We had read that Dr. Henry Markram of the Blue Brain project had given a talk at TED (technology, entertainment, design), but the video wasn’t released until this month. This talk is geared towards a general audience, rather than getting into the specific details of the Blue Brain project, as he has before. It is engaging and includes many suggestions towards the future of neuroscience and AI.
The journal, Frontiers in Neuroscience, edited by Idan Segev, has made it Volume 3, issue 1. Launching last year at the Society for Neuroscience conference, its probably the newest Neuroscience-related journal.
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.
Recently, Alexander et al. published Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors [Neuron Neurotechniques], in which they use directed evolution techniques to modify a muscarinic GPCR to selectively bind an orally-deliverable small molecule that is otherwise inert. Apparently, this is the first time a channel has been engineered such that is selective for a biologically inert molecule, providing specificity of action. (They compare their technology with the hyperpolarizing allatostatin receptor which can have off-target effects.) Because the channel is specified genetically and the drug circulates systemically, it is easier to activate large populations of neurons (viz. optogenetic methods which are constrained to neurons in the light delivery volume) without implanted devices (eg. cannulas for AlstR, fiber optics for optogenetics, etc.) Another new technique/neurotechnology… onwards marches the innovation of new circuit-cracking tools!
I came across this fantastic review of tools for the Genetic Dissection of Neural Circuits in Neuron a few days ago. It’s by Liqun Luo, Ed Callaway, and Karel Svoboda. I highly recommend it, as it spans the gamut from genetic targeting (recombination, binary logic, viral delivery) to circuit reconstruction (super resolution LM, EM, brainbow) to activity modulation and functional mapping (uncaging, artificial GPCRs, light-gated channels, MIST). I don’t think I’ve ever seen quite a review of so many cutting edge neurotechnologies in one place. I can’t recommend this piece enough really. For me, with my lack of molecular expertise, the first sections on combinatorial gene targeting/expression techniques were great, pulling together Gal4, Cre/Flp, and Tet systems into a unified framework, along with more general concepts like site-directed integration, enhancer-trap, and repressor trap (eg. Thy1 mice).
Some shortcomings of step ChR2 and future research directions:
Deisseroth expects ongoing efforts to improve key features of these channels. “One disadvantage is that some of the mutants have reduced current compared to wild type, so multiple mutations may help to bring those current levels back up to wild-type levels,” he says. Projects designed to improve membrane targeting and to apply a composite of opsins, including the red light–responsive channelrhodopsin from Volvox carteri, are also in the works in his laboratory.
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.
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.
Another channelrhodopsin breakthrough from Deisseroth’s lab. This time light is not required to keep the channel open. Light merely triggers opening and closing behavior. Blue-shifted light opens channels and red-shifted light closes them. This looks like another potentially powerful neurotechnology for interrogating circuits and systems.
The Circadian Clock in the Retina Controls Rod-Cone Coupling (Christophe Ribelayga, Yu Cao, and Stuart C. Mangel)
An amazing paper from Neuron demonstrating adaptive (circadian clock-governed) binning in the retina, based on dopamine modulation of gap junction (electrical) synapses between retinal photodetectors. During the day, abundant dopamine release weakens gap junctions coupling rods and cones together so that visual acuity is high. When light is scarce (at night), there is less dopamine and the electrical coupling between rods and cones is increased. This is analogous to on-chip binning in CCD (digital) cameras. Binning increases signal (in light-limited systems, eg. seeing at night) by increasing optical input area and by reducing single element noise (ie. noise at different photoreceptors should be independent) at the cost of resolution. So, the retina activates photoreceptor binning at night to boost low-light signals and deactivates it during the day to increase resolution. The dopamine comes from cells in the interplexiform layer, whose dopamine release is itself governed by melatonin projections.
There has been a few articles recently in the NYT about the neural mechanisms used by mosquito repellents. What a wonderful idea: Do some ephys recordings to find which neurons are sensitive to DEET (the current standard for mosquito repellents, which I can attest both doesn’t work very well and eats holes in synthetic clothing) and then build targeted compounds for those receptors/neurons/pathways. I always like this type of simple and practical neuroengineering.
Right now, it appears that there’s a bit of controversy in the field. Earlier this year, in Science, a group from Rockefeller found that DEET masked sensitivity to human odors by interfering with a particular odorant receptor. This impressive result was recently question by entomologists from UC-Davis in a PNAS paper claiming that DEET acts directly on a particular olfactory receptor neuron and does not attenuate the response to the same human-emitted odorant, as found in the earlier paper. Although the results appear to be conflicting, the studies use different techniques and thus it is likely that DEET’s action might be more complex than either paper claims. Still, the idea of identifying a target for chemical intervention by looking at electrophysiological responses to DEET is smart.
In related work, earlier this year a group from Colorado State University, as described in this PNAS overview, “conducted a rigorous search of a library of N-acylpiperidines, using an artificial neural network to identify strong candidates, and then tested them in the laboratory on human volunteers.” They found a candidate molecule that has a ~4X longer repellency effect than DEET. Here’s a photo from the experiments (DEET vs. untreated hand)… ouch!