Hot off the presses! May 01 Nat Neurosci

The May 01 issue of the Nat Neurosci is now up on Pubget (About Nat Neurosci): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Marching for science
  - Nat Neurosci 12(5):523 (2009)
  
• Kuru, moral peril and the creation of value in science
  - Nat Neurosci 12(5):525 (2009)
  
• Carrot sticks or joysticks: video games improve vision
  - Nat Neurosci 12(5):527-528 (2009)
  
• Bottoms up: transduction channels at tip link bases
  - Nat Neurosci 12(5):529-530 (2009)
  
• Inhibition by an excitatory conductance: a paradox explained
  - Nat Neurosci 12(5):530-532 (2009)
  
• The secret language of siblings
  - Nat Neurosci 12(5):532-534 (2009)
  
• Motoneurons buckling under stress
  - Nat Neurosci 12(5):534 (2009)
  
• Circular analysis in systems neuroscience: the dangers of double dipping
  - Nat Neurosci 12(5):535-540 (2009)
  A neuroscientific experiment typically generates a large amount of data, of which only a small fraction is analyzed in detail and presented in a publication. However, selection among noisy measurements can render circular an otherwise appropriate analysis and invalidate results. Here we argue that systems neuroscience needs to adjust some widespread practices to avoid the circularity that can arise from selection. In particular, 'double dipping', the use of the same dataset for selection and selective analysis, will give distorted descriptive statistics and invalid statistical inference whenever the results statistics are not inherently independent of the selection criteria under the null hypothesis. To demonstrate the problem, we apply widely used analyses to noise data known to not contain the experimental effects in question. Spurious effects can appear in the context of both univariate activation analysis and multivariate pattern-information analysis. We suggest a ! policy for avoiding circularity.
• Small voltage changes at nerve terminals travel up axons to affect action potential initiation
  - Nat Neurosci 12(5):541-543 (2009)
  Nerve terminals are generally considered to be the destination points for electrical signals, which propagate unidirectionally from the soma to nerve terminals. We found that small hyperpolarizations or depolarizations (approx10 mV) generated under physiological conditions in rat nerve terminals backpropagated up the axon (approx400–800 mum) and changed the threshold for initiating action potentials and thus firing patterns. These results suggest a mechanism for information processing in neurons and neuronal circuits.
• Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons
  - Nat Neurosci 12(5):544-546 (2009)
  Itch is relieved by scratching, but the neural mechanisms that are responsible for this are unknown. Spinothalamic tract (STT) neurons respond to itch-producing agents and transmit pruritic information to the brain. We observed that scratching the cutaneous receptive field of primate STT neurons produced inhibition during histamine-evoked activity but not during spontaneous activity or activity evoked by a painful stimulus, suggesting that scratching inhibits the transmission of itch in the spinal cord in a state-dependent manner.
• Coding of pleasant touch by unmyelinated afferents in humans
  - Nat Neurosci 12(5):547-548 (2009)
  Pleasant touch sensations may begin with neural coding in the periphery by specific afferents. We found that during soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities (1-10 cm s-1), which were perceived by subjects as being the most pleasant. Our results indicate that C-tactile afferents constitute a privileged peripheral pathway for pleasant tactile stimulation that is likely to signal affiliative social body contact.
• Enhancing the contrast sensitivity function through action video game training
  - Nat Neurosci 12(5):549-551 (2009)
  The contrast sensitivity function (CSF) is routinely assessed in clinical evaluation of vision and is the primary limiting factor in how well one sees. CSF improvements are typically brought about by correction of the optics of the eye with eyeglasses, contact lenses or surgery. We found that the very act of action video game playing also enhanced contrast sensitivity, providing a complementary route to eyesight improvement.
• Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging
  - Nat Neurosci 12(5):553-558 (2009)
