Science 28 March 2008: Vol. 319. no. 5871, pp. 1838 - 1842
Insect Odorant Receptors Are Molecular Targets of the Insect Repellent DEET
DEET (N,N-diethyl-meta-toluamide) is the world's most widely used topical insect repellent, with broad effectiveness against most insects. Its mechanism of action and molecular target remain unknown. Here, we show that DEET blocks electrophysiological responses of olfactory sensory neurons to attractive odors in Anopheles gambiae and Drosophila melanogaster. DEET inhibits behavioral attraction to food odors in Drosophila, and this inhibition requires the highly conserved olfactory co-receptor OR83b. DEET inhibits odor-evoked currents mediated by the insect odorant receptor complex, comprising a ligand-binding subunit and OR83b. We conclude that DEET masks host odor by inhibiting subsets of heteromeric insect odorant receptors that require the OR83b co-receptor. The identification of candidate molecular targets for the action of DEET may aid in the design of safer and more effective insect repellents.
Science 28 March 2008: Vol. 319. no. 5871, pp. 1842 - 1845
Aversive Learning Enhances Perceptual and Cortical Discrimination of Indiscriminable Odor Cues
Learning to associate sensory cues with threats is critical for minimizing aversive experience. The ecological benefit of associative learning relies on accurate perception of predictive cues, but how aversive learning enhances perceptual acuity of sensory signals, particularly in humans, is unclear. We combined multivariate functional magnetic resonance imaging with olfactory psychophysics to show that initially indistinguishable odor enantiomers (mirror-image molecules) become discriminable after aversive conditioning, paralleling the spatial divergence of ensemble activity patterns in primary olfactory (piriform) cortex. Our findings indicate that aversive learning induces piriform plasticity with corresponding gains in odor enantiomer discrimination, underscoring the capacity of fear conditioning to update perceptual representation of predictive cues, over and above its well-recognized role in the acquisition of conditioned responses. That completely indiscriminable sensations can be transformed into discriminable percepts further accentuates the potency of associative learning to enhance sensory cue perception and support adaptive behavior.
Science 28 March 2008: Vol. 319. no. 5871, pp. 1845 - 1849
Electric Fields Due to Synaptic Currents Sharpen Excitatory Transmission
The synaptic response waveform, which determines signal integration properties in the brain, depends on the spatiotemporal profile of neurotransmitter in the synaptic cleft. Here, we show that electrophoretic interactions between AMPA receptor–mediated excitatory currents and negatively charged glutamate molecules accelerate the clearance of glutamate from the synaptic cleft, speeding up synaptic responses. This phenomenon is reversed upon depolarization and diminished when intracleft electric fields are weakened through a decrease in the AMPA receptor density. In contrast, the kinetics of receptor-mediated currents evoked by direct application of glutamate are voltage-independent, as are synaptic currents mediated by the electrically neutral neurotransmitter GABA. Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits.
Science 28 March 2008: Vol. 319. no. 5871, pp. 1849 - 1851
Rule Learning by Rats
Using rules extracted from experience to solve problems in novel situations involves cognitions such as analogical reasoning and language learning and is considered a keystone of humans' unique abilities. Nonprimates, it has been argued, lack such rule transfer. We report that Rattus norvegicus can learn simple rules and apply them to new situations. Rats learned that sequences of stimuli consistent with a rule (such as XYX) were different from other sequences (such as XXY or YXX). When novel stimuli were used to construct sequences that did or did not obey the previously learned rule, rats transferred their learning. Therefore, rats, like humans, can transfer structural knowledge from sequential experiences.
Nature 452, 416-417 (27 March 2008) | doi:10.1038/452416a; Published online 26 March 2008
Circadian rhythms: Stem cells traffic in time
Circadian activity in the brain regulates the movement of blood stem cells into and out of the bone marrow. Perhaps this process is testing the suitability of these cell 'tenants' for their new home — the remodelling bone.
All tissue-specific stem cells move around during embryonic development. But mammalian haematopoietic stem cells (HSCs), which are precursors to all blood cell types, continue to migrate via the bloodstream throughout adulthood.
Nature 452, 420-421 (27 March 2008) | doi:10.1038/452420a; Published online 26 March 2008
Neuroscience: Strength in numbers
To store information, the brain modulates synapses, which mediate communication between neurons. A closer look hints that subcellular changes in response to groups of synapses facilitate this process.
Ever since the Spanish neuroscientist Ramón y Cajal put forward his 'neuron theory'1, synapses have been the focus of research aiming to explain learning in terms of brain plasticity, or the functional reorganization of neural pathways in response to new experiences. But synapses, which mostly spread out along highly branched neuronal processes called dendrites, are relatively tiny and have been difficult to stimulate with any precision.
