Neurobiology

Neurobiology

231 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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231

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. • ••

of special interest of outstanding interest

Current Opinion in Neurobiology 2002, 12:231–238 Contents (chosen by) 231 Development (Price) 232 Cognitive neuroscience (Silva, Kushner and Reber) 233 Signalling mechanisms (Häusser, Mittmann, Monsivais

and Bezzi) 234 235 235 236 237

Sensory systems (Wood) Neuronal and glial cell biology (Bredt) Motor systems (Chafee and Merchant) Neurobiology of behaviour (Goodwin and Kyriacou) Neurobiology of disease (Kempermann and Winkler)

Development Selected by Jack Price Institute of Psychiatry, London, UK e-mail: [email protected]

•• Glial cells generate neurons: the role of the transcription factor Pax6. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde Y-A, Götz M: Nat Neurosci 2002, 5:308-315. Significance: A remarkable finding: one gene, Pax6, can apparently turn astrocytes into neural precursor cells. Findings: Pax6 is a well-studied gene. Its role in eye development has been extensively analysed, and it also has a fundamental role in the development of the telencephalon. Its role in fate determination, however, is less clear. The expression of Pax6 in precursor cells of the dorsal telencephalon implies that it might play a role in determining the fate of these cells. Earlier studies of fate determination during eye development in Pax6-knockout mice supported this idea. In this study, the authors used gain-of-function and loss-of-function approaches in cerebral cortical cells, both in vivo and in vitro, to show that Pax6 has an important role as an intrinsic determinant of the neurogenic potential of cells. In particular, the authors of the paper report the remarkable finding that transduction of Pax6 into cultured astrocytes transformed these into cells with a broad neurogenic potential, somewhat akin to embryonic radial glial cells. We are increasingly becoming accustomed to glial cells with neurogenic potential; this paper gives us an indication of the mechanism by which this hitherto strange phenomenon is achieved. •• Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Gross C, Zhuang X, Stark K, Ramboz S, Oostling R, Kirby L, Santarelli L, Beck S, Hen R. Nature 2002, 416:396-400.

Significance: An important step in understanding the role of 5HT receptors in anxiety. Findings: 5HT1A receptor agonists are anxiolytic in humans and rodents, and 5HT1A-knockout mice show increased anxiety-like behaviour. The question is where and when does this receptor exert its effect on anxiety? In this paper, an elegant tissuespecific conditional knockout strategy addresses these issues. By using the aCaMKII promoter, which directs transgene expression specifically to cortical structures, the authors expressed 5HT1A in the cortex of 5HT1A-knockout mice, but not in the other main area of 5HT1A expression, the raphé. This expression rescued the behavioural phenotype of the knockout, showing that cortical receptors, rather than receptors in the raphé, are crucial for the modelling of anxiety-like behaviour. When, during development, is 5HT1A expression required for rescue to occur? The authors answer this question by shutting off expression of the transgene using doxycycline. They find that, as long as the 5HT1A receptor was expressed during development, the phenotype was rescued, even though the receptor was turned off in the adult (when behavioural testing took place). Conversely, if the receptor was inactive during the first three weeks of life, the increased anxiety-like behaviour of the 5HT1A-knockout was retained into adulthood, even though expression was activated after three weeks of age. These elegant experiments strongly support the contention that a critical period exists for the establishment of anxiety behaviour, and that the 5HT1A serotonin receptor is crucial for this process. •• Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Trainer PA, Ariza-McNaughton L, Krumlauf R: Science 2002, 295:1288-1291. Significance: A clarification of the intrinsic plasticity of cranial neural crest cells. Findings: The paradox in the title of this paper refers to a discrepancy between Drew Noden’s classic experiments of the 1980s and more recent studies into the plasticity of cranial neural crest cells. Noden grafted first-arch neural crest cells into more posterior locations and discovered a duplication of first-arch structures in the host animals. This led to the idea that cranial neural crest cells impose structure on the periphery, and that they are the dominant partners in the patterning process. More recent studies using molecular markers not available in Noden’s time suggested that patterning results more from a balance of interactions involving hindbrain, crest, and the branchial arch environment. Which model is right? The authors of this study repeated Noden’s grafts, but with an eye to the significance of the isthmus. We now know that this junction region between the midbrain and hindbrain regions has important signaling functions. What they show is that the outcome of Noden’s grafts depends crucially on whether the isthmus is included or not. If it is included, then they get the outcome Noden reported, as indicated in these studies by the inactivation of Hox2a. But if the isthmus is not included, then the transplanted crest cells do not cause rostral duplications, and a normal skeleton results. As would be expected from the outcome of other studies, FGF8 has a role in the signaling processes of the isthmus, but interestingly is not the only factor

