Neurobiology

Neurobiology

275 Neurobiology Paper alert A selection of interesting papers that were published in the two months before our press date in major journals most lik...

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275

Neurobiology Paper alert A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in neurobiology.

Genetic ablation reveals that the roof plate is essential for dorsal interneuron specification. Lee KJ, Dietrich P, Jessell TM: Nature 2000, 403:734-740.

Current Opinion in Neurobiology 2000, 10:275–286

The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS. Millonig JH, Millen KJ, Hatten ME: Nature 2000, 403:764-768. •• Significance: These two papers provide new insights into the cellular and molecular mechanisms of dorsal neuron specification and raise a number of questions about the specific role of the roof plate in the patterning of the neural tube. Findings: Lee et al. employ a genetic strategy for roof plate ablation by introducing the gene encoding the diphtheria toxin A subunit (DTA) into the Gdf7 locus (a dorsally expressed bone morphogenetic protein [BMP] family member). Conditional regulation of DTA expression was achieved by exploiting the cAMP response-element (CRE) recombinase-loxP system. The Gdf7-DTA mutant mouse embryos show profound abnormalities in forebrain, midbrain and spinal cord, as well as failure of neural tube closure at midbrain and hindbrain levels. Using a plethora of molecular markers, the authors show that the mutant embryos suffer the loss of two specific subsets of dorsal interneurons, D1 and D2, accompanied by the ventral expansion of the D3 interneuron pool. Millonig et al. show by positional cloning that the LIM homeodomain transcription factor Lmx1a is mutated in three different Dreher alleles. Lmx1a is expressed in the roof plate of the developing neuraxis; its impaired function (examined in a point mutation phenotype) leads to a great reduction of cerebellar structures, spinal cord dysgenesis, failure of neural arch closure and the partial loss of D1 interneurons in the spinal cord.

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Contents (chosen by) 275 Development (Lumsden et al.) 276 Cognitive neuroscience (Hamann and Reber) 277 Signalling mechanisms (Häusser and Murthy) 278 Sensory systems (Wood, Assad and Liman) 280 Neuronal and glial cell biology (Sheng, Filbin and Qiu) 282 Motor systems (Ashe, Chafee and El Manira) 283 Neurobiology of behaviour (Goodwin and Kyriacou) 284 Neurobiology of disease (Brandon and Gage) 285 Erratum (Goodwin and Kyriacou) 286 Erratum (Brandon and Gage) • ••

of special interest of outstanding interest

Development Selected by Andrew Lumsden, Susan Chapman, Stefan Jungbluth, Esther Bell, Ana Coutinho, Moheb Costandi, Niels Adams and Renee Dutton King’s College London, Guy’s Hospital, London, UK

Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Hall AC, Lucas FR, Salinas PC: Cell 2000, 100:735-744. • Significance: Using the cerebellum as a model, wnt genes are demonstrated to play a role in regulating the dynamics of synapse formation, hence allowing insight into a process that is not well understood beyond the neuromuscular junction. Findings: In vitro techniques are used to show that granulecell-derived WNT-7a promotes the terminal differentiation of afferent mossy fibre growth cones. In cultured neurons, WNT7a induces both the morphological remodelling and protein clustering associated with mossy fibre synaptogenesis. In comparison, its absence in mutant mice delays, but does not prevent, glomerulus maturation. Positioning of longitudinal nerves in C. elegans by nidogen. Kim S, Wadsworth WG: Science 2000, 288:150-154. • Significance: This is the first demonstration that variation in the molecular composition of basement membranes is able to direct specific aspects of axonal pathfinding. Findings: The nid-1 gene of C. elegans encodes a glycoprotein component of the basal lamina, nidogen, which is able to bind both laminin and collagen IV. This paper clearly shows that nidogen is required for a subset of axons to undertake specific aspects of their navigation appropriately: the transition from circumferential to longitudinal migration and the dorso-ventral positioning of nerves. How the effects of nidogen are mediated is unclear, although, by analogy to laminin, a role in modulating responses to other guidance cues is a possibility.

The organiser factors Chordin and Noggin are required for mouse forebrain development. Bachiller D, Klingensmith J, Kemp C, Belo JA, Anderson RM, May SR, McMahon JA, McMahon AP, Harland RM, Rossant J, De Robertis EM: Nature 2000, 403:658-661. • Significance: A mouse double homozygous mutant for chordin and noggin shows for the first time in vertebrates that bone morphogenetic protein (BMP) antagonists are required for the development of the head. Findings: Both the overlapping gene expression domains of chordin and noggin, and the lack of any early forebrain abnormalities in mice mutant for either gene, suggest redundant activities during gastrulation. In contrast, double homozygous mutants die before term and show holoprosencephaly, cyclopia and agnathia. At embryonic day 6.5 (E6.5), Hesx1, Lim1, Cer-like and Hnf3β are expressed in normal patterns within the anterior visceral endoderm (AVE). By E7.5, expression of Hesx1 (which is required for head development) is undetectable, even though chordin and noggin are not normally expressed in this region. Thus, chordin and noggin appear to be required for maintenance and elaboration of anterior pattern, although a mechanism (possibly the antagonism of BMP signaling) remains unclear.

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Cognitive neuroscience Selected by Stephan Hamann Emory University, Atlanta, Georgia, USA

On the neurobiology of creativity. Differences in frontal activity between high and low creative subjects. Carlsson I, Wendt PE, Risberg J: Neuropsychologia 2000, 38:873-885. • Significance: This is a provocative study that provides clues to some of the neurobiological differences that may contribute to creativity in humans. Findings: The neurobiological mechanisms underlying creativity have long been a subject of speculation and interest, but very few studies have examined these mechanisms systematically and little is known about their nature. This study used a regional cerebral blood flow (rCBF) measurement technique based on inhalation of radioactively labelled xenon gas to examine differences in brain activity between ‘high’ and ‘low’ creative subjects. The main hypothesis was that in a critical comparison between a creativity task (e.g. generating new, unusual uses for an object) and a similar task that did not involve creativity (e.g. generating words beginning with a particular letter), the high creative subjects would engage bilateral frontal regions whereas the low creative subjects would show much less involvement of frontal regions, and only on the left side. This hypothesis was largely confirmed: high creative subjects exhibited bilateral increases in frontal activity, whereas low creative subjects showed mainly decreases or no change in activity in the same regions. The results are interpreted in terms of the differential activation of divergent visuo-spatial cognitive abilities in the right hemisphere between high and low creativity individuals. Delay activity of orbital and lateral prefrontal neurons of the monkey varying with different rewards. Hikosaka K, Watanabe M: Cereb Cortex 2000, 10:263-271. • Significance: The authors compare the neuronal activity related to reward expectancy in the orbital and lateral prefrontal cortex of the monkey and propose a model that substantially clarifies the different roles of these two frontal regions in the expectancy of response outcome. Findings: Activity related to the expectation of reward is commonly observed in both the orbitofrontal cortex (OFC) and the lateral prefrontal cortex (LPFC) in several species including the monkey. This study examines neuronal activity using single-cell recording in the OFC during delay periods followed by either no reward or three different types of reward. These data are compared to earlier data on reward-expectancy-related activity in the LPFC. Over half of the OFC neurons are found to be sensitive to the expectation of the simple presence or absence of reward. A minority of OFC neurons are sensitive to the expectation of different kinds of reward (e.g. raisin versus potato) and reflect the changing preferences of the animal across trials. The authors propose a model wherein the OFC encodes the current motivational significance of the reward; in this model, neurons of the OFC can differentiate between different rewards based solely on their motivational properties and not their cognitive properties, such as visual appearance. The LPFC receives this motivational information from the OFC and combines it with the cognitive aspects of the reward such as the specific visual or olfactory attributes of the reward, and it is this integrated representation in the LPFC that guides choice behavior. Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA

Selectivity for complex shapes in primate visual area V2. Hedge J, Van Essen DC: J Neurosci 2000, 20:RC61.

