basis of incomplete information (Oxford Dictionary).

Don’t get me wrong, I think this is a neat paper, and, frankly, I don’t have a horse in this race: I don’t care whether viruses are alive or not. But I do care to distinguish between fact and opinion, an intellectual exercise that seem to have eluded the science websites and science popularization zines and e-zines like EurekaAlert, IFLS, ScienceAlert, Gizmodo, Daily Mail, Wired, Popular Science, R & D Magazine, Laboratory Equipment, and many others, who ran titles saying “Viruses are alive” in just so many words. Note that even the authors themselves put the word “living” between quotes. Know the difference between opinion (that is, we think that because x makes y, maybe x is blue) and a scientific fact (x makes y, y makes z, therefore x must make z and we know that not only because it’s logical, but also because no other wretched letter wants to make z, believe us we tried, we made sure z is where we put it, because we put dye on it, we measured it, chopped it, looked at it with 5 different instruments, and we cannot make z without x though a poor grad students tried and tried in vain, we even modeled z, and yes, it is made by x, otherwise known as we eliminated all other testable bloody possibilities that we could think of. Unless q makes z in humans, but we can’t measure that. Or r makes z under Jovian gravity, but we didn’t get a grant for that…. get my drift what a scientific fact is?).

Now, rant is not over. The authors argue that viruses have a sort of metabolism and they replicate, so they meet the requirements for being classified as alive. I argue that either these two conditions are not enough for something to be considered alive, or we have then to conclude that cave crystals are also alive. Crystals only grow in the appropriate environment of a saturated solution and bits shattered off from them go into an inert mode waiting for appropriate conditions. Crystal growth can even be looked at as a sort of metabolism. So, if they are willing to characterize crystal growth as somewhere on the continuous scale of life, viruses can be there as well. Using their analogy, the living, metabolically active form for crystals is when they are growing in a saturated solution; and bits breaking off or the bulk waiting for solution conditions to change is just an atypical reproductive scheme. It even gets more interesting with some of the more modern more complicated crystal growth theories with preassembly into nanocrystals, editing or incorporating defects, etc. Ok, I’m getting tired and I made my point anyway. Rant over. Happy debating!

Reference: Nasir, A. & Caetano-Anollés, G. (25 September 2015). A phylogenomic data-driven exploration of viral origins and evolution. Science Advances, 1(8): 1-24. DOI: 10.1126/sciadv.1500527. Article | FREE PDF

by Neuronicus, 29 September 2015

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There’s liquid water on Mars. Yes, right now.

Water flowing on Mars. Site: Hale crater, Mars. Dark brown: a hundred meters long & few meters wide streaks of hydrated salts. Credits: NASA/JPL/University of Arizona
Water flowing on Mars. Dark brown: a few hundred meters long & few meters wide streaks of hydrated salts. Site: Hale crater, Mars. Credits: NASA/JPL/University of Arizona

There’s liquid water on Mars. Yes, right now. No, we don’t know where is coming from, though NASA has a few good ideas. No, we don’t know if there’s life in it, yet (an organic compound analyzer must be send to Mars to find that out).

NASA announced today, September, 28, 2015, that they have evidence that there is flowing liquid water on today’s Mars.

Evidence comes from the spectrometer that’s on-board the Mars Recognizance Orbiter, a spacecraft launched in 2005.

Mars_Reconnaissance_Orbiter
Conceptual image of the Mars Reconnaissance Orbiter which, 10 years after its launch, brought us the news of flowing water on Mars, thanks to its spectrometer, one of the many instruments it has on-board. Credit: NASA/JPL/Corby Waste.

First, the scientists noticed long dark streaks, called recurring slope linae, that seem to appear and disappear seasonally: they appear during warm months, and disappear during cold months. Then, they used the spectrometer to record and analyze what those streaks are made of. The streaks represent salty water flowing downhill. The salts are essential because otherwise the water would not be in liquid form in the freezing temperatures of Mars (the higher the content of salt, the lower its freezing point; that’s why we salt the streets during winter).