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involved. Thus, the paradox appears to be resolved, and the significance of the isthmus as a major signaling centre in embryonic development is reinforced. • Transcriptional regulation of cortical neuron migration by POU domain factors. McEvilly RJ, Ortiz de Diaz M, Schonemann MD, Hooshmand F, Rosenfeld MG. Science 2002, 295:1528-1532. Significance: The identification of candidates for the transcriptional apparatus downstream of the Cdk5 effect on cortical neuronal migration. Findings: A number of cellular pathways have now been identified that are involved in regulating neuronal migration in the developing cerebral cortex. A question that arises therefore is how are these pathways controlled? The authors of this study analysed mice in which the POU domain transcription factors, Brn1 and Brn2 were knocked out. They discover that Brn1 knockout mice have a subtle problem with hippocampal migration, and Brn1/Brn2 double knockout mice display a more dramatic migrational deficit. Using markers of cortical lamination, the authors suggest that this deficit consists of an inversion of layers II–V, such as is observed following Cdk5/p35/p39 gene deletions. A series of experiments indeed suggest that Brn1 and Brn2 can bind to and regulate the p35 and p39 promoters. The model that emerges therefore is that these two POU domain genes regulate cortical neuronal migration by their regulation of the Cdk5/p35/p39 pathway. • Target interaction regulates distribution and stability of specific mRNAs. Hu J-Y, Meng X, Schacher S: J Neurosci 2002, 22:2669-2678. Significance: An interesting study addressing the question of how neurons target mRNAs. Findings: Mechanisms must exist that allow neurons to target specific mRNAs to particular parts of the cell. This must be the case during development and plasticity when certain neuronal targets are to be reinforced and others lost. This study addresses how this might occur during axon targeting in Aplysia neurons. The authors followed the mRNA for sensorin, a sensory neuron-specific gene. They show that interaction with a synaptic target has two effects on sensorin mRNA, effects not seen when axons fail to make a specific synaptic target. First, targeting affects the accumulation of the mRNA at the axon hillock. Second, it changes the stability of the mRNA. It seems likely that these are mechanisms by which the formation of synapses affects how mRNAs are directed within the neuron.

Cognitive neuroscience Selected by Alcino J Silva and Steven A Kushner University of California-Los Angeles, California, USA e-mail: [email protected]

• Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses. Medina JF, Nores WL, Mauk MD: Nature 2002, 416:330-333. Significance: A unique cellular mechanism for the extinction of Pavlovian eyelid conditioning is proposed. Findings: Pavlovian eyelid conditioning involves the repeated pairing of a previously neutral conditioned stimulus (CS) such as a tone, with an aversive unconditioned stimulus (US) such as a shock delivered to the eyelid. Many studies have previously

shown that the US promotes the formation of conditioned eyeblink responses (CR) by activation of climbing fiber afferents from the inferior olive. The authors used pharmacologic inhibitors to either block or mimic extinction of CRs, by manipulating inputs onto climbing fibers. Following five days of training, resulting in robust CRs, infusion of the GABA antagonist picrotoxin into the inferior olive blocked inhibitory inputs onto climbing fibers from the cerebellar nuclei during tone-alone extinction trials. This completely prevented the extinction of CRs. In a second set of experiments, infusion of the AMPA antagonist NBQX during CS–US pairings resulted in extinction of previously acquired CRs, consistent with a blockade of the US input and at a rate similar to that of normal extinction training. Computer simulations incorporating a site of plasticity in the cerebellar cortex resulted in the hypothesis that the bidirectional modulation of climbing fiber activity is responsible for acquisition and extinction of CRs through the induction of LTD and LTP, respectively. • Neuronal responses of the rat amygdala during extinction and reassociation learning in elementary and configural associative tasks. Toyomitsu Y, Nishijo H, Uwano T, Kuratsu J, Ono T: Eur J Neurosci 2002, 15:753-768. Significance: The basolateral nucleus of the amygdala (BLA) is particularly important for appetitive-conditioned instrumental learning and extinction, because it contains neurons with firing properties that are closely correlated with behavioral responses during this form of conditioning. Findings: The authors recorded from neurons throughout the amygdaloid nuclei during learning of associations between sensory stimuli and intracranial self-stimulation reinforcement. Of the amygdala neurons that responded to sensory stimuli alone, 40.3% increased their firing following reward association. A subset of animals were additionally subjected to a series of extinction trials. In 68.9% of neurons that previously responded strongly following conditioning, responses were significantly decreased during extinction. Following extinction, additional conditioning trials resulted in the resumption of strong responses in 83.9% of cells, designated as plastic neurons. This subset of cells was located primarily within the BLA and correlated most highly with the behavioral responses during learning, extinction, and relearning. • Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Tsvetkov E, Carlezon WA, Benes FM, Kandel ER, Bolshakov VY: Neuron 2002, 34:289-300. Significance: Pavlovian conditioning potentiates the cortico–amygdala pathway using LTP-like mechanisms. Findings: The authors examined an associative form of LTP by pairing presynaptic stimulation of the external capsule with postsynaptic depolarization. The necessity for a rise in postsynaptic calcium was demonstrated by including the chelator EGTA, which blocks LTP induction, in the recording pipette. The combination of the NMDA receptor antagonist APV and the L-type calcium channel antagonist nitrendipine completely abolished LTP; however, either agent alone only attenuated LTP. Behavioral conditioning 48 hours prior to slice electrophysiology resulted in a significant occlusion of LTP and paired-pulse facilitation in animals receiving paired, but not randomly paired training. The authors also provide some evidence suggesting that this form of LTP may be dependent on presynaptic mechanisms.

