A sum of destructions

Pablo Picasso once said “To me painting is a sum of destructions. I paint a motif, then I destroy it.” Unknowingly, he had an intuition about visual processing. In fact, our current understanding is that retinas, quite like Picasso, break an image into its parts. The first man to lay the foundation of this idea was Haldan Keffer Hartline, a contemporary of Picasso. Professor GG Bernhard used this quote to present Hartline in the Nobel prize award ceremony 1967.

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Sharing while caring

Today, let’s throwback to the multiple comparisons problem and relate it to something new: Open Science.

In the past years, more and more researchers, legislators and politicians have started to campaign for an open and transparent scientific conduct. The fact that the majority of scientific articles are locked behind the walls of expensive magazines and thus unreachable for the general tax payer (even though they funded the research) is upsetting. Moreover, the scientific community is struggling with reproducibility – the center for open science reproduced 100 psychology studies and found that only 39% of the effects were rated to have replicated the result of the original study! Sharing raw data and code, and publishing in open access journals can hopefully solve these problems.

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Degenerative protein aggregates: a whole body view

A few weeks ago, Vivian wrote a post about prion disease, discussing how understanding the mechanisms of Kuru could help us design treatments for other neurodegenerative disorders characterized by protein aggregations. The accumulation of protein as a pathological process has also been investigted outside the brain. Aging and degeneration are complex system-wide phenomena and studies like the one by Demontis and Perrimon (2011) show that by looking outside the brain we can unveil new whole-body regulatory mechanisms for neurodegeneration.

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The New View that our Brains Generate New Neurons

This week I’m re-visiting adult human neurogenesis: the seminal neuroscience finding that new neuronal cells are born in adult human brains after the normal developmental period in which neurons are generated. This remarkable discovery was made by Peter Eriksson and colleagues in the lab of Fred Gage at The Salk Institute for Biological Studies. Prior consensus in the field was that once neurons died (a hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s) there was no regeneration of neurons. The view was that brains generated a finite number of neurons for the life of the organism, and these neurons networked to handle all learning of new knowledge and the making of new memories and associations—quite an incredible feat! However, the Gage group questioned the current model and found that there was neurogenesis in specific areas of rodent brains, a huge finding in and of itself. But this generated some controversy-- another group published that neurogenesis was not taking place in marmosets (a higher mammal than rodents) and therefore it was likely not happening in other primates, i.e., humans. Therefore, the publication of “Neurogenesis in the Adult Human Hippocampus” in Nature (Eriksson et al., 1998) helped to resolve what had become a contentious issue and definitively showed that indeed, new neurons are being born and incorporated into the hippocampal region of adult brains.

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How falling off a horse led to discovering the opiate receptor

“Any way you can make love, somebody’s already thought of. Any crazy caper you can get up to, any great meal you can think of, any combination of children or idea of how to raise them – somebody’s already thought of. But nobody’s ever discovered an opiate receptor before.”

- Candace Pert1

 

Shortly before starting graduate school in pharmacology at Johns Hopkins University in 1970, Candace Pert broke her back in a riding accident2. She took morphine to treat the pain, and subsequently became curious as to how this miraculous drug acted to produce such profound analgesic effects.

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A hole in sight

Patients with a damaged retina or visual cortex often report hole(s) in their sight. However inconvenient they may seem, these holes in many cases do not bother the patients and are sometimes not noticed at all. How do they block these holes from their awareness? In fact, this is a question that we should all ask ourselves, because we all have natural blind spots in our visual perception. This blind spot is caused by a small region in the back of our eyes that contains no retinal neurons. Instead, this region is dedicated for the retinal output neurons to send signals to the brain. Therefore, we walk around with two holes (one on each side) in our visual field. How do we not notice them, even when we try seeing with only one eye at a time?

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The neurobiology of dreaming

What are dreams, and why do we have them? People have probably been asking these questions since the dawn of reflective thought, but it wasn’t until the 1950s that scientists first identified neurophysiological correlates of dreaming. A classic paper by Aserinsky and Kleitman1 in 1953 marked the discovery of what we now refer to as Rapid Eye Movement (REM) sleep (Figure 1). Together with non-Rapid Eye Movement (NREM) sleep, REM sleep if one of the two major sleep states that humans and other mammals pass through multiple times during each sleep episode. REM sleep is the state associated with the vivid, hallucinatory dream experiences that we (sometimes) remember after waking.

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The lessons we learned from a dead fish

Here’s to a relatively recent TBT! In 2010, Craig Bennett and colleagues submitted a poster with the following title:

"Neural Correlates of Interspecies Perspective Taking in the Post-Mortem Atlantic Salmon: An Argument For Proper Multiple Comparisons Correction"

Yes, you are reading it right, it is about the neural correlates of a dead fish!

