Inside the Minds of Mice And

TECHNOLOGY FEATURE INSIDE THE MINDS OF MICE AND MEN Monitoring technologies and genetic engineering are producing a growing array of animal models for psychiatric disorders, but researchers are still learning how best to use them. SAGE LABS SAGE There is no such thing as an autistic rat, but researchers can study human psychiatric conditions by analysing the behaviour of rodents. BY MONYA BAKER disorder known as fragile X syndrome arises factors from traumatic life experiences to in when humans lack a working copy of the gene utero conditions also contribute. Even when nyone familiar with Rett syndrome FMR1; mice without the gene show learn- researchers have decided which genes or factors will recognize the symptoms. Mouse ing deficits and hyperactivity similar to the to study, it is not always clear how to assess ani- models — animals that carry genetic symptoms of the human disorder. mal models: how can a researcher use a mouse Amutations similar to those that cause the con- But those are conditions with discrete, recog- to study diseases diagnosed by hallucinations or dition in humans — wring their paws, walk nized causes. Other neurocognitive disorders, an inability to understand figurative language? awkwardly and learn poorly. Other human such as autism, depression and schizophrenia, brain disorders have animal models, too. Mice have multiple and often mysterious causes, so FROM BEHAVIOUR TO BIOLOGY with extra copies of the genome regions dupli- mimicking them is more complicated. Studies Craig Powell, a neuroscientist at the Univer- cated in Down’s syndrome show motor prob- have implicated dozens of genetic variants in sity of Texas Southwestern Medical Center in lems and learning deficits. A developmental producing the disorders, and environmental Dallas, says that the goal of tweaking genes is 7 JULY 2011 | VOL 475 | NATURE | 123 © 2011 Macmillan Publishers Limited. All rights reserved ANIMAL MODELS TECHNOLOGY usually to uncover disease mechanisms. “So you make a mouse with a mutation that you know causes autism in humans, and you see that it has behaviours that resemble autism,” he says. Powell’s next step is to look at slices of the mouse’s brain, to see how it differs from normal mice. At that point, behaviour can help researchers C57BL/6j DBA/2 A/j PHONOMICS B. SPRUIJT/DELTA to home in on what really matters. “We might find a hundred things wrong with the brain function, but only one or two cause changes in behaviour, so we want to fix things and see what changes the behaviour,” says Powell. In work that has become a touchstone for the field, Mark Bear, a neuroscientist at the Massachusetts Institute of Technology (MIT) in Cambridge, and his colleagues showed that reducing expres- Balb/c 129S1/Sv C3H sion of a particular receptor in mice ameliorated Video tracking of different mouse strains (labelled) reveals that some explore a new cage more than others. the effects of a mutation that causes fragile X syndrome1. Several physiological abnormalities autism and developmental disorders. Tests wrong with their skin: open sores appeared were reversed, and engineered mice had fewer on the offspring showed that the sympto- on their faces. After tests showed nothing seizures and better memories. matic behaviours recurred in only some of the abnormal, video surveillance revealed that In another example, Adrian Bird, a geneticist genetic backgrounds. In another study5, mice the mice groomed themselves excessively, at the Wellcome Trust Centre for Cell Biology from a strain displaying a range of autism- literally rubbing through their fur. Further in Edinburgh, UK, and his colleagues reversed relevant symptoms were reared by and with work showed abnormalities in a region of the symptoms resembling Rett syndrome in mice2. mice from a strain known for high sociability. brain linked to obsessive–compulsive disorder They crafted a version of the defective gene The fostered mice showed no social deficits as (OCD). Although SAPAP3 had not previously that could be restored to normal activity with a adults, but other relevant symptoms, such as been implicated in the condition, drugs that supplement to a mouse’s diet, but administered repetitive grooming, were not reduced. And eased OCD symptoms in humans reduced the the supplement only after mice carrying the when a mutant version of DISC1, the first gene grooming in mice. gene began to exhibit symptoms. Activating to be implicated in schizophrenia, is present Studies8 of proteins the gene at this point was expected to have little in mice whose mother’s immune system has that interact with effect, but the mice showed marked improve- been stressed during pregnancy, the offspring SAPAP3 revealed that ment, raising hopes that recovery might also exhibit symptoms of affective disorders and they, too, had links to be possible in humans. A similar study3 into autism6. Without the environmental stressors, OCD and autism. spinal muscular atrophy found that