neurodudes

A set of two articles recently came out in Science that directly visualize two different (and likely complementary) approaches to synapse specific delivery of gene products. Plasticity at specific synapses (input specificity — we’re restricting the discussion to the dendrites of the post-synaptic neuron) requires proteins (eg. new AMPA receptors) to get to those post-synaptic compartments and membranes. But the intructions for these new proteins are contained in the nucleus with the rest of the genome. Clearly, new proteins synthesized in the soma can’t just be sent everywhere, since only specific inputs (eg. particular dendritic spines) need these new proteins. How does this happen? Hence, the postulated synaptic tag.

Two approaches

Broadly, there are two approaches to synaptic tagging: 1) mRNA is distributed widely and translated locally at tagged locations; 2) protein products are distributed widely in the bodies of dendrites but only contact/off-load at tagged synaptic specializations. This News & Views gives a nice overview of the two papers, which find approach 1) in Aplysia cultures with sensorin mRNA and approach 2) in rat hippocampal neurons with Vesl-1S/Homer-1a protein. It amazes me that both were found pretty much simultaneously, but that might have more to do with the use of the photoconvertible Dendra2 protein than anything else.

With both approaches, we still don’t know why mRNA/protein is directed to a certain location. That is, we can visualize synaptic tagging but we don’t know what is the tag, its ontogeny, or the mechanism of tagging. But that might not be so important to understanding more about neural function. These new tools might allow us to image plasticity at many synapses at once, perhaps even in vivo. But before that, more work is needed… does the optical signal (from the Dendra fusion protein) correlate with degree of potentiation? Can we detect plasticity in the opposite direction, ie. synaptic depression, through another tag?  (As a sidenote to approach 1), the use of 5′ and 3′ UTRs as a sort of molecular zipcode is also intriguing.)

Heesoo Kim sent me a note that The NeuroTubes have released a set of neuroanatomy music videos. All of them are wacky and neat… here’s a clip of Proud to Be a Neural Tube (which achieves the impressive feat of rhyming notochord with neuropores):

Hmmm…
Ray Kurzweil from Salon/bigthink.com on simulating the human brain:

I think he might be right that we can simulate the brain before we understand it, however.

Neuroscientists often use mouse models to understand learning and neural disease. Much of our understanding of mammalian biology comes from these amazing animals. It is commonly said that highly inbred lab mice are unintelligent. But is it true for wild mice too? In a talk last week at Harvard, Karl Svoboda referred to this fascinating YouTube video showing a mouse trained to complete an obstacle course:

Other training videos from the same trainer are available along with an official website with interesting tips about mouse training. Perhaps highly inbred lab mice are unable to replicate such feats but it is amazing to see in what detail this trainer understands mouse behavior and development:

An absolute necessity for any pet training is to understand the animal’s needs and to know about its generic behaviour, since appropriate animal training is only based on certain natural habits. For mouse agility, this means e.g. their great spatial orientation abilities and spatial memory which is worth bringing to light by relevant trick training. In nature, mice always prefer the familiar (= safe) route to their feeding site, no matter if it’s a long way round. This is also the reason why mice are unbeatable in maze tests – and a mouse agility course is nothing else than a maze without walls!
But many owners forget that if you expect your pet to show some natural habits and abilities, first and foremost the husbandry has to be species-appropriate. If your mice have to live in a small ground level cage, their three-dimensional consciousness and orientation abilities will surely be stunted or never fully develop.

Over the last week, it seems like everyone has sent me this NYT piece on PKM-zeta (about work in Todd Sacktor’s lab). I’m not sure why this work is being featured in the Times right now, since it’s a few years old. But it was news to me and I think it is of interest to anyone trying to understand structure-function relationships in the brain. In the original Science paper (from 2007), a pseudosubstrate inhibitor of PKM-zeta caused irreversible loss of a conditioned taste aversion memory (news and views here). I was unfamiliar with PKM-zeta, which appears to be a constitutively active form of PKC-zeta (a kinase that some might be more familiar with) and that lacks the autoinhibitory regulatory domain of PKC. The amazing phenomena is that, after treatment with ZIP (the pseudosubstrate that ties up PKM-zeta), the memory is permanently erased and doesn’t seem to return.

What’s going on? One tantalizing possibility is that the enzyme itself is directly related to the memory trace. This contradicts the (unproven) assumption of modern neuroscience that memories are stored solely in the synaptic strengths (ie. membrane-bound receptors) of a neuron. The other suggestion is that PKM-zeta is actively maintaining synapses and that enzymatic inhibition disrupts the precise maintenance of receptors or synaptic machinery. The effects happen quite fast (within 2 hours after drug injection), which seems short for receptor recycling but perhaps long enough for structural change to occur. I’m no expert on receptor movement: Is 2 hours long enough to add/remove a significant number of receptors?

