Science 29 February 2008: Vol. 319. no. 5867, pp. 1253 - 1256
Synaptic Protein Degradation Underlies Destabilization of Retrieved Fear Memory
Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memory. We found that postsynaptic proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent protein degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by protein degradation, and updated memory is reconsolidated by protein synthesis.

Science 29 February 2008: Vol. 319. no. 5867, pp. 1256 - 1260
Hybrid Neurons in a MicroRNA Mutant Are Putative Evolutionary Intermediates in Insect CO2 Sensory Systems
Carbon dioxide (CO2) elicits different olfactory behaviors across species. In Drosophila, neurons that detect CO2 are located in the antenna, form connections in a ventral glomerulus in the antennal lobe, and mediate avoidance. By contrast, in the mosquito these neurons are in the maxillary palps (MPs), connect to medial sites, and promote attraction. We found in Drosophila that loss of a microRNA, miR-279, leads to formation of CO2 neurons in the MPs. miR-279 acts through down-regulation of the transcription factor Nerfin-1. The ectopic neurons are hybrid cells. They express CO2 receptors and form connections characteristic of CO2 neurons, while exhibiting wiring and receptor characteristics of MP olfactory receptor neurons (ORNs). We propose that this hybrid ORN reveals a cellular intermediate in the evolution of species-specific behaviors elicited by CO2.

Science 29 February 2008: Vol. 319. no. 5867, pp. 1260 - 1264
Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning
The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex -> dentate gyrus -> CA3 -> CA1 -> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex -> CA1  entorhinal cortex). We developed a generally applicable tetanus toxin–based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion–based memory recall, and for spatial tuning of CA1 cells.

Science 29 February 2008: Vol. 319. no. 5867, pp. 1264 - 1267
BOLD Responses Reflecting Dopaminergic Signals in the Human Ventral Tegmental Area
Current theories hypothesize that dopamine neuronal firing encodes reward prediction errors. Although studies in nonhuman species provide direct support for this theory, functional magnetic resonance imaging (fMRI) studies in humans have focused on brain areas targeted by dopamine neurons [ventral striatum (VStr)] rather than on brainstem dopaminergic nuclei [ventral tegmental area (VTA) and substantia nigra]. We used fMRI tailored to directly image the brainstem. When primary rewards were used in an experiment, the VTA blood oxygen level–dependent (BOLD) response reflected a positive reward prediction error, whereas the VStr encoded positive and negative reward prediction errors. When monetary gains and losses were used, VTA BOLD responses reflected positive reward prediction errors modulated by the probability of winning. We detected no significant VTA BOLD response to nonrewarding events.

Nature 451, 1076-1081 (28 February 2008)
Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective
for specific pathological stages of MS and implicated participation of the coagulation cascade.

Nature 451, 1136 (27 February 2008)
Neuroscience in the developing world
Neuroscience training in Argentina, by any means necessary.
How do you teach neuroscience techniques in countries bereft of funding and infrastructure? In Argentina,
the education programme of the International Brain Research Organization (IBRO) found a creative answer: crabs.
John Hildebrand, one of the founders of the IBRO's international schools, chose Buenos Aires for a class on neuroethology, the neural basis of natural behaviour. Crabs, which provide good nervous-system models, were abundant. "Students work with little crabs they collect in mud flats near the seashore," says Hildebrand, a neuroscience professor at the University of Arizona, Tucson. "They have no animal-rearing costs.
They can work in shirtsleeves and do very beautiful work."

BMJ  2008;336:397-398 (23 February), doi:10.1136/bmj.39461.616991.80 (published 12 February 2008)
Prognostic modelling in traumatic brain injury
Can reliably estimate the probability of outcomes for groups but not for individuals
Hippocrates is said to have remarked in 400 BC that "No head injury is too severe to despair of, nor too trivial to ignore." While this prognostic scheme achieves absolute accuracy, its precision leaves something to be desired. More recently, many groups have attempted to produce more detailed risk adjustment models for predicting outcome in traumatic brain injury. In 2006, a systematic review concluded that most predictive models were inadequately validated, poorly presented, and based on studies from single centres with small samples that excluded patients from low income countries (where traumatic brain injury is most common). In the accompanying paper, the Medical Research Council CRASH Trial Collaborators provide a series of prognostic models that attempt to remedy these shortcomings.

