It's time for SfN 2013

Welcome to what is the first post from this year's Society for Neuroscience annual meeting, San Diego. It is traditional for me to upload the SfN newest logo so here it is:

Inspired by the work of neuroanatomist and SfN President, Larry Swanson.

The weather is good so let's put that out of my mind and delve into the convention centre for the first main session.


Before I do you might like to check out other bloggers (these ones are "official") or visit the SfN site itself.

Some axons fair better than others - discuss

Sometimes you come across a poster that is really visually impacting and PR Williams [Presentation #550.26] produced one of these this morning. When the cord is injured by an impact some axons that cross the injury site are seen to degenerate over time. Williams wanted to understand why one axon might befall this fate whilst a near neighbour doesn’t even after apparently experiencing a similar trauma - what causes this?

Using an elegant 2-photon microscopy technique he was able to look at what happens early during the first few hours after injury at the resolution of individual axons. He saw spontaneous and previously unappreciated dynamics of damage. Some axons could be seen to swell or “bleb” up before degenerating entirely. Others would bleb but return to normal. When he used a dye to measure calcium concentration he saw that blebbing was most often accompanied by high calcium concentrations in the axon; he was able to demonstrate the cause of this high calcium concentration was most likely due to the axon having holes in the membrane as a result of the trauma allowing calcium to flood in. This was not always the case. Sometimes axons would bleb and return to normal but this was most frequently found in those axons that had maintained their calcium levels near normal.

Overall it was a stunning piece of fundamental research and gave some insight as to importance of maintaining tight control over calcium concentrations in cells (calcium homeostasis) and perhaps even some potential for this technique to screening compounds that shift the balance in these dynamics in the favour of axonal survival after injury.

Relax - Unravelling genes

During development there is obviously a need for our nervous system to be quite plastic. Over the first few years after birth this potential for plasticity gradually diminishes until around 5 years old when our nervous system beds down and largely loses the ability to repair itself efficiently.

One of the ways the body does this is by selectively switching off those genes that allow neurons to grow axons and form new synapses. Since it cannot delete the gene it must inactivate it some other way. The DNA in our chromosomes is tightly packed and the degree of packing influences how efficiently genes are expressed.

This is the fundamental basis of something called epigenetics. Packing is modified depending on the level of chemical modification of the DNA and something called histone around which the DNA is packed. Drugs can interfere with the levels of chemical modification which in turn can lead to a relaxation of the packing structure and greater expression. This could be useful for switching back on genes that once allowed plasticity in the developing nervous system. A Petit [Presentation #450.08] examined the effects of the anticancer drug Trichostatin A, or TSA (a histone deacetylation inhibitor) on neurons in vitro and found it to increase the amount of sprouting and axonal outgrowth in tissue culture. Given once a day for two weeks starting 1hour after experimental injury, systemic injections of TSA gave rise to enhanced functional recovery, increased axonal growth in and around the lesion, enhanced tissue sparing and modification of the immune response to the injury. The data presented was from studies carried out on female rats - apparently, male rats don't respond nearly so well! I'm assured they are looking into the reasons for that.

Simple technique help rats train and regain assisted walking

There has been a lot of publicity recently on the restoration of over-ground walking in completely transected rats using a cocktail of interventions that include epidural electrical stimulation, drug combinations delivered to the motor circuitry and robotic assistance and treadmill training. An example can be seen here.

While these studies were impressive, they did suggested that rats differed from cats, for example, which can express coordinated walking patterns after a few weeks of treadmill training without the need for all that epidural stimulation and drug cocktail. Are mammals really that different in their locomotor circuitry? A poster by O Alluin [Presentation #378.15] argued against this. The group from Montreal, Canada took completely spinalised rats (complete cord transection at T8) and trained them on a treadmill for 11 weeks for 10 mins per day whilst mechanically stimulating the perineal area with a pinch. The mechanical and sensory information flows to the cord and stimulating the lumbar region containing the central pattern generators for locomotion. It was interesting to see the data and video evidence that this simple technique brought about robust recovery of alternating, coordinated hind limb motion. Alluin explained the intensity of the pinch needs to be quite strong at the beginning of training but that this could be reduced significantly as time went on. One obvious extension of this will be to test whether external electrical stimulation in the perineal region also elicits a response. I got the impression they had tried this but weren’t prepared to comment at this stage.

Potential new avenue for overcoming Glial scar

I’ve talked before about the glial scar and chondroitin sulphate proteoglycans (CSPGs) and how this inhibits axonal regeneration. CSPGs inhibit growing axons or cause them to stall by stabilising the growth cones. Chondroitinase treatment helps to overcome this inhibition by cleaving the side chains of the CSPGs leading to numerous beneficial effects [252.01, 270.01, 270.02, 270.04, 270.06, 270.07, 270.08].

One important advance in our understanding came with the identification of receptors for CSPGs on neurons and with it the potential to develop new treatments centred on these receptors. Towards this BT Lang et al. [Presentation #252.07] have generated small peptides (protein molecules) against these recently discovered receptors, the LAR phosphatase and PTPsigma.  The peptides have been developed to penetrate cells and unlock the growth cone from the CSPG increasing axonal motility, extension in tissue culture experiments.