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Selected by Paul J Reber Northwestern University, Evanston, Illinois, USA e-mail: [email protected]

• The medial frontal cortex and the rapid processing of monetary gains and losses. Gehring WJ, Willough AR: Science 2002, 295:2279-2282. Significance: Processing negative outcomes affects cognition as early as 265ms in a manner that is independent of errormonitoring and affects future risk-taking behavior. Findings: Event-related potentials were used to identify differential processing of reward and loss outcomes as early as 265ms after presentation of trial feedback in a gambling task. A mid-frontal negativity (MFN) was identified that occurred during loss events regardless of whether the participant’s choice had been correct, suggesting that the MFN is not related to error-monitoring. The MFN instead appears to reflect rapid assessment of the trial outcome, as part of the event’s impact on the participant’s motivational state. Consistent with this idea, risk-taking behavior on subsequent trials was strongly correlated with the magnitude of the MFN. • Temporal evolution of a decision-making process on medial premotor cortex. Hern Hernandez A, Zainos A, Romo R: Neuron 2002, 33:959-972. Significance: Correlation of neuronal activity in the medial premotor cortex (MPC) with all cognitive processing steps, not just the motor demands, in a tactile comparison task. Findings: During a tactile comparison task, neuronal activity in the MPC was found to correlate with processing demands in every stage of the cognitive task, including processing of sensory stimuli, maintenance of information over a delay, comparison of stimuli, and selecting a response. Thus, the MPC does not simply wait for information about the response evoked by the task, but participates in every step of the task by integrating working memory and sensory inputs. This result reinforces the idea that cognitive tasks, such as tactile vibration matching, are supported by interacting networks of cortical regions, rather than by a series of encapsulated processing modules and indicates that the MPC is not simply involved in decoding a response signal into a motor program.

Signalling mechanisms Selected by Michael Häusser, Wolfgang Mittmann and Pablo Monsivais University College London, London, UK e-mail: [email protected]

•• Identification of a cold receptor reveals a general role for TRP channels in thermosensation. McKemy DD, Neuhausser WM, Julius D: Nature 2002, 416:52-58. •• A TRP channel that senses cold stimuli and menthol. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A: Cell 2002, 108:705-715. Significance: Strong indication that TRP channels are the primary molecular substrates for thermoreception. Findings: These papers describe the cloning and characterization of a member of the TRP family of channels that senses cold. The new cold-sensing receptor (named CMR1 or TRPM8) shares several common features with its heat-sensing family members (VR1, VRL1): they are non-selective cation

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channels, expressed in a subset of small diameter neurons in trigeminal and dorsal root ganglia. Compounds such as menthol and icilin that induce cold sensations also activated the cold-sensing receptor. Expression of the channel in CHO or HEK cells showed that it is outwardly rectifying and calciumpermeable; thus, cold stimuli raise intracellular calcium levels in cells expressing the channel. The findings open up possibilities for understanding the transduction from stimulus (thermal energy) to neuronal activity on a molecular level. In particular, identifying the channel structure that senses thermal energy is an exciting issue that remains to be resolved. • Functional roles of presynaptic GABAA receptors on glycinergic nerve terminals in the rat spinal cord. Jang I-S, Jeong H-J, Katsurabayashi S, Akaike N: J Physiology 2002, in press. DOI: 10.1113/jphysiol.2001.016535. Significance: The first demonstration of GABAA-dependent inhibition of glycinergic terminals onto spinal neurons, by a mechanism that depends on the Na+/K+/Cl– cotransporter NKCC in the glycinergic terminals. Findings: Neurons of the sacral dorsal commissural nucleus (SDCN) in the spinal cord receive both glycinergic and GABAergic input, and retain the terminals of these synaptic inputs even after mechanical isolation. The authors recorded glycinergic inhibitory poststynaptic currents (IPSCs) from isolated SDCN neurons and found that muscimol, a GABAAspecific agonist both increases the frequency of spontaneous IPSCs and reduces the amplitude of evoked events. Muscimol’s action is presynaptic, and — as has been shown in presynaptic inhibition of excitatory terminals in the spinal cord and other preparations — its mechanism depends on depolarization caused by the efflux of Cl– from the terminal. The authors show that blocking the activity of a specific ion transporter, NKCC, inhibits the effect of muscimol, suggesting that this transporter is crucial for maintaining the elevated intraterminal [Cl–] that is required for GABAergic inhibition of glycinergic terminals. The results point to the possibility that GABAergic circuits presynaptically adjust the strength of both excitatory and inhibitory signals being integrated in the spinal cord. Selected by Paola Bezzi University of Lausanne, Lausanne, Switzerland e-mail: [email protected]

