Hot off the presses! Jul 28 Neuron

The Jul 28 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:

• Noradrenaline Enhances Signal-to-Noise Ratio of Inhibitory Inputs in the Dorsal Cochlear Nucleus
  - Neuron 71(2):197-198 (2011)
  What are the mechanisms that enhance the response to behaviorally relevant external stimuli? In this issue of Neuron, Kuo and Trussell show that in the dorsal cochlear nucleus, noradrenaline functions to simultaneously reduce spontaneous inhibitory inputs while increasing evoked inhibition.
• How Glutamate Receptor Subunits Mix and Match: Details Uncovered
  - Neuron 71(2):198-200 (2011)
  Until now, the atomic details explaining why certain subunits prefer to coassemble has been lacking in our understanding of glutamate receptor biogenesis. In this issue, Kumar et al. describe the structural basis by which preferential subunit assembly occurs for homomeric and heteromeric kainate-type glutamate receptors.
• A Prestabilized Harmony
  - Neuron 71(2):201-202 (2011)
  The appearance of discontinuous network events and their transformation into continuous oscillatory activity are fundamental milestones in cortical circuit development. In this issue, Brockmann et al. demonstrate a protracted development of activity patterns in the prefrontal cortex in neonatal rats and a possible role for hippocampal theta bursts in the maturation of PFC connectivity.
• How to Perfect a Chocolate Soufflé and Other Important Problems
  - Neuron 71(2):203-205 (2011)
  When learning to achieve a goal through a complex series of actions, humans often group several actions into a subroutine and evaluate whether the subroutine achieved a specific subgoal. A new study reports brain responses consistent with such "hierarchical reinforcement learning."
• David Colman: A Tribute
  - Neuron 71(2):206-208 (2011)
  
• Cognitive and Perceptual Functions of the Visual Thalamus
  - Neuron 71(2):209-223 (2011)
  The thalamus is classically viewed as passively relaying information to the cortex. However, there is growing evidence that the thalamus actively regulates information transmission to the cortex and between cortical areas using a variety of mechanisms, including the modulation of response magnitude, firing mode, and synchrony of neurons according to behavioral demands. We discuss how the visual thalamus contributes to attention, awareness, and visually guided actions, to present a general role for the thalamus in perception and cognition.
• Consolidation and Reconsolidation: Two Lives of Memories?
  - Neuron 71(2):224-233 (2011)
  Most studies on memory consolidation consider the new information as if it were imposed on a tabula rasa, but considerable evidence indicates that new memories must be interleaved within a large network of relevant pre-existing knowledge. Early studies on reconsolidation highlighted that a newly consolidated memory could be erased after reactivation, but new evidence has shown that an effective reactivation experience must also involve memory reorganization to incorporate new learning. The combination of these observations on consolidation and reconsolidation highlights the fundamental similarities of both phenomena as the integration of new information and old, and it suggests reconsolidation = consolidation as a neverending process of schema modification.
• Pathway-Specific Genetic Attenuation of Glutamate Release Alters Select Features of Competition-Based Visual Circuit Refinement
  - Neuron 71(2):235-242 (2011)
  A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections by competitive activity-dependent processes. In the developing visual system retinal ganglion cell (RGC) axons from the two eyes undergo activity-dependent competition for territory in the dorsal lateral geniculate nucleus (dLGN). The direct contributions of synaptic transmission to this process, however, remain unclear. We used a genetic approach to reduce glutamate release selectively from ipsilateral-projecting RGCs and found that their release-deficient axons failed to exclude competing axons from the ipsilateral eye territory in the dLGN. Nevertheless, the release-deficient axons consolidated and maintained their normal amount of dLGN territory, even in the face of fully active competing axons. These results show that during visual circuit refinement glutamatergic transmission plays a direct role in excluding competing axons from inappropriate target regions, bu! t they argue that consolidation and maintenance of axonal territory are largely insensitive to alterations in synaptic activity levels.