Nature 452, 436-441 (27 March 2008) | doi:10.1038/nature06725; Received 23 October 2007; Accepted 24 January 2008
Compartmentalized dendritic plasticity and input feature storage in neurons
Although information storage in the central nervous system is thought to be primarily mediated by various forms of synaptic plasticity, other mechanisms, such as modifications in membrane excitability, are available. Local dendritic spikes are nonlinear voltage events that are initiated within dendritic branches by spatially clustered and temporally synchronous synaptic input. That local spikes selectively respond only to appropriately correlated input allows them to function as input feature detectors and potentially as powerful information storage mechanisms. However, it is currently unknown whether any effective form of local dendritic spike plasticity exists. Here we show that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-d-aspartate receptor (NMDAR)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggest that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatio-temporal correlation. We propose that this 'branch strength potentiation' represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.
Nature 452, 473-477 (27 March 2008) | doi:10.1038/nature06808; Received 20 December 2007; Accepted 8 February 2008; Published online 27 February 2008
The Drosophila pheromone cVA activates a sexually dimorphic neural circuit
Courtship is an innate sexually dimorphic behaviour that can be observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate this behaviour are developmentally programmed. In Drosophila, courtship involves a complex yet stereotyped array of dimorphic behaviours that are regulated by FruM, a male-specific isoform of the fruitless gene. FruM is expressed in about 2,000 neurons in the fly brain, including three subpopulations of olfactory sensory neurons and projection neurons (PNs). One set of Fru+ olfactory neurons expresses the odorant receptor Or67d and responds to the male-specific pheromone cis-vaccenyl acetate (cVA). These neurons converge on the DA1 glomerulus in the antennal lobe. In males, activation of Or67d+ neurons by cVA inhibits courtship of other males, whereas in females their activation promotes receptivity to other males. These observations pose the question of how a single pheromone acting through the same set of sensory neurons can elicit different behaviours in male and female flies. Anatomical or functional dimorphisms in this neural circuit might be responsible for the dimorphic behaviour. We therefore developed a neural tracing procedure that employs two-photon laser scanning microscopy to activate the photoactivatable green fluorescent protein. Here we show, using this technique, that the projections from the DA1 glomerulus to the protocerebrum are sexually dimorphic. We observe a male-specific axonal arbor in the lateral horn whose elaboration requires the expression of the transcription factor FruM in DA1 projection neurons and other Fru+ cells. The observation that cVA activates a sexually dimorphic circuit in the protocerebrum suggests a mechanism by which a single pheromone can elicit different behaviours in males and in females.
Nature 452, 478-482 (27 March 2008) | doi:10.1038/nature06739; Received 13 September 2008; Accepted 24 January 2008
Molecular identification of a retinal cell type that responds to upward motion
The retina contains complex circuits of neurons that extract salient information from visual inputs. Signals from photoreceptors are processed by retinal interneurons, integrated by retinal ganglion cells (RGCs) and sent to the brain by RGC axons. Distinct types of RGC respond to different visual features, such as increases or decreases in light intensity (ON and OFF cells, respectively), colour or moving objects. Thus, RGCs comprise a set of parallel pathways from the eye to the brain. The identification of molecular markers for RGC subsets will facilitate attempts to correlate their structure with their function, assess their synaptic inputs and targets, and study their diversification. Here we show, by means of a transgenic marking method, that junctional adhesion molecule B (JAM-B) marks a previously unrecognized class of OFF RGCs in mice. These cells have asymmetric dendritic arbors aligned in a dorsal-to-ventral direction across the retina. Their receptive fields are also asymmetric and respond selectively to stimuli moving in a soma-to-dendrite direction; because the lens reverses the image of the world on the retina, these cells detect upward motion in the visual field. Thus, JAM-B identifies a unique population of RGCs in which structure corresponds remarkably to function.
BMJ 2008;336:658-662 (22 March), doi:10.1136/bmj.39493.511759.BE
Clinical Review Diagnosis and management of motor neurone disease
Motor neurone disease is a devastating illness which leads to progressive paralysis and eventual death. We will discuss the presentation of motor neurone disease in primary care and update non-specialists on progress with regards to life prolonging interventions, better control of disease symptoms, and an increased understanding of disease mechanisms. Motor neurone disease is rare but patients often are aware of it, so this review should help non-specialists reassure patients in whom it is unlikely to be the diagnosis.
JAMA. 2008;299(12):1417.