• Significance: Electrophysiological recordings in area V2 of alert macaques show that many cells in this area respond more effectively to complex stimuli than to simple oriented bars or sinusoidal gratings, indicating a role for V2 in the representation of complex shape information. Findings: Neuronal responses in primate V2 are tested with a broad repertoire of stimulus features and dimensions to examine the response properties of these neurons to complex stimuli (e.g. angles, arcs, circles, intersecting lines, hyperbolic and polar gratings) compared with simple stimuli (e.g. bars and sinusoidal gratings). Many V2 neurons are found to respond preferentially to the complex stimuli and to exhibit selective responses based on the orientation, shape or size of the stimuli. These results suggest that these cells extract higher-order visual information related to the identification of object and surface boundaries. Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging. Klingberg T, Hedehus M, Temple E, Salz T, Gabrieli JDE, Moseley ME, Poldrack RE: Neuron 2000, 25:493-500. • Significance: A new technique in magnetic resonance imaging demonstrates that the microstructure of white matter in the temporo-parietal area of the left hemisphere is related to reading ability in dyslexics and normal controls. Findings: Diffusion tensor magnetic resonance imaging (MRI) produces a measure of anisotropy that uses coherence in water molecule movement to derive a measure of the microstructure of white matter tracts through the brain. This measure was found to differ in temporo-parietal regions between dyslexic participants and controls and to correlate well with reading ability in both groups. This supports the idea that disruption of communication from posterior cortical areas to the frontal lobes is related to difficulties in reading. This new imaging technique, which can be combined with existing MRI and functional MRI (fMRI), provides additional information about the neural substrate of complex cognitive processes such as reading. Functional MRI evidence for a role of frontal and inferior temporal cortex in amodal components of priming. Buckner RL, Koutstaal W, Schacter DL, Rosen BR: Brain 2000, 123:620-640. • Significance: Three functional magnetic resonance imaging (fMRI) studies of priming in word generation and completion tasks using auditory and visual cues reveal reductions in activity in left inferior frontal cortex and inferior temporal cortex, suggesting that these areas contribute to amodal lexical/semantic processes and exhibit reductions in activity that correlate with facilitated task performance. Findings: Repetition priming is a well-studied mnemonic phenomenon that is associated behaviorally with improved performance on tasks such as word completion and verb generation when the stimulus cues are repeated. Previous neuroimaging studies reported decreased activity, particularly in inferior temporal cortex, that is thought to be related to the visual presentation of cues. The current report replicates these findings and shows that the same areas exhibit primingrelated deactivations when cues are presented auditorily, indicating that these effects result from a more general, amodal lexical semantic process rather than a specific reduction in visual processing.

Paper alert

Signalling mechanisms Selected by Michael Häusser University College London, London, UK

A novel family of mammalian taste receptors. Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS: Cell 2000, 100:693-702. AND

T2Rs function as bitter taste receptors. Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ: Cell 2000, 100:703-711. AND

A family of candidate taste receptors in human and mouse. Matsunami H, Montmayeur JP, Buck LB: Nature 2000, 404:601-604. •• Significance: These three papers represent a major breakthrough in the molecular physiology of taste, describing a new family of receptors (T2R or TRBs) that detect bitter taste in humans and mice. This family is predicted to contain a surprisingly large number of genes (50–90), suggesting that the taste system has evolved for maximal sensitivity to a wide range of different bitter compounds. Findings: The groups involved in this cloning effort searched for genes encoding putative G-protein-coupled receptors (GPCRs) in a region of the human genome known to code for sensitivity to a bitter substance, 6-n-propyl-2-thiouracil (PROP). This yielded a novel family of seven transmembrane domain receptor sequences clustered on human chromosomes 5, 7 and 12, with homologous receptor sequences found in the mouse genome. The mRNA encoding the T2R receptors is present in subsets of taste receptor cells, with coexpression of multiple T2R receptors in single cells. Chandrashekar et al. further show that expression of mouse T2R receptors in cultured cells confers sensitivity to specific bitter tastants, and that receptors activate gustducin, a G-protein known to be involved in the signalling of bitter tastes. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Talley EM, Lei Q, Sirois JE, Bayliss DA: Neuron 2000, 25:399-410. AND

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Millar JA, Barratt L, Southan AP, Page KM, Fyffe RE, Robertson B, Mathie A: Proc Natl Acad Sci USA 2000, 97:3614-3618. •• Significance: Over the last four years, a new superfamily of potassium channels has emerged, characterized by two poreforming domains (hence 2-PK or KT channels). These papers provide the first demonstration that a member for this family, TASK1, underlies a prominent leak potassium conductance in neurons; this conductance is a major target for modulation by neurotransmitters. Given their widespread expression, these findings suggest that 2-PK channels may underlie the resting potential and mediate modulation of excitability in many neuronal types. Findings: The authors demonstrate that TASK-1 mRNA is found in hypoglossal motoneurons and cultured cerebellar granule neurons, and use antibody staining to verify surface membrane expression of TASK-1 in granule neurons. Both cell types reveal a voltage-independent, non-inactivating potassium conductance that is active at the resting potential and displays the biophysical and pharmacological hallmarks of TASK-1. In both cell types, the conductance is inhibited by a variety of neurotransmitters, indicating that it plays a central role in the regulation of excitability.

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NMDA spikes in basal dendrites of cortical pyramidal neurons. Schiller J, Major G, Koester HJ, Schiller Y: Nature 2000, 404:285-289. • Significance: Demonstrates a new mechanism for localized regenerative spikes in dendrites. These spikes are mediated primarily by NMDA receptor activation and are triggered by synchronous synaptic input to the basal dendrites of cortical pyramidal neurons. This provides a mechanism for amplification of concomitantly activated inputs in dendrites. Findings: The authors used two-photon calcium imaging and somatic patch-clamp recording in cortical slices. They show that focal stimulation of synaptic inputs onto the basal dendrites of layer 5 pyramidal neurons can elicit local calcium signals and regenerative electrical responses with a stimulation threshold that increases with hyperpolarization. Pharmacological tools, in combination with glutamate uncaging and computer simulations, reveal that while these events also involve activation of dendritic voltage-gated calcium and sodium channels, they depend primarily on relief of the highly voltage-dependent block of NMDA receptor channels by extracellular magnesium ions. Selected by Venkatesh N Murthy Harvard University, Cambridge, Massachusetts, USA

Real-time measurements of vesicle-SNARE recycling in synapses of the central nervous system. Sankaranarayanan S, Ryan TA: Nat Cell Biol 2000, 2:197-204. • Significance: A long-standing question in synaptic biology is whether multiple modes of endocytosis exist and if they are differentially recruited by stimuli of different intensities. This study presents new data suggesting that the same mechanism underlies endocytosis following different stimulus intensities. Findings: The kinetics and the mode (e.g. ‘kiss-and-run’ versus clathrin-mediated) of endocytosis at synapses have come under increasing scrutiny. The small size of most central synapses has posed significant technical challenges. Now, using a pH-sensitive green fluorescent protein (GFP) attached to a vesicle-associated membrane protein (VAMP), the authors have monitored endocytosis at synapses of cultured hippocampal neurons. They find that the time taken for protein retrieval, and, by inference, the overall process of endocytosis, is linearly related to the number of vesicles exocytosed. The authors suggest that endocytosis has an initial speed of about one vesicle per second and is easily saturated, which leads to its apparent slowing down after stronger stimulation. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Lendvai B, Stern E, Chen B, Svoboda K. Nature 2000, 404:876-881. •• Significance: This study provides direct and striking visual evidence for high motility of dendritic spines in vivo, and for regulation of this motility by sensory deprivation. Such changes in spine motility might drive reorganization of neural connectivity. Findings: The physical basis of plasticity in neural circuits is of fundamental interest. Structural changes have typically been addressed by examining preparations fixed at different times and conducting a population analysis across samples. The strength of this paper is the direct visualization of dendritic spines in the barrel cortex of rats using two-photon microscopy. This allows the authors to repeatedly monitor individual dendritic spines in identified barrels. When whiskers are clipped, leading to a decrease in sensory inputs to the barrel cortex, the high motility of spines is reduced. This plasticity is confined to a critical period of 11 to 13 postnatal days.

