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22 Οκτ 2013 (πριν από 3 χρόνια και 5 μήνες)

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This Week in The Journal
Doc2b Ensures Synchronous Vesicle
Release in Two Ways
Paulo S.Pinheiro,Heidi de Wit,
Alexander M.Walter,Alexander J.Groffen,
Matthijs Verhage,et al.
(see pages 16459–16470)
In synaptic terminals,vesicles are held in
different pools distinguished by how likely
member vesicles are to be released by cal-
cium entry.Many proteins associate with
vesicles in these pools and regulate move-
ment between pools.This regulation not
only ensures that many vesicles are released
simultaneously when an action potential
occurs,but also ensures that some vesicles
are reserved for release by the next spike.
Synaptotagmins are thought to maintain
vesicles in a readily releasable pool (RRP)
until calcium enters the terminal,but the
functionof agroupof closelyrelatedcalcium-
binding proteins—the Doc2 family—has re-
mained elusive.By measuring release of
dense core vesicles from chromaffin cells,
however,Pinheiro et al.have identified two
roles for Doc2b.At resting calcium levels,
Doc2b promotes filling of the RRP.But
when calcium levels increase during re-
peated stimulation,Doc2b inhibits this ves-
icle priming.Because primed vesicles are
immediately released when calcium con-
centration is high,inhibition of priming
limits sustained release and prevents vesicle
Actin and Drebrin Promote
Microtubule Invasion of Spines
Elliott B.Merriam,MatthewMillette,
Derek C.Lumbard,Witchuda Saengsawang,
Thomas Fothergill,et al.
(see pages 16471–16482)
Synaptic plasticity is often accompanied
by changes in the shape of dendritic spines.
Althoughspine shape is primarily regulated
by the actin cytoskeleton,microtubules
sometimes enter spines.Such entries in-
crease after activation of synaptic NMDA
receptors (NMDARs),suggesting that mi-
crotubules contribute to synaptic plasticity.
Merriamet al.have discovered some of the
molecular mechanisms linking NMDAR
activation to microtubule invasion of
spines.In cultured mouse hippocampal
neurons,NMDAR activation caused in-
creases in calcium and f-actin in some
spines.Microtubules preferentially entered
spines that had the largest increases in cal-
ciumand f-actin.Chelating calciumor de-
polymerizing actin filaments reduced
microtubule entry,whereas stabilizing actin
filaments increased microtubule invasion.
NMDAR activation also increased expres-
sion of drebrin,a protein that interacts not
only with actin but also with a protein at
microtubule tips.Drebrin overexpression
increased,whereas knockdown decreased
microtubule invasion of spines.Together,
these data suggest that calcium influx
throughactivatedNMDARs causes local in-
creases in f-actin,which,through drebrin,
promotes microtubule entry.
Presynaptic MechanismUnderlies
Short-TermOdor Habituation
Madhumala K.Sadanandappa,
Beatriz Blanco Redondo,Birgit Michels,
Veronica Rodrigues,BertramGerber,et al.
(see pages 16576–16585)
Drosophila olfactory sensory neurons (OSNs)
project to the antenna lobe,where they syn-
apse on projection neurons (PNs) and local
interneurons (LNs).LNs also receive inputs
fromPNs andtheyinhibit PNs andafferents
in the same and other glomeruli.Potentia-
tion of GABAergic synapses between LNs
and PNs leads to olfactory habituation,in
which avoidance of an odor decreases with
repeated exposure.Sadanandappa et al.
provide evidence that the potentiation
underlying short-term odor habituation
(STH) is presynaptic,involving phosphory-
lation of synapsin.Although synapsin-null
flies did not exhibit STH,STHwas rescued
by expressing wild-type synapsin—but not
nonphosphorylatable synapsin—selectively
hibiting calcium/calmodulin-dependent ki-
nase II (CaMKII) in LN1 interneurons
CaMKII is thought to enable vesicles in the
reserve pool to move to the active pool,
which is expected to result in increased
GABArelease andthus increasedinhibition
of PNs.Interestingly,synapsin-null flies
exhibited normal long-term habituation
(LTH) indicating that LTHcan occur with-
out STH.
Neurobiology of Disease
Stress-Inducible Phosphoprotein
Reduces A￿Toxicity
Valeriy G.Ostapchenko,Flavio H.Beraldo,
Amro H.Mohammad,Yu-Feng Xie,
Pedro H.F.Hirata,et al.
(see pages 16552–16564)
Alzheimer’s disease (AD),appear to exert
some of their toxic effects by binding to the
cellular prionprotein(PrP
).A￿also affects
cholinergic signaling (which is disrupted
in AD),in part through interactions
with ￿7 nicotinic acetylcholine receptors
by astrocytes,binds to PrP
near the A￿
binding site and exerts neuroprotective ef-
fects by activating ￿7nAChRs.Therefore,
Ostapchenko et al.hypothesized that STI1
wouldinhibit thetoxiceffects of A￿.Indeed,
STI1 reduced binding of A￿both to PrP
and to mouse hippocampal neurons in cul-
ture.Whereas A￿reduced the number of
synaptic puncta,STI1 increased puncta and
blocked the effect of A￿.STI1 also pre-
ventedA￿-inducedreductions inlong-term
potentiation in hippocampal slices and re-
duced A￿-induced neuron death.STI1 did
not increase survival of neurons from
￿7nAChR-null mice,however.Interest-
ingly,STI1levels wereelevatedinADbrains,
possibly representing an endogenous at-
tempt to counteract A￿accumulation.
Whole-mount fly brain labeled with antibodies against syn-
apsin.Phosphorylationof synapsininLN1interneurons inthe
antenna lobe is requiredfor short-termolfactory habituation.
See the article by Sadanandappa et al.for details.
The Journal of Neuroscience,October 16,2013

