Parkinson's disease is one of the most common neurodegenerative diseases, affecting about 1% of all people over the age of 65. It is characterized by rigidity, bradykinesia (reduced movement) and tremors, which are caused by the progressive degeneration of dopamine-containing neurons in a brain region called the substantia nigra. Another characteristic feature of the disease is that the brains of Parkinson's patients contain microscopic protein deposits, known as Lewy bodies. Although some cases of Parkinson's disease can be attributed to genetic risk factors, the majority of cases are still unexplained; these so-called 'sporadic' cases have been proposed to result from environmental factors. In the December issue of Nature Neuroscience, Tim Greenamyre and colleagues (Emory University) show that rotenone, a commonly used organic pesticide, can induce the major features of Parkinson's disease in rats. These results not only provide a new animal model for testing potential treatments, they also support the idea that chronic exposure to environmental pesticides may contribute to the incidence of Parkinson's disease in humans.
Before this study, the most realistic animal model of Parkinson's disease was the so-called MPTP model, in which mice or monkeys are treated with a drug known as 1,2,3,6-tetrahydropyridine (MPTP). This model originates from the early 1980s, when a number of heroin addicts developed sudden and irreversible symptoms of Parkinsonism after injecting themselves with an illicit drug preparation contaminated by MPTP. The reason for the toxic effect is that MPTP (or more strictly, its derivative MPP+) inhibits one of the enzymes in mitochondria, intracellular organelles that provide the cell with energy.
Rotenone, like many other pesticides, inhibits the same mitochondrial enzyme (called complex I) as MPP+, and so Greenamyre and colleagues hypothesized that chronic treatment with low levels of rotenone might produce Parkinsonian symptoms in rats. They administered rotenone intravenously over a period of several weeks, and observed gradual degeneration of the dopamine neurons, accompanied by behavioral features of Parkinsonism and the formation of structures that closely resemble Lewy bodies. A likely explanation, as yet untested, is that rotenone acts by causing the mitochondria to produce free radicals, reactive chemicals that produce oxidative damage in a variety of contexts and have been implicated in many human degenerative diseases.
Rotenone is a naturally occurring pesticide, and it is widely used both as an insecticide and as a method for killing fish (as part of water management programs). It is considered relatively benign compared to many other pesticides. Although the new study does not prove that rotenone causes Parkinsonism in humans, it is likely to raise new questions about rotenone's safety. More generally, it lends credence to the idea that chronic exposure to environmental toxins, including pesticides, may contribute to the incidence of the disease. The main risk factor for Parkinson's disease is age, and it has also been claimed, more controversially, that the disease is associated with living in rural environments. Determining to what extent pesticide exposure can account for Parkinsonism will require a great deal of further work. The present findings, however, are consistent with the idea that chronic exposure to low levels of environmental toxin may cause cumulative damage to the brain's dopamine system, eventually leading to the clinical symptoms of the disease.
Benoit Giasson and Virginia Lee of the University of Pennsylvania discuss the implications of these findings in an accompanying News & Views article.
Chronic systemic pesticide exposure reproduces features of Parkinson's diseasepp 1301 - 1306 Ranjita Betarbet, Todd B. Sherer, Gillian MacKenzie, Monica Garcia-Osuna, Alexander V. Panov and J. Timothy Greenamyre doi:10.1038/81834 Abstract|Full
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A new link between pesticides and Parkinson's diseasepp 1227 - 1228 Benoit I. Giasson & Virginia M.-Y. Lee doi:10.1038/81737 Full
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Why is sleep necessary? One prevailing theory is that sleep is important for consolidating memories, the process by which experience or training is transformed into improvements in performance. Two studies in this issue further support this hypothesis by demonstrating that sleep is absolutely required for a particular type of memory consolidation. Sleep deprivation has long been used to test the importance of sleep for memory and learning. However, the results have been difficult to interpret because of complicating side effects, such as fatigue and reduced alertness. Stickgold and colleagues circumvent these complications by allowing two nights of recovery sleep before performance is assessed: subjects are trained, allowed to sleep or sleep deprived on the first night, then allowed two nights of normal sleep before being tested on the third day. The discrimination task, which resembles a video game, requires subjects to identify targets within a mask of visual distractions. Subjects who were sleep deprived on the first night after training showed no significant improvement in task performance on the third day, while control subjects who were allowed sleep on the first night showed a substantial improvement. This demonstrates that there is an absolute requirement for sleep within the first 30 hours after training for consolidation of learning.