α. Beattie EC, • Control of synaptic strength by glial TNFα Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC: Science 2002, 295:2282-2285. Significance: A glia-derived factor, TNFα, exerts control on synaptic strength at excitatory synapses, by tuning the surface expression of postsynaptic AMPA receptors (AMPARs). Findings: Exposure of mixed hippocampal cultures to exogenous TNFα leads to an increase in the surface expression of postsynaptic AMPARs, as well as an increase in the efficacy of excitatory synapses, mainly seen as enhanced miniature excitatory postsynaptic current (mEPSC) frequency. The authors provide evidence for a direct correlation between the two events, although they do not rule out that the effect on mEPSC frequency involves additional TNFα-dependent events presynaptically. Blocking the action of endogenous TNFα has opposite effects, which implies a tonic control by the cytokine on synaptic function. The authors suggest that astrocytes rather than neurons are the source of TNFα because administration of conditioned media from astrocyte cultures reproduces the effect of

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the cytokine on AMPAR surface expression and this effect is inhibited by TNFα blockers. Finally, the authors validate their cell culture studies by showing that the application of a soluble TNF receptor 1, which acts as a sink of endogenous TNFα, decreased AMPAR/NMDAR-dependent EPSC ratio and mEPSC frequency at excitatory synapses in hippocampal slices. These results suggest a novel role for TNFα in the control of synaptic strength and reinforce the emerging concept that glial cells actively participate in synaptic function. However, the mechanism of TNFα action and the signals that trigger its release from glial cells now await elucidation. (See also Bredt pp235.) • Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Zaccolo M, Pozzan T: Science 2002, 295:1711-1715 Significance: The first direct evidence that local gradients of cAMP are formed within cardiac myocytes stimulated by β-adrenergic agonists. Findings: Much is already understood about the existence of subcellular compartmentation of cAMP action in the heart. In cardiac myocytes, G-proteins, adenylyl cyclase, PKA, A-kinase-anchoring proteins (AKAPs) and L-type Ca2+ channels are found in discrete subcellular regions (the T-tubular network) providing the anatomical basis for a confined activation of cAMP-dependent signalling. Here, the authors directly monitored cAMP rises induced by β-adrenergic stimulation in cardiac myocytes in real time, using a cAMP sensor based on fluorescence resonance energy transfer (FRET) and tagged PKA subunits. Rises of cAMP in a restricted domain, with a range of action of about 1 µm, are necessary to selectively activate a pool of PKA molecules anchored to the T-tubule membrane through AKAPs. Diffusion of cAMP within the cytosol is prevented by the activity of phosphodiesterases. Thus, in the presence of a broad-spectrum phophodiesterase inhibitor, a dissipation of cAMP gradients and a subsequent generalized activation of PKA were observed. To support the potential physiological role of local compartments of enhanced cAMP levels, the authors generated a variant of the cAMP sensor (a deletion mutant of the tagged PKA subunit) unable to bind AKAPs and therefore unable to specifically localize to T-tubule membranes. In this case, the sensor could not efficiently report the increase in cAMP level induced by β-adrenergic stimulation, indicating that such an increase was confined to the T-tubule membrane area.

Sensory systems Selected by John N Wood University College London, London, UK e-mail: [email protected]

•• Chondroitinase ABC promotes functional recovery after spinal cord injury. Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB: Nature 2002, 416:636-640. Significance: The description of a mechanism for facilitating recovery of damaged central sensory and motor circuits. Findings: A striking difference between the peripheral and central nervous systems is the irreversible nature of most central injuries. Thus, even with restored sensory input, spinal cord injuries preclude full recovery in many accident victims. At sites of CNS injury, a glial scar develops containing extracellular matrix molecules

including chondroitin sulphate proteoglycans (CSPGs) that block axonal growth. Here, intrathecal treatment of the glial scar with chondroitinase ABC was found to promote regeneration of both ascending sensory projections and descending corticospinal tract axons. The treatment also restored postsynaptic activity below the lesion and most importantly promoted functional recovery of locomotor and proprioceptive behaviours. These results demonstrate that CSPGs are significant inhibitory molecules in the CNS, and suggest that their manipulation will be useful for treatment of human spinal injuries.(See also Kempermann and Winkler pp237.) • c-fos regulates neuronal excitability and survival. Zhang J, Zhang D, McQuade JS, Behbehani M, Tsien JZ, Xu M: Nat Genet 2002, 30:416-420. Significance: The role of c-fos in gene regulation and control of neuronal survival is addressed, using a tissue-specific null mutant. Findings: c-fos staining has been used as a marker of neuronal activation and has been useful in mapping pain pathways. Evidence suggests that c-fos is essential in regulating neuronal cell survival versus death. The c-fos proteins form heterodimers with Jun family proteins and the resulting AP1 complexes regulate transcription by binding to the AP1 sequence found in many cellular genes. Mutant mice with little c-fos in the hippocampus had more severe kainic acid-induced seizures and increased neuronal excitability and neuronal cell death, compared with control mice. The expression of BDNF and the kainic acid receptor GluR6, both in vivo and in vitro, were disrupted. Thus, c-fos seems to be an important regulator of mechanisms mediating neuronal excitability and survival. •• The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Wemmie JA, Chen J, Askwith CC, Hruska-Hageman AM, Price MP, Nolan BC, Yoder PG, Lamani E, Hoshi T, Freeman JH et al.: Neuron 2002, 34:463-477 Significance: An unsuspected involvement of acid sensing ion channels (ASICs) in LTP is demonstrated. Findings: ASICs have been the focus of intense interest as potential mechanosensors as well as damage sensors in the peripheral nervous system. Using null mice to eliminate ASIC1, the authors abolished H+-gated currents in hippocampal neurons. This loss of ASIC1 also impaired hippocampal LTP. ASIC1-null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, ASIC1-null mice also displayed defective spatial learning and eyeblink conditioning. These results identify ASIC1 as a significant component in processes underlying synaptic plasticity, learning and memory. Whether mediators other than protons gate these channels still remains an open question, however. •• Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Lonze BE, Riccio A, Cohen S, Ginty DD: Neuron 2002, 34:371-385. Significance: Description of a critical role for CREB phosphorylation in peripheral neuron survival and axon outgrowth. Findings: The transcriptional regulatory events downstream of neurotrophin signaling are still being elucidated. CREB is phosphorylated on its transcriptional regulatory site, Ser133, in a neurotrophin-dependent manner in vivo. In CREB-null mice, sensory neurons exhibit excess apoptosis and degeneration, and display impaired axonal growth and projections; however, increased apoptosis is not observed in the central nervous

