Friday, October 3, 2014

New research from our lab shows that individual neurons can produce timed responses

Previously, when I have blogged I have mostly written about other people's research. Yet sometimes our research group in Lund also publishes first class, revolutionary research. This monday (sep 29th 2014), Fredrik Johansson and colleagues (of which I am one), published a study that I believe will have a huge impact, not only within our own field of research (we study the cellular mechanisms underlying classical conditioning), but for neuroscience at large.

To understand the findings a little background is necessary. Since the 80s we have known that the cerebellum is required for the acquisition of conditioned eye-blink responses. If a subject repeatedly hears a tone and then, right after the tone, is hit with an air-puff on the eye, then eventually that subject will learn to blink in response to the tone. However, if one removes the cerebellum, subjects can no longer acquire these conditioned blink responses. Removing the cortex as well as the mid brain, on the other hand, has little effect on this type of learning.

An important feature of the conditioned blink response is that it is adaptively timed. This means that even if a very long tone precedes the air-puff, the subject will still blink just before the air-puff arrives. This may not seem particularly interesting however, no one know how the brain can produce such delayed responses. Neurons communicate with each other using action potentials which propagate at certain speeds, however, they never slow down anywhere near as much as would be necessary to achieve the type of delay seen during eyeblink conditioning (>100 milliseconds). This means that somewhere within the brain there must be a delay or a memory trace that essentially keeps track of time, thus allowing the subject to execute a certain action at the appropriate time. Such delays are not only seen following eyeblink conditioning, but in pretty much any type of behavior. If you move your lips 10-20 milliseconds too early or too late then your speech will no longer be comprehensible, and when Cristiano Ronaldo runs up to score a free kick, even minor timing errors will cause the ball to hit the stands instead of the net...

Recent research have shown that during eye-blink conditioning, Purkinje cells in the cerebellum acquire conditioned pause responses which are directly linked to the conditioned blink responses. These pauses are, just like the eye-blinks, delayed with respect to the tone, meaning that if we can understand how the delayed pause responses are generated then we may also be able to understand how delays in general appear. The long standing assumption has been that there are so called "delay lines" somewhere along the signal pathway that transmit information about the tone to the Purkinje cells. The tone activates sensory cells in the cochlea which activates cells in the brainstem which in turn passes the signal on to the cerebellum. If one cell type along this pathway maintain a change in its firing rate following this input, then this could explain how the delayed responses arise. However, Fredrik have now shown that this cannot be the case...

Fredrik, instead of using a tone (or equivalent), for conditioning, used stimulation of parallel fibers. These tiny fibers project directly to the Purkinje cell dendrites meaning that there is no possibility of any delay lines. We wanted to see whether the Purkinje cells would still have a delayed response when using parallel fiber stimulation. The results convincingly showed that this was the case. That is, even when stimulating the fibers right next to the Purkinje cells, we still got delayed responses. The implications of this finding are huge. The results show that individual neurons can produce delayed responses to a certain input. In neuroscience this is represents a paradigm shift because previously it has been assumed that we can understand the brain if map all connections between cells as well as the strength of those connections. This study shows that there is much more to the story than this. Unknown processes within the cells evidently play a key role in determining the firing pattern... Johansson F, Jirenhed DA, Rasmussen A, Zucca R, & Hesslow G (2014). Memory trace and timing mechanism localized to cerebellar Purkinje cells. Proceedings of the National Academy of Sciences of the United States of America PMID: 25267641

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