http://www.nature.com/nature/journal/vaop/ncurrent/full/nature09817.html

Abstract after the break.

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.

A very cool article on a new open source, online system to crowd source the assemblage of data in neuroscience from the Voice of San Diego.  From the article:

Traditionally, the study of the brain was organized somewhat like an archipelago. Neuroscientists would inhabit their own island or peninsula of the brain, and see little reason to venture elsewhere.

Molecular neuroscientists, who study how DNA and RNA function in the brain, didn’t share their work with cognitive specialists who study how psychological and cognitive functions are produced by the brain, for example.

But there has been an awakening to the idea that brains of humans and mammals should be studied like the complex, and interrelated systems that they are. Neuroscientists realized that they had to start collaborating across disciplines and sharing their data if they wanted to make advances in their own field.

[...]

Ellisman and his UCSD colleagues have devised a solution: crowdsource a brain. And this week they unveiled their years-long project — the Whole Brain Catalog — at the annual convention of the Society for Neuroscience, the largest gathering of brain experts in the world.

You can also see an impressive  artists rendition of the Whole Brain Catalog on YouTube.

UPDATE 10/27: Looks like Voice of San Diego scooped the New York Times, who just posted on this topic in today’s bits blog.

Full disclosure: I am intimately involved with this project.

http://www.nytimes.com/2009/08/16/opinion/16gopnik.html

Eight-month-old babies were shown a box full of mixed-up Ping-Pong balls: mostly white but with some red ones mixed in. The babies were more surprised, and looked longer and more intently at the experimenter when four red balls and one white ball were taken out of the box — a possible, yet improbable outcome — than when four white balls and a red one were produced.

I’m a fan of it because it is an open-access journal featuring a “tiered system” and more.  From their website:

The Frontiers Journal Series is not just another journal. It is a new approach to scientific publishing. As service to scientists, it is driven by researchers for researchers but it also serves the interests of the general public. Frontiers disseminates research in a tiered system that begins with original articles submitted to Specialty Journals. It evaluates research truly democratically and objectively based on the reading activity of the scientific communities and the public. And it drives the most outstanding and relevant research up to the next tier journals, the Field Journals.

I’m a big fan of the variety of specialty journals they have:

• Aging Neuroscience
• Behavioral Neuroscience
• Cellular Neuroscience
• Computational Neuroscience
• Enteric Neuroscience
• Evolutionary Neuroscience
• Human Neuroscience
• Integrative Neuroscience
• Molecular Neuroscience
• Neural Circuits
• Neuroanatomy
• Neuroenergetics
• Neuroengineering
• Neurogenesis
• Neurogenomics
• Neuroinformatics
• Neuromethods
• Neuropharamacology
• Neuroprosthetics
• Neurorobotics
• Synaptic Neuroscience
• Systems Neuroscience

We mentioned the innovative MARCM technique in a previous post. Here, Lee and colleagues extend MARCM (Mosaic Analysis with a Repressible Cell Marker, pronounced mark-em) to twin-spot MARCM, where both cells from a mitotic event are labeled with different colors fluorescent proteins. In regular MARCM, only one cell is labeled and the other daughter cell remained unlabeled. Like the original MARCM, this technique lets you distinguish between what would otherwise be identical pairs/clonal populations of cells during development and gain insight into the (lack of) stereotypy in development. Under the hood, twin-spot MARCM is a bit different: Instead of relying on GAL80 suppression of GAL4-driven transcription (regular MARCM), twin-spot MARCM uses RNAi directed against the protein-coding transcripts.

Since MARCM can be difficult to understand, here’s an excellent, detailed yet easy-to-understand description written for a bio lab class from Richard Vogt at the University of South Carolina:

1. A fly is constructed with the following genotype: (promotor)Gal4; UAS-GFP. In this fly, the promoter drives the expression of a transcription factor called Gal4, and Gal4 binds to and activates a regulatory site referred to as “UAS” (upstream activating sequence). Activation of the UAS site drives expression of GFP (green fluorescent protein) which fluoresces green when stimulated by blue light.
2. This fly also contains a gene encoding and expressing a protein called “Gal80″; Gal80 suppresses the action of Gal4. If Gal80 is expressed, no GFP is made and no green fluorescence can occur.
3. This fly also contains a complex of genes referred to as the FLP/FRT system; FLP is a transcription factor that activates the FRT site, which is situated adjacent to the Gal80 site. Further more, at least in our case, the FLP is driven by a “heat shock” promoter (hs). All this means is that when you raise the temperature of the animal to 37^oC, this activates the hs promoter which activates the expression of FLP which activates the FRT site.

           Something I’ve not mentioned yet… there is also an FRT site adjacent to the UAS-GFP site. Something else I’ve not mentioned yet, the FRT-UAS-GFP site and the FRT-Gal80 site are on the same chromosome, but importantly on different chromatids.

4. So we make a bunch of fly embryos that have all this stuff in them. Procedurally this is really easy, since the genes have already been put in the flies, and all we have to do is take virgin females of one stain (FRT-Gal80) and mate them to males of another strain (FRT-UAS-GFP) and… POW… we have fly embryos that have all this stuff in them.
5. All the cells in the embryos we now have are capable of expressing GFP except for the one problem… all the cells are expressing Gal80 which is blocking the expression of GFP. We need to turn off Gal80 expression. We do this by activating the FLP/FRT system.
6. Normally, a cell has two copies of each chromosome called chromatids. In our case, the chromatids are different, one containing by FRT-Gal80 and the other containing FRT-UAS-GFP. This cell can not express GFP because Gal80 is present. During mitosis, the chromatids are duplicated and sort to produce two identical chromatid pairs, both pairs consisting of a FRT-Gal80 chromatid and a FRT-UAS-GFP chromatid. Like their mother, neither daughter cell would be able to express GFP, again because Gal80 is present.