Lang and his colleagues went on to test the effect of these penetrating proteins in a model of severe contusion injury in rats.  Interestingly, it was possible to deliver the peptides via a simple subcutaneous injection and, in the case of the peptide targeted against the PTPsigma receptor, saw fairly robust improvements in locomotor, sensorimotor, coordination and bladder function.

Note added: It is worth looking here to see some decenting views on what the ligand is for PTPsigma.

Tell me when you feel something

Louis Armstrong New Orleans International Airport at 1am in the morning didn’t look good. It was tired, run down and in need of a facelift. After 24hrs traveling to get there – that’s another story – I felt like it looked. To be fair it was clearly undergoing some sort of refit. With 40,000 scientists descending on New Orleans for this year’s Society for Neuroscience Meeting the city clearly wasn’t bothering about first impressions. I guess that’s in keeping with the city they call the “Big Easy”.

SfN finally came up with the long-awaited app to help navigate the meeting. First impressions are it’s not bad. It has the whole programme loaded, social media feeds and the facility to create your own schedule. This last bit might need a bit of tweaking for next year as it lacks some of the power search facilities of the web-based meeting planner. In theory all you need now carry is something like an iPad but for me I still felt more comfortable with my carefully researched itinerary printed on paper, scribbled with like to see, must see and numerous question marks.

So, SfN is embracing technology, which is apt given the first session I planned to visit on Saturday. Before I get to that let’s consider a couple of basic options we have for the restoration of function for someone suffering a SCI. In general terms we can either look to biology to find ways to help the body repair itself or we can look to technology. For a while now I have noticed that there is a growing field looking to apply high-end technology to replace lost function. Advances in engineering have made sophisticated robotics a reality. Neural prosthetics and computer-brain interfaces are very actively researched but it is fair to say that the majority of this research has focused on the “easier” issue of replacing motor function. A classic example is recording and mapping neuronal activity in the brain associated with the intention to move a limb using micro-electrode arrays and using this information to drive a prosthetic limb (or stimulator) via some clever computer wizardry. While there are still problems to overcome this is feasible and has been demonstrated in humans.

To really own a limb you need to be able to feel it or at least feel what it is doing. And for many practical and dextrous functions, such as writing or manipulating items, you need feedback; not least so you don’t underdo the pressure required to maintain grip or overdo it leading to damage. Getting and perceiving sensory feedback from a prosthetic is a bit of a holy grail. G. A. Tabot [Presentation # 15.02] described some work towards this goal in non-human primates. Placing microelectrodes into the regions of the brain involved in sensory perception they recorded patterns of neuronal activation after stimulating different areas of the hand. At the same time the animal was trained to look at the part of the hand that was being stimulated. To prove the principle they then stimulated the appropriate region of the brain artificially using the same electrodes and found they looked at the correct region of the hand. The animal was reacting as though it had been touched even though the hand wasn’t actually receiving any stimulation. Using a similar approach they demonstrated the animal could distinguish force. This leads the way to integrating this with touch and pressure sensors on artificial prosthetics limbs and perhaps a more natural experience.

Bacterial enzyme aids recovery

I have posted before on the Glial scar and an inhibitory component of this, chondroitin sulphate proteoglycans, or CSPGs. The Glial scar is a particular consequence of CNS injury but CSPGs are also found everywhere in the extra cellular matrix (ECM) of the central nervous system. CSPGs have many known and unknown functions. For example, they form lattice-like nets around synapses between cells to stabilise these signalling junctions. They are likely to influence how cells move around the CNS, thus playing an important part in repair by resident stem and precursor cells which need to migrate to the area in need of repair, and they may harbour important molecules that sustain cells. Recently, two putative receptors have been identified giving insight into how CSPGs might act at the molecular level.
The inhibitory aspects of CSPGs are most problematic. The bacterial enzyme chondroitinase ABC (ChABC) degrades CSPGs, and experimentally, it has been shown to have a number of reparative effects making it a very promising treatment option for SCI. Nevertheless, there are concerns relating to how we should deliver this bacterial protein in the clinic. For one, ChABC activity is short-lived and therefore repeated injections or delivery by intrathecal catheter is needed which is unattractive.

Gene therapy approaches may provide the answer. Modified viruses have long been used as a tool to carry inserted genes into cells, “infecting” them with a copy of the gene which in turn causes the cell to produce (express) the protein. Obviously, concerns surround gene therapy as well, but the prospect of only needing a single administration of a therapeutic viral vector which gives rise to long-term expression of the therapeutic gene is compelling.

A number of groups are looking at a gene therapy approach for the delivery of chondroitinase. K Bartus (#892.21) presented a poster in the last session of the SfN meeting which got much attention. The poster presented data on sustained and widespread degradation of CSPGs following a single early injection of a lentiviral vector carrying a gene of ChABC optimised for expression in mammalian cells. The treatment led to a dramatic reduction of lesion pathology: sparing of neuronal tissue and dramatic reduction in cavity volume. The treatment also significantly improved signal conduction across the injury site coupled with improved performance on a horizontal ladder test.

With such sustained and active remodelling of the CSPG content of the cord there was a worry that there might be adverse effects such as development of pain syndromes. The authors tested for this and found no evidence of heightened sensitivity in the treated group of animals. The injury site was heavily vascularised with many tissue bridges associated with numerous axons.

Perhaps the most striking aspect of this study was that it was done in a contusion injury model, the most clinically relevant model of injury.