  Hair cells detect vibrations of their stereociliary bundle by activation of mechanically sensitive transducer channels. Although evidence suggests the transducer channels are near the stereociliary tops and are opened by force imparted by tip links connecting contiguous stereocilia, the exact channel site remains controversial. We used fast confocal imaging of fluorescence changes reflecting calcium entry during bundle stimulation to localize the channels. Calcium signals were visible in single stereocilia of rat cochlear inner hair cells and were up to tenfold larger and faster in the second and third stereociliary rows than in the tallest first row. The number of functional stereocilia was proportional to transducer current amplitude, indicating that there were about two channels per stereocilium. Comparable results were obtained in outer hair cells. The observations, supported by theoretical simulations, suggest there are no functional mechanically sensitive transdu! cer channels in first row stereocilia and imply the channels are present only at the bottom of the tip links.
• Tubulin tyrosination navigates the kinesin-1 motor domain to axons
  - Nat Neurosci 12(5):559-567 (2009)
  Neurons form distinctive axonal and dendritic compartments that are important for directional signaling, but the mechanisms that discriminate between axons and dendrites remain elusive. Previous studies have demonstrated that the kinesin-1 motor domain is capable of distinguishing the axon from dendrites. Here we found that the amino acid substitutions in the beta5-loop8 region transformed truncated kinesin-1 from a uni-destination (that is, the axon-specific destination) to a bi-destination (that is, axons and dendrites) state. Furthermore, tyrosinated tubulins that are abundant in somatodendrites prevent the wild-type kinesin-1 from binding to microtubules, whereas the bi-destination–type kinesin-1 does not have this inhibition. Consistently, inhibition of tubulin tyrosination in rat hippocampal neurons resulted in the distribution of truncated kinesin-1 in both axons and dendrites. Our study identifies a molecular mechanism that discriminates the axonal microtubul! es from somatodendritic microtubules, as well as a previously unknown linkage between tubulin modification and polarized trafficking in neurons.
• Myosin-dependent targeting of transmembrane proteins to neuronal dendrites
  - Nat Neurosci 12(5):568-576 (2009)
  The distinct electrical properties of axonal and dendritic membranes are largely a result of specific transport of vesicle-bound membrane proteins to each compartment. How this specificity arises is unclear because kinesin motors that transport vesicles cannot autonomously distinguish dendritically projecting microtubules from those projecting axonally. We hypothesized that interaction with a second motor might enable vesicles containing dendritic proteins to preferentially associate with dendritically projecting microtubules and avoid those that project to the axon. Here we show that in rat cortical neurons, localization of several distinct transmembrane proteins to dendrites is dependent on specific myosin motors and an intact actin network. Moreover, fusion with a myosin-binding domain from Melanophilin targeted Channelrhodopsin-2 specifically to the somatodendritic compartment of neurons in mice in vivo. Together, our results suggest that dendritic transmembrane pr! oteins direct the vesicles in which they are transported to avoid the axonal compartment through interaction with myosin motors.
• HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K+ channels
  - Nat Neurosci 12(5):577-584 (2009)
  The processing of synaptic potentials by neuronal dendrites depends on both their passive cable properties and active voltage-gated channels, which can generate complex effects as a result of their nonlinear properties. We characterized the actions of HCN (hyperpolarization-activated cyclic nucleotide-gated cation) channels on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. The HCN channels generated an excitatory inward current (Ih) that exerted a direct depolarizing effect on the peak voltage of weak EPSPs, but produced a paradoxical hyperpolarizing effect on the peak voltage of stronger, but still subthreshold, EPSPs. Using a combined modeling and experimental approach, we found that the inhibitory action of Ih was caused by its interaction with the delayed-rectifier M-type K+ current. In this manner, Ih can enhance spike firing in response to an EPSP when spike threshold is low and can inhibit firing! when spike threshold is high.
• BK channels modulate pre- and postsynaptic signaling at reciprocal synapses in retina
  - Nat Neurosci 12(5):585-592 (2009)
  In the mammalian retina, A17 amacrine cells provide reciprocal inhibitory feedback to rod bipolar cells, thereby shaping the time course of visual signaling in vivo. Previous results have indicated that A17 feedback can be triggered by Ca2+ influx through Ca2+-permeable AMPA receptors and can occur independently of voltage-gated Ca2+ (Cav) channels, whose presence and functional role in A17 dendrites have not yet been explored. We combined electrophysiology, calcium imaging and immunohistochemistry and found that L-type Cav channels in rat A17 amacrine cells were located at the sites of reciprocal synaptic feedback and that their contribution to GABA release was diminished by large-conductance Ca2+-activated potassium (BK) channels, which suppress postsynaptic depolarization in A17s and limit Cav channel activation. We also found that BK channels, by limiting GABA release from A17s, regulate the flow of excitatory synaptic transmission through the rod pathway.
• Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors
  - Nat Neurosci 12(5):593-601 (2009)
  In contrast with conventional NMDA receptor–dependent synaptic plasticity, the synaptic events controlling the plasticity of GluR2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) remain unclear. At parallel fiber synapses onto cerebellar stellate cells, Ca2+ influx through AMPARs triggers a switch in AMPAR subunit composition, resulting in loss of Ca2+ permeabilty. Paradoxically, synaptically induced depolarization will suppress this Ca2+ entry by promoting polyamine block of CP-AMPARs. We therefore examined other mechanisms that may control this receptor regulation under physiological conditions. We found that activation of both mGluRs and CP-AMPARs is necessary and sufficient to drive an AMPAR subunit switch and that by enhancing mGluR activity, GABABR activation promotes this plasticity. Furthermore, we found that mGluRs and GABABRs are tonically activated, thus setting the basal tone for EPSC amplitude and rectification. Regulation by both excitatory and inhibi! tory inputs provides an unexpected mechanism that determines the potential of these synapses to show dynamic changes in AMPAR Ca2+ permeability.
• Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine
  - Nat Neurosci 12(5):602-610 (2009)
  Plastic changes in glutamatergic synapses that lead to endurance of drug craving and addiction are poorly understood. We examined the turnover and trafficking of NMDA receptors and found that chronic exposure to the psychostimulant amphetamine (AMPH) induced selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. This downregulation was a long-lived event and was a result of the destabilization of surface-expressed NR2B caused by accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translated to the modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induced and restoration of NR2B loss prevented behavioral sensitization to AMPH. Our data identify NR2B as an important regulator in th! e remodeling of excitatory synapses and persistent psychomotor plasticity in response to AMPH.
• Oxidation of a potassium channel causes progressive sensory function loss during aging
  - Nat Neurosci 12(5):611-617 (2009)
  Potassium channels are key regulators of neuronal excitability. Here we show that oxidation of the K+ channel KVS-1 during aging causes sensory function loss in Caenorhabditis elegans and that protection of this channel from oxidation preserves neuronal function. Chemotaxis, a function controlled by KVS-1, was significantly impaired in worms exposed to oxidizing agents, but only moderately affected in worms harboring an oxidation-resistant KVS-1 mutant (C113S). In aging C113S transgenic worms, the effects of free radical accumulation were significantly attenuated compared to those in wild type. Electrophysiological analyses showed that both reactive oxygen species (ROS) accumulation during aging and acute exposure to oxidizing agents acted primarily to alter the excitability of the neurons that mediate chemotaxis. Together, these findings establish a pivotal role for ROS-mediated oxidation of voltage-gated K+ channels in sensorial decline during aging in invertebrates.
• The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death
  - Nat Neurosci 12(5):618-626 (2009)
  Dysregulation of Akt signaling is important in a broad range of diseases that includes cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. We found that global ischemia in intact rats triggered expression and activation of the Akt inhibitor CTMP (carboxyl-terminal modulator protein) in vulnerable hippocampal neurons and that CTMP bound and extinguished Akt activity and was essential to ischemia-induced neuronal death. Although ischemia induced a marked phosphorylation and nuclear translocation of Akt, phosphorylated Akt was not active in post-ischemic neurons, as assessed by kinase assays and phosphorylation of the downstream targets GSK-3beta and FOXO3A. RNA interference–mediated depletion of CTMP in a clinically relevant model of stroke restored Akt activity and rescued hippocampal neurons. Our results indicate that CTMP is important in the neurodegeneration that is associated with stroke and identify CTMP as a therapeuti! c target for the amelioration of hippocampal injury and cognitive deficits.
• A role for motoneuron subtype–selective ER stress in disease manifestations of FALS mice
  - Nat Neurosci 12(5):627-636 (2009)