BMJ  2008;336:425-429 (23 February), doi:10.1136/bmj.39461.643438.25 (published 12 February 2008)
Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients
Objective To develop and validate practical prognostic models for death at 14 days and for death or severe disability six months after traumatic brain injury.
Design Multivariable logistic regression to select variables that were independently associated with two patient outcomes. Two models designed: "basic" model (demographic and clinical variables only) and
"CT" model (basic model plus results of computed tomography). The models were subsequently developed for high and low-middle income countries separately.
Setting Medical Research Council (MRC) CRASH Trial.
Subjects 10 008 patients with traumatic brain injury. Models externally validated in a cohort of 8509.
Results The basic model included four predictors: age, Glasgow coma scale, pupil reactivity, and the presence of major extracranial injury. The CT model also included the presence of petechial haemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated haematoma. In the derivation sample the models showed excellent discrimination (C statistic above 0.80). The models showed good calibration graphically. The Hosmer-Lemeshow test also indicated good calibration, except for the CT model in low-middle income countries. External validation for unfavourable outcome at six months in high income countries showed that basic and CT models had good discrimination (C statistic 0.77 for both models) but poorer calibration.
Conclusion Simple prognostic models can be used to obtain valid predictions of relevant outcomes in patients with traumatic brain injury.

BMJ  2008;336:435-439 (23 February), doi:10.1136/bmj.39478.609097.BE
Management of depression in adults
A study by the World Health Organization ranked depression the fourth global burden of disease and found it to be the largest non-fatal burden of disease, with nearly 12% of total years lived with disability. According to the cross sectional WHO world health survey, carried out in all regions of the world (60 countries), the one year prevalence of a depressive episode (international classification of diseases, 10th revision) was 3.2% (95% confidence interval 3.0% to 3.5%). In patients with several medical conditions the prevalence of depression exceeds that of the general population, with 5-10% of patients affected in primary care and 10-14% of patients under general hospital care. The diagnosis and treatment of depression by general practitioners is not, however, always optimal. We review the presentation and assessment of depression and discuss the options for its effective treatment and management.

JAMA. 2008;299(8):937-946, February 27, 2008      
Spinal Cord Compression in Patients With Advanced Metastatic Cancer
"All I Care About Is Walking and Living My Life"
As 1 of the 12 700 US cancer patients who, each year, develops metastatic spinal cord compression, Ms H wishes to walk and live her life. Sadly, this wish may be difficult to fulfill. Before diagnosis, 83% to 95% of patients experience back pain, which often is referred, obscuring the site(s) of the compression(s). Prediction of ambulation depends on a patient's ambulatory status before therapy and time between developing motor defects and starting therapy. Ambulatory patients with no visceral metastases and more than 15 days between developing motor symptoms and receiving therapy have the best rate of survival. To preserve ambulation and optimize survival, magnetic resonance imaging should be performed for cancer patients with new back pain despite normal neurological findings. At diagnosis, counseling, pain management, and corticosteroids are begun. Most patients are offered radiation therapy. Surgery followed by radiation is considered for selected patients with a single high-grade epidural lesion caused by a radioresistant tumor who also have an estimated survival of more than 3 months. Team discussions with the patient and support network help determine therapy options and include patient goals; assessment of risks, benefits, and burdens of each treatment; and discussion of the odds of preserving prognosis of ambulation and of the effect of therapy on the patient's overall prognosis. Rehabilitation improves impaired function and its associated depression. Clinicians can help patients cope with transitions in self-image, independence, family and community roles, and living arrangements and can help patients with limited prognoses identify their end-of-life goals and preferences about resuscitation and entering hospice.

JAMA Vol. 299 No. 8, February 27, 2008      
JAMA Patient Page   Spinal Stenosis
Spinal stenosis is a term used to describe a narrowing of the spinal canal, which contains the spinal cord and emerging nerve roots. It can occur in any portion of the spine. Because of limited space, changes in the bone (vertebral bodies) or soft tissues (spinal ligaments) can result in compression of the affected spinal cord and blood vessels. This narrowing can be congenital (genetic) or acquired (arthritis, trauma, bone disease, tumor) or a combination of both. Stenosis can be classified by location: central (involving the spinal cord) or lateral (affecting the nerve roots). Cord compression can also occur in patients with advanced cancer. The February 27, 2008, issue of JAMA includes an article about treatment options for cord compression due to metastatic cancer.

The Lancet Volume 371, Issue 9613, 23 February 2008-29 February 2008, Pages 649-650
Lamotrigine and the risk of fulminant hepatic failure
We write in response to the letter by Ivan Iniesta (Dec 22, p 2101), written as a rebuttal to our letter in which we cautioned physicians to be aware of the risks of severe hepatic dysfunction when prescribing lamotrigine, after publication of the SANAD study. We were not given the chance to respond to Iniesta's letter, which suggested that we withheld relevant information on one of the cases we reported and detracted from the message we were trying to convey.
Although the symptoms that developed 2 weeks after the patient started lamotrigine were typical of a mononucleosis syndrome, idiosyncratic adverse drug reactions to lamotrigine commonly present with hepatotoxicity, often as part of the DRESS (drug reaction with eosinophil and systemic symptoms) syndrome whereby patients typically develop fever, maculopapular rash, eosinophilia, atypical lymphocytosis, arthralgia, lymphadenopathy, and hepatosplenomegaly.