What the Rat Brain Tells Us About Yours

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The evolution of animal models for neuroactive medicine.

Alittle more than a decade ago, Mike Mendl developed a new test for gauging a laboratory rat’s level of happiness. Mendl, an animal welfare researcher in the veterinary school at the University of Bristol in England, was looking for an objective way to tell whether animals in captivity were suffering. Specifically, he wanted to be able to measure whether, and how much, disruptions in lab rats’ routines—being placed in an unfamiliar cage, say, or experiencing a change in the light/dark cycle of the room in which they were housed—were bumming them out.

He and his colleagues explicitly drew on an extensive literature in psychology that describes how people with mood disorders such as depression process information and make decisions: They tend to focus on and recall more negative events and to judge ambiguous things in a more negative way. You might say that they tend to see the proverbial glass as half-empty rather than half-full. “We thought that it’s easier to measure cognitive things than emotional ones, so we devised a test that would give us some indication of how animals responded under ambiguity,” Mendl says. “Then, we could use that as a proxy measure of the emotional state they were in.”

First, they trained rats to associate one tone with something positive (food, of course) and a different tone with something negative (hearing an unpleasant noise). They also trained them to press a lever upon hearing the good tone. Then, for the test, they’d play an intermediate tone and watch how the animals responded. Rats have great hearing, and the ones whose cage life wasn’t disturbed were pretty good judges of where the new tone fell between the other two sounds. If it was closer to the positive tone they’d hit the lever, and if it was closer to the negative one they’d lay off. But the ones whose routine had been tweaked over the past two weeks judged this auditory information more negatively. Essentially, their negative responses bled into the positive half of the sound continuum.

Since Mendl published his so-called judgment bias task in 2004, it’s been shown to work in at least 15 other species, including dogs, sheep, bees, and even us humans. Some scientists—himself included—have begun to ask whether there’s a role for it beyond animal welfare. Considering that it probes one of the core clinical measures of depression, could it be used to evaluate the efficacy of much-needed new medicines for that condition?

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RAT FUNK: For years the pharmaceutical industry depended on the “forced swim test” to validate antidepressants. It showed rats given the drug would paddle longer in water before giving up than rats not doped.Frank Greenaway / Getty Images

Drug discovery in neuroscience has hit a wall, with just 1 in 10 drugs tested in the final stage of clinical trials reaching the finish line of approval. With very few exceptions, no new types of drugs for mind disorders have been approved for decades. You might think drugs fail because they’re found to be toxic, but most die in clinical trials because they aren’t shown to work. Trace that back to the root of the problem, and one big stumbling stone along the drug development pathway is the point where animal tests—and most are done in rodents—wrongly predicted they would.

“We have lots of experience with this—15 to 20 years of failure,” says Ricardo Dolmetsch, the global head of neuroscience at the Novartis Institutes for Biomedical Research. “I can name 14 or 15 examples [of tested drugs] that were just fantastic in animals and did not do anything at all in humans.”

Even as these failures have accrued, neuroscientists armed with increasingly potent tools for pinpointing the genes that play a role in psychiatric disorders and the brain circuits those genes control are getting closer to understanding the pathologies of these illnesses. As drug companies—which had largely abandoned or strongly curtailed their efforts in neuroscience and mental health over the past several years—begin to dip their toes back into the water, it seems a fitting time to ask whether modeling aspects of the human mind in rodents is even possible.

One word explains why testing neuropsychiatric drugs in animal models is hard, and that word is language. If we want people to tell us how they feel, we ask them. Animals, of course, have to show us—and it turns out some of our widely used methods for guiding them to do so haven’t been that great. That’s particularly true for depression. How do we know a rat is depressed?

An experiment called the “forced swim test” or “Porsolt test,” after its founder Roger Porsolt, has been widely used since the late 1970s, at least by pharmaceutical companies and drug regulators.

It’s a remarkable story. Before the mid 20th century, treatments for mental or psychiatric disorders consisted primarily of psychotherapy or interventions like sleep cures, insulin shock therapy, surgeries such as lobotomy, or electrical brain stimulation—most prominently, electroconvulsive therapy. Quite suddenly, spurred by the accidental discovery of an antipsychotic drug called chlorpromazine in 1952, these conditions were re-imagined as chemical imbalances that could be corrected with a well-designed pill…

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http://nautil.us/issue/47/consciousness/what-the-rat-brain-tells-us-about-yours

WIKK WEB GURU
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