33(42):i • i
Cover legend:Subdivisions of the ventrolateral
frontal cortex summarized fromthe macaque monkey
literature (top left),schematized depiction of unique
connectivity patterns (background),and presented in
the human brain based on individual-level functional
connectivity analysis (bottomright).For more
information,see Margulies and Petrides
i This Week in The Journal
Journal Club
16409 Seizure Initiation and Propagation in the Pilocarpine Rat Model of Temporal Lobe
Moran Furman
Brief Communications
16790 Optic FlowStimuli Update Anterodorsal Thalamus Head Direction Neuronal Activity
in Rats
Angelo Arleo,Cyril De´jean,Pierre Allegraud,Mehdi Khamassi,
Michael B.Zugaro,and Sidney I.Wiener
16459 Doc2b Synchronizes Secretion fromChromaffin Cells by Stimulating Fast
and Inhibiting Sustained Release
Paulo S.Pinheiro,Heidi de Wit,Alexander M.Walter,Alexander J.Groffen,
Matthijs Verhage,and Jakob B.Sørensen
16627 Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition
Irina Vetter,Alexander Hein,Simon Sattler,Sabine Hessler,Filip Touska,
Elisangela Bressan,Andres Parra,Ulrich Hager,Andreas Leffler,
Stepana Boukalova,Matthias Nissen,Richard J.Lewis,Carlos Belmonte,
Christian Alzheimer,Tobias Huth,Viktorie Vlachova,Peter W.Reeh,
and Katharina Zimmermann
16698 Titration of Syntaxin1 in Mammalian Synapses Reveals Multiple Roles in Vesicle
Docking,Priming,and Release Probability
Marife Arancillo,Sang-Won Min,Stefan Gerber,Agnieszka Mu¨nster-Wandowski,
Yuan-Ju Wu,Melissa Herman,Thorsten Trimbuch,Jong-Cheol Rah,
Gudrun Ahnert-Hilger,Dietmar Riedel,Thomas C.Su¨dhof,
and Christian Rosenmund
16729 Erg PotassiumCurrents of Neonatal Mouse Purkinje Cells Exhibit Fast Gating
Kinetics and Are Inhibited by mGluR1 Activation
Dragos Niculescu,Wiebke Hirdes,So¨nke Hornig,Olaf Pongs,
and Ju¨rgen R.Schwarz
16767 Cell-Specific Fine-Tuning of Neuronal Excitability by Differential Expression of
Modulator Protein Isoforms
James Jepson,Amanda Sheldon,Mohammad Shahidullah,Hong Fei,
Kyunghee Koh,and Irwin B.Levitan
The Journal of Neuroscience
October 16,2013 • Volume 33 Number 42 • www.jneurosci.org
16805 Oligodendrocyte/Type-2 Astrocyte Progenitor Cells and Glial-Restricted Precursor
Cells Generate Different Tumor Phenotypes in Response to the Identical Oncogenes
Jun Wang,Jared Bushman,Xi Wang,Margot Mayer-Proschel,Mahlon Johnson,
and Mark Noble
16828 The Neural Cell Adhesion Molecule Promotes Maturation of the Presynaptic
Endocytotic Machinery by Switching Synaptic Vesicle Recycling fromAdaptor
Protein 3 (AP-3)- to AP-2-Dependent Mechanisms
Aparna Shetty,Vladimir Sytnyk,Iryna Leshchyns’ka,Dmytro Puchkov,
Volker Haucke,and Melitta Schachner
16471 Synaptic Regulation of Microtubule Dynamics in Dendritic Spines by Calcium,
F-Actin,and Drebrin
Elliott B.Merriam,Matthew Millette,Derek C.Lumbard,Witchuda Saengsawang,
Thomas Fothergill,Xindao Hu,Lotfi Ferhat,and Erik W.Dent
16490 Opposing Action of Nuclear Factor ￿Band Polo-like Kinases Determines a
Homeostatic End Point for Excitatory Synaptic Adaptation
Anca B.Mihalas,Yoichi Araki,Richard L.Huganir,and Mollie K.Meffert
16540 ￿2-Chimaerin Regulates a Key Axon Guidance Transition during Development of the
Oculomotor Projection
Christopher Clark,Oliver Austen,Ivana Poparic,and Sarah Guthrie
16673 Gap Junction-Dependent Homolog Avoidance in the Developing CNS
Michael W.Baker,Neema Yazdani,and Eduardo R.Macagno
16778 Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA
Receptors in Dopamine Neurons
Yvonne Schmitz,Candace Castagna,Ana Mrejeru,Jose´ E.Lizardi-Ortiz,
Zoe Klein,Craig W.Lindsley,and David Sulzer
16427 Structural Basis of Cerebellar Microcircuits in the Rat
Nadia L.Cerminara,Hanako Aoki,Michaela Loft,Izumi Sugihara,
and Richard Apps
16483 Integration of Direction Cues Is Invariant to the Temporal Gap between Them
Roozbeh Kiani,Anne K.Churchland,and Michael N.Shadlen
16565 The Neuromuscular Transformof the Lobster Cardiac SystemExplains the Opposing
Effects of a Neuromodulator on Muscle Output
Alex H.Williams,Andrew Calkins,Timothy O’Leary,Renee Symonds,
Eve Marder,and Patsy S.Dickinson
16594 Visual Response Properties of V1 Neurons Projecting to V2 in Macaque
Yasmine El-Shamayleh,Romesh D.Kumbhani,Neel T.Dhruv,
and J.Anthony Movshon
16642 Object Representation in Inferior Temporal Cortex Is Organized Hierarchically in a
Mosaic-Like Structure
Takayuki Sato,Go Uchida,Mark D.Lescroart,Jun Kitazono,Masato Okada,
and Manabu Tanifuji
16715 Diverse Suppressive Influences in Area MT and Selectivity to Complex Motion
Yuwei Cui,Liu D.Liu,Farhan A.Khawaja,Christopher C.Pack,
and Daniel A.Butts
16796 Large-Scale Brain Networks in the Awake,Truly Resting Marmoset Monkey
Annabelle M.Belcher,Cecil C.Yen,Haley Stepp,Hong Gu,Hanbing Lu,
Yihong Yang,Afonso C.Silva,and Elliot A.Stein
16818 Relationship between the Local Structure of Orientation Map and the Strength of
Orientation Tuning of Neurons in Monkey V1:A2-Photon CalciumImaging Study
Koji Ikezoe,Yoshiya Mori,Kazuo Kitamura,Hiroshi Tamura,and Ichiro Fujita
16846 Distinct Parietal and Temporal Connectivity Profiles of Ventrolateral Frontal Areas
Involved in Language Production
Daniel S.Margulies and Michael Petrides
16443 Frontal and Parietal Cortical Interactions with Distributed Visual Representations
during Selective Attention and Action Selection
Natalie Nelissen,Mark Stokes,Anna C.Nobre,and Matthew F.S.Rushworth
16502 The Hand Sees Visual Periphery Better Than the Eye:Motor-Dependent Visual
Motion Analyses
Hiroaki Gomi,Naotoshi Abekawa,and Shinsuke Shimojo
16510 miR-9 and miR-140-5p Target FoxP2 and Are Regulated as a Function of the Social
Context of Singing Behavior in Zebra Finches
Zhimin Shi,Guanzheng Luo,Lijuan Fu,Zhide Fang,XiuJie Wang,
and XiaoChing Li
16522 Modeling Fall Propensity in Parkinson’s Disease:Deficits in the Attentional Control
of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic
Aaron Kucinski,Giovanna Paolone,Marc Bradshaw,Roger L.Albin,
and Martin Sarter
16576 Synapsin Function in GABA-ergic Interneurons Is Required for Short-TermOlfactory
Madhumala K.Sadanandappa,Beatriz Blanco Redondo,Birgit Michels,
Veronica Rodrigues,BertramGerber,K.VijayRaghavan,Erich Buchner,
and Mani Ramaswami
16606 AHierarchy of Attentional Priority Signals in Human Frontoparietal Cortex
Taosheng Liu and Youyang Hou
16657 Medial and Lateral Networks in Anterior Prefrontal Cortex Support Metacognitive
Ability for Memory and Perception
Benjamin Baird,Jonathan Smallwood,Krzysztof J.Gorgolewski,
and Daniel S.Margulies
16684 Saccade Modulation by Optical and Electrical Stimulation in the Macaque Frontal Eye
Shay Ohayon,Piercesare Grimaldi,Nicole Schweers,and Doris Y.Tsao
16741 Musical Training Enhances Neural Processing of Binaural Sounds
Alexandra Parbery-Clark,Dana L.Strait,Emily Hittner,and Nina Kraus
16748 Functional Subdomains within Human FFA
Tolga C¸ ukur,Alexander G.Huth,Shinji Nishimoto,and Jack L.Gallant
16412 ￿
￿-1 Gene Deletion Affects Somatosensory Neuron Function and Delays Mechanical
Hypersensitivity in Response to Peripheral Nerve Damage
Ryan Patel,Claudia S.Bauer,Manuela Nieto-Rostro,Wojciech Margas,
Laurent Ferron,Kanchan Chaggar,Kasumi Crews,Juan D.Ramirez,
David L.H.Bennett,Arnold Schwartz,Anthony H.Dickenson,
and Annette C.Dolphin
16552 The Prion Protein Ligand,Stress-Inducible Phosphoprotein 1,Regulates Amyloid-￿
Oligomer Toxicity
Valeriy G.Ostapchenko,Flavio H.Beraldo,Amro H.Mohammad,Yu-Feng Xie,
Pedro H.F.Hirata,Ana C.Magalhaes,Guillaume Lamour,Hongbin Li,
Andrzej Maciejewski,Jillian C.Belrose,Bianca L.Teixeira,Margaret Fahnestock,
Sergio T.Ferreira,Neil R.Cashman,Glaucia N.M.Hajj,Michael F.Jackson,
Wing-Yiu Choy,John F.MacDonald,Vilma R.Martins,Vania F.Prado,
and Marco A.M.Prado
16586 Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/Autism
Mutation Kv10.2–R327HDemonstrate the Role of This Residue in Stabilizing the
Channel Closed State
Yang Yang,Dmytro V.Vasylyev,Fadia Dib-Hajj,Krishna R.Veeramah,
Michael F.Hammer,Sulayman D.Dib-Hajj,and Stephen G.Waxman
16617 Long-Lasting Spinal Oxytocin Analgesia Is Ensured by the Stimulation of
Allopregnanolone Synthesis Which Potentiates GABA
Receptor-Mediated Synaptic
Pierre-Eric Juif,Jean-Didier Breton,Mathieu Rajalu,Alexandre Charlet,
Yannick Goumon,and Pierrick Poisbeau
16666 Shared Vulnerability of Two Synaptically-Connected Medial Temporal Lobe Areas to
Age and Cognitive Decline:ASeven Tesla Magnetic Resonance Imaging Study
Geoffrey A.Kerchner,Jeffrey D.Bernstein,Michelle C.Fenesy,Gayle K.Deutsch,
Manojkumar Saranathan,Michael M.Zeineh,and Brian K.Rutt
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Optic FlowStimuli Update Anterodorsal Thalamus Head Direction Neuronal Activity in Rats
Angelo Arleo,
Cyril De´jean,
Pierre Allegraud,
Mehdi Khamassi,
Michael B.Zugaro,
and Sidney I.Wiener
Laboratory of Physiology of Perception and Action,CNRS–Colle`ge de France,UMR 7152,75231 Paris Cedex 05,France,
Laboratory of Neurobiology of
Adaptive Processes,CNRS–University Pierre and Marie Curie,UMR 7102,75005 Paris,France,and
Memolife Laboratory of Excellence,Paris Science and
Letters University,75005,Paris,France
Headdirection(HD) neurons fire selectively according toheadorientationinthe yawplane relative toenvironmental landmarkcues.Headmovements provoke optic field
flowsignals that enter the vestibular nuclei,indicating head velocity,and hence angular displacements.To test whether optic field flowalone affects the directional firing
of HDneurons,rats walkedabout ona circular platformas a spot array was projectedontothe surrounding floor-to-ceiling cylindrical blackcurtain.Directional responses
in the anterodorsal thalamus of four rats remained stable as they moved about with the point field but in the absence of landmark cues.Then,the spherical projector was
rotatedabout its yawaxis at 4.5°/s for ￿90s.In27sessions themeandrift speedof thepreferreddirections (PDs) was 1.48°/s (SD￿0.78°/s;range:0.15to2.88°/s).Thus,optic
flowstimulationentrainedPDs,albeit at drift speeds slower thanthefieldrotation.This couldbeduetoconflicts withvestibular,motor command,andefferent copysignals.
After field rotation ended,20/27 PDs drifted back to within 45° of the initial values over several minutes,generally following the shortest path to return to the initial value.
Poststimulation drifts could change speed and/or direction,with mean speeds of 0.68￿0.64°/s (range 0 to 1.36°/s).Since the HD cell pathway (containing anterodorsal
thalamus) is the only known projection of head direction information to entorhinal grid cells and hippocampal place cells,yaw plane optic flow signals likely influence
representations in this spatial reference coordinate systemfor orientation and navigation.
The Journal of Neuroscience,October 16,2013

