University of Illinois at Chicago

A neuroscientist argues for a broader approach to brain mapping.

Efforts to map all of the connections between the brain’s neurons — known as synapses — are gathering momentum. Neural ‘wiring diagrams’ have even garnered a label: the ‘connectome’. But I worry that the connectome
will be a waste of time and money, and that we’ll eventually need to redo the whole thing.

Why am I so negative? Although the connectome is ambitious, it’s not ambitious enough. As currently envisioned, it ignores most brain cells as well as possible functional connections between those cells.

Although you wouldn’t know it from all the attention they receive, neurons are a relatively minor type of brain cell, making up less than 10% of the human brain. And synapses between neurons comprise only a small subset of all possible functional connections in the brain. Most brain cells are actually glia, which have long been neglected by neuroscientists owing to their lack of electrical signalling. But glia are increasingly being recognized as having important roles in brain function.

For example, consider the recent study of adenosine and sleep led by Philip Haydon and Marcos Frank at the University of Pennsylvania in Philadelphia (M. M. Halassa et al. Neuron 61, 213–219; 2009). Adenosine binds to receptors on neurons, thereby regulating neuronal signalling. Interestingly, adenosine seems to represent
‘sleepiness’: it accumulates during wakefulness, and dissipates during sleep. Where does it come from? It is generated from adenosine triphosphate (ATP), which is secreted by astrocytes — a major type of glia.

Therefore, if we want to map the functional brain connections controlling sleep, we need to include glia and the extracellular space between glia and neurons. If we’re going to understand brain function by mapping the brain, we need to include most of the brain in our map.

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University of Maryland, College Park

A neuroscientist marvels at our ability to learn unnatural tasks.

I find driving mind-boggling. As a neuroscientist studying motor control, I am amazed that nervous systems can adapt to the unnatural demands of operating a car. After all, humans did not evolve in habitats with steering wheels or accelerator pedals. What makes our ability to drive so curious is that it requires the modification of reflexes — twisting the steering wheel, for instance, rather than jumping aside, when an obstacle approaches.

Mark Wagner and Maurice Smith have shed some light on this curiosity. They show that the brain generalizes unnatural physical regimes, such as driving, to produce an appropriate corrective response to an unexpected change, even when that change has not been met before (M. J. Wagner and M. A. Smith J. Neurosci. 28, 10663–10673; 2008).

The duo trained undergraduates to reach quickly for a target with one hand while holding on to a motorized arm with the other. The faster the students reached, the stronger the motorized arm pushed them off course.

Initially, the students made large errors, but they soon compensated for the lateral forces. Were their brains learning the dynamics of the new force, though, or were they reassigning the activation of muscles in the spinal cord from those for reaching towards those that normally help to generate sideways pushes?

Surprising the students with a sudden pulse of force in the reaching direction provided an answer. They compensated with almost ideal corrective forces, which spinal reflexes alone could not have achieved. The slight delay in the students' responses also indicates that their brains were working from an internal model of the new force regime. How the brain develops such a model is unknown, but this paper should drive that research.

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University College London

Two neuroscientists are surprised by the link between a brain-chemical transporter and sexual orientation.

Many nerve cells in the brain release the chemical neurotransmitter glutamate to signal to other neurons via receptors. Dedicated transporters then remove glutamate from the extracellular space to end signalling.

Cystine–glutamate exchangers are unusual glutamate transporters because they do the reverse, adding glutamate to the extracellular space while removing cystine. David Featherstone of the University of Illinois, Chicago, and his colleagues have found that in the fruitfly Drosophila melanogaster, knocking down expression of a cystine–glutamate exchanger in non-neuronal glial cells leads to a dramatic change in the sexual behaviour of male flies: they mate with both males and females owing to altered processing of sex-specific chemosensory cues (Y. Grosjean et al. Nature Neurosci. 11, 54–61; 2008).

This behaviour may be caused by an increase in the number of glutamate signalling receptors, which is induced by the fall in extracellular glutamate concentration that follows transporter knockdown. Indeed, the effect of the knockdown could be reversed by feeding the flies a drug that reduces glutamate signalling, and could be mimicked by feeding normal flies a drug that enhances glutamate signalling.

These studies raise questions about whether human sexual orientation, long assumed to be due to a mix of genes and environment, could also be altered by perturbations of neurotransmitter signalling. Could differences in such signalling contribute to different sexual preferences?

The possibility of altering sexual preference pharmacologically is worrying. We cannot rule out a future regression to the twentieth-century idea that sexual behaviour should be regulated by society.

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Max Planck Institute of Neurobiology, Martinsried, Germany

A neuroscientist asks whether neurons are enough when it comes to learning.

One of my main scientific interests is understanding how the brain adapts to and learns from experience. By 'brain' I normally mean networks of neurons, because the electrical impulses they produce are the common currency of sensation and perception; learning involves changes in the synaptic connections between these cells driven by sensory experience. But it's beginning to seem that the brain's plasticity depends on more than neurons alone.

A few months ago, I found myself debating with a colleague what role glial cells might play. I was sceptical. Some years ago, the various sorts of non-neuronal cells that go by the name of glia were thought of simply as a glue (which is what glia means in greek) that holds the brain together. More recently, though, these cells have been shown to form extensive networks important for regulating the local brain environment and to communicate with neurons.

Despite knowing all of this, I had not considered glia as serious players in neuronal plasticity. My thinking changed after reading two recent studies showing that glia not only change their activity after sensory stimulation (X. Wang et al. Nature Neurosci. 9, 816–823; 2006) but also influence the strength of synaptic connections on neurons via a secreted soluble protein (D. Stellwagen and R. Malenka, Nature 440, 1054–1059; 2006). Because the amount of secreted factor depended on the level of surrounding neuronal activity, these results may provide a glial link between sensory experience and synaptic plasticity. The challenge is now to show this directly in the intact brain. I am willing to give it a try — the glia may have changed my mind!

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