restor- they show symptoms of schizophrenia. As human genetic ing a defective gene’s function four days after studies reveal gene birth essentially eliminated signs of the disease; HIDDEN SYMPTOMS variants with increas- doing so ten days after birth had little effect. Even the cleverest assays cannot capture some ingly smaller impacts Such studies could help researchers to predict important aspects of human disease, such as the on disease, there is which patients are most likely to benefit in paranoid delusions common in schizophrenia. “When in increasing demand clinical trials. (In fact, because the models will always be doubt, the for new behavioural Research into behaviour can also probe imperfect, most behavioural researchers object experimenter tests to assess them. how genetic variants interact with each other to phrases such as ‘schizophrenic mice’.) Mikhail needs to look at Results of assays are and with environmental factors. In one study Pletnikov, a neurobehaviourologist at Johns what the animal highly variable, and published this year4, wild-type males from five Hopkins University in Baltimore, Maryland, is is doing.” they may not measure mouse strains were bred with females carrying one of many scientists hoping to complement Douglas Wahlsten the most meaning- C. TOUMA/MAX PLANCK INST. PSYCH. PLANCK INST. C. TOUMA/MAX a mutation that causes symptoms resembling behavioural tests with more readily measured ful symptoms, says biomarkers. People with schizophrenia exhibit Jeffrey Mogil, a neuroscientist at McGill Uni- a wide range of behavioural symptoms, but their versity in Montreal, Canada. “We’ve made a lot lateral ventricles — fluid-filled cavities on either of advances in making ever-fancier mice, but at side of the brain — tend to be larger than aver- the end of the day the question is, what’s your age, so Pletnikov is using brain scans to measure assay and what’s your measure and are they these structures in mice. It is not always nec- relevant?” he says. “The slow link in the chain, essary to see a behavioural change to probe a the messy link in the chain, has always been the diease’s biology, he says. “With humility, you can behavioural assays.” use mice or rats or even worms.” Current tests of animal behaviour are Unexpected behaviours have revealed unan- blunt tools. The Morris water-navigation ticipated biology. Several years ago, Guoping task evaluates an animal’s cognitive ability by Feng, a neuroscientist now at MIT, was trying assessing how it learns to use spatial cues to to work out the function of various proteins swim to an underwater platform that it can’t found on either side of the synapses that con- see. Changes in the animal’s performance can nect neurons. Knocking out one such protein, be used to measure learning and memory. SAPAP3, had no apparent effect on brain func- Tests for anxiety include the open-field test, tion: the mice walked and learned normally7. which measures the time a mouse spends in Less-anxious mice spend longer in open spaces. They did, however, seem to have something enclosed spaces or along the edges of its cage; 7 JULY 2011 | VOL 475 | NATURE | 125 © 2011 Macmillan Publishers Limited. All rights reserved TECHNOLOGY ANIMAL MODELS nervous animals avoid exposed areas. For both, of children without autism playing together psychiatric drugs effective in humans change and the ones with autism being off to the side, the outcomes. playing with a train or a computer,” she recalls. Such tests can be effective at screening new So Crawley designed a task that would assess drugs that act by the same mechanisms as whether a mouse chose to spend time with existing ones. But they are less useful for con- a social partner or an inanimate object. The ditions for which no effective drugs exist, or for assay is now used in many laboratories. gaining insight into pathology. So researchers Clinical tests have inspired other animal are trying to develop tests that capture more- counterparts. Mogil and his colleagues pro- specific components of human disorders. duced the mouse-grimace scale for pain “We talk more to the clinical researchers,” says assessment9, based on a scale that used facial Jacqueline Crawley, chief of behavioural neuro- expressions to determine pain in infants and science at the US National Institute of Mental other humans incapable of speaking. Mogil NORTH CAROLINA GREENSBORO D. WAHLSTEN/UNIV. Health in Bethesda, believes his scale will prove a more reliable The colours of mice and their bedding can confuse Maryland. “There are measure of chronic pain than commonly used video-tracking systems. opportunities for us assays such as the tail-flick test, which meas- to sit down and say, ures how quickly a mouse moves its tail out of mouse models of autism. ‘what do these dis- a beam of light. It should also help researchers Tim Bussey and Lisa Saksida, neuroscientists eases look like, what to design more-humane experiments.

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