Tuesday, March 15, 2011

Published online 13 March 2011 | Nature | doi:10.1038/news.2011.155

Rats wake up for behavioural research

Tiny imaging device allows scans of animals while they are awake.

Tiffany O'Callaghan

The RatCAP scanner allows researchers to study neurochemistry and behaviour at the same time.
A miniaturized positron emission tomography (PET) scanner has opened a fresh window for research into behaviour and brain function simultaneously.

The 'wearable' PET, known as the RatCAP, was developed by a team of researchers led by physicist Paul Vaska at Brookhaven National Laboratory in Upton, New York, and allows scans on animals that are awake and moving around. The findings are published online today in Nature Methods1.

PET uses radioactive tracers to show the metabolism of chemicals in the body in real time. It is a key tool for examining organ function, evaluating blood flow, diagnosing cancer early and researching neurological conditions from Alzheimer's disease to epilepsy. But PET use for behavioural research in animals has been limited — whereas humans can lie still during a PET scan, enabling analysis while they are awake, it is a lot trickier to get animals to do as they're told. That largely limits the use of PET to anaesthetized animals, ruling out simultaneous behavioural studies.

The tiny PET developed by the team attaches to the rat's head using a bracket screwed onto the skull, has an inner diameter of 38 mm and weighs just 250 g. For a rat, that is still pretty heavy — nearly the weight of an adult male rat — so to optimize the rat's movement while wearing the RatCAP, the team attached the device to a system of long springs and motion stabilisers fastened to the top of the observation chamber to reduce the weight and allow rat movement.

Using the portable PET, the rat can only move in a complete circle in one direction before having to turn back the other way, says Daniela Schulz, a behavioural neuroscientist at Brookhaven and first author on the study. "That creates some limitation in terms of where the animal can go," she says, but adds that the rats can still move to all parts of the 40 x 40 cm observation chamber.

Jeff Dalley, a behavioural neuroscientist at the University of Cambridge, UK, applauds the development of the RatCAP. Other techniques to simultaneously track brain function and behaviour, such as the more invasive in vivo microdialysis, which involves inserting a probe into brain tissue, are limited to small regions of the brain. By contrast, he says, the RatCAP enables researchers to "look globally across the brain".

Still, Dalley expresses some concern over how much the shape and weight of the device might undermine its use for certain experiments — such as those that involve nose-poking into narrow spaces in search of food rewards. "This is very exciting," he says, but adds that, "In its present format it would be challenging to use in behaviourally demanding experiments."

Up to the minute

For the initial RatCAP tests, the researchers assessed levels of the neurotransmitter dopamine by using a radiotracer to track receptor occupancy among D2 dopamine receptors in the brain. They chose to assess dopamine because of its association with a range of brain functions that can be reflected in behaviour, from motor control to reward processing. The team analysed receptor occupancy in different brain areas — in both the striatum, which has many D2-specific receptors, and as a control, in the cerebellum, which has none. Vaska and colleagues compared dopamine levels in anaesthetized rats using conventional PET with those in awake rats using the RatCAP, and found differences — unexpectedly in both the striatum and cerebellum. What's more, they noted that, counterintuitively, dopamine levels in the awake rats were lower. Traditionally, more behavioural activity would be associated with higher levels of dopamine. The researchers speculate that the possible reason for the unexpected changes in tracer uptake in the cerebellum, and the inverse relationship between dopamine levels and behavioural activity in awake rats may indicate that anaesthesia influences uptake, perhaps by affecting metabolism of the tracer.

"It's a methodological issue," says Vaska, and one that could have implications for future PET research. "If you start to make assumptions that what you're seeing under anaesthesia is what you'll see awake, you may make a mistake in your interpretation."

The researchers also noted a strong correlation between the extent of behavioural activity — such as head turns and body motion — and dopamine levels, an indication that the technique uniquely enables them to assess neurochemistry and behaviour simultaneously. What's more, Vaska and colleagues were particularly encouraged to find that in one experiment, they were able to monitor behavioural changes and associated alterations in dopamine levels on a minute to minute basis — a significant achievement considering that currently, PET studies tend to average changes in biochemistry over the course of a half hour- to hour-long scan.

Luc Zimmer, a neuropharmacologist at the University of Lyon, France, who was not involved in the research, says that they technology should be of interest to "a broad range" of researchers. "The current results presented in this article are convincing. The researchers present a real proof of concept of their RatCAP device," Zimmer says.

As a next step, they aim to use the RatCAP to observe changes in dopamine levels during other types of behaviour, but suggest that the technology will have broader applications for behavioural studies using a range of radiotracers to track different neurotransmitters.

"The advantage of being able to correlate behaviour and neurochemistry is far-reaching," says Schulz. "We do lose a lot of information by looking at them separately. To be able to analyse both processes simultaneously would allow us very different insight."

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