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system. CREB is also required within sensory and sympathetic neurons for axon outgrowth as measured in cultured neurons from CREB-null mice. Thus, peripheral neurons require CREB-mediated gene expression for both survival and growth in vivo during development.

Neuronal and glial cell biology Selected by David S Bredt University of California at San Francisco, San Francisco, California e-mail: [email protected]

• Mobile NMDA receptors at hippocampal synapses. Tovar KR, Westbrook GL: Neuron 2002, 34:255-264. Significance: This paper reports the surprising finding that NMDA receptors move between synaptic and extra-synaptic pools, suggesting that they are dynamic at the postsynaptic density (PSD). Findings: Glutamate receptors are concentrated in the PSD in association with cytoskeletal clustering molecules. However, recent work indicates that AMPA-type glutamate receptors are highly mobile and cycle on and off the synaptic membrane to control synaptic strength. This paper examines the mobility of NMDA-type glutamate receptors. The authors used the openchannel blocker MK801 and ketamine to tag synaptic NMDA receptors. Interestingly, they find that NMDA receptor-mediated EPSCs showed an anomalous recovery following the MK801 block. A variety of pharmacological and physiological experiments indicated that this recovery could not be explained by either MK801 unbinding or insertion of new receptors. These experiments suggest instead that NMDA receptors move laterally into the synapse, and — like AMPA receptors — are highly mobile at the PSD. α. Beattie EC, • Control of synaptic strength by glial TNFα Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC: Science 2002, 295:2282-2285. Significance: Glial-derived TNFα modulates synaptic plasticity and may respond to neural injury. Findings: Activity-dependent changes in synaptic strength represent a primary mechanism for information storage in brain. How glia influence synaptic strength has not yet been explored in detail. Here, the authors show that a cytokine released from glia, TNFα, enhances synaptic efficacy by increasing surface expression of AMPA receptors. Using cultured hippocampal neurons, they find that exposure to TNFα caused an increase in functional AMPA receptors at the synapse. By contrast, NMDA receptor levels were not changed. Conversely, blocking TNFα action decreased surface AMPA receptors. The authors also show that TNFα is the active component in glial-conditioned media that increases surface AMPA receptors. These results suggest a novel role for glia in rapid regulation of synaptic strength by a secreted cytokine. (See also Bezzi, pp233.)

Motor systems Selected by Matthew Chafee* and Hugo Merchant Brain Sciences Center, VAMC, Minneapolis, Minnesota, USA *e-mail: [email protected]

• Direct visuomotor transformations for reaching. Buneo CA, Jarvis MR, Batista AP, Andersen RA: Nature 2002, 416:632-636.