The water can come from absorption from atmosphere (but Mars doesn’t have enough water vapor in the atmosphere, so that’s unlikely), from ice melting (but they found ice near equator, so that’s a no-no), or from an aquifer (but they found water flowing on top of peaks, so no aquifer there). The abstract presented at the European Planetary Science Congress say there may be all of the above.

As for life… we need to send some instrument there with an organic compound analyzer to take a closer look at that brine.

Reference: Ojha, L., Wilhelm, M. B., Murchie, S. L., McEwen, A. S., Wray, J. J., Hanley, J., Massé, M., & Chojnacki, M. (2015). Spectral Evidence for Hydrated Salts in Seasonal Brine Flows on Mars. European Planetary Science Congress 2015 Abstracts, Vol. 10, EPSC2015-838-1. EPSC Abstracts PDF | NASA announcement | Animation of Site of Seasonal Flows in Hale Crater, Mars

P.S. Generally, I try to stay away from the media-grabbers, i.e. those findings covered by everybody. But sometimes, something is just too good to miss. Even if it’s not neuroscience ;).

By Neuronicus, 28 September 2015

I’m not like you, inside and out

Credit: Dawn of the Planet of the Apes
Screenshot from “Dawn of the Planet of the Apes” (Director: Tim Burton, 2001)

One mistake than many neuroscientists make (myself included) is the implicit assumption that the human brain is a rodent brain scaled-up, plus a few more bits. Here is a remainder that “a rat is not a monkey is not a human”, in the famous words of A. D. (Bud) Craig (2009).

Mohan et al. (2015) analyzed a portion of the brain (Brodmann area 21) obtained from 28 individuals that had to undergo neurosurgery and have it removed for various illnesses. Using some good microscopy, fancy statistics, and 3-D modeling, they reconstructed the shape of individual neurons from that region. The main finding is that 88% of human pyramidal neurons were distinctly different than their mouse or macaque counterparts. Also, they managed to record the electrical activity of these neurons in less than 10 minutes after resection. So it appears that this morphological distinctness of ours results in unique electrical properties of human neurons, which may account for the “distinct cognitive capabilities of humans”, as the authors put it.

Approximate location of Brodmann Area 21, corresponding to gyrus temporalis medium. Credit: Brain template to _DJ_; Area tracing to Neuronicus
Approximate location of Brodmann Area 21, corresponding to gyrus temporalis medium. Credit: Brain template to _DJ_; Area tracing to Neuronicus

Citation: Mohan, H., Verhoog, M. B., Doreswamy, K. K., Eyal, G., Aardse, R., Lodder, B. N., Goriounova, N. A., Asamoah, B., B. Brakspear, A. B. C., Groot, C., van der Sluis, S., Testa-Silva, G., Obermayer, J., Boudewijns, Z. S., Narayanan, R. T., Baayen, J. C., Segev, I., Mansvelder, H. D., de Kock, C. P. (28 August 2015; Epub ahead of print). Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex. Cerebral Cortex, 1-15. doi: 10.1093/cercor/bhv188. Article + FREE PDF

Obscure protein restores memory decline

In the not-too-distant-future, your grandma may give you a run for your money on your video games. Photo credit: http://www.funtoosh.com/pictures/
In the not-too-distant-future, your grandma may give you a run for your money on your video games. Photo credit: Funtoosh

Aging comes with all sorts of maladies, but one of the most frustrating is the feeling that you are not as sharp as you used to be. Cognitive decline has been previously linked, at least in part, to a dysregulation in the neuronal calcium homeostasis in the hippocampus, which is a brain region essential for learning and memory. One player that keeps in check the proper balance of calcium use is the protein FKBP1b, and, not surprisingly, its amounts are reduced in aging rats and Alzheimer’s suffering patients.

