Neurons do not have on/off switches

A post actually about science!

Physiologists have spent decades doing squishy work about electrochemical happenings in our brains. And squishy it is… a fatty mass of weird cells perfused with an incredibly complex, dynamic, and heterogeneous bath of proteins, peptides, ions, compounds, you name it. We’ve learned a lot about neuronal diversity, but probably a small fraction of what there is to find. All neurons release multiple kinds chemical signals, and all neurons detect and respond to a wide array of chemical signals in a variety of ways. Many, but far from all, of these input/output events are mediated in part by membrane voltage. Many, but far from all, occur at synapses.

From the point of view of about 80% of the literature, however, voltage-mediated synaptic release of neurotransmitters may as well be all that’s happening in your brain. Everyone knows this is a simplification (except for the physicists who have become computational neuroscientists: they literally cannot hear this. It should be studied). But it gets reinforced by a number of factors: 1) The tools at hand. When all you have is a patch electrode, all signaling looks voltage-dependent. We have really amazing, precise tools for electrically measuring (and controlling) neurons. For other kinds of signaling, almost nothing.  2) Connectomics and modeling: these people do NOT want to hear about non-synaptic signaling. 3) Modeling in general requires that we make the assumption that most of the organization and most of what happens in the brain doesn’t matter, and so we model approximations of the 5% that we think might.

There are some problems with this. For example, all neuromodulatory signaling. There are on the order of 10x more neuromodulators than there are neurotransmitters. We know the properties of a given, hardwired circuit can be radically different depending on the exact constituents of the soup it’s in. We think of this signaling as “on top of” or in addition to (or, indeed, merely modulatory with respect to) “real” neuronal signaling. However, given that modulators are the critical mediators of every important thing animals do—eat, sleep, mate, run away, fight, etc—and probably are evolutionarily older than “classical” transmitter systems, we could rethink who is modulating who.

So we have a revolutionary tool like optogenetics and it seems like now we can really bring causality into neural circuit studies instead of just correlation. Yes, it is amazing. Yes, I use it and am suitably awed with my flashy god-like powers when it works. But the point here is to push back a little. We really don’t know as much as we think about the neuron(s) we’re studying. Maybe we have an ephys profile, some pharmacology. How does firing it up with ChR2 compare to its repertoire of in vivo states? How does ChR2 (or electrodes) affect all the other types of signaling that might contribute to its function? Its responses to modulators? Its tonic properties?

We know little about neuronal diversity and the range of states and signaling properties of most classes of neurons. Our tools are unbelievably crude here… a neuron “type” based on rough morphology, location, or a handy Cre line. It is a fallacy to think that because (most) neurons fire yes/no action potentials that neurons themselves are yes/no nodes in a network.  No one thinks so if you present it like that, but this assumption is often hidden in experimental design and models.

I have no problem with charging ahead with an exciting new technology, but we don’t even really know what the caveats are yet, and optogenetics is not always the best tool or even a relevant tool. I swear, I’ve had 3 papers now where a reviewer suggests something like “You should see what happens if you optogenetically stimulate X.” Or treat it as some kind of gold standard for causality. This kind of stimulation is as likely as not a radical intervention and disruption in the normal properties of the network under study, and you are never looking at more than a tiny fraction of that network’s activity.

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