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Significance: Demonstration that parietal area 5 participates in the visuomotor transform necessary to move the hand toward a visible target. Findings: In the experiments presented here, monkeys reached toward peripheral targets. The starting hand position and the point of ocular fixation were varied — target position shifted with hand position so that the same movement directions were tested in each case. Firing rate around the time of movement initiation depended upon both hand movement direction and the retinal location of the target — in other words, firing rate was maximal for a particular conjunction of the two factors. For example, when eye position remained constant, and starting hand position varied, the preferred movement directions of neurons shifted by an amount indicating partial dependence upon both spatial frames (eye and hand). Thus, the authors specifically show that individual neurons in parietal area 5 encode reach targets simultaneously in eye-centered and handcentered coordinate frames. This pattern is distinct from that observed in the parietal reach region, where reaching movements are coded in an eye-centered coordinate frame. • A neural correlate of oculomotor sequences in supplementary eye field. Lu X, Matsuzawa M, Hikosaka O: Neuron 2002, 34:317-325. Significance: Neurons in the supplementary eye field encode not only saccade direction but also the order in which a sequence of saccades is made. Findings: How movement sequences are controlled by the motor system remains a central question in the control of complex movement. Five pairs of stimuli (sets) appeared in a sequence (hyperset). One stimulus of each pair served as a saccade target, one as a distractor. Which stimulus was the target depended upon the spatial locations of both stimuli and the serial position of the pair in the sequence. Monkeys were rewarded for making a saccade to the target stimulus in each pair. One type of neuron was active before saccades in a preferred direction, irrespective of sequence factors. A second group was active for saccades of preferred directions, but also depended upon the location of the distractor stimulus. The third group (accounting for the largest proportion of the sample) was selective for both the target and distractor locations, but only became active when this preferred stimulus pair appeared at a specific serial position in the sequence. • Temporal relation of population activity in visual areas MT/MST and in primary motor cortex during visually guided tracking movements. Kruse W, Dannenberg S, Kleiser R, Hoffmann K: Cereb Cortex 2002, 12:466-476. Significance: Description of a clear coactivation of directional visual and motor populations of neurons during a hand tracking task. Findings: The activity of neurons in MT/MST and motor cortex was recorded while monkeys performed a hand-tracking task of rectilinear moving targets. In this task, the animals maintained eye fixation during a moving stimulus period and during a moving stimulus plus hand tracking period. To perform the task, then, the visual information was essential for an accurate motor response. Population vectors during the tracking task were computed using the activity of cells that were tuned to the direction of hand movement in the motor cortex, and to the direction of visual motion in MT/MST. The authors find several significant results. First, the direction of movement was coded faithfully and was colinear in both areas at the population level.

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Second, the temporal evolution of the activation in the motor and in the visual areas was related to the velocity profile of the corresponding hand and target movement, respectively. Third, by using a multiple regression model, the authors showed that the motor cortical population coded the kinematics of the upcoming movement with a lead time of ~300 ms; the population of cells in MT/MST followed the onset of the stimulus motion by ~80 ms. Fourth, despite the coactivation of both population coding similar movement directions, the neural activity in motor cortex and MT/MST was not synchronized.

honeybees also had elevated PKG levels. Pharmacological elevation of PKG levels also produced precocious foraging, whereas similar treatments that elevated PKC did not, providing an element of specificity in these experimental interventions. Amfor is highly expressed in the lamina of the optic lobes, and in the mushroom bodies of the brain that receive visual input, suggesting that it integrates visual input with foraging and orientation. Thus, the for gene plays an important role in feeding behaviour in both Drosophila and Apis, and one wonders where this conservation of function may lead. Mammals?

• Differences in the corticospinal projection from primary motor cortex and supplementary motor areas to macaque upper limb motorneurons: an anatomical and electrophysiological study. Maier MA, Armand J, Kirkwood PA, Yand W, Davis JN, Lemon RN: Cereb Cortex 2002, 12:281-296. Significance: An indication that the cortico–motoneuronal connections originating from the SMA and M1 may function in parallel; however, those from M1 are more numerous and exert stronger excitatory effects. Findings: In this study, the tracing agent WGA–HRP was focally injected into the carefully identified hand representations of M1 and SMA. Densitometric analysis showed that, even if the pattern of projections from M1 and SMA in the lower cervical cord was similar, the corticospinal projection from M1 was denser and occupied a larger area of lamina IX in the hand and finger motor nuclei. At the electrophysiological level, the authors find that the corticospinal volleys evoked from M1 stimulation were two to three times larger than those from the SMA. This can be explained by the difference in the number of fibers provided by these areas to the cervical and thoracic segments. Furthermore, intracellular recordings of upper limb motor neurons showed that the excitatory postsynaptic potentials evoked from M1 stimulation were larger and more frequent that those from the SMA.

• Television viewing and aggressive behavior during adolescence and adulthood. Johnson JG, Cohen P, Smailes EM, Kasen S, Brook JS: Science 2002, 295:2468-2471. Significance: Discovery of a significant association between the intensity of exposure to TV violence and subsequent aggressive acts against others. Findings: The question of whether violence on television plays a role in the development of aggressive behaviour has a long and chequered history within psychology. In this longitudinal study over a 17-year period, 707 families in the USA monitored their children’s (ages 1–10 years) viewing of television violence from 1975 onwards. Interviews were conducted with the families periodically until 1993, and a large number of additional variables (e.g. socio-economic status, IQ, etc.) were considered. There was a positive correlation between the documented levels of aggression at the ages of 16 and 22 years and the number of hours per day spent watching television at the earlier mean age of 14 years, and this was particularly true for the males. However, this situation was reversed in older females, as the correlation was significantly higher in 22-year-old females than in males. Interestingly, property crimes, including vandalism, arson and theft, were not correlated with television viewing. The authors conclude that extensive exposure to television by adolescents and young adults is associated with an increased probability of committing aggressive acts against others. This relationship is only slightly modulated by other environmental factors that predispose towards more television viewing or aggression, such as living in unsafe neighbourhoods, parental neglect, or low family income. Although not indicating causality, as other, unidentified factors may not have been controlled for, this study asks serious questions about the role of television in the development of young people.