Doc2b Synchronizes Secretion fromChromaffin Cells by Stimulating Fast and Inhibiting
Sustained Release
Paulo S.Pinheiro,
Heidi de Wit,
Alexander M.Walter,
Alexander J.Groffen,
Matthijs Verhage,
and Jakob B.Sørensen
Department of Neuroscience and Pharmacology,Faculty of Health Sciences,and
Lundbeck Foundation Center for Biomembranes in Nanomedicine,
University of Copenhagen,2200 Copenhagen N,Denmark,
Center for Neurogenomics and Cognitive Research,Department of Functional Genomics,
Neuroscience Campus Amsterdam,Vrije Universiteit Amsterdam,1081 HVAmsterdam,The Netherlands,and
VUMedical Center,1081 HVAmsterdam,
The Netherlands
Synaptotagmin-1 and -7 constitute the main calciumsensors mediating SNARE-dependent exocytosis in mouse chromaffin cells,but the role of a closely related
calcium-binding protein,Doc2b,remains enigmatic.We investigated its role in chromaffin cells using Doc2b knock-out mice and high temporal resolution
measurements of exocytosis.We found that the calciumdependence of vesicle priming and release triggering remained unchanged,ruling out an obligatory role
for Doc2b in those processes.However,in the absence of Doc2b,release was shifted from the readily releasable pool to the subsequent sustained component.
Conversely,upon overexpression of Doc2b,the sustained component was largely inhibited whereas the readily releasable pool was augmented.Electron micros-
copy revealedanincrease inthe total number of vesicles uponDoc2b overexpression,ruling out vesicle depletionas the cause for the reducedsustainedcomponent.
Further experiments showed that,in the absence of Doc2b,the refilling of the readily releasable vesicle pools is faster,but incomplete.Faster refilling leads to an
increase in the sustained component as newly primed vesicles fuse while the [Ca
following stimulation is still high.We conclude that Doc2b acts to inhibit
vesicle priming during prolonged calcium elevations,thus protecting unprimed vesicles from fusing prematurely,and redirecting them to refill the readily
releasable pool after relaxation of the calciumsignal.In sum,Doc2b favors fast,synchronized release,and limits out-of-phase secretion.
The Journal of Neuroscience,October 16,2013

