Bistable current photoswitches in neurons

Bi-stable neural state switches : Article : Nature Neuroscience

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.

Relevant fig:

photoswitching channelrhodopsin traces
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Adaptive binning in the retina

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.

Also, I never knew that gap junction strengths were directly modifiable. It looks like the D2 receptors are G-protein coupled to PKA, which acts on the gap junctions.

Neuroengineering mosquito repellents

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!

Lots of flies on the untreated hand!

Where are we with this whole free will thing?

Haim Sompolinsky has written an excellent book chapter on the scientific view of free will and choice, pulling in good ideas from physics and neuroscience along with contemporary philosophical commentary.

I think this chapter might be helpful for neuroscientists outside of the lab. Often a dinner table discussion has moved to the idea of “quantum consciousness” or “quantum free will”. Often, someone will mention Roger Penrose, who has become something of a poster boy for this idea that quantum indeterminacy (eg. Heisenberg’s uncertainty principle) is one possible way that free will is really free. And then, people look around and say, “Well, you’re a neuroscientist. Do we have free will?” (And that’s when I take another big drink or bite while I figure out something semi-coherent to say.)

Sompolinsky does a nice job of evaluating such claims (in the end, he says we cannot rule out the possibility that the brain is an indeterministic system but it seems unlikely) and provides nice scientific insight. In his view, it is far more likely that the brain’s apparent randomness (eg. individual cell spike rasters vary across repeated presentations of the same stimulus) is more simply explained by thermal noise (think of varying channel gating properties) and chaotic brain dynamics. (Recall, a chaotic system is still deterministic; it simply exhibits aperiodic behavior due to exquisite sensitivity to initial conditions. It is difficult to predict the long-term behavior of chaotic systems. The more we know the initial conditions in detail, the better our prediction.) On the other hand, he argues that the relevant length and time scales for neurons (micrometers and milliseconds) are far larger by many orders of magnitude than those of quantum noise. Chaos might amplify such quantum events, but this is far from being the simplest, most parsimonious explanation. Given the current level of neuroscience understanding, this is almost idle speculation. Regardless of the (in)determinacy of the world, Sompolinsky effectively argues against any non-physical, purely mental (ie. dualistic) agent of causation.

Thus, in sum, the world and our brains might not be determined but, even given that, there’s no reason to believe we have any causative ability to change things in the sense of traditional free will. These observations seem right on the mark to me. I hope they bring some insight for others. Or at least a way to fend off the dinner-table-free-will-conversation barrage of questions.

More halorhodopsin

This week’s Nature has quite a few additional halorhodopsin articles for photochannel fans.

Halorhodopsin article from Deisseroth’s lab:
Multimodal fast optical interrogation of neural circuitry [News & Views]

Also, there is an intriguing article on both the general excitement in the neuroscience community with this new technology and a possible intellectual property dispute over it.

Optical silencing Cl- channel

Ed strikes again!
Two-Color, Bi-Directional Optical Voltage Control of Genetically-Targeted Neurons

Having found a powerful method for activating neurons with blue light in the protein Channelrhodopsin-2 (ChR2) [1], we sought to augment the toolbox by finding a single-component system capable of mediating light-elicited neuronal inhibition. We identified a powerful tool, the mammalian codon-optimized version of the light-driven chloride pump halorhodopsin, from the archaebacterium Natronobacterium pharaonis (here abbreviated Halo) [2].