Hot off the presses! May 14 Neuron

The May 14 issue of the Neuron is now up on Pubget (About Neuron): 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:

• Rethinking How Hearing Happens
  - Neuron 62(3):305-307 (2009)
  Inner ear hair cells convert hair bundle deflection into mechanical force sensed by ion channels via extracellular tip links between adjacent stereocilia. In this Neuron issue, Grillet and colleagues show the protein harmonin mechanically reinforces tip link upper insertion sites. Harmonin loss at this site reduces mechanotransduction kinetics and sensitivity.
• Reading the Clock: How Purkinje Cells Decode the Phase of Olivary Oscillations
  - Neuron 62(3):308-309 (2009)
  Climbing fiber responses in cerebellar Purkinje cells are described as being invariant. In this issue of Neuron, Mathy et al. show that the complex spike waveform changes with the number of spikes in a climbing fiber burst, which depends on the phase of olivary oscillations. In turn, different complex spike profiles affect synaptic plasticity at parallel fiber synapses. Thus, information on inferior olive oscillation states is reflected in both the complex spike waveform and the parallel fiber input gain.
• Poisson or Not Poisson: Differences in Spike Train Statistics between Parietal Cortical Areas
  - Neuron 62(3):310-311 (2009)
  The variability of neuronal responses is proportional to the mean in many brain areas, which suggests that neural responses might follow a Poisson distribution. In this issue of Neuron, Maimon and Assad document a surprising violation of Poisson firing. Specifically, they show that there are differences in the amount of periodic structure in spike trains across cortical areas, with multimodal sensory areas being more regular than visual areas.
• Alternative Functions of Core Cell Cycle Regulators in Neuronal Migration, Neuronal Maturation, and Synaptic Plasticity
  - Neuron 62(3):312-326 (2009)
  Recent studies have demonstrated that boundaries separating a cycling cell from a postmitotic neuron are not as concrete as expected. Novel and unique physiological functions in neurons have been ascribed for proteins fundamentally required for cell cycle progression and control. These "core" cell cycle regulators serve diverse postmitotic functions that span various developmental stages of a neuron, including neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis, and synaptic maturation and plasticity. In this review, we detail the nonproliferative postmitotic roles that these cell cycle proteins have recently been reported to play, the significance of their expression in neurons, mechanistic insight when available, and future prospects.
• Genetic Identification of an On-Off Direction- Selective Retinal Ganglion Cell Subtype Reveals a Layer-Specific Subcortical Map of Posterior Motion
  - Neuron 62(3):327-334 (2009)
  Motion detection is an essential component of visual processing. On-Off direction-selective retinal ganglion cells (On-Off DSGCs) detect objects moving along specific axes of the visual field due to their precise retinal circuitry. The brain circuitry of On-Off DSGCs, however, is largely unknown. We report a mouse with GFP expressed selectively by the On-Off DSGCs that detect posterior motion (On-Off pDSGCs), allowing two-photon targeted recordings of their light responses and delineation of their complete map of central connections. On-Off pDSGCs project exclusively to the dorsal lateral geniculate nucleus and superior colliculus and in both targets form synaptic lamina that are separate from a lamina corresponding to non-DSGCs. Thus, individual On-Off DSGC subtypes are molecularly distinct and establish circuits that map specific qualities of directional motion to dedicated subcortical areas. This suggests that each RGC subtype represents a unique parallel pathway wh! ose synaptic specificity in the retina is recapitulated in central targets.
• Genome-wide Analysis of Chromatin Regulation by Cocaine Reveals a Role for Sirtuins
  - Neuron 62(3):335-348 (2009)
  Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of ΔFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine—including a new role for sirtuins (Sirt1 and Sirt2)—which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.
• Sonic Hedgehog Guides Axons through a Noncanonical, Src-Family-Kinase-Dependent Signaling Pathway
  - Neuron 62(3):349-362 (2009)
  Sonic hedgehog (Shh) plays essential roles in developmental events such as cell fate specification and axon guidance. Shh induces cell fate specification through canonical Shh signaling, mediated by transcription. However, the mechanism by which Shh guides axons is unknown. To study this, we developed an in vitro assay for axon guidance, in which neurons can be imaged while responding to a defined gradient of a chemical cue. Axons of dissociated commissural neurons placed in a Shh gradient turned rapidly toward increasing concentrations of Shh. Consistent with this rapid response, we showed that attraction by Shh does not require transcription. Instead, Shh stimulates the activity of Src family kinase (SFK) members in a Smoothened-dependent manner. Moreover, SFK activity is required for Shh-mediated guidance of commissural axons, but not for induction of Gli transcriptional reporter activity. Together, these results indicate that Shh acts via a rapidly acting, noncanon! ical signaling pathway to guide axons.
• Subcellular Dynamics of Type II PKA in Neurons
  - Neuron 62(3):363-374 (2009)
  Protein kinase A (PKA) plays multiple roles in neurons. The localization and specificity of PKA are largely controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA in neurons and the roles of specific AKAPs are poorly understood. We imaged the distribution of type II PKA in hippocampal and cortical layer 2/3 pyramidal neurons in vitro and in vivo. PKA was concentrated in dendritic shafts compared to the soma, axons, and dendritic spines. This spatial distribution was imposed by the microtubule-binding protein MAP2, indicating that MAP2 is the dominant AKAP in neurons. Following cAMP elevation, catalytic subunits dissociated from the MAP2-tethered regulatory subunits and rapidly became enriched in nearby spines. The spatial gradient of type II PKA between dendritic shafts and spines was critical for the regulation of synaptic strength and long-term potentiation. Therefore, the localization and activity-dependent translocation of type II PKA are i! mportant determinants of PKA function.
• Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells
  - Neuron 62(3):375-387 (2009)
  In hair cells, mechanotransduction channels are gated by tip links, the extracellular filaments that consist of cadherin 23 (CDH23) and protocadherin 15 (PCDH15) and connect the stereocilia of each hair cell. However, which molecules mediate cadherin function at tip links is not known. Here we show that the PDZ-domain protein harmonin is a component of the upper tip-link density (UTLD), where CDH23 inserts into the stereociliary membrane. Harmonin domains that mediate interactions with CDH23 and F-actin control harmonin localization in stereocilia and are necessary for normal hearing. In mice expressing a mutant harmonin protein that prevents UTLD formation, the sensitivity of hair bundles to mechanical stimulation is reduced. We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement.
• Encoding of Oscillations by Axonal Bursts in Inferior Olive Neurons
  - Neuron 62(3):388-399 (2009)
  Inferior olive neurons regulate plasticity and timing in the cerebellar cortex via the climbing fiber pathway, but direct characterization of the output of this nucleus has remained elusive. We show that single somatic action potentials in olivary neurons are translated into a burst of axonal spikes. The number of spikes in the burst depends on the phase of subthreshold oscillations and, therefore, encodes the state of the olivary network. These bursts can be successfully transmitted to the cerebellar cortex in vivo, having a significant impact on Purkinje cells. They enhance dendritic spikes, modulate the complex spike pattern, and promote short-term and long-term plasticity at parallel fiber synapses in a manner dependent on the number of spikes in the burst. Our results challenge the view that the climbing fiber conveys an all-or-none signal to the cerebellar cortex and help to link learning and timing theories of olivocerebellar function.
• Motor Behavior Activates Bergmann Glial Networks
  - Neuron 62(3):400-412 (2009)
  Although it is firmly established that neuronal activity is a prime determinant of animal behavior, relationships between astrocytic excitation and animal behavior have remained opaque. Cerebellar Bergmann glia are radial astrocytes that are implicated in motor behavior and exhibit Ca2+ excitation. However, Ca2+ excitation in these cells has not previously been studied in behaving animals. Using two-photon microscopy we found that Bergmann glia exhibit three forms of Ca2+ excitation in awake, behaving mice. Two of these are ongoing within the cerebellar vermis. During locomotor performance concerted Ca2+ excitation arises in networks of at least hundreds of Bergmann glia extending across several hundred microns or more. Concerted Ca2+ excitation was abolished by anesthesia or blockade of either neural activity or glutamatergic transmission. Thus, large networks of Bergmann glia can be activated by specific animal behaviors and undergo excitation of sufficient magnitude! to potentially initiate macroscopic changes in brain dynamics or blood flow.
• Spontaneous Events Outline the Realm of Possible Sensory Responses in Neocortical Populations
  - Neuron 62(3):413-425 (2009)
  Neocortical assemblies produce complex activity patterns both in response to sensory stimuli and spontaneously without sensory input. To investigate the structure of these patterns, we recorded from populations of 40–100 neurons in auditory and somatosensory cortices of anesthetized and awake rats using silicon microelectrodes. Population spike time patterns were broadly conserved across multiple sensory stimuli and spontaneous events. Although individual neurons showed timing variations between stimuli, these were not sufficient to disturb a generally conserved sequential organization observed at the population level, lasting for approximately 100 ms with spiking reliability decaying progressively after event onset. Preserved constraints were also seen in population firing rate vectors, with vectors evoked by individual stimuli occupying subspaces of a larger but still constrained space outlined by the set of spontaneous events. These results suggest that population! spike patterns are drawn from a limited "vocabulary," sampled widely by spontaneous events but more narrowly by sensory responses.
• Beyond Poisson: Increased Spike-Time Regularity across Primate Parietal Cortex
  - Neuron 62(3):426-440 (2009)
  Cortical areas differ in their patterns of connectivity, cellular composition, and functional architecture. Spike trains, on the other hand, are commonly assumed to follow similarly irregular dynamics across neocortex. We examined spike-time statistics in four parietal areas using a method that accounts for nonstationarities in firing rate. We found that, whereas neurons in visual areas fire irregularly, many cells in association and motor-like parietal regions show increasingly regular spike trains by comparison. Regularity was evident both in the shape of interspike interval distributions and in spike-count variability across trials. Thus, Poisson-like randomness is not a universal feature of neocortex. Rather, many parietal cells have reduced trial-to-trial variability in spike counts that could provide for more reliable firing-rate signals. These results suggest that spiking dynamics may play different roles in different cortical areas and should not be assumed to ! arise from fundamentally irreducible noise sources.
• Learning Shapes the Representation of Behavioral Choice in the Human Brain
  - Neuron 62(3):441-452 (2009)
  Making successful decisions under uncertainty due to noisy sensory signals is thought to benefit from previous experience. However, the human brain mechanisms that mediate flexible decisions through learning remain largely unknown. Comparing behavioral choices of human observers with those of a pattern classifier based on multivoxel single-trial fMRI signals, we show that category learning shapes processes related to decision variables in frontal and higher occipitotemporal regions rather than signal detection or response execution in primary visual or motor areas. In particular, fMRI signals in prefrontal regions reflect the observers' behavioral choice according to the learned decision criterion only in the context of the categorization task. In contrast, higher occipitotemporal areas show learning-dependent changes in the representation of perceived categories that are sustained after training independent of the task. These findings demonstrate that learning shapes ! selective representations of sensory readout signals in accordance with the decision criterion to support flexible decisions.