33(42):16459 –16470
Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition
Irina Vetter,
* Alexander Hein,
* Simon Sattler,
* Sabine Hessler,
* Filip Touska,
Elisangela Bressan,
Andres Parra,
Ulrich Hager,
Andreas Leffler,
Stepana Boukalova,
Matthias Nissen,
Richard J.Lewis,
Carlos Belmonte,
Christian Alzheimer,
Tobias Huth,
Viktorie Vlachova,
Peter W.Reeh,
and Katharina Zimmermann
Institute for Molecular Bioscience,The University of Queensland,St.Lucia 4072,Queensland,Australia,
Department of Physiology andPathophysiology,
Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg,91054 Erlangen,Germany,
Department of Cellular Neurophysiology,Institute of Physiology,Academy of
Sciences of the CzechRepublic,CZ-14220 Prague,CzechRepublic,
Institutode Neurociencias de Alicante,UniversidadMiguel Hernandez-ConsejoSuperior de
Investigaciones Cientificas,03550 SanJuande Alicante,Spain,
Department of Anesthesiology andIntensive Care,Medical School Hannover,30625 Hannover,
Department of Gynecology andObstetrics,Friedrich-Alexander-Universita¨t Erlangen-Nürnberg,91054 Erlangen,Germany
Topically appliedcamphor elicits a sensationof cool,but nothing is knownabout howit affects coldtemperature sensing.We foundthat camphor sensitizes a subpopulationof menthol-
sensitivenativecutaneousnociceptorsinthemousetocold,but desensitizesandpartiallyblocksheterologouslyexpressedTRPM8(transient receptorpotential cationchannel subfamilyM
member8).Incontrast,camphorreducespotassiumoutwardcurrentsinculturedsensoryneuronsand,incoldnociceptors,thecold-sensitizingeffectsofcamphorandmenthol areadditive.
M-channel blockingeffectsofXE991andcamphorarenotsufficienttoinitiatecoldtransductionbutrequireacold-activatedinwardcurrentgeneratedbyTRPM8.Thecold-sensitizingeffects
of XE991andcamphor arelargest inhigh-thresholdcoldnociceptors.Low-thresholdcorneal coldthermoreceptors that express highlevels of TRPM8andlackpotassiumchannels arenot
affectedbycamphor.We alsofoundthat menthol—like camphor—potentlyinhibits K
7.2/3channels.The apparent functional synergismarisingfromTRPM8activationandM-current
blockcanimprovetheeffectivenessof topical coolantsandcoolinglotions,andmayalsoenhanceTRPM8-mediatedanalgesia.
TheJournal of Neuroscience,October16,2013

Titration of Syntaxin1 in Mammalian Synapses Reveals Multiple Roles in Vesicle Docking,
Priming,and Release Probability
Marife Arancillo,
Sang-Won Min,
Stefan Gerber,
Agnieszka Mu¨nster-Wandowski,
Yuan-Ju Wu,
Melissa Herman,
Thorsten Trimbuch,
Jong-Cheol Rah,
Gudrun Ahnert-Hilger,
Dietmar Riedel,
Thomas C.Su¨dhof,
and Christian Rosenmund
Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,Texas 77030,
NeuroCure Cluster of Excellence,Charite´-
Universita¨tsmedizin Berlin,10117 Berlin,Germany,
Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute,Stanford
University,Stanford,California 94305,
AG Functional Cell Biology,Institute for Integrative Neuroanatomy,Charite´ Centre 2 for Basic Medicine,10115
Department of Neurobiology,Max-Planck-Institute for Biophysical Chemistry,37077 Go¨ttingen,Germany
Synaptic vesicles undergo sequential steps in preparation for neurotransmitter release.Individual SNARE proteins and the SNARE complex itself have been implicated in
these processes.However,discrete effects of SNARE proteins on synaptic function have been difficult to assess using complete loss-of-function approaches.We therefore
useda genetic titrationtechnique inculturedmouse hippocampal neurons toevaluate the contributionof the neuronal SNAREproteinSyntaxin1 (Stx1) invesicle docking,
priming,and release probability.We generated graded reductions of total Stx1 levels by combining two approaches,namely,endogenous hypomorphic expression of the
isoformStx1B and RNAi-mediated knockdown.Proximity of synaptic vesicles to the active zone was not strongly affected.However,overall release efficiency of affected
neurons was severely impaired,as demonstrated by a smaller readily releasable pool size,slower refilling rate of primed vesicles,and lower release probability.Interest-
ingly,dose–response fitting of Stx1 levels against readily releasable pool size andvesicular release probability showedsimilar K
(dissociationconstant) values at 18%and
19%of wild-type Stx1,with cooperativity estimates of 3.4 and 2.5,respectively.This strongly suggests that priming and vesicle fusion share the same molecular stoichi-
ometry,and are governed by highly related mechanisms.
The Journal of Neuroscience,October 16,2013

