- Email: [email protected]
NSAIDs action in the CNS
News & Comment
TRENDS in Neurosciences Vol.24 No.6 June 2001
315
could provide. Using a DNA methylating agent to kill proliferating cells, researchers from Rutgers and Princeton Universities correlated a decrease in the number of newly generated hippocampal cells with a decrease in the ability of rats to associate two stimuli separated in time, a task that is hippocampal dependent. Memory tasks known to involve other parts of the brain were not effected. Furthermore, after toxin treatment was ended in these animals, cell production resumed and the hippocampas memory impairment was also resolved.
and Princeton Universities have mapped brain circuits involved in feeding and satiety. The virus, which was engineered so that it would encode green fluorescent protein (GFP), was injected into the arcuate nucleus of mice engineered to express Cre in neuropeptide Y or leptin receptor cells. Only virus taken up into these neurons replicates and moves retrogradely through synaptic contacts, so researchers were able to visualize the upstream neural inputs into the neuropeptide Y or leptin receptor cells – a specific subset of hypothalamic neurons involved in feeding. Higher cortical centers, as well as the hypothalamus, amygdala and brainstem were labeled in this study, indicating the anatomic basis of the complex factors controlling decisions about whether or not to eat. The paper is published in the March 30 issue of Science.
In Brief
Hints about Huntington’s disease Scientists from Johns Hopkins University have defined a mechanism linking abnormal huntingtin protein to neuronal cell death. Mutant huntingtin, with an expanded polyglutamine stretch, interacts with CREB binding protein (CBP), recruits it into cellular aggregates, and prevents it from participating as a co-activator in CREBmediated transcription. This nuclear depletion and aggregate enrichment of CBP was observed in Huntington’s disease (HD) culture and transgenic mice models as well as in human postmortem HD brain tissue. Furthermore, the cell death seen with mutant huntingtin expression in cells grown in culture is decreased following overexpression of CBP, supporting the current hypothesis that the toxic gain-offunction seen with mutant huntingtin involves transcriptional disruption of cellsurvival programs. The full paper is published in the March 23 issue of Science.
Frustrating results from fetal transplant trial in Parkinson’s disease In the March 8 New Engl. J. Med., researchers report that although some Parkinson’s patients who received intracranial fetal cell injections experienced significant improvement, several patients were troubled by significant side effects. This study, which is the first that compares the effects of transplantation to that of control sham surgery, is important in that it specifically proves specific graft-induced clinical improvements. The severe dyskinesias developed by five of the twenty transplant patients, however, indicate a need to better tailor and regulate transplantation material. The second placebo-controlled fetal cell transplantation study at the University of South Florida will be completed next year.
Neurogenesis and memory formation As neuroscientists now appreciate that new neurons can be formed in adult mammals, a study published in the March 15 issue of Nature indicates a possible function they
Remember to forget that
Molecular switch for LTP
Prompted by an interest in examples where abuse victims have suppressed certain memories, researchers from the University of Oregon investigated the ability of individuals to control what they remember and what they forget. After subjects had memorized 40 pairs of unrelated words, the researchers directed the subjects to actively put some of the pairs out of their mind. After several times of actively suppressing the second word in the pair, subjects were much less able to recall that word, even when prompted by the first letter of the word or when offered money. This indicates that individuals have some executive control over memory formation and/or retrieval. Whether this mechanism works to suppress emotionally-charged memories, however, is yet to be seen. The full study is published in the March 15 issue of Nature.
Viral mapping of feeding circuits Using a modified pseudorabies virus combined with Cre recombinase technology, researchers from Rockefeller
Using an inducible and reversible genetic mouse model, a collaboration of researchers from the US, UK, France and Switzerland have shown certain memory behaviors to be dependent on phosphorylation and dephosphorylation of cellular proteins. Mice were engineered to express an inhibitor of the phosphatase calcineurin in response to the drug doxycycline. These mice exhibited enhanced PKC-dependent LTP and learning in spatial and nonspatial memory tasks only when doxycycline was administered. Furthermore, these synaptic potentiations and memory enhancements are fully reversed when doxycycline is withheld and expression of the calcineurin inhibitor is suppressed. The full paper is published in the March 9 issue of Cell.
NSAIDs action in the CNS Non-steroidal anti-inflammatory drugs (NSAIDs) are known to relieve pain by acting at the local site of injury, but they have also now been shown to relieve pain by CNS mechanisms. NSAIDs reduce inflammation and pain locally by inhibiting the enzyme cyclooxygenase-2 (COX-2), which inhibits formation of prostaglandin E2 (PGE2). PGE2 increases the sensitivity of peripheral nerves to pain. Scientists at Massachusetts General Hospital in Boston, however, now show that peripheral injury also induces COX-2 expression in the brain and spinal cord, and
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
316
News & Comment
PGE2 increases the excitability of CNS neurons so that even nonpainful stimuli are perceived as painful, explaining why inflamed tissue feels sensitive and tender. Furthermore, inhibiting COX-2 in the CNS also decreases pain and hypersensitivity. The researchers suggest that targeting the widespread CNS production of COX-2 might more-effectively relieve pain as well as improve secondary symptoms such as lethargy, depression and loss of appetite. The study is in the March 22 issue of Nature.