• Differences between Neural Activity in Prefrontal Cortex and Striatum during Learning of Novel Abstract Categories
  - Neuron 71(2):243-249 (2011)
  Learning to classify diverse experiences into meaningful groups, like categories, is fundamental to normal cognition. To understand its neural basis, we simultaneously recorded from multiple electrodes in lateral prefrontal cortex and dorsal striatum, two interconnected brain structures critical for learning. Each day, monkeys learned to associate novel abstract, dot-based categories with a right versus left saccade. Early on, when they could acquire specific stimulus-response associations, striatum activity was an earlier predictor of the corresponding saccade. However, as the number of exemplars increased and monkeys had to learn to classify them, PFC activity began to predict the saccade associated with each category before the striatum. While monkeys were categorizing novel exemplars at a high rate, PFC activity was a strong predictor of their corresponding saccade early in the trial before the striatal neurons. These results suggest that striatum plays a greater r! ole in stimulus-response association and PFC in abstraction of categories. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (13022 K)
• Persistent Sonic Hedgehog Signaling in Adult Brain Determines Neural Stem Cell Positional Identity
  - Neuron 71(2):250-262 (2011)
  Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.
• Anatomical Coupling of Sensory and Motor Nerve Trajectory via Axon Tracking
  - Neuron 71(2):263-277 (2011)
  It is a long-standing question how developing motor and sensory neuron projections cooperatively form a common principal grid of peripheral nerve pathways relaying behavioral outputs and somatosensory inputs. Here, we explored this issue through targeted cell lineage and gene manipulation in mouse, combined with in vitro live axon imaging. In the absence of motor projections, dorsal (epaxial) and ventral (hypaxial) sensory projections form in a randomized manner, while removal of EphA3/4 receptor tyrosine kinases expressed by epaxial motor axons triggers selective failure to form epaxial sensory projections. EphA3/4 act non-cell-autonomously by inducing sensory axons to track along preformed epaxial motor projections. This involves cognate ephrin-A proteins on sensory axons but is independent from EphA3/4 signaling in motor axons proper. Assembly of peripheral nerve pathways thus involves motor axon subtype-specific signals that couple sensory projections to discrete m! otor pathways.
• Endocytosis Promotes Rapid Dopaminergic Signaling
  - Neuron 71(2):278-290 (2011)
  D1 dopamine receptors are primary mediators of dopaminergic signaling in the CNS. These receptors internalize rapidly following agonist-induced activation, but the functional significance of this process is unknown. We investigated D1 receptor endocytosis and signaling in HEK293 cells and cultured striatal neurons using real-time fluorescence imaging and cAMP biosensor technology. Agonist-induced activation of D1 receptors promoted endocytosis of receptors with a time course overlapping that of acute cAMP accumulation. Inhibiting receptor endocytosis blunted acute D1 receptor-mediated signaling in both dissociated cells and striatal slice preparations. Although endocytic inhibition markedly attenuated acute cAMP accumulation, inhibiting the subsequent recycling of receptors had no effect. Further, D1 receptors localized in close proximity to endomembrane-associated trimeric G protein and adenylyl cyclase immediately after endocytosis. Together, these results suggest a ! previously unanticipated role of endocytosis, and the early endocytic pathway, in supporting rapid dopaminergic neurotransmission.
• Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability
  - Neuron 71(2):291-305 (2011)
  Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nit! ric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours.