Erg PotassiumCurrents of Neonatal Mouse Purkinje Cells Exhibit Fast Gating Kinetics and Are
Inhibited by mGluR1 Activation
Dragos Niculescu,Wiebke Hirdes,So¨nke Hornig,Olaf Pongs,and Ju¨rgen R.Schwarz
Institute for Molecular Neurogenetics,Center for Molecular Neurobiology (ZMNH),University of Hamburg,D-20251 Hamburg,Germany
We investigatedthe subthresholdproperties of anerg(ether-a`-go-go-relatedgene) K
current inPurkinje cells of neonatal mice.Actionpotentials recordedfromPurkinje
cells in cerebellar slices exhibited a decreased threshold potential and increased frequency of spontaneous and repetitive activity following application of the specific erg
channel blocker E-4031.Accommodation was absent before and after drug application.The erg current of these Purkinje cells activated at membrane potentials near ￿60
mVand exhibited fast gating kinetics.The functional importance of fast gating subthreshold erg channels in Purkinje cells was corroborated by comparing the results of
actionpotential clampexperiments witherg1a,erg1b,erg2,anderg3 currents heterologously expressedinHEKcells.Computer simulations basedona NEURONmodel of
Purkinje cells only reproduced the effects of the native erg current when an erg channel conductance like that of erg3 was included.Experiments with subunit-sensitive
toxins (BeKm-1,APETx1) indicated that erg channels in Purkinje cells are presumably mediated by heteromeric erg1/erg3 or modified erg1 channels.Following mGluR1
activation,the native erg current was reduced by ￿70%,brought about by reduction of the maximal erg current and a shift of the activation curve to more positive
potentials.The Purkinje cell erg current contributed to the sustained current component of the biphasic mGluR1 response.Activation of mGluR1 by the agonist 3,4-
dihydroxyphenylglycol increasedPurkinje cell excitability,similar tothat inducedby E-4031.The results indicatedthat erg currents canbe modulatedandmay contribute
to the mGluR1-induced plasticity changes in Purkinje cells.
The Journal of Neuroscience,October 16,2013

Cell-Specific Fine-Tuning of Neuronal Excitability by Differential Expression of Modulator
Protein Isoforms
James Jepson,* Amanda Sheldon,* Mohammad Shahidullah,Hong Fei,Kyunghee Koh,and Irwin B.Levitan
Department of Neuroscience and Farber Institute for Neurosciences,Thomas Jefferson University,Philadelphia,Pennsylvania 19107
SLOB(SLOWPOKE-binding protein) modulates the Drosophila SLOWPOKEcalcium-activated potassiumchannel.We have shown previously that SLOBdeletion or RNAi
knockdown decreases excitability of neurosecretory pars intercerebralis (PI) neurons in the adult Drosophila brain.In contrast,we found that SLOBdeletion/knockdown
enhances neurotransmitter release from motor neurons at the fly larval neuromuscular junction,suggesting an increase in excitability.Because two prominent SLOB
isoforms,SLOB57andSLOB71,modulate SLOWPOKEchannels inopposite directions invitro,we investigatedwhether divergent expressionpatterns of these twoisoforms
might underlie the differential modulationof excitability inPI andmotor neurons.By performingdetailedinvitroandinvivoanalysis,we foundstrikingly different modes
of regulatory control by the slob57 and slob71 promoters.The slob71,but not slob57,promoter contains binding sites for the Hunchback and Mirror transcriptional
repressors.Furthermore,several core promoter elements that are absent in the slob57 promoter coordinately drive robust expression of a luciferase vector by the slob71
promoter in vitro.In addition,we visualized the expression patterns of the slob57 and slob71 promoters in vivo and found clear spatiotemporal differences in promoter
activity.SLOB57is expressedprominentlyinadult PI neurons,whereas larval motor neurons exclusivelyexpress SLOB71.Incontrast,at thelarval neuromuscular junction,
SLOB57 expressionappears to be restrictedmainly to a subset of glial cells.Our results illustrate howthe use of alternative transcriptional start sites withinanionchannel
modulator locus coupled with functionally relevant alternative splicing can be used to fine-tune neuronal excitability in a cell-specific manner.
The Journal of Neuroscience,October 16,2013

Oligodendrocyte/Type-2 Astrocyte Progenitor Cells and Glial-Restricted Precursor Cells
Generate Different Tumor Phenotypes in Response to the Identical Oncogenes
Jun Wang,
Jared Bushman,
Xi Wang,
Margot Mayer-Proschel,
Mahlon Johnson,
and Mark Noble
Department of Biomedical Genetics and University of Rochester StemCell and Regenerative Medicine Institute,University of Rochester School of Medicine
and Dentistry,Rochester,NewYork 14642,
NewJersey Center for Biomaterials,Piscataway,NewJersey 08854,
Cleveland Clinic,Cleveland,Ohio,44109,
Department of Pathology and Laboratory Medicine,University of Rochester School of Medicine and Dentistry,Rochester,NewYork 14642
Despitethegreat interest inidentifyingthecell-of-originfor different cancers,littleknowledgeexists regardingtheextent towhichthespecific originof atumor contributes
to its properties.To directly examine this question,we expressed identical oncogenes in two types of glial progenitor cells,glial-restricted precursor (GRP) cells and
oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs),and in astrocytes of the mouse CNS (either directly purified or generated from GRP cells).In vitro,
expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells,generation of 3D
aggregates whengrownas adherent cultures,andsensitivity to the chemotherapeutic agent BCNU.Invivo,cells differedintheir ability to formtumors,inmalignancy and
even in the type of host-derived cells infiltrating the tumor mass.Moreover,identical genetic modification of these different cells yielded benign infiltrative astrocytomas,
malignant astrocytomas,or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas,indicating a contribution of cell-of-origin to the charac-
teristic properties expressed by these different tumors.Our studies also revealed unexpected relationships between the cell-of-origin,differentiation,and the order of
oncogene acquisition at different developmental stages in enabling neoplastic growth.These studies thus provide multiple novel demonstrations of the importance of the
cell-of-origin in respect to the properties of transformed cells derived fromthem.In addition,the approaches used enable analysis of the role of cell-of-origin in tumor
biology in ways that are not accessible by other more widely used approaches.
The Journal of Neuroscience,October 16,2013