FKBP1b overexpression in hippocampal neurons reversed spatial memory deficits in aged rats. Fig. 3 (partial) from Gant, J. C., Chen, K. C., Kadish, I., Blalock, E. M., Thibault, O., Porter, N. M., Landfield, P. W. (29 July 2015). Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. The Journal of Neuroscience, 35(30):10878 –10887. doi: 10.1523/JNEUROSCI.1248-15.2015.
FKBP1b overexpression in hippocampal neurons reversed spatial memory deficits in aged rats. Fig. 3 (partial) from Gant et al. (2015): doi: 10.1523/JNEUROSCI.1248-15.2015.

Gant et al. (2015) sought to increase the expression of the FKBP1b protein in the hippocampus, in the hopes that its increase would result in better calcium homeostasis and, as a result, better memory performance in aging rats. They built a virus that carried the gene for making the FKBP1b protein and they injected this directly in the hippocampus. After they waited 5-6 weeks for the gene to be expressed, they tested the rats in the Morris water maze, a test for spatial memory. The old rats that received the injection performed as well as the young rats, and far better than the old rats who didn’t get the injection. Then the researchers made sure that the injection is the one responsible for the results, by checking the levels of the FKBP1b protein in the hippocampus (increased, as per specs), by recording from those neurons (they were awesome), and by imaging the calcium to make sure the balance was restored (ditto).

Reference: Gant, J. C., Chen, K. C., Kadish, I., Blalock, E. M., Thibault, O., Porter, N. M., Landfield, P. W. (29 July 2015). Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. The Journal of Neuroscience, 35(30):10878 –10887. doi: 10.1523/JNEUROSCI.1248-15.2015. Article + FREE PDF + Journal of Neuroscience cover

Golf & Grapes OR Grandkids (but not both!)

Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license
Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license

Transgenerational epigenetic inheritance (TGI) refers to the inheritance of a trait from one generation to another without altering the DNA code (normally, evolution is driven by changes in the DNA itself). Instead, it happens by modifying the proteins that wrap around the DNA, the histones; these histones, in turn, control what genes will be expressed and when. Until a decade ago, TGI was considered impossible, nay, a scientific heresy since it had too close of a resemblance to Lamarckian evolution. But, true to its guiding principles, the scientific endeavor had to bite the bullet in front of amassing evidence and accept the fact that it may have been a kernel of truth to the so called ‘soft inheritance’.

Anway et al.’s paper was one of the first to promote the concept, ten years ago. They exposed pregnant rats to the pesticides vinclozolin or methoxychlor (only vinclozolin is still used widely in U.S.A. and several EU countries, particularly in agriculture, wine production, and turf maintenance; methoxychlor was banned in the early noughts). The authors found out that more than 90% of the male offspring had “increased incidence of male infertility”. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined” up to great great grandsons, inclusively (Anway et al., 2005). (I don’t want to speculate how they managed to breed the low fertility males…). That doesn’t mean that the F5 generation was OK (the great great great gransons); it means that they stopped investigating after the F4 generation (or they couldn’t breed the F4s). Moreover, the mechanism of inheritance seems to be altered methylation of the DNA histones of the male germline, and not alteration of the DNA itself. Females were affected too, but they didn’t have enough data on that experiment (the Ph.D. student that did the work had to graduate sometime…).

Although the authors used higher amounts of pesticides than they suspected back then, in 2005, to be found in the environment, the study still gives pause for thought. After all, it has been 10 years since this paper plus the previous 20 years of use of the stuff. And no, you cannot get rid of it by washing your grapes and vegetables really thoroughly.