  The mechanisms underlying disease manifestations in neurodegeneration remain unclear, but their understanding is critical to devising effective therapies. We carry out a longitudinal analysis in vivo of identified motoneurons selectively vulnerable (VUL) or resistant (RES) to motoneuron disease (amyotrophic lateral sclerosis, ALS) and show that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations. VUL motoneurons were selectively prone to ER stress and showed gradually upregulated ER stress markers from birth on in three mouse models of familial ALS (FALS). 25–30 days before the earliest denervations, ubiquitin signals increased in both VUL and RES motoneurons, but an unfolded protein response coupled with microglial activation was initiated selectively in VUL motoneurons. This transition was followed by selective axonal degeneration and spreading stress. The ER stress–protective agent salubrinal attenuated disease manifest! ations and delayed progression, whereas chronic enhancement of ER stress promoted disease. Thus, whereas all motoneurons are preferentially affected in ALS, ER stress responses in specific motoneuron subtypes influence the progressive manifestations of weakening and paralysis.
• A precise form of divisive suppression supports population coding in the primary visual cortex
  - Nat Neurosci 12(5):637-645 (2009)
  The responses of neurons in the primary visual cortex (V1) to an optimally oriented grating are suppressed when a non-optimal grating is superimposed. Although cross-orientation suppression is thought to reflect mechanisms that maintain a distributed code for orientation, the effect of superimposed gratings on V1 population responses is unknown. Using intrinsic signal optical imaging, we found that patterns of tree shrew V1 activity evoked by superimposed equal-contrast gratings were predicted by the averages of patterns evoked by individual component gratings. This prediction held across contrasts, for summed sinusoidal gratings or nonsumming square-wave gratings, and was evident in single-unit extracellular recordings. Intracellular recordings revealed consistent levels of suppression throughout the time course of subthreshold responses. These results indicate that divisive suppression powerfully governs population responses to multiple orientations. Moreover, the sp! ecific form of suppression that we observed appears to support independent population codes for stimulus orientation and strength and calls for a reassessment of mechanisms that underlie cross-orientation suppression.
• Engaging in an auditory task suppresses responses in auditory cortex
  - Nat Neurosci 12(5):646-654 (2009)
  Although systems that are involved in attentional selection have been studied extensively, much less is known about nonselective systems. To study these preparatory mechanisms, we compared activity in auditory cortex that was elicited by sounds while rats performed an auditory task ('engaged') with activity that was elicited by identical stimuli while subjects were awake but not performing a task ('passive'). We found that engagement suppressed responses, an effect that was opposite in sign to that elicited by selective attention. In the auditory thalamus, however, engagement enhanced spontaneous firing rates but did not affect evoked responses. These results indicate that neural activity in auditory cortex cannot be viewed simply as a limited resource that is allocated in greater measure as the state of the animal passes from somnolent to passively listening to engaged and attentive. Instead, the engaged condition possesses a characteristic and distinct neural signatu! re in which sound-evoked responses are paradoxically suppressed.
• Reinforcement learning can account for associative and perceptual learning on a visual-decision task
  - Nat Neurosci 12(5):655-663 (2009)
  We recently showed that improved perceptual performance on a visual motion direction–discrimination task corresponds to changes in how an unmodified sensory representation in the brain is interpreted to form a decision that guides behavior. Here we found that these changes can be accounted for using a reinforcement-learning rule to shape functional connectivity between the sensory and decision neurons. We modeled performance on the basis of the readout of simulated responses of direction-selective sensory neurons in the middle temporal area (MT) of monkey cortex. A reward prediction error guided changes in connections between these sensory neurons and the decision process, first establishing the association between motion direction and response direction, and then gradually improving perceptual sensitivity by selectively strengthening the connections from the most sensitive neurons in the sensory population. The results suggest a common, feedback-driven mechanism for! some forms of associative and perceptual learning.