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Glutamate spillover suppresses inhibition by activating presynaptic mGluRs. Mitchell SJ, Silver RA: Nature 2000, 404:498-502. AND

Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Semyanov A, Kullmann DM: Neuron 2000, 25:663-672. AND

GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity. Scanziani M: Neuron 2000, 25:673-681. • Significance: These three new reports emphasize the role of transmitter spillover to neighboring synapses in the function of neural circuits. Whether transmitter released at one synapse can activate neighboring synapses is an important question, the answer to which will inform us about the extent to which individual synapses are independent of each other. Findings: In the first paper, the authors show that glutamate released by mossy fibers of the cerebellum spills over and activates metabotropic glutamate receptors in the presynaptic terminals of GABA-releasing Golgi cells. This leads to a reduction in inhibitory postsynaptic currents in the granule cells. Functionally, this implies that excitatory drive can be increased by locally suppressing inhibition. In the second paper, the authors show that a similar mGluR-dependent reduction in inhibitory transmitter release occurs in the interneurons of hippocampus. Again, presynaptic mGluRs (type III) could be activated by excitatory stimulation, implying spill over of glutamate from neighboring synapses. In the third paper, GABA itself is shown to spill over and activate postsynaptic GABAB receptors at adjacent synapses. This activation is enhanced by blocking GABA reuptake. GABA spillover and activation of GABAB receptors also occurs during rhythmic activity seen in the hippocampus, the frequency of which can be modified by blocking GABA reuptake or by blocking GABAB receptors.

Sensory systems Selected by John N Wood University College London, UK

Nitric oxide is an autocrine regulator of Na+ currents in axotomized C-type DRG neurons. Renganathan M, Cummins TR, Hormuzdiar WN, Black JA, Waxman SG: J Neurophysiol 2000, 83:2431-2442. • Significance: Reports that nitric oxide (NO), a diffusible messenger that activates guanylate cyclase, is able to inhibit sodium currents in sensory neurons, and may thus play a role in regulating excitability in peripheral sensory neurons. Findings: Nitric oxide synthase (NOS) is upregulated in small dorsal root ganglion (DRG) neurons by 60% after axotomy. Both the fast-inactivating tetrodotoxin-sensitive (TTX-S) Na+ (‘fast’) current and the slowly inactivating tetrodotoxin-resistant (TTX-R) Na+ (‘slow’) current densities are concomitantly reduced. It seems likely that the increased NOS and NO production may be responsible for this effect, because incubation of cultures with 1 mM N(G)-nitro-L-arginine methyl ester (L-NAME) causes a partial return to normal current densities of both fast and slow sodium currents. The persistent TTX-R Na+ current, normally present in DRG neurons, was not observed in axotomized neurons. These results suggest that NO may function as an autocrine regulator of Na+ currents in injured DRG neurons. Axotomized and intact muscle afferents but not skin afferents develop ongoing discharges of dorsal root ganglion

origin after peripheral nerve lesion. Michaelis M, Liu X, Janig W: J Neurosci 2000, 20:2742-2748. •• Significance: Ectopic action potential propagation is considered to be a crucial step in the induction of pain resulting from peripheral nerve injury (neuropathic pain) — a syndrome with 1.8 million sufferers in the US alone. For the first time, the experiments described here suggest that muscle afferents but not skin afferents respond to nerve injury in terms of increased discharge activity. Findings: The rat gastrocnemius soleus (GS) nerve innervating skeletal muscle and the sural (SU) nerve supplying skin were transected in rats. Several days after injury, 20% of myelinated axons projecting into the GS nerve produced ongoing discharges of irregular or bursting pattern. In contrast, all SU neurons were silent. Without a nerve lesion, almost no GS neurons (1.1%) fired spontaneously. Most afferent neurons with ongoing activity had an axonal conduction velocity of 5–30 ms–1, indicating that some of these neurons are nociceptors. These findings provide the first evidence that after peripheral nerve injury, axotomized as well as intact afferent neurons supplying skeletal muscle — but not skin afferents — generate on-going spontaneous actions potentials. This is probably because of altered gene expression in the dorsal root ganglion triggered by the loss of trophic support following axotomy. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Patel TD, Jackman A, Rice FL, Kucera J, Snider WD: Neuron 2000, 25:345-357. •• Significance: The trophic actions and regulatory effects of nerve growth factor (NGF) on sensory neuron development and function are distinguished by the use of double TrkA/BAX knockout mice — that is, mice in which the genes for TrkA (tyrosine kinase A), the high-affinity NGF receptor, and BAX (a BCl-2 antagonist with pro-apoptotic effects) have been deleted. The paper suggests that the trophic actions of NGF on sensory neuron survival may be mediated by an inhibition of the apoptotic actions of BAX. Findings: To study peripheral neuron development in the absence of neurotrophin signaling, two different types of knockout mice are generated: mice that are double null for BAX (a pro-apoptotic factor) and nerve growth factor (NGF); and mice that are double null for BAX and the NGF receptor TrkA. All dorsal root ganglion (DRG) neurons that normally die in the absence of NGF/TrkA signaling survive in both double mutants. However, although sensory neurons extend axons through the dorsal roots and collateral branches into the dorsal horn, cutaneous innervation is absent. The surviving sensory neurons also fail to express markers characteristic of the nociceptive phenotype. Thus NGF/TrkA signaling, quite apart from providing trophic support, regulates peripheral target field innervation and is required for the differentiation of specialised sensory neurons that respond to tissue damage. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase. Ratcliffe CF, Qu Y, McCormick KA, Tibbs VC, Dixon JA, Scheuer T, Catterall WA: Nat Neurosci 2000, 3:437-444. •• Significance: Sodium channel activity has long been known to be regulated by phosphorylation. This paper provides the first demonstration of a role for phosphorylation on tyrosine residues as a regulatory mechanism, and demonstrates the existence of a sodium-channel–tyrosine-phosphatase complex within the CNS.

Paper alert

Findings: Voltage-gated sodium channels in rat are found to associate with both the extracellular domain and the intracellular catalytic domain of a receptor protein tyrosine phosphatase (RPTP) and its catalytically active, secreted isoform phosphacan. Very interestingly, sodium channels are found to be at least partially tyrosine phosphorylated using anti-phosphotyrosine antibodies. Evidence that tyrosine phosphorylation is functionally significant comes from studies of co-expressed type IIA sodium channels and RPTP. Dephosphorylation slowed sodium channel inactivation, positively shifted its voltage dependence, and increased whole-cell sodium current. Thus a sodium channel signaling complex containing RPTP seems to have a potentially significant regulatory role within the CNS. Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin. Evans AL, Müller U: Nat Genet 2000, 81:424-428. •• Significance: The complexity of mammalian mechanotransduction mechanisms is underlined by the demonstration that stereocilia fail to develop on hair cells of the inner ear in the absence of integrin α-8-β-1. This demonstrates a role for the extracellular matrix in the development of mechanosensitive hair cells. Findings: Most integrin α-8 null mutant mice die soon after birth as a result of kidney defects. However, the few survivors show structural deficits in the inner ear and have difficulty balancing. Hair cell differentiation and sterocilia formation are shown to be deficient in these mice. Normally, integrin α-8, fibronectin and a focal adhesion kinase all co-localise at the sites of stereocilia formation, suggesting some role for this signalling complex in sterocilia formation. A role for extracellular proteins in mechanosensitive neuron function has already been demonstrated in C. elegans. The present findings suggest that extracellular matrix proteins also play an important role in the development of mammalian mechanosensory structures. Selected by John A Assad Harvard Medical School, Boston, Massachusetts, USA

Interruption of a basal ganglia-forebrain circuit prevents plasticity of learned vocalizations. Brainard MS, Doupe AJ: Nature 2000, 404:762-766. • Significance: Provides important evidence that the basal ganglia may be involved in recalibrating a complex sensorimotor behavior. Findings: A variety of evidence suggests that the song pattern of zebra finches requires auditory feedback. Even in adult birds, deafening leads to song degradation. To locate the neuronal correlate of this sensorimotor plasticity, the authors lesioned the lateral magnocellular nucleus (LMAN) of the anterior neostriatum, the bird homologue of frontal cortex, which forms part of a motor-control loop with the bird’s basal ganglia (area X). Whereas the song of LMAN-spared deafened birds gradually deteriorated, the song of LMANlesioned deafened animals remained normal for up to one year following deafening. These results indicate that the removal of auditory feedback leads to active, non-adaptive changes in song, which may be driven by the forebrain–basal ganglia circuit. Moreover, these data also suggest that this circuit may be involved in the normal developmental sensorimotor calibration of bird song.

