Hot off the presses! Apr 30 Neuron

The Apr 30 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:

• The Dawning of Primate Optogenetics
  - Neuron 62(2):159-160 (2009)
  In this issue of Neuron, Han and colleagues bring optogenetic methods into use in nonhuman primates by demonstrating the feasibility of achieving cell-type-specific photoactivation of macaque neocortical neurons. The use of optogenetic approaches in nonhuman primates promises to revolutionize our understanding of the neural circuitry that mediates complex cognitive functions.
• Deos the Bairn Not Raed Ervey Lteter by Istlef, but the Wrod as a Wlohe?
  - Neuron 62(2):161-162 (2009)
  In this issue of Neuron, Glezer et al. find higher sensitivity to changes in real words than pseudowords in the left visual word form area (VWFA). Here we discuss the implications of their findings and the constraints they impose on neural coding in the lVWFA.
• A Lethal Convergence of Dopamine and Calcium
  - Neuron 62(2):163-164 (2009)
  The controversy about whether dopamine contributes to cell loss in Parkinson's disease takes a new turn as Mosharov et al. in this issue of Neuron demonstrate that Ca2+ influx through L-type channels elevates dopamine synthesis to potentially toxic levels in vulnerable ventral mesencephalon neurons.
• AMPA Receptor Subunits Get Their Share of the Pie
  - Neuron 62(2):165-168 (2009)
  Determining the precise subunit composition of AMPARs in situ has been an enduring challenge. In this issue of Neuron, Lu et al. make significant headway into this pesky problem by using a clever single-cell genetic knockout approach. In a Herculean effort, they provide the field with the completeness of a pie chart outlining the contribution of each AMPAR subunit to basal synaptic transmission at CA1 hippocampus synapses—and we get a pie chart for somatic extrasynaptic receptors, too.
• The Speed of Categorization in the Human Visual System
  - Neuron 62(2):168-170 (2009)
  A new study by Liu et al. in this issue of Neuron looks at how information about object category can be extracted from intracerebral recordings from the visual cortical areas in epileptic patients. It shows that information about whether the object is a face, an animal, a chair, a fruit, or a vehicle is present as early as 100 ms after the onset of a stimulus.
• Rapid Neocortical Dynamics: Cellular and Network Mechanisms
  - Neuron 62(2):171-189 (2009)
  The highly interconnected local and large-scale networks of the neocortical sheet rapidly and dynamically modulate their functional connectivity according to behavioral demands. This basic operating principle of the neocortex is mediated by the continuously changing flow of excitatory and inhibitory synaptic barrages that not only control participation of neurons in networks but also define the networks themselves. The rapid control of neuronal responsiveness via synaptic bombardment is a fundamental property of cortical dynamics that may provide the basis of diverse behaviors, including sensory perception, motor integration, working memory, and attention.
• Millisecond-Timescale Optical Control of Neural Dynamics in the Nonhuman Primate Brain
  - Neuron 62(2):191-198 (2009)
  To understand how brain states and behaviors are generated by neural circuits, it would be useful to be able to perturb precisely the activity of specific cell types and pathways in the nonhuman primate nervous system. We used lentivirus to target the light-activated cation channel channelrhodopsin-2 (ChR2) specifically to excitatory neurons of the macaque frontal cortex. Using a laser-coupled optical fiber in conjunction with a recording microelectrode, we showed that activation of excitatory neurons resulted in well-timed excitatory and suppressive influences on neocortical neural networks. ChR2 was safely expressed, and could mediate optical neuromodulation, in primate neocortex over many months. These findings highlight a methodology for investigating the causal role of specific cell types in nonhuman primate neural computation, cognition, and behavior, and open up the possibility of a new generation of ultraprecise neurological and psychiatric therapeutics via cel! l-type-specific optical neural control prosthetics.