Dyslexia as neurologic deficit In the search for a universal neurologic basis for dyslexia despite differences in prevalence amongst countries, an
TRENDS in Neurosciences Vol.24 No.6 June 2001
international research team found that English, French, and Italian individuals with demonstrated reading and phonological deficits also exhibit decreased left brain activity by PET scan. During reading and naming tasks, they show reduced activation in the left temporal lobe and middle occipital gyrus compared with normal readers. Why, then, is dyslexia so less prevelant in Italy compared with France, the UK or the US? The authors of the March 16 Science article argue that the same phonological deficits are more likely to cause literacy problems in languages with more irregular writing systems. Therefore, individuals with deficits would have more trouble with English, in which 40 sounds are represented by over a thousand different letter combinations and
some of them arbitrarily. By comparison, Italian has less ambiguity and uses only 33 combinations for 25 sounds.
proceeds1. It seems unlikely that this interesting result is the consequence of a mechanism that prevents us from perceiving intra-saccadic motion. Ideally, we would expect such a mechanism to be efficient during the whole course of the saccade, especially for long amplitude saccades, whose durations outlast the reported duration of saccadic suppression. At least, if the postulated mechanism operates in a gradual way, it should be most efficient when retinal velocity is highest, that is, near the saccadic peak velocity rather than near the beginning of the saccade. Third, the most convincing evidence that ‘saccadic suppression’ does not have the function postulated by Ross et al. is that intra-saccadic motion can be easily experienced when visual factors are optimized. We recently showed that saccades made in the direction of rapidly moving gratings produced a vivid intrasaccadic motion percept4. This occurred when the retinal speed of the grating around the peak saccadic velocity was optimal for motion detection. Ross et al.1 note that our study ‘highlights the important point that centrally driven saccadic suppression attenuates visual motion but does not eliminate it’. If we all agree that ‘saccadic suppression’ is so inefficient, then regarding this phenomenon as a functional mechanism seems a highly controversial hypothesis. Finally, if suppressing the contrast of intra-saccadic images was really the mechanism (regardless of its origin) used
by the visual system to blunt our perception during saccades, our environment should be greyed out every time we make a saccade. Altogether, the aforementioned points show that the interpretation of ‘saccadic suppression’ is controversial because this phenomenon does not appear to have a clear function. However, it is still possible in principle, as Ross et al.1 believe, that ‘saccadic suppression’ although inefficient is caused by an extra-retinal signal. In our opinion, the only evidence, which up to now has supported this view, is based on striking results reported by Burr and his colleagues. The essence of their data is that ‘saccadic suppression’ specifically alters the magnocellular system leaving the parvocellular system unimpaired. Here we propose a new interpretation of this magno-specific sensitivity reduction that does not postulate any central signal but is based on visual information processing only. We first assume that the photoreceptors during the saccade are not aligned with the optical axis of the eye because the acceleration of the eyeball creates shearing forces near the vitreous–scleral boundary. This trailing of the photoreceptors, still present at the end of the saccade, has already been suggested by psychophysical data5. From studies of the Stiles–Crawford effect, it is known that rays of light that strike receptors at an angle are less efficient than those entering directly into the receptors. Therefore, the intra-saccadic tilt of the
This months ‘In Brief’ articles were written by Lianna Orlando ([email protected])
If you would like to write short news articles for TINS please see p.360 for more information.
Letters
‘Saccadic suppression’ – no need for an active extraretinal mechanism In their recent review article on intrasaccadic visual perception, Ross et al.1 concluded that motion of the world during saccades is not perceived because motion sensitivity is selectively reduced by an extra-retinal signal – although they concede that visual masking might also play an important role. However, we believe that extant data favour a more parsimonious interpretation, namely that the phenomenon called ‘saccadic suppression’2 has no functional role and is not the result of an extra-retinal signal. Instead, we propose a new interpretation based only on visual information processing. The first general reason to doubt that the decrease in contrast sensitivity observed during saccades2 has a function is its lack of effectiveness. Three aspects of experimental data are worth considering. First, it has long been recognized that the threshold elevations reported in the literature are too small to account for the lack of motion perception when the scene contains high contrasts3. Second, ‘saccadic suppression’ does not seem very useful when considering its temporal course: it is maximal at the beginning of the saccade and becomes less-marked as the saccade
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
TRENDS in Neurosciences Vol.24 No.6 June 2001
315
could provide. Using a DNA methylating agent to kill proliferating cells, researchers from Rutgers and Princeton Universities correlated a decrease in the number of newly generated hippocampal cells with a decrease in the ability of rats to associate two stimuli separated in time, a task that is hippocampal dependent. Memory tasks known to involve other parts of the brain were not effected. Furthermore, after toxin treatment was ended in these animals, cell production resumed and the hippocampas memory impairment was also resolved.