           HOWEVER, AND HERE IS THE TRICK… if the FRT is activated during mitosis, it induces a recombination event (recombination normally only occurs during meiosis), creating one chromatid pair that contains only UAS-GFP and another chromatid pair that contains only Gal80. One of the resulting daughter cells now contains no Gal80, and suddenly is able to express GFP and fluoresce green light. And any additional cells produced by this daughter will also express GFP.

[Suzanne] Corkin delivered Cryopaks to his nursing home in Windsor Locks, Connecticut. “They kept them in the freezer so that the moment he died they could wrap his head to preserve the brain,” she says. When Molaison [ie. H.M.] died of respiratory failure at 5:05 p.m. on 8 December 2008, the plan sprang into action. A hearse took his body to Massachusetts General Hospital (MGH) in Charlestown, where researchers began collecting anatomical magnetic resonance imaging (MRI) scans of his brain at about 9 p.m.—and continued until 6 a.m. the next day, when Annese arrived on a red-eye flight from San Diego.

Jacopo Annese, a neuroanatomist at UCSD, is planning on putting H.M.’s whole brain online on his website. But before that happens, he has a rather huge task before him:

Using a microtome, he will slice the brain into very thin sections. “Like prosciutto,” he says, but less than 1/20 the thickness and a lot more fragile. Annese aims to slice the brain whole instead of first cutting it into smaller chunks as is more routinely done. Small chunks are much easier to work with, but the resulting slices are hard to keep in register with one another. Whole-brain slices will keep more of the tissue intact and result in a more faithful reconstruction of the brain, he says. Annese estimates he will end up with about 2600 slices of Molaison’s brain. He and his colleagues will mount some of these, perhaps every 12th one to start, on extra-large glass slides—13 by 18 centimeters—and treat them with a stain that colors cell bodies purple. A camera attached to a microscope will photograph each slice at 20x magnification, sufficient to distinguish different cell types. At that magnification, photographing a single slice will require a mosaic of about 40,000 individual images.

And there is some stress that comes from dealing with such a one-of-a-kind specimen:

But a lot could go wrong. The MRI scans reveal deterioration of the white matter, Annese says, which might make the slices especially delicate and prone to tearing. An even more nightmarish scenario is a cracked brain, he says. Sometimes, a brain will freeze unevenly and break apart—destroying it before it can be sliced. Annese is taking every precaution, but he’s not taking anything for granted. “Cutting will make or break the project,” he says. “But if the brain cracks, I go back to Italy.”

Guest speakers on May 9th will include MIT professors (Roz Picard, Hugh Herr, myself, etc.) and many acclaimed speakers such as Oliver Sacks and John Donoghue. Registration may be close to being full, but it will be webcast.

More information at:
http://h20.media.mit.edu

- Ed

This dramatic example of human neural plasticity is amazing! Someone should go study this kid and his parents and find out more about how he developed his echolocation strategy. Are there other examples of this occurring in the medical literature? I’ve heard that blind people have very good hearing (and other senses) but this seems like a little more than “good hearing.” Also, thanks to Ben Huh for pointing me to this!

(UPDATE 03-05-2007 – Upon closer inspection, it is clear that while the surgery has enabled the woman to have sensation in the nerves of her missing hand when the surface of her chest is touched, the arm she is fitted with at the time of publication did not relay sensory signals from the arm back to her chest. As soon as she is fitted with an arm that has the appropriate sensors, however, she will not have to undergo further surgery to have this kind of direct feedback. Thanks to astute readers for pointing this out.)

The Guardian reports on an article published today in the Lancet about a successful surgical procedure giving an amputee a bionic arm that both responds to motor commands from her remaining motor nerves to control it and provides sensory feedback to sensory nerves when it is touched. If there was any doubt left, the worlds of neural prosthetics and brain-machine interfaces have officially collided.

The Lancet article is accompanied by two movies of the woman using the arm that you should really check out.

Given the recent progress in the decoding of motor signals from the brain and older progress on sensory feedback from neural prosthetics, this was to be expected. Nonetheless, watching this woman use her arm brings the message home in a visceral way. The spooky thesis of MIT CSAIL’s Rodney Brooks that “we will become a merger between flesh and machines” is one step closer today.

From the article:

Targeted reinnervation surgery was successful in this young woman. Four independent myoelectric sites were created that allowed improved control of a motorised artificial arm. Transfer sensation also developed; when the patient was touched on her reinnervated chest skin, she perceived the sensation to be in her missing hand.

An additional comment in the Lancet explains targeted reinnervation surgery:

Rather than record from these nerves directly, Todd Kuiken and colleagues report in today’s Lancet their development of targeted motor reinnervation (TMR), in which the disconnected ends of peripheral nerves are reimplanted into proximal musculature. Contraction of these proximal muscles shows the intended activation of the missing distal muscles. When combined with a myoelectric prosthesis, a command in the CNS to open the hand travels through its usual peripheral nerves, is amplified by the associated patch of reinnervated muscle, and is detected by myoelectric sensors, which trigger the prosthetic hand to open.

Todd A Kuiken, Laura A Miller, Robert D Lipschutz, Blair A Lock, Kathy Stubblefield, Paul D Marasco, Ping Zhou and Gregory A Dumanian, Targeted reinnervation for enhanced prosthetic arm function in a woman with a proximal amputation: a case study, The Lancet, Volume 369, Issue 9559, 3 February 2007-9 February 2007, Pages 371-380.