Reference: Anway, M. D., Cupp, A. S., Uzumcu, M., & Skinner, M. K. (3 June 2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science, 308(5727): 1466-1469. DOI:10.1126/science.1108190. Article + Science Cover + FREE PDF

by Neuronicus, 25 September 2015

The song of a fly… the courtship of another

Drosophila melanogaster image illustrating sexual dimorphism and mating behavior. Credit: TheAlphaWolf (Wikimedia Commons)
Drosophila melanogaster image illustrating sexual dimorphism and mating behavior. Credit: TheAlphaWolf (Wikimedia Commons)

Did you know that flies sing? True to the dictum that I just made up – ‘where is song, there is lust’ – it turns out not only that flies can sing, but they even have courtship songs! Granted, since they don’t have a larynx, the male flies sing by vibrating their wings in a certain way, which is unique to each fly species, and females listen with the feather-looking bit on top of their antennae, called arista. The behavior has generated enough research that a fairly hefty review about it has been published two years ago in Nature Reviews Neuroscience, pointing to a gene central to the male courtship circuitry and expressed only in the fly’s neurons, the fru gene (I bet it was called that way because when you make mutants you get fru/fru …).

Zhou et al. (2015) used a series of complicated experiments to successively activate or inhibit the neurons which express the fru gene, in order to identify the neural circuitry underlying hearing and processing the courtship songs. This circuitry is different in males and females, which makes sense since the serenading male expects different behaviors from his audience, depending on their sex; the listening males hurry to compete for the intended female and the females slow down and… listen carefully. Mind wondering: if I was the one serenading, wouldn’t I want to drive away the competitors, instead of drawing them in towards the object of my desire? Perhaps I want the competitors to also engage in courtship behavior so I can show off my wing vibrating prowess… Anyway, digression aside, in addition to figuring out which neuron does what, the authors managed to elicit courtship behavior in the listening males by optogenetically stimulating the 3rd and 4th order neurons in the newly identified circuit.

Besides being strangely interesting in itself, the research fills a gap in the understanding how courtship behavior is recognized, at least in fruit flies, which may be very useful information for other species as well, humans included.

Reference: Zhou, C., Franconville, R., Vaughan, A. G., Robinett, C. C., Jayaraman, V., & Baker, B. S. (21 September 2015). Central neural circuitry mediating courtship song perception in male Drosophila. Elife, 4:1-15. doi: 10.7554/eLife.08477. Article + FREE PDF

For the interested specialist, the MATLAB source code for analyzing calcium-imaging data can be found here.

By Neuronicus, 24 September 2015

Wireless mice, batteries not included (optrodes and electrodes in one wireless contraption)

A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute Courtesy: National Science Foundation
A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute. Courtesy: National Science Foundation

Optogenetics is the new (and very popular) kid on the block of neurotechniques arsenal. Before optogenetics, in order to manipulate how the neurons behave in a particular brain region, one had to do so electrically or chemically by inserting into that region an electrode or a tube, respectively. The trouble with that is that you never know exactly which neurons you are manipulating, given that any brain regions has many kinds of cells that project to many other regions and they are not nicely arranged in clumps but interspersed in a messy mesh. But with optogenetics, you can select exactly which neurons you want to manipulate. You take a mouse and you genetically engineer it to express in your favorite neurons a particular protein that is sensitive to a certain light wavelength (like a rhodopsin). Then, you shine the light in the mouse’s brain, turning on and off the neurons of your interest. The technique, besides having tremendous success in fundamental research, also shows promise for neuroprosthetics for some diseases, like Parkinson’s.

Despite rapid improvements of the technique due to increasing demand form the neuroscience community, it is still difficult to record from the freely-moving animal, mainly because the animal is attached to the fiber optic that delivers the light pulses. There have been some wireless attempts (some successful), but because the resultant contraption was too big and heavy for the animal, they have reduced options as compared to the wired devices. Gagnon-Turcotte et al. (2015) describe here a way to build a wireless headtsage that can deliver light pulses AND record the electrophysiological activity of the neurons. And, equally important, is cheap and can be build with off-the-shelf components.