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• Significance: This is an intriguing demonstration that the neuronal correlates of the unfolding of a simple sensorimotor decision process are evident surprisingly far along in the sensory–motor processing pathway. Findings: The authors trained monkeys to make saccades to one of two targets to indicate the direction of motion of a noisy random-dot motion display. At the end of the motion stimulus, but before the animal makes the saccade to indicate its perceived direction, electrical microstimulation is applied to the frontal eye fields (FEF) to induce a preliminary saccade orthogonal to the axis of the two saccade targets. The endpoint of this preliminary saccade is found to be deviated in the direction of the ultimate saccade target, suggesting that the unfolding perceptual decision is ‘read out’ in the FEF as a developing oculomotor command — assuming that the motion stimulus does not directly bias eye position. The amount that saccades deviate depends on the strength and duration of the motion stimulus, as does the perceptual decision itself. These data suggest that, for a simple sensorimotor behavior, the dynamics of the perceptual decision process may be evident in the motor read-out. Selected by Emily R Liman University of Southern California, Los Angles, CA, USA

A Drosophila mechanosensory transduction channel. Walker RG, Willingham AT, Zuker CS: Science 2000, 287:2229-2234. •• Significance: In this comprehensive and groundbreaking report, the authors use a combination of molecular genetics and electrophysiology to identify a mechanosensitive ion channel that mediates touch in D. melanogaster. This channel, which is related to the transient receptor potential (TRP) ion channel, appears to define a new subfamily of ion channels that plays a role in mechanosensation in diverse species, including C. elegans and possibly humans. Findings: To identify components of mechanosensory signaling in D. melanogaster, the authors screened a series of mutant lines for specific defects in the electrophysiological responses of their sensory bristles. In one complementation group, the mechanically gated current was reduced or showed altered kinetics, indicating that this locus (nompC) might contain a gene for a mechanically gated ion channel. Sequencing of the nompC gene revealed similarity to the TRP family of ion channels, other members of which have previously been implicated in sensory transduction of visual and olfactory stimuli. Interestingly, the NOMPC protein contains a unique amino-terminal sequence with 29 ankryn repeats, which may anchor the channel to the cytoskeleton and allow it to transduce mechanical force. Functional similarity between the bristle and the hair cells of the inner ear suggest the exciting possibility that vertebrate homologs of this channel may play a role in hearing. A family of candidate taste receptors in human and mouse. Matsunami H, Montmayeur JP, Buck LB: Nature 2000, 404:601-604. AND

A novel family of mammalian taste receptors. Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS: Cell 2000, 100:693-702. AND

Representation of a perceptual decision in developing oculomotor commands. Gold JI, Shadlen MN: Nature 2000, 404:390-394.

T2Rs function as bitter taste receptors. Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ: Cell 2000, 100:703-711.

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•• Significance: These reports resolve the mystery of how toxins with diverse chemical structures can evoke a similar bitter taste and set the stage for a more detailed understanding of coding in the gustatory system. Findings: Both groups searched for genes encoding bitter taste receptors in regions of the genome that have been linked to bitter taste sensitivity in mice and humans. This strategy resulted in the identification of a novel family of putative G-protein-coupled receptors, consisting of an estimated 40–80 members (in humans), with distant homology to vomeronasal receptors and opsins. Both groups show that individual taste receptor cells express multiple receptor genes, suggesting that individual cells may not distinguish between bitter taste compounds. To show that members of this family indeed encode bitter taste receptors, Chandrashekar et al. examined functional properties of the receptors in a heterologous system. One mouse receptor (mT2R-5) responded to the bitter compound cyclohexamide while a mouse receptor and human receptors responded to bitter substances denatonium and 6n-propyl-2-thiouracil. In addition, mouse strains that differ in their sensitivity to cyclohexamide were found to have different alleles of the mT2R-5 gene, and these allelic differences resulted in a decrease in the sensitivity of the receptor to cyclohexamide. These results represent unequivocal evidence that this gene family encodes bitter taste receptors, and provide the molecular tools for a comprehensive understanding of bitter taste transduction.

Neuronal and glial cell biology Selected by Morgan Sheng Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA

Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation. Manabe T, Aiba A, Yamada A, Ichise T, Sakagami H, Kondo H, Katsuki M: J Neurosci 2000, 20:2504-2511. • Significance: Small GTPases of the Ras family (N-ras, H-ras, K-ras) are abundantly expressed in the brain and are implicated in synaptic plasticity, but their precise functions are not understood. This paper reveals a role for H-ras in the regulation of tyrosine phosphorylation of NMDA receptors and of long-term potentiation (LTP) in mammalian brain. Findings: Mice with a targeted disruption of H-ras showed normal behavior and brain morphology. In hippocampus, tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B increased, with no apparent change in subunit composition. NMDA-receptor-mediated responses were also enhanced in Hras mutant mice, probably as a result of increased single-channel conductance or an increased number of active NMDA receptor channels. Correlated with the increased NMDA receptor response, the magnitude of LTP in the CA1 region of the hippocampus was greatly enhanced in these knockout mice. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Hsueh YP, Wang TF, Yang FC, Sheng M: Nature 2000, 404:298-302. •• Significance: This paper reveals a novel function for membrane-associated guanylate kinase (MAGUK) proteins, which are usually associated with cell–cell junctions such as synapses. CASK, the mammalian homologue of the C. elegans protein LIN-2, can enter the nucleus, bind a specific transcription factor,

and regulate transcription of a gene required for neuronal migration and cortical development (reelin). Findings: A T-box transcription factor (T-brain-1) is identified as a binding partner for CASK in a yeast two-hybrid screen. CASK translocates into the nucleus in a T-brain-1-dependent manner and cooperates with T-brain-1 to activate transcription of the reelin gene, which contains a T-element-like regulatory sequence in its upstream region. CASK and T-brain-1 are associated in a complex in nuclei of cortical neurons during embryonic development. Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Misura KM, Scheller RH, Weis WI: Nature 2000, 404:355-362. •• Significance: The conserved protein neuronal-Sec1 (nSec1, also known as Munc18) interacts with the SNARE protein syntaxin and is essential for vesicle exocytosis. This paper reveals the structural basis of nSec1–syntaxin1a binding. The nSec1bound conformation of syntaxin1a resembles a ‘closed’ conformation (unable to bind other partner SNARE proteins), but it differs from this conformation in the core SNARE complex and in isolation. This structure suggests potential mechanisms by which nSec1 may regulate formation and specificity of the SNARE complex. Findings: The crystal structure of nSec1 in a complex with the cytoplasmic domain of syntaxin1a is determined at 2.6 Å resolution. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS: Nat Neurosci 2000, 3:323-329. • Significance: The neurotrophin BDNF (brain-derived neurotropic factor) can enhance synaptic transmission, at least in part via a presynaptic mechanism. This study identifies the synaptic vesicle-associated protein synapsin as one potential effector of the presynaptic action of BDNF. BDNF activates MAP (mitogen-activated protein) kinases that phosphorylate synapsin. However, the results of inhibiting the MAP kinase cascade suggest there are additional unidentified MAP kinase substrates in nerve terminals that play an important role in the modulation of neurotransmitter release by neurotrophins. Findings: BDNF stimulates the release of glutamate from rat brain synaptosomes. This effect correlates with increased phosphorylation of TrkB receptors, p42 and p44 MAP kinases, and synapsin I. Enhancement of glutamate release by BDNF is reduced in mice lacking synapsin I and/or synapsin II. PD98059, an inhibitor of MAP kinase kinase (MEK), causes a partial reduction of MAP kinase-dependent phosphorylation of synapsin I and abolishes glutamate release. Regulation of AMPA-receptor mediated synaptic transmission by clathrin-dependent receptor internalization. Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE, Sheng M, Wang YT: Neuron 2000, 25:649-662. • Significance: This study shows that AMPA receptors can be rapidly internalized via dynamin-dependent endocytosis and that this internalization can be regulated by extracellular factors acting on postsynaptic receptor tyrosine kinases. Moreover, AMPA receptor internalization is a critical mechanism for longlasting synaptic depression. Findings: Insulin stimulates AMPA receptor internalization in HEK293 cells and in neurons, via a mechanism requiring clathrin, dynamin and the GluR2 subunit. Insulin-induced AMPA receptor internalization in hippocampal slices is