Predicting Naltrexone Response
Genetic tests may predict which patients with alcohol dependence will benefit from treatment with naltrexone, according to results from a large clinical trial funded by the National Institute on Alcohol Abuse and Alcoholism. Patients carrying 1 or more copies of the Asp40 allele of the gene encoding the µ opioid receptor drank less and stayed abstinent longer when treated with naltrexone compared with patients who were homozygous for an alternate allele (Asn40) who also received the drug (Anton RF et al. Arch Gen Psychiatry. 2008;65[2]:135-144). These results are based on genetic analysis of a subset of about 600 patients from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence Study. The study, a multisite clinical trial involving more than 1300 patients, compared the effectiveness of various therapies for alcohol dependence.
JAMA. 2008;299(12):1417.
Botox Risks Under Review
Patients treated with botulinum toxin type A (Botox and Botox Cosmetic) and botulinum toxin type B (Myobloc) for a variety of conditions have experienced adverse reactions, including respiratory failure and death, according to a February notice from the FDA.
The FDA is reviewing safety data from clinical trials of these products and postmarketing adverse event reports. The agency said there is no evidence of a defect in the product and that the reactions may be related to overdosing.
The reactions mimic the symptoms of botulism, which may include difficulty swallowing, weakness, and breathing problems, and appear to be related to the toxin spreading to areas of the body far from the injection site. More information is available at the FDA's Web site (http://www.fda.gov/cder/drug/early_comm/botulinium_toxins.htm).
The Lancet Volume 371, Issue 9617, 22 March 2008-28 March 2008, Pages 969-970
Leprosy strategy is about control, not eradication
At the end of 2000, WHO declared that leprosy had been eliminated as a global public-health problem. Elimination is defined as a prevalence, per 10 000 population, of less than one patient diagnosed with leprosy and registered for treatment. The global prevalence fell from 5·35 million (12 per 10 000) in 1985 to 597 035 (one per 10 000) at the end of 2000.
Elimination was achieved by implementation of short-course multidrug therapy (dapsone, rifampicin, and clofazimine for 6 or 12 months depending on the type of leprosy), simplified diagnosis without examination of slit-skin smears for acid-fast bacilli, and accessible treatment with drugs in blister packs that are free at the point of delivery. The shortened course of treatment, reduced from more than 5 years with dapsone alone, reduced the prevalence without changing the number of new cases detected annually. The 17th International Leprosy Congress (in Hyderabad, India) ended on Feb 4, 2008, with calls to now move from an elimination strategy for leprosy to one of eradication. Is that call the logical progression from elimination and does the evidence support such a change in strategy?
The Lancet Volume 371, Issue 9617, 22 March 2008-28 March 2008, Page 1044
Stiff and partly blind—after a first dose of steroid
In June, 2006, a 29-year-old woman, flying back to England after a 2-week holiday in Cyprus, started to feel unwell and feverish. The day after landing, she saw her general practitioner—who sent her to us, since she had a 13-year history of systemic lupus erythematosus (SLE), manifesting as rash, joint pains, lymphopenia, and feeling tired and unwell. She had no other medical history of note, and took no drugs, other than methotrexate 12·5 mg weekly.
NEJM Volume 358:1399-1401 March 27, 2008 Number 13
Corticosteroids for Bacterial Meningitis
To the Editor: Mai et al. (Dec. 13 issue) report that dexamethasone improved survival among patients with definite bacterial meningitis. However, dexamethasone was associated with decreased survival in the group of patients with probable meningitis, which was hypothesized to be due to delayed antituberculosis treatment in patients with presumed tuberculous meningitis. Since it is recommended that corticosteroids be given before or at the time of the initial dose of antibiotics, do the authors recommend that only patients with positive Gram's staining of cerebrospinal fluid receive corticosteroids? Should this restriction be applied only to countries with a high incidence of tuberculous meningitis?
NEJM Volume 358:1408-1409 March 27, 2008 Number 13
An Adult with Type 2 Citrullinemia Presenting in Europe
To the Editor: Type 2 citrullinemia is an adult-onset, autosomal recessive disorder characterized by episodes of hyperammonemic encephalopathy. It is caused by mutations in the SLC25A13 gene, which encodes the liver-specific isoform of the mitochondrial aspartate–glutamate carrier (AGC2).1,2
A 38-year-old Pakistani man with episodic confusion was found to have an elevated plasma ammonia level during an episode; citrullinemia and raised arginine, normal glutamine, and low serine levels were also noted, suggesting the diagnosis of type 2 citrullinemia. Unfortunately, despite aggressive treatment, the patient died from hyperammonemic encephalopathy.