Neurobiology of behaviour Selected by Stephen Goodwin* and Bambos Kyriacou† *University of Glasgow, Glasgow, UK e-mail: [email protected] †University of Leicester, Leicester, UK e-mail: [email protected]

• Influence of gene action across different time scales on behavior. Ben-Shahar Y, Robichon A, Sokolowski MB, Robinson GE: Science 2002, 296:741-744. Significance: Revelation of the conservation of function for the foraging (for) gene between diptera and hymenoptera. Findings: The authors show that a single gene that plays a role in determining a polymorphic complex behaviour pattern in Drosophila, also plays a similar role in the development of bees from nurses to foragers. A polymorphism in the for gene was identified in natural Drosophila populations many years ago. The two haplotypes generate different types of food-related behaviour, in that ‘rovers’ go out and forage for food, whereas ‘sitters’, simply linger around a food source. This study reveals that as bees develop and move from the nursing to the foraging stage, they upregulate their for orthologue (amfor), which encodes a cGMP-dependent protein kinase (PKG). This effect was independent of age, because manipulations of colony social structure that generated precocious foragers showed that these

• Embryonic assembly of a central pattern generator without sensory input. Suster ML, Bate M: Nature 2002, 416:174-178. Significance: Sensory feedback is important for the development of coordination between movements, but not for the development of movements themselves. Findings: A key issue in understanding motor systems is whether sensory feedback is required for their normal development. These authors generated transgenic Drosophila larvae in which peripheral sensory systems were genetically ablated. Drosophila larvae crawl using coordinated peristaltic waves of muscle contractions that pass along their body segments generating forward and backward movements. Pharmacological interventions that block neurotransmission in the CNS also eliminate peristalsis. To examine whether the larval sensory nervous system is implicated in the normal development of the pattern generators that produce peristalsis, a tetanus toxin light chain was targeted to these peripheral organs and multidendritic neurons, using the binary UAS/GAL4 system. Transgenic

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larvae were able to make forward and backward movements, but the number of normal forward movements was significantly impaired. Thus, the central circuits required for these movements were present, but they were not coordinated correctly. Similar results were obtained with a mutation eliminating most sensory neurons. Therefore, the basic pattern generator does not require sensory input for the development of the basic peristaltic movement. However the ‘fine-tuning’ of the coordination between forward and backward movement is affected by removal of the peripheral sensory system.

flow in the cerebral cortex of rats by laser-speckle-contrast imaging. Picking the cerebral surface away from the middle meningeal artery (MMA) caused a delayed and transient strong increase in cortical blood flow, including in the MMA. This increase propagated across the cortical surface and was paralleled by a wave of cortical depolarization (cortical spreading depression). Transection of the trigeminal nerve or parasympathetic efferents inhibited this delayed increase in blood flow in the MMA, suggesting that the response was indeed mediated by brain stem centers.

• Annotated expressed sequence tags and cDNA microarrays for studies of brain and behavior in the honeybee. Whitfield CW, Band MR, Bonaldo MF, Kumar CG, Liu L, Pardinas JR, Robertson HM, Soares MB, Robinson GE: Genome Res 2002, 12:555-566. Significance: A comprehensive approach to the molecular analysis of the honeybee Apis mellifera. Findings: The authors produced an expressed sequence tag (EST) resource for the honey bee brain. Honeybees of different ages performing a wide range of natural behaviours were gathered from a field colony. Brains were then dissected and mRNA extracted. The authors made a normalised, unidirectional brain cDNA library. The library was then subtracted. More than 20,000 cDNA clones were partially sequenced from the normalised and subtracted libraries, resulting in 15,311 vectortrimmed, high-quality, ESTs representing 8,912 putatively unique sequences. These sequences were tested for similarity to sequences in the public databases with a variety of BLAST searches. The honeybee ESTs were tentatively assigned molecular function and biological process using the Gene Ontology classification system based on corresponding gene sequences in Drosophila. Approximately half of the Drosophila genes concerned with synaptic transmission and behaviour are represented in the honeybee EST set. In the future, the DNA microarrays will be exploited to test whether variation in gene expression in the brain is a mechanism that brings about behavioural diversity in the honeybee. Such studies of the honeybee will contribute to our understanding of the relationship between genes and behaviour, most notably to complex social behaviours. (See also Ben-Shahar et al. above.)

• Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. Zink WE, Anderson E, Boyle J, Hock L, Rodriguez-Sierra J, Xiong H, Gendelman HE, Persidsky Y: J Neurosci 2002, 22:2096-2105. Significance: Usefulness of a mouse model of HIV-1 encephalitis with regard to assessing cognitive symptoms. Findings: The authors studied HIV-1 infected mice in the Morris water maze and found severe and increasing failure to acquire and use spatial reference memory. At various times after intracerebral injection of HIV-1, slice preparations were made and decreased LTP was demonstrated in the infected animals. At the same time, a decreased expression of neurofilament and synaptophysin, a membrane protein associated with active synapses, was visualized by means of immunohistochemistry in the hippocampal subregion CA2. This study is unusual in that it correlates behavioral measures with synaptic physiology and the assessment of cell death and of cellular morphology, thus narrowing the experimental gap that often exists between behavioral and morphological data.