Paper alert

correlated with synaptic depression that occludes and is occluded by long-term depression induced by low-frequency stimulation. Thus, insulin-induced depression shares a common mechanism with low-frequency-stimulation-induced long-term depression. Selected by Marie T Filbin and Jin Qiu Hunter College of the City University of New York, New York, USA

Semaphorin 3A is a chemoattractant for cortical apical dendrites. Polleux F, Morrow T, Ghosh A: Nature 2000, 404:567-573. •• Significance: This elegant study demonstrates for the first time that two neurites from the same cell respond in an opposite fashion to the same guidance signal. It brings a unifying element to research on axonal and dendritic guidance. Moreover, it highlights the role of cyclic nucleotides in creating nervous system patterning. Findings: The authors show that there is a gradient of Semaphorin 3A (Sema3A) in the developing cortex; its concentration is high near the pial surface and low in the subcortical white matter. Meanwhile, the asymmetric localisation of soluble guanylate cyclase (SGC) in pyramidal neurons confers distinct responses of axons and dendrites to Sema3A. Thus, Sema3A is a chemoattractant for apical dendrites with a high concentration of SGC, and this effect is mediated through the cGMP signaling pathway. In contrast, cortical axons have little SGC and are repelled by Sema3A. Response of Schwann cells to action potentials in development. Stevens B, Fields RD: Science 2000, 287:2267-2271. •• Significance: This study demonstrates for the first time that Schwann cells (SCs) can detect impulse activity in extrasynaptic and premyelinated axons before the formation of nodes of Ranvier and, in response, arrest in a non-proliferative and pre-differentiated state. In this way, functional activity in the developing nervous system could delay terminal differentiation of SCs until exposure to appropriate axon-derived signals. Findings: The authors show that impulse activity in premyelinated axons can inhibit proliferation and differentiation of SCs. This neuronal–glial signalling is mediated via the release of ATP by axons, which acts through P2Y-purinergic receptors on SCs and triggers intracellular signaling pathways involving Ca2+, Ca2+/calmodulin-dependent kinase, mitogen-activated protein kinase, cAMP response element binding protein (CREB), and expression of c-fos and Crox-24. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Ramon-Cueto A, Cordero MS, Santos-Benito FF, Avila J: Neuron 2000, 25:425-435. •• Significance: The authors demonstrate that transplantation with olfactory ensheathing glia (OEG) provides a useful repair strategy in adult mammals with traumatic spinal cord injuries. This discovery could lead to new therapies for the treatment of spinal cord lesions in humans. Findings: In adult rats, OEG transplants successfully lead to functional and structural recovery after complete spinal cord transection. Between 3 and 7 months post surgery, all OEGtransplanted animals recover locomotor functions and sensorimotor reflexes. In addition, relevant motor axons (corticospinal, raphespinal and coeruleospinal) regenerate for long distances within caudal cord stumps.

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Schwann cell myelination requires timely and precise targeting of P0 protein. Yin X, Kidd GJ, Wrabetz L, Feltri ML, Messing A, Trapp BD: J Cell Biol 2000, 148:1009-1020. •• Significance: The authors suggest a mechanism whereby overexpression of a myelin gene, P0, can result in the loss of myelin formation. Findings: In mice overexpressing P0, P0 protein accumulates in inappropriate domains of the Schwann cell plasma membrane and results in arrested myelination. It is proposed that P0 prevents myelin formation by blocking spiral mesaxon growth via homophilic interactions. P0 glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. Wrabetz L, Feltri ML, Quattrini A, Imperiale D, Previtali S, D’Antonio M, Martini R, Yin X, Trapp BD, Zhou L et al.: J Cell Biol 2000, 148:1021-1033. •• Significance: The results demonstrate that different P0 gene doses arrest myelination at different stages. In addition, the study suggests a novel basis for hereditary neuropathy. Findings: Overexpression of P0 in mice causes a dose-dependent, dysmyelinating neuropathy manifested by delayed nerve development and the inability of Schwann cells to segregate axons. Two plausible pathogenetic mechanisms are identified. First, increasing P0 overexpression disregulates the stoichiomeric expression of other myelin genes. Second, P0 overexpression promotes inappropriate trafficking of P0 to Schwann cell surface membranes. A dual role of erbB2 in myelination and in expansion of the Schwann cell precursor pool. Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C: J Cell Biol 2000, 148:1035-1046. • Significance: The authors identify a novel role of the neuregulin signaling system in the process of accurate myelination. They show that neuregulin–erbB interactions are vital during the entire life span of myelinating Schwann cells. Findings: It has been shown previously that null mutations of the neuregulin-1, erbB2 or erbB3 mouse genes cause severe deficits in early Schwann cell development. By using CreloxP technology, the authors ablated the erbB2 gene perinatally in peripheral nerves and at embryonic day 11 within spinal roots. The mutant mice exhibit a widespread peripheral neuropathy characterised by abnormally thin myelin sheaths that contain few myelin wraps. In addition, in spinal roots, the Schwann cell precursor pool is not correctly established. Furthermore, a postnatal loss of motor axons occurs. Semaphorin 3A enhances endocytosis at sites of receptorF actin colocalisation during growth cone collapse. Fournier AE, Nakamura F, Kawamoto S, Goshima Y, Kalb RG, Strittmatter SM: J Cell Biol 2000, 149:411-421. • Significance: This study provides direct evidence that increased endocytosis in the growth cone is directly associated with agents that induce growth cone collapse. Thus, the balance of exocytosis and endocytosis at the growth cone is likely to play a critical role in growth cone morphology, axonal extension/retraction, and navigational decisions. Findings: Semaphorin3A (Sema3A) induces a coordinated rearrangement of Sema3A receptors, Rac1 and F-actin during growth cone collapse. The sites of F-actin reorganisation correlate with discrete vacuoles — structures involved in