Reference: Gagnon-Turcotte, G., Kisomi, A. A., Ameli, R., Camaro, C.-O. D., LeChasseur, Y., Néron, J.-L., , Bareil, P. B., Fortier, P., Bories, C., de Koninck, Y., & Gosselin, B. (9 September 2015). A Wireless Optogenetic Headstage with Multichannel Electrophysiological Recording Capability. Sensors, 15(9): 22776-22797; doi:10.3390/s150922776. Article + FREE PDF

By Neuronicus, 22 September 2015

Update (27 September 2015). The author Gabriel Gagnon-Turcotte wins the Mitacs 2015 prize for exceptional innovation for the development of a wireless system to study the brain

Zap the brain to get more lenient judges

Neuronicus3
Reference: Buckholtz et al. (2015). Credit: Neuronicus

Humans manage to live successfully in large societies mainly because we are able to cooperate. Cooperation rests on commonly agreed rules and, equally important, the punishment bestowed upon their violators. Researchers call this norm enforcement, while the rest of us call it simply justice, whether it is delivered in its formal way (through the courts of law) or in a more personal manner (shout at the litterer, claxon the person who cut in your lane etc.). It is a complicate process to investigate, but scientists managed to break it into simpler operations: moral permissibility (what is the rule), causal responsibility (did John break the rule), moral responsibility (did John intend to break the rule, also called blameworthiness or culpability), harm assessment (how much harm resulted from John breaking the rule) and sanction (give the appropriate punishment to John). Different brain parts deal with different aspects of norm enforcement.

The approximate area where the stimulation took place. Note that the picture depicts the left hemisphere, whereas the low punishment judgement occured when the stimulation was mostly on the right hemisphere.
The approximate area where the stimulation took place. Note that the picture depicts the left hemisphere, whereas the low punishment judgement occurred when the stimulation was mostly on the right hemisphere.

Using functional magnetic resonance imaging (fMRI), Buckholtz et al. found out that the dorsolateral prefrontal cortex (DLPFC) gets activated when 60 young subjects decided what punishment fits a crime. Then, they used repetitive transcranial magnetic stimulation (rTMS), which is a non-invasive way to disrupt the activity of the neurons, to see what happens if you inhibit the DLPFC. The subjects made the same judgments when it came to assigning blame or assessing the harm done, but delivered lower punishments.

Reference: Buckholtz, J. W., Martin, J. W., Treadway, M. T., Jan, K., Zald, D.H., Jones, O., & Marois, R. (23 September 2015). From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms. Neuron, 87: 1–12, http://dx.doi.org/10.1016/j.neuron.2015.08.023. Article + FREE PDF

by Neuronicus, 22 September 2015

Alzheimer’s disease can be transmissible (by a prion-like mechanism)

ADCreutzfeldt–Jakob disease (CJD) is a deadly prion disease; a prion is a protein that has an abnormal shape (which is very bad, toxic) and has the capacity of infecting other proteins so that the normal proteins became prions themselves. Between 1958 and 1985, several tens of thousands people – mostly children – received growth hormone injections for growth deficiencies. This drug has been developed from the pituitary glands of dead humans. All the glands have been pooled together, homogenized, and then the hormone extracted, so if there was only one infected with the CJD all of them became infected. After a long and variable period of incubation (5 to 40 years), a few hundred of the injection recipients died of CJD.

Jaunmuktane et. al (2015) found that the brains of four of these people that died of CJD also had amyloid-β pathology, which is a sign of Alzheimer’s disease (AD), a type of dementia. These people were unusually young to develop AD, between 36-51 years old. In almost all cases we know of early-onset AD, beside amyloid deposits, the patients also have some particular genetic mutations, e.g. APOE ε4 alleles. The people from the Jaunmuktane study did not have any genetic mutations, therefore, the amyloid deposits were a direct result of the contaminated injections given as children. Which means that some of those injections were having not only CJD prions, but also Alzheimer’s seed.

Reference: Jaunmuktane, Z., Mead, S. Ellis, M., Wadsworth, J. D. F., Nicoll, A. J., Kenny, J., Launchbury, F., Linehan, J., Richard-Loendt, A., Walker, A. S., Rudge, P., Collinge, J. & Brandner, S. (10 September 2015). Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature, 525: 247–250, DOI:doi:10.1038/nature15369. Article | FREE PDF | Nature cover | BBC cover

By Neuronicus, 21 September 2015