Neurobiology of disease Selected by Gerd Kempermann* and Juergen Winkler† *Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany e-mail: [email protected] †Department of Neurology, University of Regensburg, Germany e-mail: [email protected]

• Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA: Nat Med 2002, 8:136-142. Significance: A better understanding of how two very different aspects of migraine — cortical spreading depression and activation of perivascular trigeminal afferents — could be linked. Findings: Pain syndromes and particularly headaches are notoriously difficult to investigate in animal models. This study shows how an event on the level of brain activity (cortical spreading depression) could lead to extracerebral vasodilation and how the trigeminal nerve might become involved in transmitting the migraine pain signals. The authors visualized blood

• Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM: Science 2002, 295:2264-2267. Significance: In a mouse model of AD, a correlation between the measurable plasma amyloid loads and amyloid burden in the hippocampus and cortex is achieved. Findings: To date, no useful biochemical marker for Alzheimer disease (AD) exists that would allow simplified screening and longitudinal follow-up procedures in order to estimate the amyloid burden in patients with presumed AD. This study shows that the systemic application of a monoclonal antibody against β-amyloid (Aβ) protein causes a strong increase in Aβ that is measurable in the plasma. In contrast to baseline levels of Aβ isoforms, this antibody-mediated level of Aβ correlated well with amyloid burden in the hippocampus. It remains to be shown if this strong link exists in humans and whether the method used can be readily applied in humans. •• Chondroitinase ABC promotes functional recovery after spinal cord injury. Bradbury EJ, Moon LDF, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB: Science 2002, 416:636-640. Significance: The removal of chondroitin sulphate proteoglycans (CSPGs) promotes axonal outgrowth after spinal injury. Findings: After traumatic spinal cord injury, very limited xonal regeneration occurs, leading to devastating clinical consequences such as complete and permanent paralysis. The extracellular matrix represents one of the major components of the glial scar blocking nerve regeneration across the severed spinal cord. The authors intrathecally infused chondroitinase

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ABC, a bacterial enzyme, into the lesion site of rats with dorsal column crush lesions. Chondroitinase ABC treatment degraded CSPGs around the lesion and stimulated the regeneration of newly formed ascending sensory and descending motor axons. More importantly, this enzyme-based treatment promoted functional recovery, as assessed by using a broad battery of behavioral tests determining locomotor and proprioceptive behaviors. In addition, electrophysiological data indicated that regenerated corticospinal tract axons established new, appropriate connections. This approach in combination with the use of other peptides could open the window for a better treatment in humans with traumatic spinal cord injury. (See also Wood, pp234.) • Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinmann L: Nat Med 2002, 8:143-149. Significance: Systemic application of the transglutaminase (TGase) inhibitor cystamine improves motoric abnormalities and life expectancy in Huntington’s disease (HD) mice. Findings: HD is a progressive neurodegenerative disorder leading to chorea, severe cognitive impairments and weight loss, without any effective treatment at present. HD is linked to an expanded polyglutamine domain with more than 36 repeats near the N-terminus of huntingtin. TGase crosslinks huntingtin and may play a major role in the pathogenesis of HD. Intraperitoneal administration of cystamine, a competitor for TGase, into transgenic mice expressing exon 1 of huntingtin, reduced their associated tremor after the onset of motor symptoms. Additionally, their body weight loss was significantly less severe compared to control injected animals.

However, the severity of neuronal nuclear inclusions was not affected by cystamine. Interestingly, neuroprotective genes belonging to the chaperone family that are able to suppress aggregate formation were upregulated both in human HD specimens and mice treated with cystamine. This study supports the importance of further testing these compounds in HD patients. Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. Boncritiano S, Calhoun ME, Kelly PH, Pfeifer M, Bondolfi L, Stalder M, Phinney AL, Abramowski D, Sturchler-Pierrat C, Enz A et al.: J Neurosci 2002, 22:3234-3243. Significance: An insight into cholinergic hypofunction in AD that may be caused by the cholinergic neuronal loss of the basal forebrain and regionally by neocortical amyloidosis in transgenic mice. Findings: The relationship between cortical deposition of Aβ peptide and the cholinergic deficit in AD is poorly understood. The neuroanatomical analysis of aged amyloid precursor protein transgenic mice (APP23) carrying the Swedish AD mutation showed a modest disruption and loss of cholinergic fibers associated with a decrease of choline acetyltransferase and acetylcholinesterase enzyme activity in the neocortex. However, no loss of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and the medial septum, the two major cholinergic nuclei of the basal forebrain, was present. These findings indicate both that the dysfunction of the cholinergic terminals is caused by Aβ accumulation and that the cholinergic neurons of the basal forebrain are not the primary target of AD-related neurodegenerative processes. In addition, electrolytic NBM lesioning did not promote cortical amyloidosis in aged APP23 mice.