• Spontaneous Spiking and Synaptic Depression Underlie Noradrenergic Control of Feed-Forward Inhibition
  - Neuron 71(2):306-318 (2011)
  Inhibitory interneurons across diverse brain regions commonly exhibit spontaneous spiking activity, even in the absence of external stimuli. It is not well understood how stimulus-evoked inhibition can be distinguished from background inhibition arising from spontaneous firing. We found that noradrenaline simultaneously reduced spontaneous inhibitory inputs and enhanced evoked inhibitory currents recorded from principal neurons of the mouse dorsal cochlear nucleus (DCN). Together, these effects produced a large increase in signal-to-noise ratio for stimulus-evoked inhibition. Surprisingly, the opposing effects on background and evoked currents could both be attributed to noradrenergic silencing of spontaneous spiking in glycinergic interneurons. During spontaneous firing, glycine release was decreased due to strong short-term depression. Elimination of background spiking relieved inhibitory synapses from depression and thereby enhanced stimulus-evoked inhibition. Our f! indings illustrate a simple yet powerful neuromodulatory mechanism to shift the balance between background and stimulus-evoked signals.
• Structure and Assembly Mechanism for Heteromeric Kainate Receptors
  - Neuron 71(2):319-331 (2011)
  Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5–7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of Kd 11 nM, 32,000-fold lower than the Kd for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesi! s of functional heteromeric receptors.
• Coupled Oscillations Mediate Directed Interactions between Prefrontal Cortex and Hippocampus of the Neonatal Rat
  - Neuron 71(2):332-347 (2011)
  The coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta-modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and matura! tion of functional units underlying information storage at adulthood.
• The Y Cell Visual Pathway Implements a Demodulating Nonlinearity
  - Neuron 71(2):348-361 (2011)
  Neural encoding of sensory signals involves both linear and nonlinear processes. Determining which nonlinear operations are implemented by neural systems is crucial to understanding sensory processing. Here, we ask if demodulation, the process used to decode AM radio signals, describes how Y cells in the cat LGN nonlinearly encode the visual scene. In response to visual AM signals across a wide range of carrier frequencies, Y cells were found to transmit a demodulated signal, with the firing rate of single-units fluctuating at the envelope frequency but not the carrier frequency. A comparison of temporal frequency tuning properties between LGN Y cells and neurons in two primary cortical areas suggests that Y cells initiate a distinct pathway that carries a demodulated representation of the visual scene to cortex. The nonlinear signal processing carried out by the Y cell pathway simplifies the neural representation of complex visual features and allows high spatiotempor! al frequencies to drive cortical responses.
• Binocular Rivalry Requires Visual Attention
  - Neuron 71(2):362-369 (2011)
  An interocular conflict arises when different images are presented to each eye at the same spatial location. The visual system resolves this conflict through binocular rivalry: observers consciously perceive spontaneous alternations between the two images. Visual attention is generally important for resolving competition between neural representations. However, given the seemingly spontaneous and automatic nature of binocular rivalry, the role of attention in resolving interocular competition remains unclear. Here we test whether visual attention is necessary to produce rivalry. Using an EEG frequency-tagging method to track cortical representations of the conflicting images, we show that when attention was diverted away, rivalry stopped. The EEG data further suggested that the neural representations of the dichoptic images combined without attention. Thus, attention is necessary for dichoptic images to be engaged in sustained rivalry and may be generally required for ! resolving conflicting, potentially ambiguous input and giving a single interpretation access to consciousness.
• A Neural Signature of Hierarchical Reinforcement Learning
  - Neuron 71(2):370-379 (2011)
  Human behavior displays hierarchical structure: simple actions cohere into subtask sequences, which work together to accomplish overall task goals. Although the neural substrates of such hierarchy have been the target of increasing research, they remain poorly understood. We propose that the computations supporting hierarchical behavior may relate to those in hierarchical reinforcement learning (HRL), a machine-learning framework that extends reinforcement-learning mechanisms into hierarchical domains. To test this, we leveraged a distinctive prediction arising from HRL. In ordinary reinforcement learning, reward prediction errors are computed when there is an unanticipated change in the prospects for accomplishing overall task goals. HRL entails that prediction errors should also occur in relation to task subgoals. In three neuroimaging studies we observed neural responses consistent with such subgoal-related reward prediction errors, within structures previously impl! icated in reinforcement learning. The results reported support the relevance of HRL to the neural processes underlying hierarchical behavior.