The Neural Cell Adhesion Molecule Promotes Maturation of the Presynaptic Endocytotic
Machinery by Switching Synaptic Vesicle Recycling fromAdaptor Protein 3 (AP-3)- to AP-2-
Dependent Mechanisms
Aparna Shetty,
* Vladimir Sytnyk,
* Iryna Leshchyns’ka,
* Dmytro Puchkov,
Volker Haucke,
and Melitta Schachner
Zentrumfu¨r Molekulare Neurobiologie,Universita¨t Hamburg,20246 Hamburg,Germany,
School of Biotechnology and Biomolecular Sciences,The
University of NewSouth Wales,Sydney,NewSouth Wales 2052,Australia,
Leibniz Institut fu¨r Molekulare Pharmakologie and Freie Universita¨t Berlin,
13125 Berlin,Germany,
Keck Center for Collaborative Neuroscience,Rutgers University,Piscataway,NewJersey 08854-8082,and
Center for
Neuroscience,Shantou University Medical College,Shantou 515041,People’s Republic of China
Newlyformedsynapses undergomaturationduringontogenetic development viamechanisms that remainpoorlyunderstood.We showthat maturationof the presynaptic
endocytotic machinery in CNS neurons requires substitution of the adaptor protein 3 (AP-3) with AP-2 at the presynaptic plasma membrane.In mature synapses,AP-2
associates with the intracellular domain of the neural cell adhesion molecule (NCAM).NCAMpromotes binding of AP-2 over binding of AP-3 to presynaptic membranes,
thus favoring the substitutionof AP-3 for AP-2 during formationof mature synapses.The presynaptic endocytotic machinery remains immature inadult NCAM-deficient
(NCAM￿/￿) mice accumulating AP-3 instead of AP-2 and its partner protein AP180 in synaptic membranes and vesicles.NCAMdeficiency or disruption of the NCAM/
AP-2 complex in wild-type (NCAM￿/￿) neurons by overexpression of AP-2 binding-defective mutant NCAM interferes with efficient retrieval of the synaptic vesicle
v-SNAREsynaptobrevin2.Abnormalities insynaptic vesicle endocytosis andrecycling may thus contribute toneurological disorders associatedwithmutations inNCAM.
The Journal of Neuroscience,October 16,2013

Synaptic Regulation of Microtubule Dynamics in Dendritic Spines by Calcium,F-Actin,and
Elliott B.Merriam,
Derek C.Lumbard,
Witchuda Saengsawang,
Thomas Fothergill,
Xindao Hu,
Lotfi Ferhat,
and Erik W.Dent
Neuroscience Training Program,
Department of Neuroscience,University of Wisconsin School of Medicine and Public Health,Madison,Wisconsin
Department of Physiology,Faculty of Science,Mahidol University,Bangkok 10400,Thailand,and
Aix-Marseille University,Neurobiologie des
Interactions Cellulaires et Neurophysiopathologie,13385 Marseille,France
Dendritic spines are actin-rich compartments that protrude fromthe microtubule-rich dendritic shafts of principal neurons.Spines contain receptors and postsynaptic
machinery for receiving the majority of glutamatergic inputs.Recent studies have shownthat microtubules polymerize fromdendritic shafts intospines andthat signaling
through synaptic NMDA receptors regulates this process.However,the mechanisms regulating microtubule dynamics in dendrites and spines remain unclear.Here we
showthat inhippocampal neurons frommaleandfemalemice,themajorityof microtubules enter spines fromhighlylocalizedsites at thebaseof spines.Theseentries occur
in response to synapse-specific calciumtransients that promote microtubule entry into active spines.We further document that spine calciumtransients promote local
actinpolymerization,andthat F-actinis bothnecessaryandsufficient for microtubuleentry.Finally,weshowthat drebrin,aproteinknowntomediateinteractions between
F-actinandmicrotubules,acts as apositiveregulator of microtubuleentryintospines.Together theseresults establishfor thefirst timetheessential mechanisms regulating
microtubule entry into spines and contribute importantly to our understanding of the role of microtubules in synaptic function and plasticity.
The Journal of Neuroscience,October 16,2013

Opposing Action of Nuclear Factor ￿B and Polo-like Kinases Determines a Homeostatic End
Point for Excitatory Synaptic Adaptation
Anca B.Mihalas,
Yoichi Araki,
Richard L.Huganir,
and Mollie K.Meffert
Department of Biological Chemistry and
Solomon H.Snyder Department of Neuroscience,School of Medicine,Johns Hopkins University,Baltimore,
Maryland 21205
Homeostaticresponsescriticallyadjust synapticstrengthstomaintainstabilityinneuronal networks.Compensatoryadaptationstoprolongedexcitationincludeinduction
of Polo-like kinases (Plks) anddegradationof spine-associatedRapGTPase-activating protein(SPAR) toreduce synaptic excitation,but mechanisms that limit overshoot-
ing andallowrefinement of homeostatic adjustments remainpoorly understood.We report that Plks produce canonical pathway-mediatedactivationof the nuclear factor
￿B(NF-￿B) transcriptionfactor ina process that requires the kinase activity of Plks.Chronic elevatedactivity,whichinduces Plkexpression,alsoproduces Plk-dependent
activation of NF-￿B.Deficiency of NF-￿B,in the context of exogenous Plk2 expression or chronic elevated neuronal excitation,produces exaggerated homeostatic
reductions in the size and density of dendritic spines,synaptic AMPA glutamate receptor levels,and excitatory synaptic currents.During the homeostatic response to
chronic elevated activity,NF-￿Bactivationby Plks subsequently opposes Plk-mediated SPARdegradationby transcriptionally upregulating SPARinmouse hippocampal
neurons in vitro and in vivo.Exogenous SPAR expression can rescue the overshooting of homeostatic reductions at excitatory synapses in NF-￿B-deficient neurons
responding to elevated activity.Our data establish an integral feedback loop involving NF-￿B,Plks,and SPAR that regulates the end point of homeostatic synaptic
adaptation to elevated activity and are the first to implicate a transcription factor in the regulation of homeostatic synaptic responses.
The Journal of Neuroscience,October 16,2013