and Princeton Universities have mapped brain circuits involved in feeding and satiety. The virus, which was engineered so that it would encode green fluorescent protein (GFP), was injected into the arcuate nucleus of mice engineered to express Cre in neuropeptide Y or leptin receptor cells. Only virus taken up into these neurons replicates and moves retrogradely through synaptic contacts, so researchers were able to visualize the upstream neural inputs into the neuropeptide Y or leptin receptor cells – a specific subset of hypothalamic neurons involved in feeding. Higher cortical centers, as well as the hypothalamus, amygdala and brainstem were labeled in this study, indicating the anatomic basis of the complex factors controlling decisions about whether or not to eat. The paper is published in the March 30 issue of Science.
In Brief
Hints about Huntington’s disease Scientists from Johns Hopkins University have defined a mechanism linking abnormal huntingtin protein to neuronal cell death. Mutant huntingtin, with an expanded polyglutamine stretch, interacts with CREB binding protein (CBP), recruits it into cellular aggregates, and prevents it from participating as a co-activator in CREBmediated transcription. This nuclear depletion and aggregate enrichment of CBP was observed in Huntington’s disease (HD) culture and transgenic mice models as well as in human postmortem HD brain tissue. Furthermore, the cell death seen with mutant huntingtin expression in cells grown in culture is decreased following overexpression of CBP, supporting the current hypothesis that the toxic gain-offunction seen with mutant huntingtin involves transcriptional disruption of cellsurvival programs. The full paper is published in the March 23 issue of Science.
Frustrating results from fetal transplant trial in Parkinson’s disease In the March 8 New Engl. J. Med., researchers report that although some Parkinson’s patients who received intracranial fetal cell injections experienced significant improvement, several patients were troubled by significant side effects. This study, which is the first that compares the effects of transplantation to that of control sham surgery, is important in that it specifically proves specific graft-induced clinical improvements. The severe dyskinesias developed by five of the twenty transplant patients, however, indicate a need to better tailor and regulate transplantation material. The second placebo-controlled fetal cell transplantation study at the University of South Florida will be completed next year.
Neurogenesis and memory formation As neuroscientists now appreciate that new neurons can be formed in adult mammals, a study published in the March 15 issue of Nature indicates a possible function they
Remember to forget that
Molecular switch for LTP
Prompted by an interest in examples where abuse victims have suppressed certain memories, researchers from the University of Oregon investigated the ability of individuals to control what they remember and what they forget. After subjects had memorized 40 pairs of unrelated words, the researchers directed the subjects to actively put some of the pairs out of their mind. After several times of actively suppressing the second word in the pair, subjects were much less able to recall that word, even when prompted by the first letter of the word or when offered money. This indicates that individuals have some executive control over memory formation and/or retrieval. Whether this mechanism works to suppress emotionally-charged memories, however, is yet to be seen. The full study is published in the March 15 issue of Nature.
Viral mapping of feeding circuits Using a modified pseudorabies virus combined with Cre recombinase technology, researchers from Rockefeller
Using an inducible and reversible genetic mouse model, a collaboration of researchers from the US, UK, France and Switzerland have shown certain memory behaviors to be dependent on phosphorylation and dephosphorylation of cellular proteins. Mice were engineered to express an inhibitor of the phosphatase calcineurin in response to the drug doxycycline. These mice exhibited enhanced PKC-dependent LTP and learning in spatial and nonspatial memory tasks only when doxycycline was administered. Furthermore, these synaptic potentiations and memory enhancements are fully reversed when doxycycline is withheld and expression of the calcineurin inhibitor is suppressed. The full paper is published in the March 9 issue of Cell.
NSAIDs action in the CNS Non-steroidal anti-inflammatory drugs (NSAIDs) are known to relieve pain by acting at the local site of injury, but they have also now been shown to relieve pain by CNS mechanisms. NSAIDs reduce inflammation and pain locally by inhibiting the enzyme cyclooxygenase-2 (COX-2), which inhibits formation of prostaglandin E2 (PGE2). PGE2 increases the sensitivity of peripheral nerves to pain. Scientists at Massachusetts General Hospital in Boston, however, now show that peripheral injury also induces COX-2 expression in the brain and spinal cord, and
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
316
News & Comment
PGE2 increases the excitability of CNS neurons so that even nonpainful stimuli are perceived as painful, explaining why inflamed tissue feels sensitive and tender. Furthermore, inhibiting COX-2 in the CNS also decreases pain and hypersensitivity. The researchers suggest that targeting the widespread CNS production of COX-2 might more-effectively relieve pain as well as improve secondary symptoms such as lethargy, depression and loss of appetite. The study is in the March 22 issue of Nature.