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endocytosis — and colocalise with accumulations of Sema3A receptors and Rac1. Furthermore, enhanced endocytosis occurs in multiple neuronal cell types in response to Sema3A treatment or other growth cone collapsing agents. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. Wahl S, Barth H, Ciossek T, Aktories K, Mueller BK: J Cell Biol 2000, 149:263-270. • Significance: The authors demonstrate that activation of Rho and its downstream effector, Rho kinase, are important elements of the ephrin-5A signal transduction pathway mediating growth cone collapse. Findings: In ephrin-A5-treated retinal ganglion cell cultures, Rho is found to be activated and Rac downregulated. Pretreatment of ganglion cell axons with specific inhibitors of either the Rho GTPase or Rho kinase strongly reduces the collapse rate of retinal growth cones. Application of neutralizing antibodies against NI-35/250 myelin-associated neurite growth inhibitory proteins to the adult rat cerebellum induces sprouting of uninjured Purkinje cell axons. Buffo A, Zagrebelsky M, Huber AB, Skerra A, Schwab ME, Strata P, Rossi F: J Neurosci 2000, 20:2275-2286. • Significance: This study provides evidence that the myelinassociated proteins NI-35/250 regulate axon growth processes in order to confine plasticity to restricted regions and to prevent the formation of aberrant connections. Findings: Application of neutralising IN-1 antibody Fab fragment against NI-35/250 proteins to the uninjured adult cerebellum induces a profuse sprouting of Purkinje axons along their intracortical course. The IN-1 Fab fragment-induced cellular changes and axon remodelling can be essentially reproduced by applying affinity-purified antibody 472 raised against a peptide sequence of the recombinant protein NI-220, thus confirming the specificity of the applied treatments to these myelin-associated molecules. Neurocan is upregulated in injured brain and in cytokinetreated astrocytes. Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, Levine JM, Margolis RU, Rogers JH, Fawcett JW: J Neurosci 2000, 20:2427-2438. • Significance: The authors raise the possibility that chondroitin sulfate proteoglycan (CSPG) neurocan is upregulated and accumulated at CNS injury sites and impedes nerve regeneration. Findings: CSPG neurocan is shown to exert a repulsive effect on growing cerebellar axons in vitro. The expression of neurocan is significantly upregulated around the lesion site in response to CNS damage. Furthermore, in highly purified rat astrocytes, neurocan is expressed either as a soluble form or deposited on the substrate around and under, but not on, the cells; its expression is increased by transforming growth factor β (TGFβ) and epidermal growth factor (EGF) and decreased by platelet-derived growth factor (PDGF) and interferon γ.

Motor systems Selected by James Ashe and Matthew Chafee Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA

Motor disorder in Huntington’s disease begins as a dysfunction in error feedback control. Smith MA, Brandt J, Shadmehr R: Nature 2000, 403:544-549.

•• Significance: This study demonstrates that persons carrying the gene defect causing Huntington’s disease (HD) exhibit abnormal reaching movements years before they develop chorea, suggesting that an analysis of reaching movements might assist early diagnosis. The results further suggest that circuits through the basal ganglia that are damaged in HD normally function in feedback correction of errors committed during movement execution. Findings: Movement jerk is defined as cumulative squared acceleration change across a trajectory. Normal reaching movements minimize this variable, and are of near-maximal smoothness. Both HD patients and asymptomatic gene carriers (AGCs) were found to make jerky reaching movements in comparison to control subjects, particularly in the decelerating phase of the movement as the hand approached the target. The quantity of jerk in this later phase of movement was found to vary as a function of early motor error (here defined as the distance between the midpoint of the trajectory and the peak speed position) for all subjects. However, both HD and AGC groups were particularly sensitive to this early error, finishing their movements with greater jerk than controls. This suggests that jerks in the movements made by HD and AGC subjects represent inefficient attempts to correct movement errors on-line. Immediate neural plasticity shapes motor performance. Dorris MC, Paré M, Munoz DP: J Neurosci 2000, 20: RC52. • Significance: This study identifies an immediate form of motor plasticity operating over a short time span (seconds to minutes) and identifies a neural correlate of this plasticity in a motor control structure. Findings: Single-neuron recordings were obtained from the superior colliculus while monkeys performed a gap-saccade task. The degree of neural activation in anticipation of the target reflected the combination of saccades made on the previous two trials. The level of this anticipatory activity was greatest if both of the two previous saccades were in the direction of the movement field of the neuron. Progressively less activity was observed when one or both of the previous saccades were in the opposite direction. Saccadic reaction times exhibited a similar dependency on motor history, exhibiting a systematic reduction with the number of recent saccades made in the same direction. What and when: parallel and convergent processing in motor control. Sakai K, Hikosaka O, Takino R, Miyauchi S, Nielsen M, Tamada T: J Neurosci 2000, 20:2691-2700. • Significance: Successful motor behaviour often requires both the selection and the precise timing of the appropriate response. It is thought that in response-time tasks there are separate processing stages for response selection and timing adjustment. These data indicate for the first time that these processing stages have distinct neural substrates. Findings: PET (positron emission tomography) scans are made in human subjects while they perform motor reaction-time tasks in which either the response selection or the timing of the response (or both) is uncertain. The neural substrate underlying response selection is primarily the pre-supplementary motor area (pre-SMA); that subserving timing adjustment is the cerebellum. The lateral premotor cortex is at its most active when both response selection and timing decisions are made in the same condition; this suggests that it may be involved in the integration of the two separate aspects of the response.

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Selected by Abdel El Manira Karolinska Institute, Stockholm, Sweden

Population reconstruction of the locomotor cycle from interneuron activity in the mammalian spinal cord. Tresch MC, Kiehn O: J Neurophysiol 2000, 83:1972-1978. • Significance: The organisation of the neural circuit generating locomotion is largely unknown in mammals. This study reveals the importance of a population of interneurons in the generation of locomotor patterns. Findings: Lesion studies of the newborn rat spinal cord have shown that interneurons in the ventromedial regions are critical for the generation of locomotor activity. This study examines how neuronal populations can encode the locomotor cycle. The results show that although the spike activity of individual spinal interneurons is weak and varies from cycle to cycle, the locomotor phase can be accurately predicted when information from the entire population is combined. This provides further support for the hypothesis that interneurons in the ventromedial regions are involved in the production of locomotor patterns. The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice. Thoby-Brisson M, Telgkamp P, Ramirez JM: J Neurosci 2000, 20:2994-3005. • Significance: The generation of a rhythmic motor pattern relies on intrinsic properties of the neurons involved and their synaptic connections. This study provides a detailed characterization of how a given type of ion channel contributes to the final motor output of the neural network controlling respiration. Findings: The importance of the hyperpolarization-activated inward current (Ih current) in respiratory rhythm generation is investigated using a spontaneously active brainstem slice from mouse. Blockade of the Ih current increases the respiratory frequency. This effect is mainly due to a modulation of the activity of pacemaker neurons. The Ih current appears to play a different role in the respiratory network compared to its role in other systems in which blockade of the Ih current decreases the frequency of the rhythmic activity. This study thus provides evidence that a single conductance can have opposite functional roles in different neural networks. Selected by James Ashe*, Matthew Chafee* and Abdel El Manira† *Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA †Karolinska Institute, Stockholm, Sweden

Interruption of a basal ganglia–forebrain circuit prevents plasticity of learned vocalizations. Brainard MS, Doupe AJ: Nature 2000, 403:762-766. •• Significance: The authors demonstrate that motor plasticity in song production induced by experimentally altered sensory feedback depends upon the normal function of a basal-ganglia–forebrain circuit in the zebra finch. The present study provides novel insights into the neural mechanisms involved in the maintenance of vocal motor pattern. Findings: The song of adult zebra finches becomes progressively more disorganized in the absence of appropriate acoustic feedback after experimental deafening. This loss of song structure does not occur in birds deprived of their hearing if a lesion is made in the anterior forebrain pathway. Importantly, the song retains its structure in spite of the loss of acoustic feedback in deafened birds that have also received a lesion of the lateral magnocellular nucleus of the anterior neostriatum. The data suggest that activity in this pathway normally employs feedback in the analysis of the sensory consequences of movement (such as

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acoustic feedback during song production) to adjust motor programs in response to detected errors. Therefore in the case of deafening, aberrant sensory feedback induces deleterious control signals in this pathway that actively disrupt song integrity.