￿2-Chimaerin Regulates a Key Axon Guidance Transition during Development of the
Oculomotor Projection
Christopher Clark,Oliver Austen,Ivana Poparic,and Sarah Guthrie
MRC Centre for Developmental Neurobiology,King’s College,Guy’s Campus,London SE1 1UL,United Kingdom
The ocular motor systemconsists of three nerves which innervate six muscles to control eye movements.In humans,defective development of this systemleads to eye
movement disorders,such as Duane RetractionSyndrome,which canresult frommutations inthe￿2-chimaerinsignaling molecule.We have used the zebrafish to model
the role of ￿2-chimaerin during development of the ocular motor system.We first mapped ocular motor spatiotemporal development,which occurs between 24 and 72 h
postfertilization(hpf),withtheoculomotor nervefollowinganinvariant sequenceof growthandbranchingtoits muscletargets.Weidentified52hpf as akeyaxonguidance
“transition,” when oculomotor axons reach the orbit and select their muscle targets.Live imaging and quantitation showed that,at 52 hpf,axons undergo a switch in
behavior,withstriking changes inthe dynamics of filopodia.We testedthe role of ￿2-chimaerininthis guidance process andfoundthat axons expressing gain-of-function
￿2-chimaerinisoforms failedtoundergothe 52 hpf transitioninfilopodial dynamics,leading toaxonstalling.￿2-chimaerinloss of functionledtoecotopic andmisguided
branching and hypoplasia of oculomotor axons;embryos had defective eye movements as measured by the optokinetic reflex.Manipulation of chimaerin signaling in
oculomotor neurons in vitro led to changes in microtubule stability.These findings demonstrate that a correct level of ￿2-chimaerin signaling is required for key
oculomotor axon guidance decisions,and provide a zebrafish model for Duane Retraction Syndrome.
The Journal of Neuroscience,October 16,2013

Gap Junction-Dependent Homolog Avoidance in the Developing CNS
Michael W.Baker,Neema Yazdani,and Eduardo R.Macagno
Section of Cell and Developmental Biology,University of California,San Diego,La Jolla,California 92093
Oppositely directed projections of some homologous neurons in the developing CNS of the medicinal leech (Hirudo verbana),such as the AP cells,undergo a formof
contact-dependent homologavoidance.Embryonic APs extendaxons withintheconnectivenervetowardadjacent ganglia,inwhichtheymeet andformgapjunctions (GJs)
with the oppositely directed axons of their segmental homologs,stop growing,and are later permanently retracted (Wolszonet al.,1994a,b).However,early deletionof an
AP neuron leads to resumed growth and permanent maintenance of the projections of neighboring APs.Here we test the hypothesis that a GJ-based signaling mechanism
is responsible for this instance of homolog avoidance.We demonstrate that selective knockdownof GJ gene Hve–inx1 expressioninsingle embryonic APs,by expressing a
short-hairpin interfering RNA,leads to continued growth of the projections of the cell toward,into,and beyond adjacent ganglia.Moreover,the projections of the APs in
adjacent ganglia also resume growth,mimicking their responses to cell deletion.Continued growth was also observed when two different INX1 mutant transgenes that
abolishdyecouplingbetweenAPs wereexpressed.Theseincludeamutant transgenethat effectivelydownregulates all GJ plaques that includetheINX1proteinandaclosed
channel INX1 mutant that retains the adhesive cellular binding characteristic of INX1 GJs but not the open channel pore function.Our results add GJ intercellular
communication to the list of molecular signaling mechanisms that can act as mediators of growth-inhibiting cell–cell interactions that define the topography of neuronal
The Journal of Neuroscience,October 16,2013

Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDAReceptors in
Dopamine Neurons
Yvonne Schmitz,
Candace Castagna,
Ana Mrejeru,
Jose´ E.Lizardi-Ortiz,
Zoe Klein,
Craig W.Lindsley,
and David Sulzer
Departments of Neurology,
Pharmacology,Columbia University Medical Center,NewYork,NewYork 10032,and
Vanderbilt Center for
Neuroscience Drug Discovery,Vanderbilt University Medical Center,Nashville,Tennessee 37232
NMDAreceptor activityis involvedinshapingsynaptic connections throughout development andadulthood.We recentlyreportedthat brief activationof NMDAreceptors
on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching.To test whether this mechanismwas relevant to axon
regrowth in adult animals,we examined the reinnervation of dorsal striatumfollowing nigral dopamine neuron loss induced by unilateral intrastriatal injections of the
toxin 6-hydroxydopamine.We used a pharmacological approach to enhance NMDAreceptor-dependent signaling by treatment with an inhibitor of glycine transporter-1
that elevates levels of extracellular glycine,a coagonist required for NMDAreceptor activation.All mice displayed sprouting of dopaminergic axons fromspared fibers in
the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion,but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was
approximately twice as dense as in untreated mice.The treated mice also displayed higher levels of striatal dopamine and a complete recovery fromlateralization in a test
of sensorimotor behavior.We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine
neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons.Glycine transport inhibitors promote functionally relevant sprouting of
surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson’s disease.
The Journal of Neuroscience,October 16,2013

Structural Basis of Cerebellar Microcircuits in the Rat
Nadia L.Cerminara,
Hanako Aoki,
Michaela Loft,
Izumi Sugihara,
* and Richard Apps
School of Physiology and Pharmacology,University of Bristol,Bristol BS8 1TD,United Kingdom,and
Department of Systems Neurophysiology and
Center for Brain Integration Research,Tokyo Medical and Dental University,Tokyo 113-8519,Japan
The topography of the cerebellar cortex is describedby at least three different maps,withthe basic units of eachmaptermed“microzones,” “patches,” and“bands.” These
are defined,respectively,by different patterns of climbing fiber input,mossy fiber input,and Purkinje cell (PC) phenotype.Based on embryological development,the
“one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aimof the present study was to test this possibility.In barbiturate
anesthetized adult rats,nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the
hindlimb C1 zone in copula pyramidis.Injection sites were mapped relative to PCbands defined by the molecular marker zebrin II and were correlated with the pattern of
retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches,respectively,and also with the
distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei.Zebrin bands were found to be related to both climbing fiber and mossy fiber
inputs andalsotocortical representationof different parts of theipsilateral hindpaw,indicatingaprecisespatial organizationwithincerebellar microcircuitry.This precise
connectivity extends to PCterminal fields in the cerebellar nuclei and olivonuclear projections.These findings strongly support the one-map hypothesis and suggest that,
at the microcircuit level of resolution,the cerebellar cortex has a common plan of spatial organization for major inputs,outputs,and PC phenotype.
The Journal of Neuroscience,October 16,2013

