How does the brain pick which neurons to use?

ResearchBlogging.orgWiring. That’s one answer to this question. We know this from topographic maps in the thalamus and neocortex, where the basic units of sensory information are neatly represented in spatially-arranged populations of neurons – the various body parts are represented in specific locations, as are the different frequencies of sound, the different parts of the retina, and different odors and tastes. This basic sensory information has to be represented (i.e. we all need a faithful representation of visual elements, we all need to hear the various frequencies of sound that make up human speech etc.) so why not hard-wire it and make its representation the same for all of us?

It’s often thought that things change as you move into parts of the brain that represent more complex and abstract concepts. For example, in the hippocampus, many neurons receive the same inputs so it’s generally assumed that different neurons are equally capable of representing a given piece of information. While wiring between neurons must play a role in determining which neurons are activated, the diffuseness of the wiring means that related information need not be stored in spatially neighboring neurons as in the sensory regions of neocortex. Indeed, if you look at hippocampal neurons activated by a given experience they don’t appear to have any particular spatial arrangement but are randomly distributed, anatomically. Alternatively, it could be that certain hippocampal neurons are hard-wired to respond to specific stimuli, it’s just that we don’t understand the wiring.

I’ve mentioned before (here and here) how anatomical patterns of activity in the hippocampus are not always so random – in the dentate gyrus the same neurons are often repeatedly activated and by very different experiences. Furthermore, half of the dentate gyrus (the infrapyramidal blade) never seems to be noticeably active, period. But anatomical biases have been reported outside of the dentate gyrus too. Hampson and Deadwyler showed that spatial and nonspatial information is segregated in distinct septotemporal regions of CA1/CA3. Also, Nakamura et al. have suggested that CA1 neurons that represent a given spatial environment are more likely to be spatially clustered together.

While these studies suggest there may be a hard-wired anatomical pattern by which information is represented in regions such as the hippocampus, we really have have no idea how that pattern might be established. I was therefore intrigued to see a couple papers shed new light on this issue. One is a recent paper by Yassin et al. who used a Fos-GFP mouse to identify and record from neurons recently activated by behavioral experience. Fos is an immediate-early gene that is upregulated in neurons that are involved in learning and so, in this mouse, those neurons fluoresced green and could be examined electrophysiologically. They found that the Fos-GFP neurons fired at higher rates than neighboring neurons that were not expressing GFP and that they tended to be more connected to one another (and thus they were dubbed Facebook neurons), suggesting that there may be a subset of neurons that is preselected to be involved in representing experiences (perhaps not unlike the population of highly-active dentate gyrus neurons). There is a bit of a chicken and egg problem here, because we don’t know if the GFP+ neurons always fire at higher rates (and are hard-wired to be more involved in representing experience) or if they only fire at higher rates because they were recently activated (i.e. behavior-induced plasticity changed them). Intriguing nonetheless and a good approach for future studies I think.

The other study is pretty revolutionary I think and also has to do with predetermined, hard-wired patterns of neuronal activity. One of the exciting developments of the last 15 years has been the finding that patterns of neuronal activity are replayed during sleep. It is thought that this “replay” is the physiological correlate of memory consolidation, i.e. the rehearsal of recent experience and integration of that new information into the brain’s circuitry. Now, Dragoi and Tonegawa have found that the patterns of neuronal activity, seen as a mouse explores a novel environment, can also be seen during rest/sleep episodes before the mouse has ever been in that environment. Essentially, they discovered that the brain has created a representation (or at least a fraction) of an experience that has not even happened yet. They call the phenomenon “preplay”.

The preplay phenomenon does fit with previous data. The Mosers, in their News and Views piece on this study, note that “…place cells continue to fire in regular sequences when an animal’s position is fixed, for example, when a rat is running in a wheel. Moreover, rat pups exploring an open space for the first time show adult-like place cell sequences, which indicates that path sequences are hard-wired in the synaptic connection matrix by either genetic programs or early experience.” Also relevant is the finding from John Guzowski’s lab showing that very brief experiences (perhaps too brief to be even remembered) are capable of inducing transcription of the plasticity-related gene, Arc, in a full complement of CA3 neurons. In contrast, CA1 neurons were only fully activated after multiple experiences over multiple days, suggesting less of a role for hard-wiring and more of a role for plasticity and learning in shaping neural representations in this region.

Why preplay? One interesting hypothesis is that the hippocampus is needed to imagine the future (a reasonable role for a structure responsible for remembering the past). Could preplay be an attempt to predict future experience? Or might a shared pattern of activity simply be a way to bind together two events and create a coherent history? Don’t worry – I’m sure that, as we speak, there are rodents with implanted electrode arrays running around, working hard, to give us the answer.

Yassin L, Benedetti BL, Jouhanneau JS, Wen JA, Poulet JF, & Barth AL (2010). An embedded subnetwork of highly active neurons in the neocortex. Neuron, 68 (6), 1043-50 PMID: 21172607
Dragoi G, & Tonegawa S (2011). Preplay of future place cell sequences by hippocampal cellular assemblies. Nature, 469 (7330), 397-401 PMID: 21179088


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  2. Beautiful. Agree it’s unlikely that the distribution of neurons in the CA1 and CA3 is truly random. Question, then, is what devo mechanisms lead to the spatial determinism. Same as ones in sensory topographic maps? Presumably not, if the CA1 / CA3 distribution is not as easily recognized to be topographic. Maybe if we look at how the cells that go to each of those areas act (e.g., express their genes, remodel their chromatin) in early devo, we could see what the differences are. Probably some group has already done this…

    • Maybe it is the same mechanisms as in the sensory cortices – it’s just harder for us to recognize/detect the pattern here because we’re only now developing good tools to parse the anatomy and we don’t understand as well the types of information represented in hippocampal neurons compared to primary sensory neurons. I like your idea of looking at the various properties of individual neurons and the neurons they connect to, to both identify subnetworks but also perhaps just visualize them – I don’t think it’s been done (quick – do it!). Also, in the meantime, this has come out, which appears relevant…

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