Neurobiology of behaviour Selected by Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK †University of Leicester, Leicester, UK

Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D: Science 2000, 288:306-313. •• Significance: This study demonstrates an essential requirement of the capsaicin (vanilloid) receptor VR1, with respect to particular sensory perception of pain and tissue-injury-induced thermal hyperalgesia (i.e. abnormally heightened sensitivity to pain). These findings may ultimately lead to the development of novel drugs for chronic internal pain that can follow tissue damage. Findings: Caterina et al. genetically altered mice to remove the VR1 receptor, a cation channel selectively found in primary sensory neurons that mediate pain. Previous experiments had shown that cultured neurons containing the VR1 receptor can be activated by heat, protons, capsaicin and other vanilloid compounds. The authors demonstrate that sensory neurons from mice lacking VR1 receptors are severely deficient in their responses to each of these harmful stimuli. VR1-deficient mice behaved normally in many respects, but exhibited less sensitivity to high temperatures and willingly drank capsaicin-infused water. The genome sequence of Drosophila melanogaster. Adams MD, Celniker SE, Holt RA, Evans CA, Gocayne JD, Amanatides PG, Scherer SE, Li PW, Hoskins RA, Galle RF: Science 2000, 287:2185-2195. •• Significance: This paper, and others in this edition of Science, represents a massive undertaking and an outstanding achievement. The fruitfly Drosophila melanogaster is the second organism with a nervous system to have its euchromatic genome completely sequenced. D. melanogaster is one of the most intensively studied organisms in biology and serves as an excellent model system for the examination of many developmental and cellular processes shared by higher eukaryotes, including humans. The hope is that comparison of the Drosophila and human genomes will yield many new insights into how genes control neural development, function and ultimately behaviour. Indeed, there are areas of behavioural research that are already showing exciting parallels (see selected papers below by Shaw et al., Science 2000, 287:1834-1837 and Hendricks et al., Neuron 2000, 25:129-138). Findings: Nearly all of the euchromatic portion (120 megabases) of the fly genome has been sequenced. A wholegenome shotgun sequencing strategy was used, assisted by extensive clone-based sequencing and a high-quality bacterial artificial chromosome physical map. About 14,000 genes were identified which have been classified into about 8000 families — so some are single members whereas others are duplicated. In addition, of 289 human disease genes examined, 177 were found to have Drosophila counterparts (Rubin et al., Science 2000, 287:2204-2215). Forebrain peptides modulate sexually polymorphic vocal circuitry. Goodson JL, Bass AH: Nature 2000, 403:769-772.

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•• Significance: The plainfin mishipman fish, Porichthys notatus, has two male behavioural morphs, type I and type II, which show different reproductive tactics and vocalisations. Some of the acoustic signals of type II males are similar to those of females. Application of neuropeptides to a specific brain region has different effects on type I male vocalisations compared to type II males and females. Hormonal mechanisms can thus regulate reproductive elements that can be decoupled from gonadal sex, providing additional evolutionary flexibility in behaviour. Findings: Arginine–vasotocin (AVT; AVP in mammals) and isotocin (IT) are applied to the preoptic area–anterior hypothalamus (POA–AH), a region of the brain rich in vasopressin–oxytocin receptors. The physiological basis of vocalisations, as recorded from the hindbrain motor-circuitry, has a one-to-one correspondence with the behaviour. Vocalisations in type 1 males were inhibited by AVT, enhanced by an AVP V1 receptor antagonist, and no effects were observed with the structurally similar IT or an oxytocin antagonist. In contrast, females and type II males showed significant dose-dependent increases in physiological responses with IT, and a modest facilitation with AVT. Thus, behavioural differences between the two male types are associated with a female-like change in responsiveness to AVT and IT, revealing a role for forebrain neuropeptides in defining intra-sexual behavioural strategies. Correlates of sleep and waking in Drosophila melanogaster. Shaw PJ, Cirelli C, Greenspan RJ, Tononi G: Science 2000, 287:1834-1837. AND

Rest in Drosophila is a sleep-like state. Hendricks JC, Finn SM, Panckeri KA, Chavkin J, Williams JA, Sehgal A, Pack AI: Neuron 2000, 25:129-138. •• Significance: Both groups show that at rest Drosophila has features that are characteristic of mammalian sleep. This now opens up the exciting possibility of using Drosophila as a genetic and molecular model system for sleep research. Findings: Both groups observe that resting periods in fruitflies are characterised by reduced responsiveness to arousing vibratory stimuli. When flies are deprived of rest, they show a rest rebound. Flies fed caffeine, an antagonist of adenosine A1 receptors, show reduced resting behaviour, whereas cyclohexyladenosine, a selective A1 receptor agonist, and hydroxyzine, an antagonist of the H1 histamine receptor, increased rest. All these features of Drosophila rest are characteristic of mammalian sleep. In addition, Shaw et al. also showed that the amount of rest required is high after eclosion, stabilises during adulthood, and declines during senescence, again mirroring the development of sleep in mammals. Differential display of fly-head mRNA taken from flies resting, rest-deprived, or spontaneously active, identifies several restrelated or waking-related genes, including BiP, which encodes a chaperone protein implicated in long-term memory formation, and Dat, which encodes an enzyme involved in monoamine catabolism. Dat mutants reveal increased levels of rest rebound, confirming the association between monoamine metabolism and fly rest, and underscoring the well-established importance of monoamines in mammalian sleep. Hendricks et al. observe that the rest rebound phenomenon is altered in timeless but not period circadian clock mutants, suggesting new functions for timeless beyond its immediate role in regulation of the circadian clock.

Neurobiology of disease Selected by Eugene P Brandon and Fred H Gage The Salk Institute, San Diego, California, USA

Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A et al.: JAMA 2000, 283:1007-1015. • Significance: This study indicates that estrogen replacement therapy (ERT) provides no clinical benefit to women with established Alzheimer’s disease (AD). It remains unknown whether ERT could help prevent or delay the onset of AD. Findings: A multicenter placebo-controlled trial of almost 100 hysterectomized women with mild to moderate AD was conducted. Over the course of 15 months, ERT tested at two different doses did not slow disease progression, and did not improve global, cognitive, or functional outcomes. ERT-treated patients actually showed a greater impairment than control patients on the Clinical Dementia Rating Scale. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Yamamoto A, Lucas JJ, Hen R: Cell 2000, 101:57-66. •• Significance: A conditional transgenic mouse model of Huntington’s disease (HD) is established. Interestingly, the results indicate that the disease process is to some extent reversible. Because the expression of mutant huntingtin peptide can be spatially and temporally regulated with some precision in these mice, they should be very useful for future HD research. Findings: Transgenic mice are generated that express a polyglutamine-expanded huntingtin peptide (polyQ-htt) under a tetracycline regulatable system. These mice develop nuclear and cytoplasmic aggregates of polyQ-htt and a limbclasping behavioral phenotype upon transgene activation, and a loss of polyQ-htt immunoreactivity and clasping upon subsequent inactivation. A Drosophila model of Parkinson’s disease. Feany MB, Bender WW: Nature 2000, 404:394-398. AND

Genetic suppression of polyglutamine toxicity in Drosophila. Kazemi-Esfarjani P, Benzer S: Science 2000, 287:1837-1840. •• Significance: Drosophila models of human neural diseases are of great utility because these organisms can be readily used to screen genetic elements and pharmacological manipulations that affect outcome, and therefore can reveal novel insights into disease etiology and/or treatment. In these two reports, a Drosophila model of Parkinson’s disease (PD) is described, and genes that suppress the disease of a Drosophila model of Huntington’s disease (HD) are discovered and characterized. Findings: Feany and Bender generated flies with neural-specific expression of normal or mutant human α-synuclein. These flies showed aging-related Lewy-body-type cytoplasmic aggregates, degeneration of dopaminergic neurons, and locomotor dysfunction. Kazemi-Esfarjani and Benzer expressed normal and expanded polyglutamine peptides in the Drosophila eye as a model of HD and other trinucleotide disorders. These flies were crossed with 7000 P-element insertion strains to find genes that ameliorate the phenotype. Two rescuing genes are described, both of which contain a chaperone-related J domain. J domains are believed to be important in preventing protein aggregation.

