Neural mechanisms underlying timed movement and perception of time

The general purpose of the project is to understand the mechanisms underlying timing of behaviour, in particular the contribution of the cerebellum to timing. We have been using the eyeblink conditioning paradigm in which a neutral stimulus is followed by a blink–eliciting stimulus. After a number of paired trials the neutral stimulus will elicit a conditioned blink response just before the onset of the blink–eliciting stimulus. This response is very precisely timed and if the expected onset of the blink–eliciting stimulus changes, the timing of the response adapts to the new situation.

We have previously identified Purkinje cells in the cerebellar cortex which control the blink and which change their responsiveness during training. We know which pathways transmit the two stimuli to the cerebellum and we have shown that direct stimulation of these pathways gives rise to a response in the Purkinje cell that seems to have the same temporal properties as the overt blink response. For instance, it changes its timing if the delay between the stimuli is changed and it can be speeded up by manipulations that influence the overt blink. This experimental paradigm is well suited to study the factors controlling the timing of cerebellar output.

Most theories of timing assume that timing is achieved by delays in the input to the Purkinje cells. Different inputs may have different delays and only those that temporally coincide with the reinforcement signal (blink–eliciting stimulus) will lead to synapse strengthening. We have previously shown that delays in the mossy fibre system cannot explain timing but it is possible that the cortical circuitry, involving granule cells and Golgi cells could provide the necessary delays.

If you get a puff of air to your eye, you will blink reflexively to protect the eye. If the air is repeatedly preceded by a neutral stimulus that does not elicit a blink, such as tone or a light, the neutral stimulus will eventually acquire the ability to elicit a blink in advance of the puff.

This learned blink, a “conditioned blink reflex” is adaptively timed. That means that it always occurs just before the air puff and the latter is delayed, then after additional training, the conditioned response will also be delayed.

This adaptation of experiments pioneered by the Russian physiologist Ivan Pavlov, can be used to study mechanisms of association in the brain as well as mechanisms of timing.

We know that the learning occurs in the cerebellum at the back of the brain. Neurones called Purkinje cells, which control blinking, receive information via mossy and paralell from all sensory systems. They also receive a special kind of signal via climbing fibres when the cornea of eye is irritated. When a sensory signal is followed by signal from the eye, connections in the cerebellum are changed so that the sensory signal in the future will be able to elicit a blink.

In our research, we study the properties of the Purkinje cells and other kinds of nerve cells in the cerebellum during training.