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Nothing to fear but fear itself

Late one night, a woman strolls through an urban park, and a belligerent man yells at her to come to the bench where he is sitting. The woman casually walks over to the man, who puts a knife to her throat. In a gentle voice she tells him, "If you're going to kill me, you're gonna have to go through my God's angels first." The man is so freaked out by this statement and the women's calm demeanor that he immediately lets her go. The next day, she takes another solitary walk through the park, as if nothing had happened.1 The woman described above, who is still alive today, is a famous case study in the neuroscience of human emotion. If you didn't know any better, little about her would strike you as odd - extremely outgoing and somewhat coquettish, but certainly not pathological. In fact, professional psychologists naive to her case don't seem to notice much about her that is strange. After speaking to her about her life and experiences, which include many personal hardships, they describe her as being a "survivor" with "exceptional coping skills." After learning that this woman is patient S.M., the same psychologists reinterpret their assessments of the woman: she is now said to display, "an abnormally low level of negative emotional phenomenology".2

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Recovery From The Passage Of An Iron Bar Through The Head' (1868)

This Thursday let’s throw it all the way back to 1868 when a doctor named John M. Harlow finally had enough. For twenty years he had endured incredulous disbelief at his initial report of a patient – a man named Phineas Gage - who survived a tamping iron exploding through his head. Now that the man had unfortunately passed away, and the doctor had the good fortune of procuring the skull as indubitable proof of the event, he compiled his notes and published a case study: Clipboard.jpg

 

You can read it here in full (and I strongly encourage you to do so. Far from the dry, esoteric tone of many academic journals today, the paper is full of action, drama, and opinion). Here are some personal highlights.

Harlow begins the paper acknowledging that many doctors and surgeons believed the story of Phineas Gage to be physiologically impossible….

Title

…but now he’s about to change everyone’s mind.

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He goes on to recount the incident of the tamping iron blasting through Gage’s brain in great detail, as well as the immediate aftermath (he got up immediately with little assistance, was able to walk up a flight of stairs, and upon seeing the doctor (Harlow), proclaimed ‘I hope I am not much hurt’). His recovery over the next few months is astonishing.  But what’s even more incredible than his survival is the observation that, upon not dying, Gage appeared to live on with a different personality than he had previous to the injury. Harlow observes:

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nolongerGage.jpg

His description of Gage's selective deficits in executive functioning and decorum is among (if not exclusively) the first insights into understanding the role of the prefrontal cortex. Harlow's observations above were also a defining moment for the burgeoning theory of 'cerebral localization': that specific parts of the brain are specialized in different functions (now a fact we take for granted, this was a controversial and hotly debated topic in the 20th century). That last sentence - 'In his regard his mind was radically changed, so decidedly that his friends and acquaintances said he was "no longer Gage"' could probably be considered somewhat of a birthplace for 'cognitive neuroscience'. Harlow's account (in combination with others) was so influential that the change in Gage's personality following his brain damage has become inextricably mired in our biological understanding of what it means to be oneself.

The impetus for writing this case study twenty years following the incident was the unfortunate event of Gage's death. Harlow was saddened to learn of his death, and  gravely disappointed that an autopsy had not been performed to analyze the condition of Gage's cortex.  However, Gage's mother entrusted his skull to Harlow, which bore the gruesome evidence of the injury decades before. Armed with this new data, Harlow finally felt ready to defend his initial account of the incident which he had published 18 years previously and had been widely discredited as impossible. He included drawings of the skull and tamping iron to scale.

skull.jpg

Harlow ends on a philosophical note on the recuperative powers of nature and the role of the intervening surgeon.

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It is difficult to imagine a case study published in the 21st century concluding in such a manner.

 

Citations:

  1. Harlow, J.M. Recovery From The Passage Of An Iron Bar Through The Head. Massachusetts Medical Society, 3 June 1868

TBT: Responses of Neurons of Primary Visual Cortex of Awake Unrestrained Rats to Visual Stimuli

In my research on the rat visual system, I have been designing an apparatus that would allow me to record neuronal responses to visual stimuli in freely moving rats. Most visual neuroscience experiments are now performed on restrained animals, who are usually treated with different drugs to suppress movement (anesthetics, muscle relaxants). But as anyone who has tried reading while falling asleep knows, just because your eyes are open does not mean that information is getting through to the brain. It makes more sense to study how neurons respond to images when the research subject is awake and paying attention.

While few researchers are studying vision in unrestrained rats today, I was surprised to find that the basic setup I have been working on for my experiments had already been created — in 1980’s Soviet Russia.

Working at the Moscow State University, Sergei Girman wanted to study the visual system in freely moving animals. So Girman chose to perform his experiments on rats, noting two features that made them convenient to use -  “the eyes in this animal are relatively immobile,” making it easy to know where they are looking (researchers go through a lot of trouble training a monkey to look at computer monitors in visual experiments), "while the visual analyzer is well developed” (analyzer being perhaps the fashionable word of the time to refer, in this case, to the visual areas of the brain).

The goal of Girman’s 1985 paper was to compare the responses of neurons in primary visual cortex in awake and attentive rats compared to those in restrained, anesthetized rats.