Paper alert

A second cytotoxic proteolytic peptide derived from amyloid β-protein precursor. Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH, Bredesen DE: Nat Med 2000, 6:397-404. • Significance: It is well known that cleavage of the β-amyloid precursor protein (βAPP) at the γ- and β-secretase sites produces cytotoxic Aβ protein. Here it is shown that βAPP cleavage at a caspase-sensitive carboxy-terminal site produces an additional cytotoxic peptide termed C31. Thus, C31 may be important in Alzheimer’s disease (AD)-associated neuronal cell death. Findings: Treatment of mutant and wild-type βAPP by caspases in vitro reveals a novel proteolytic cleavage site at Asp664 that releases a 31 amino acid carboxy-terminal fragment. C31 is shown to promote apoptosis in cultured cells, and evidence for cleavage of βAPP at Asp664 in AD but not control brains is presented. Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. Wong PC, Waggoner E, Subramaniam JR, Tessarollo L, Bartnikas TB, Culotta VC, Price DL, Rothstein J, Gitlin JD: Proc Natl Acad Sci USA 2000, 97:2886-2891. • Significance: Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for a subset of familial amyotrophic lateral sclerosis (FALS) cases, and these mutations may affect the incorporation of copper into SOD1. Here it is shown that a copper chaperone for superoxide dismutase (CCS) is critical for SOD activity in mice. These results suggest that regulation of CCS might provide a novel therapeutic approach to SODlinked FALS. Findings: Mice lacking CCS were generated through gene targeting. These mice show reduced copper incorporation into SOD, reduced SOD activity, and like SOD-deficient mice, increased sensitivity to the free radical generating compound, paraquat.

Erratum Due to an error, these two paper alerts, selected by Stephen Goodwin and Bambos Kyriacou, were truncated in the Neurobiology of behaviour Paper alert section of the previous issue. They are correctly printed here:

Mushroom body ablation impairs short-term memory and long-term memory of courtship conditioning in Drosophila melanogaster. McBride SMJ, Giuliani G, Choi C, Krause P, Correale D, Watson K, Baker G, Siwicki KK: Neuron 1999, 24:967-977. • Significance: McBride et al. assess the role of mushroom bodies (MBs) in Drosophila. These brain structures are known to be involved in some olfactory learning processes, as has been shown by experience-dependent courtship conditioning tests. In contrast to previous studies, these authors report that the MBs are not required for learning and immediate recall of courtship conditioning. However, MBs are shown to be required for consolidation of short- and longterm associative memory. Findings: Previous studies have used a non-genetic approach to generate mushroom body-ablated flies. By feeding hydroxyurea (HU) to newly hatched larvae one can selectively kill the four neuroblasts that are the precursors for the MBs. Adult flies devoid of MBs behave normally but are unable to learn in a classical olfactory conditioning paradigm. McBride et al. extend this MB ablation analysis by using a more complex

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behavioural test— experience-dependent courtship modification (EDCM). Most stages of Drosophila courtship are innately programmed, but some responses are modifiable by experience. For example in EDCM, male courtship is depressed following rejection by a fertilised female, and the rejected male avoids any female, including receptive virgins, for some hours afterwards. The authors report an early, MB-independent phase of memory for courtship conditioning and show that MBs are required in order for such memories to last more than 30 min. Furthermore, they demonstrate that HU-induced damage to antennal lobes can impair memory, supporting a function for the sensory neuropil in MB-independent plasticity. Using a modified form of the EDCM paradigm in which memory is permitted to persist for 9 days, the authors define a requirement for the MBs in long-term memory formation. Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila. Bainton RJ, Tsai LT-Y, Singh CM, Moore MS, Neckameyer WS, Heberlein U: Curr Biol 2000, 10:187-194. AND

Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Li H, Chaney S, Forte M, Hirsh J: Curr Biol 2000, 10:211-214. •• Significance: Both groups exploit the recent findings that have demonstrated behavioural sensitization in Drosophila in response to repeated exposure to cocaine. Bainton et al. present evidence that dopamine plays a role in the responses of Drosophila to cocaine, ethanol or nicotine. Using a variety of behavioural assays to measure the effects of psychostimulants on fly behaviour, they show that responses elicited by cocaine, nicotine or ethanol in flies are similar to the responses in mammals, and that dopaminergic systems play a role in the manifestation of these behaviours. In contrast, Li et al. show that the development of sensitization to cocaine in Drosophila can be blocked by targeted expression of G-protein subunits or tetanus toxin light chain (an inhibitor of transmitter release) in dopamine and serotonin neurons. Findings: To explore the role of dopamine in acute responses to cocaine, nicotine or ethanol, Bainton et al. fed flies 3-iodotyrosine (3IY) to deplete dopamine pharmacologically. They used geotactic and locomotor behavioural assays to measure the effect of these stimulants on the behaviour of dopaminedepleted flies. They observed that acute responses to cocaine and nicotine are diminished in dopamine-depleted flies. Moreover, they observed that dopamine is involved in the acute locomotor-activating effect, but not the sedating effect, of ethanol. Conversely, Li et al. observed increased sensitivity to cocaine in transgenic fly lines in which the evoked synaptic release from dopaminergic and serotonergic neurons had been manipulated by targeted expression of either an inhibitory (Gαi) or stimulatory (Gαs) Gα subunit, or tetanus toxin light chain. How does one account for the observed differences between the groups’ findings? In the study by Bainton et al., the pharmacological treatment results in a systemic depletion of dopamine within the population. Although introduction of different drugs affecting dopamine transmission yields consistent results, DA levels within the CNS of an individual fly may not be completely depleted. It is possible that circulating dopamine is responsible for potentiating the effects of cocaine; however, given that the actions of the DA antagonist reserpine affect these pathways in the same way as 3IY, this seems unlikely. Li

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Paper alert

et al. used transgenic flies in which both dopaminergic and serotonergic neurons were affected during development, whilst Bainton et al.’s pharmacological approach appears not to target serotonin neurons selectively.

Erratum Due to an error, these two paper alerts, selected by Eugene P Brandon and Fred H Gage, were truncated in the Neurobiology of disease Paper alert section of the previous issue. They are correctly printed here:

Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y et al.: Nat Cell Biol 1999, 1:479-485. AND

A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Niwa M, Sidrauski C, Kaufman RJ, Walter P: Cell 1999, 99:691-702. • Significance: Mutations in the presenilin-1 gene (PS-1) represent a major genetic cause of early-onset familial Alzheimer’s disease (FAD). The normal cellular functions of PS-1 protein have not been established, but in these reports PS-1 is linked to the unfolded protein response (UPR), which includes generation of chaperone proteins following endoplasmic reticulum (ER) stress. These findings suggest that the etiology of FAD may involve altered cellular responsiveness to ER stress. Findings: Katayama et al. show that cells expressing dominantmutant forms of PS-1 linked to FAD have impaired induction of the molecular chaperone GRP78/Bip in response to ER stress. Ire1, a signalling protein that responds to ER conditions, showed decreased phosphorylation in these cells. Niwa et al.

demonstrate that the absence of PS-1 also reduces Ire1 function and the UPR. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L: Science 2000, 287:1265-1269. AND

Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho W-H, Castillo PE, Shinsky N, Verdugo JMG, Armanini M, Ryan A et al.: Neuron 2000, 25:239-252. •• Significance: It has previously been shown that mutations in α-synuclein — a protein of largely unknown function — cause a genetic form of Parkinson’s disease (PD). Here, a novel mouse model for PD is established by overexpression of human αsynuclein. Additionally, the requirement for α-synuclein in normal nigrostriatal function is demonstrated by α-synuclein knockout in mice. Findings: Masliah et al. made transgenic mice expressing human α-synuclein in the brain. These mice had ubiquitinated intraneuronal inclusions of aggregated protein similar to those observed in several neurodegenerative disorders including PD. The mice also showed degeneration of nigrostriatal projection neurons and loss of motor function. Abeliovich et al. generated α-synuclein knockout mice. These null mutants showed alterations in electrically evoked dopamine release from nigrostriatal terminals, reduced levels of striatal dopamine, and reduced locomotor responsiveness to amphetamine.