Born and colleagues use a similar visual discrimination task to address what type of sleep is required for memory consolidation. There are two basic types of sleep, slow wave sleep, which predominates early in the night, and REM or rapid eye movement sleep, which occurs late in the night. The authors found that slow wave sleep alone was sufficient for task learning, but that both types of sleep were required for the maximal increase in performance. This suggests that there is a sequential mechanism for memory consolidation, which requires an initial period of slow wave sleep followed by periods of REM sleep. Does this invalidate the typical college student's all night study session approach? It remains to be seen how implicit (unconscious) memory—addressed in these studies—relates to the explicit (conscious) memory needed for History 101.
The work is discussed by Pierre Maquet in an accompanying News and Views article, and by John Spiro in the Editorial.
What visual cues do athletes use to produce rapid and accurate motor responses to exceedingly brief stimuli? In this issue, Land and McLeod approach this problem by using close-up video to monitor the eye movements of cricket batsmen attempting hit balls from a bowling machine (or pitching machine in baseball terms) to monitor what information they are actually collecting. They find that the frequently heard coach's advice, "Keep your eye on the ball," may not be the best approach, or at least not the most common. Previous theories proposed that a batsman must use direct visual measurements, such as image expansion or the rate of change of the difference between inputs to the two eyes, to predict the ball's trajectory. However, given that the batsman has only a fraction of a second to monitor such visual cues, it has been controversial whether these parameters could be measured accurately enough to guide the correct response. The authors monitored the eye movements of three cricket batsman of widely varying skill, and found that, in general, all three made a similar sequence of eye movements. Their eyes followed the ball's trajectory for a short period after release, then made a rapid movement below the ball to the site where it would be predicted to bounce. They then fixated again on the ball as it bounced and followed its upward trajectory for a short period afterward. The parameters that best distinguished most skilled from least skilled batsmen were the speed and timing of the initial rapid eye movement. The best batsman had the shortest delay between the ball's release and eye movement initiation, and also used different types of eye movements for different ball trajectories. Therefore, the cricket batsman does not continually follow the ball; instead he quickly assesses its predicted trajectory and then directs visual attention to appropriate regions of the visual field. It will be interesting to determine if a baseball batter uses a similar approach, given that there is no 'bounce point' at which to focus.
Vivid imagination can lead people to so-called 'reality-monitoring errors,' in which an imagined event is remembered as if it had actually happened. In this issue, Brian Gonsalves and Ken Paller at Northwestern University report differences in brain activity during the formation and retrieval of true and false memories. In the study phase, the authors recorded event-related potentials (ERPs) from scalp electrodes over the back of the brain while subjects were presented with written words and asked to visualize the named objects. For half the words, an actual picture of the object was presented after the visualization period. In the test phase, subjects heard spoken words and were asked to determine whether or not they had seen a picture of that object. During the study phase, words (presented without pictures) that would later form false memories elicited larger posterior ERP responses than those that were correctly remembered, which is interesting because the authors have previously shown that these ERP responses become larger with more vivid visualization. However, in the test phase, words that had actually been presented with pictures elicited larger ERP responses than words (presented without pictures) that were falsely remembered as being presented with pictures. Because people are known to be more likely to believe a memory is real if it is more detailed, the authors suggest that events that lead to later false memories contain more perceptual detail than events correctly remembered as imagined, but less perceptual detail than real memories, and that posterior ERP responses can be used to measure the amount of perceptual detail associated with individual memories.