Fascinating work but the method is blunt, wiping all experimentally-induced memories (and probably others too). Last month, another group reported (also in Science) selective erasure of a fear-conditioned memory using an interesting new genetic tool. Here, neurons in the amgydala that overexpressed CREB were found to be preferentially recruited into a fear memory trace (as shown in a previous Science paper). Incorporation into the memory trace was assayed by expression of the immediate-early gene (ie. activity-dependent) Arc. In the present study, they combine overexpression of CREB in a subset of neurons with cell death (via Diphtheria toxin in a transgenic mouse vulnerable to diphtheria). Apparently, normal mice lack the receptor (here a simian version is used) that confers pathogenicity for diphtheria. Thus, the viral construct both overexpresses CREB in a subset of neurons and selectively makes the same subset vulnerable to diphtheria. Ablation of just these neurons causes a permanent loss of the memory. Subsequent similar learning proceeds just fine (using the remaining neurons).

Can we say that the race is officially on to ablate just the synapses involved in the memory? I think so. Extra points if the ablation is reversible too!

Although I’ve been a longtime fan of Ramachandran’s excellent book Phantoms in the Brain, this TED talk is like a compressed summary of the highlight’s of his research. He’s a great speaker and he covers in 20 minutes my two favorite examples in the book (Capgras delusion and mirror treatment for phantom limb syndrome). Perhaps the best part of the talk is that, after listening to it, I was convinced more than ever before of the statistical nature of sensory perception (ie. the brain attempts to find the most likely explanation for sensory observations) and the integrative nature of central processing of multiple modalities. 

Atul Gawande also recently wrote a New Yorker article about treating phantom itch with Ramachandran’s mirror box. I found this part of Gawande’s article on statistical inference in perception most interesting:

You can get a sense of this from brain-anatomy studies. If visual sensations were primarily received rather than constructed by the brain, you’d expect that most of the fibres going to the brain’s primary visual cortex would come from the retina. Instead, scientists have found that only twenty per cent do; eighty per cent come downward from regions of the brain governing functions like memory. Richard Gregory, a prominent British neuropsychologist, estimates that visual perception is more than ninety per cent memory and less than ten per cent sensory nerve signals. When Oaklander theorized that M.’s itch was endogenous, rather than generated by peripheral nerve signals, she was onto something important.

I’m not familiar with this field but I wonder if anyone has tried to quantify what percent of our conscious experience that we normally believe to be 100% due to sensory input is actually recall from memory/inference based on past observation. Also, can this percentage adaptively change? Perhaps there are situations where the brain chooses to rely more heavily on memory and other cases where it relies more on primary sensory input.

Although it’s a few months old, Larry Abbott has an excellent article in Neuron on the recent (last 20 years) contributions of theoretical neuroscience. (He came by MIT last week to give a talk and that’s when I found out about the article.) It’s a review that is not too long and provides a good overview with both sufficient (though not overwhelming) detail and original perspective. It’s rare to find a short piece that is so informative. (And for a more experimentally-oriented review with an eye toward the future, see Rafael Yuste’s take on the grand challenges.)

Click on for some of my favorite passages from the Abbott piece. (more…)

As has become a hallmark of the Svoboda lab, this new paper in Nature (advance online publication) combines several cutting edge technologies (rAAV-delivered ChR2, most prominently, and 2-photon 1-photon laser stimulation) to do some interesting synaptic physiology.

The subcellular organization of neocortical excitatory connections : Article : Nature.

They used ChR2 (with TTX and 4-AP to block action potentials) to find where on the dendritic tree particular inputs synapsed onto L3 and L5 cells and to measure the strength of those inputs. ChR2 depolarizes the input axon locally (60um spot diameter) at points of (potential) axodendritic contact. If you’ve heard the term “potential synapse” before, then think of this technique as a way of checking potential synapses and seeing if there really is an actual synapse there.

The technique allowed them to map on a L3 barrel cortex pyramidal cell where different thalamic inputs (VPm, POm) and cortical inputs (M1, barrel L2/3, barrel L4):

sCRACM stands for subcellular ChR2-assisted circuit mapping.

(more…)

NSF:ENG:EFRI:Home Page

NSF’s Emerging Frontiers in Research and Innovation (EFRI) office funded 4 very futuristic neuroengineering grants.

1. Deep learning in mammalian cortex
2. Studying neural networks in vitro with an innovative patch clamp array
3. Determining how the brain controls the hand for robotics
4. In vitro power grid simulation using real neurons

Disclaimer: I was involved with the second proposal on this page.