Dyslexia as neurologic deficit In the search for a universal neurologic basis for dyslexia despite differences in prevalence amongst countries, an
TRENDS in Neurosciences Vol.24 No.6 June 2001
international research team found that English, French, and Italian individuals with demonstrated reading and phonological deficits also exhibit decreased left brain activity by PET scan. During reading and naming tasks, they show reduced activation in the left temporal lobe and middle occipital gyrus compared with normal readers. Why, then, is dyslexia so less prevelant in Italy compared with France, the UK or the US? The authors of the March 16 Science article argue that the same phonological deficits are more likely to cause literacy problems in languages with more irregular writing systems. Therefore, individuals with deficits would have more trouble with English, in which 40 sounds are represented by over a thousand different letter combinations and
some of them arbitrarily. By comparison, Italian has less ambiguity and uses only 33 combinations for 25 sounds.
proceeds1. It seems unlikely that this interesting result is the consequence of a mechanism that prevents us from perceiving intra-saccadic motion. Ideally, we would expect such a mechanism to be efficient during the whole course of the saccade, especially for long amplitude saccades, whose durations outlast the reported duration of saccadic suppression. At least, if the postulated mechanism operates in a gradual way, it should be most efficient when retinal velocity is highest, that is, near the saccadic peak velocity rather than near the beginning of the saccade. Third, the most convincing evidence that ‘saccadic suppression’ does not have the function postulated by Ross et al. is that intra-saccadic motion can be easily experienced when visual factors are optimized. We recently showed that saccades made in the direction of rapidly moving gratings produced a vivid intrasaccadic motion percept4. This occurred when the retinal speed of the grating around the peak saccadic velocity was optimal for motion detection. Ross et al.1 note that our study ‘highlights the important point that centrally driven saccadic suppression attenuates visual motion but does not eliminate it’. If we all agree that ‘saccadic suppression’ is so inefficient, then regarding this phenomenon as a functional mechanism seems a highly controversial hypothesis. Finally, if suppressing the contrast of intra-saccadic images was really the mechanism (regardless of its origin) used
by the visual system to blunt our perception during saccades, our environment should be greyed out every time we make a saccade. Altogether, the aforementioned points show that the interpretation of ‘saccadic suppression’ is controversial because this phenomenon does not appear to have a clear function. However, it is still possible in principle, as Ross et al.1 believe, that ‘saccadic suppression’ although inefficient is caused by an extra-retinal signal. In our opinion, the only evidence, which up to now has supported this view, is based on striking results reported by Burr and his colleagues. The essence of their data is that ‘saccadic suppression’ specifically alters the magnocellular system leaving the parvocellular system unimpaired. Here we propose a new interpretation of this magno-specific sensitivity reduction that does not postulate any central signal but is based on visual information processing only. We first assume that the photoreceptors during the saccade are not aligned with the optical axis of the eye because the acceleration of the eyeball creates shearing forces near the vitreous–scleral boundary. This trailing of the photoreceptors, still present at the end of the saccade, has already been suggested by psychophysical data5. From studies of the Stiles–Crawford effect, it is known that rays of light that strike receptors at an angle are less efficient than those entering directly into the receptors. Therefore, the intra-saccadic tilt of the
This months ‘In Brief’ articles were written by Lianna Orlando ([email protected])
If you would like to write short news articles for TINS please see p.360 for more information.
Letters
‘Saccadic suppression’ – no need for an active extraretinal mechanism In their recent review article on intrasaccadic visual perception, Ross et al.1 concluded that motion of the world during saccades is not perceived because motion sensitivity is selectively reduced by an extra-retinal signal – although they concede that visual masking might also play an important role. However, we believe that extant data favour a more parsimonious interpretation, namely that the phenomenon called ‘saccadic suppression’2 has no functional role and is not the result of an extra-retinal signal. Instead, we propose a new interpretation based only on visual information processing. The first general reason to doubt that the decrease in contrast sensitivity observed during saccades2 has a function is its lack of effectiveness. Three aspects of experimental data are worth considering. First, it has long been recognized that the threshold elevations reported in the literature are too small to account for the lack of motion perception when the scene contains high contrasts3. Second, ‘saccadic suppression’ does not seem very useful when considering its temporal course: it is maximal at the beginning of the saccade and becomes less-marked as the saccade
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.