He outfitted the rats with a metal platform, glued to the head, that contained electrodes to record neural activity.  He then trained the animals to enter a vestibule that would constrain the head, so that when the visual stimuli were presented on a computer screen, the head would always be in the same position. While this may sound gruesome, by today’s experimental standards Girman’s procedure was quite original.

At the time, most experiments in visual neurophysiology were done in one long session - researchers would prepare the animal, insert electrodes and present visual stimuli for hours on end; at the end of the session, the electrodes were removed and the animal euthanized (in some cases the experiment could be repeated, but the electrodes would be placed in different brain areas each time). Girman was interested, in part, in recording the activity of neurons for long periods of time. If a neuron responds to particular visual stimuli today, would it respond to the same stimuli in the same way again, tomorrow? To be able to answer questions like this, Girman needed to construct an apparatus that would stay on the animal’s head for months without causing so much damage that the body would reject the implant.

One of Girman's rats with electrodes and head implant attached.

Today, researchers routinely record neuronal activity in rodents for months at a time (techniques such as calcium imaging allow one to examine the activity of the same neurons from one day to the next), but the surgical procedure of attaching head implants is quite drastic. In most cases, the animals are scalped (nonviolently, of course), holes are drilled in the skull, and after the electrodes are inserted into the brain, the scalp is replaced with glue (usually dental cement). Researchers take great care to perform such procedures in a sterile environment to reduce the risk of infections. Inevitably, however, after months (or in lucky cases, perhaps a year), the implants fall off.

Girman’s original solution to this problem was to not scalp the animals in the first place. Instead, he would only make holes large enough for the electrodes to pass through (0.12 mm, according to his paper). Then, he would create a platform for the electronic equipment by threading stiff metal wires under the scalp. While this sounds like a less invasive solution, it must be quite difficult to perform (although I haven’t tried it in my own experiments yet).

Girman’s papers are quite fascinating, partially because of his unique methods, which make me wonder if they really do work better than today's established techniques. Is it just the no one read Girman’s work (which was originally published in Soviet Russian journals and translated later)? Or is Girman's idea of keeping the scalp intact really not all that better than removing it?

It is both encouraging and frustrating to learn about obscure research techniques: the wheel does get reinvented over and over, but perhaps we learn something new each time.

Girman, S. V. (1985). Responses of neurons of primary visual cortex of awake unrestrained rats to visual stimuli. Neuroscience and Behavioral Physiology, 15(5), 379–386.

(Please tweet us @harvardneurosci if you have trouble accessing the paper)

 

 

A microfluidic culture platform for CNS axonal injury, regeneration and transport

Nature Methods - 2, 599 - 605 (2005)Published online: 21 July 2005; | doi:10.1038/nmeth777

Many memorable journal articles are those that present a new method to the science community. For this week’s TBT I’m posting about an article that literally made the experiments in my own thesis possible. Anne Taylor and colleagues published a novel way to compartmentalize cultured neurons in Nature Methods, 10 years ago (yikes!). One of the fundamental properties of neurons is that they consist of molecularly and functionally distinct compartments. Axons, cell bodies, and dendrites all have their unique roles to ensure proper growth and maintenance of the neuron, as well as for completing the neuron’s mission to transmit information from one neuron to another. The complexity of this compartmentalization is really quite beautiful; and can really be quite difficult to understand. This article presents a microfluidic chamber as a way to isolate (and thus study) separate parts of the cell, in vitro.  

 

microfluidic chamber

The paper describes their fabrication of the microfluidic device; essentially, the device is made up of two narrow chambers that are separated by tiny microgrooves. It is a simple design that takes advantage of the properties of diffusion—when there is a volume difference between the chambers the high fluidic resistance of the microgrooves (given by their “micro” size) produces a small but sustained flow from one chamber to the other. Importantly, this unidirectional flow will counteract any diffusion of small molecules (or drugs or growth factors, etc.) from the lower volume chamber. The establishment of flow allows for manipulation of one compartment and one compartment only. For example, one can ask if the action of a neuronal survival factor is necessary in axons or in cell bodies. The especially novel advantage of this method is that the chamber is made of a clear plastic polymer (PDMS) and is affixed to a glass coverslip, which allows for immunocytochemistry  and live cell imaging in a compartmentalized culture system. In this paper specifically, they used the chamber as a model for studying axonal injury and regeneration. The authors showed that cutting the axons (axotomy) resulted in a host of proteins being upregulated in the cell body (despite the cell body being protected from injury), thus illustrating the axonal environment of a cell does have important effects on the biochemistry of the cell body.

The fun of a TBT is that we can look back and see which publications ended up being impactful in our field. This paper is an example of a methods paper that has really helped the field advance. This microfluidic system has been shown to be quite adaptable; many different versions of these chambers now exist for asking unique questions not only about injury and regeneration but also about synapses. And one day soon my own paper will be adding to the scientific conversation of how neuronal compartments compare, thanks to this novel method!

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