• Evidence for Highly Selective Neuronal Tuning to Whole Words in the "Visual Word Form Area"
  - Neuron 62(2):199-204 (2009)
  Theories of reading have posited the existence of a neural representation coding for whole real words (i.e., an orthographic lexicon), but experimental support for such a representation has proved elusive. Using fMRI rapid adaptation techniques, we provide evidence that the human left ventral occipitotemporal cortex (specifically the "visual word form area," VWFA) contains a representation based on neurons highly selective for individual real words, in contrast to current theories that posit a sublexical representation in the VWFA.
• Uncoupling Dendrite Growth and Patterning: Single-Cell Knockout Analysis of NMDA Receptor 2B
  - Neuron 62(2):205-217 (2009)
  N-methyl-D-aspartate receptors (NMDARs) play important functions in neural development. NR2B is the predominant NR2 subunit of NMDAR in the developing brain. Here we use mosaic analysis with double markers (MADM) to knock out NR2B in isolated single cells and analyze its cell-autonomous function in dendrite development. NR2B mutant dentate gyrus granule cells (dGCs) and barrel cortex layer 4 spiny stellate cells (bSCs) have similar dendritic growth rates, total length, and branch number as control cells. However, mutant dGCs maintain supernumerary primary dendrites resulting from a pruning defect. Furthermore, while control bSCs restrict dendritic growth to a single barrel, mutant bSCs maintain dendritic growth in multiple barrels. Thus, NR2B functions cell autonomously to regulate dendrite patterning to ensure that sensory information is properly represented in the cortex. Our study also indicates that molecular mechanisms that regulate activity-dependent dendrite pat! terning can be separated from those that control general dendrite growth and branching.
• Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons
  - Neuron 62(2):218-229 (2009)
  The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DAcyt) in cultured midbrain neurons, we confirm that elevated DAcyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DAcyt provide neuroprotection. L-DOPA increased DAcyt in SN neurons to levels 2- to 3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DAcyt was not altered by α-synuclein deletion, although dopaminergic neurons lacking α-synuclein were resistant to L-DOPA-induced cell death. Thus, an i! nteraction between Ca2+, DAcyt, and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.
• Synaptic and Extrasynaptic Factors Governing Glutamatergic Retinal Waves
  - Neuron 62(2):230-241 (2009)
  In the few days prior to eye-opening in mice, the excitatory drive underlying waves switches from cholinergic to glutamatergic. Here, we describe the unique synaptic and spatiotemporal properties of waves generated by the retina's glutamatergic circuits. First, knockout mice lacking vesicular glutamate transporter type 1 do not have glutamatergic waves, but continue to exhibit cholinergic waves, demonstrating that the two wave-generating circuits are linked. Second, simultaneous outside-out patch and whole-cell recordings reveal that retinal waves are accompanied by transient increases in extrasynaptic glutamate, directly demonstrating the existence of glutamate spillover during waves. Third, the initiation rate and propagation speed of retinal waves, as assayed by calcium imaging, are sensitive to pharmacological manipulations of spillover and inhibition, demonstrating a role for both signaling pathways in shaping the spatiotemporal properties of glutamatergic retinal! waves.
• Expression of Long-Term Plasticity at Individual Synapses in Hippocampus Is Graded, Bidirectional, and Mainly Presynaptic: Optical Quantal Analysis
  - Neuron 62(2):242-253 (2009)
  Key aspects of the expression of long-term potentiation (LTP) and long-term depression (LTD) remain unresolved despite decades of investigation. Alterations in postsynaptic glutamate receptors are believed to contribute to the expression of various forms of LTP and LTD, but the relative importance of presynaptic mechanisms is controversial. In addition, while aggregate synaptic input to a cell can undergo sequential and graded (incremental) LTP and LTD, it has been suggested that individual synapses may only support binary changes between initial and modified levels of strength. We have addressed these issues by combining electrophysiological methods with two-photon optical quantal analysis of plasticity at individual active (non-silent) Schaffer collateral synapses on CA1 pyramidal neurons in acute slices of hippocampus from adolescent rats. We find that these synapses sustain graded, bidirectional long-term plasticity. Remarkably, changes in potency are small and ins! ignificant; long-term plasticity at these synapses is expressed overwhelmingly via presynaptic changes in reliability of transmitter release.
• Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach
  - Neuron 62(2):254-268 (2009)
  The precise subunit composition of synaptic ionotropic receptors in the brain is poorly understood. This information is of particular importance with regard to AMPA-type glutamate receptors, the multimeric complexes assembled from GluA1-A4 subunits, as the trafficking of these receptors into and out of synapses is proposed to depend upon the subunit composition of the receptor. We report a molecular quantification of synaptic AMPA receptors (AMPARs) by employing a single-cell genetic approach coupled with electrophysiology in hippocampal CA1 pyramidal neurons. In contrast to prevailing views, we find that GluA1A2 heteromers are the dominant AMPARs at CA1 cell synapses (not, vert, similar80%). In cells lacking GluA1, -A2, and -A3, synapses are devoid of AMPARs, yet synaptic NMDA receptors (NMDARs) and dendritic morphology remain unchanged. These data demonstrate a functional dissociation of AMPARs from trafficking of NMDARs and neuronal morphogenesis. This study provide! s a functional quantification of the subunit composition of AMPARs in the CNS and suggests novel roles for AMPAR subunits in receptor trafficking.
• The Orbitofrontal Cortex and Ventral Tegmental Area Are Necessary for Learning from Unexpected Outcomes
  - Neuron 62(2):269-280 (2009)
  Humans and other animals change their behavior in response to unexpected outcomes. The orbitofrontal cortex (OFC) is implicated in such adaptive responding, based on evidence from reversal tasks. Yet these tasks confound using information about expected outcomes with learning when those expectations are violated. OFC is critical for the former function; here we show it is also critical for the latter. In a Pavlovian overexpectation task, inactivation of OFC prevented learning driven by unexpected outcomes, even when performance was assessed later. We propose this reflects a critical contribution of outcome signaling by OFC to encoding of reward prediction errors elsewhere. In accord with this proposal, we report that signaling of reward predictions by OFC neurons was related to signaling of prediction errors by dopamine neurons in ventral tegmental area (VTA). Furthermore, bilateral inactivation of VTA or contralateral inactivation of VTA and OFC disrupted learning dri! ven by unexpected outcomes.
• Timing, Timing, Timing: Fast Decoding of Object Information from Intracranial Field Potentials in Human Visual Cortex
  - Neuron 62(2):281-290 (2009)
  The difficulty of visual recognition stems from the need to achieve high selectivity while maintaining robustness to object transformations within hundreds of milliseconds. Theories of visual recognition differ in whether the neuronal circuits invoke recurrent feedback connections or not. The timing of neurophysiological responses in visual cortex plays a key role in distinguishing between bottom-up and top-down theories. Here, we quantified at millisecond resolution the amount of visual information conveyed by intracranial field potentials from 912 electrodes in 11 human subjects. We could decode object category information from human visual cortex in single trials as early as 100 ms poststimulus. Decoding performance was robust to depth rotation and scale changes. The results suggest that physiological activity in the temporal lobe can account for key properties of visual recognition. The fast decoding in single trials is compatible with feedforward theories and prov! ides strong constraints for computational models of human vision.
• State-Dependent Variability of Neuronal Responses to Transcranial Magnetic Stimulation of the Visual Cortex
  - Neuron 62(2):291-303 (2009)
  Electrical brain stimulation is a promising tool for both experimental and clinical applications. However, the effects of stimulation on neuronal activity are highly variable and poorly understood. To investigate the basis of this variability, we performed extracellular recordings in the visual cortex following application of transcranial magnetic stimulation (TMS). Our measurements of spiking and local field potential activity exhibit two types of response patterns which are characterized by the presence or absence of spontaneous discharge following stimulation. This variability can be partially explained by state-dependent effects, in which higher pre-TMS activity predicts larger post-TMS responses. These results reveal the possibility that variability in the neural response to TMS can be exploited to optimize the effects of stimulation. It is conceivable that this feature could be utilized in real time during the treatment of clinical disorders.