Integration of Direction Cues Is Invariant to the Temporal Gap between Them
Roozbeh Kiani,
Anne K.Churchland,
and Michael N.Shadlen
Center for Neural Science,NewYork University,NewYork,NewYork 10003,
Cold Spring Harbor Laboratory,Cold Spring Harbor,NewYork 11724,
Howard Hughes Medical Institute,Kavli Institute and Department of Neuroscience,Columbia University,NewYork,NewYork 10038,and
Department of
Physiology and Biophysics,University of Washington,Seattle,Washington 98195
Many decisions involve integration of evidence conferred by discrete cues over time.However,the neural mechanismof this integration is poorly understood.Several
decision-making models suggest that integration of evidence is implemented by a dynamic systemwhose state evolves toward a stable point representing the decision
outcome.Theinternal dynamics of suchpoint attractor models render themsensitivetothetemporal gaps betweencues becausetheir internal forces pushthestateforward
once it is dislodged fromthe initial stable point.We asked whether humansubjects are as sensitive to such temporal gaps.Subjects reported the net directionof stochastic
randomdot motion,which was presented in one or two brief observation windows (pulses).Pulse strength and interpulse interval varied randomly fromtrial to trial.We
foundthat subjects’ performance was largely invariant to the interpulse intervals upto at least 1 s.The findings questionthe implementationof the integrationprocess via
mechanisms that relyonautonomous changes of networkstate.The mechanismshouldbe capable of freezingthe state of the networkat avarietyof firingrate levels during
temporal gaps between the cues,compatible with a line of stable attractor states.
The Journal of Neuroscience,October 16,2013

The Neuromuscular Transformof the Lobster Cardiac SystemExplains the Opposing Effects of a
Neuromodulator on Muscle Output
Alex H.Williams,
Timothy O’Leary,
Renee Symonds,
Eve Marder,
and Patsy S.Dickinson
Biology Department and Volen Center,Brandeis University,Waltham,Massachusetts 02454,and
Neuroscience Program,Bowdoin College,Brunswick,
Maine 04011
Motor neuronactivity is transformedinto muscle movement througha cascade of complex molecular andbiomechanical events.This nonlinear mapping of neural inputs
tomotor behaviors is calledthe neuromuscular transform(NMT).We examinedthe NMTinthe cardiac systemof the lobster Homarus americanus by stimulatinga cardiac
motor nerve with rhythmic bursts of action potentials and measuring muscle movements in response to different stimulation patterns.The NMT was similar across
preparations,which suggested that it could be used to predict muscle movement fromspontaneous neural activity in the intact heart.We assessed this possibility across
semi-intact heart preparations in two separate analyses.First,we performed a linear regression analysis across 122 preparations in physiological saline to predict muscle
movements fromneural activity.Under theseconditions,theNMTwas predictiveof contractiondutycyclebut was unabletopredict contractionamplitude,likelyas aresult
of uncontrolled interanimal variability.Second,we assessed the ability of the NMT to predict changes in motor output induced by the neuropeptide C-type allatostatin.
Wiwatpanit et al.(2012) showed that bath application of C-type allatostatin produced either increases or decreases in the amplitude of the lobster heart contractions.We
showthat animportant component of these preparation-dependent effects canarise fromquantifiable differences inthe basal state of each preparationand the nonlinear
formof the NMT.These results illustrate howproperly characterizing the relationships between neural activity and measurable physiological outputs can provide insight
into seemingly idiosyncratic effects of neuromodulators across individuals.
The Journal of Neuroscience,October 16,2013

Visual Response Properties of V1 Neurons Projecting to V2 in Macaque
Yasmine El-Shamayleh,Romesh D.Kumbhani,Neel T.Dhruv,and J.Anthony Movshon
Center for Neural Science,NewYork University,NewYork,NewYork 10003
Visual area V2 of the primate cortex receives the largest projectionfromarea V1.V2 is thought to use its striate inputs as the basis for computations that are important for
visual formprocessing,such as signaling angles,object borders,illusory contours,and relative binocular disparity.However,it remains unclear howselectivity for these
stimulus properties emerges in V2,in part because the functional properties of the inputs are unknown.We used antidromic electrical stimulation to identify V1 neurons
that project directly to V2 (10% of all V1 neurons recorded) and characterized their electrical and visual responses.V2-projecting neurons were concentrated in the
superficial andmiddle layers of striate cortex,consistent withthe knownanatomy of this cortico-cortical circuit.Most were fast conducting andtemporally precise intheir
electrical responses,andhadbroadspike waveforms consistent withpyramidal regular-spiking excitatory neurons.Overall,projectionneurons were functionally diverse.
Most,however,were tunedfor orientationandbinocular disparityandwere stronglysuppressedbylarge stimuli.Projectionneurons includedthose selective andinvariant
to spatial phase,with roughly equal proportions.Projection neurons found in superficial layers had longer conduction times,broader spike waveforms,and were more
responsive to chromatic stimuli;those found in middle layers were more strongly selective for motion direction and binocular disparity.Collectively,these response
properties may be well suited for generating complex feature selectivity in and beyond V2.
The Journal of Neuroscience,October 16,2013

33(42):16594 –16605
Object Representation in Inferior Temporal Cortex Is Organized Hierarchically in a Mosaic-Like
Takayuki Sato,
Go Uchida,
Mark D.Lescroart,
Jun Kitazono,
Masato Okada,
and Manabu Tanifuji
RIKENBrain Science Institute,Wako,Saitama 351-0198,Japan,
Helen Wills Neuroscience Institute,University of California at Berkeley,Berkeley,
California 94720,
Department of Complexity Science and Engineering,Graduate School of Frontier Sciences,The University of Tokyo,Kashiwa,Chiba
Department of Life Science and Medical Bio-Science,Faculty of Science and Engineering,Waseda University,Shinjuku,Tokyo 169-8555,
Institute of Neuroscience and Brain Research Center,National Yang-Ming University,Taipei 112,Taiwan
There are two dominant models for the functional organization of brain regions underlying object recognition.One model postulates category-specific modules while the
other proposes a distributed representation of objects with generic visual features.Functional imaging techniques relying on metabolic signals,such as fMRI and optical
intrinsic signal imaging (OISI),have been used to support both models,but due to the indirect nature of the measurements in these techniques,the existing data for one
model cannot be used to support the other model.Here,we used large-scale multielectrode recordings over a large surface of anterior inferior temporal (IT) cortex,and
densely mapped stimulus-evoked neuronal responses.We found that IT cortex is subdivided into distinct domains characterized by similar patterns of responses to the
objects in our stimulus set.Each domain spanned several millimeters on the cortex.Some of these domains represented faces (“face” domains) or monkey bodies
(“monkey-body” domains).We also identified domains with low responsiveness to faces (“anti-face” domains).Meanwhile,the recording sites within domains that
displayedcategoryselectivityshowedheterogeneous tuningprofiles todifferent exemplars withineachcategory.This local heterogeneitywas consistent withthe stimulus-
evoked feature columns revealed by OISI.Taken together,our study revealed that regions with common functional properties (domains) consist of a finer functional
structure (columns) in anterior IT cortex.The “domains” and previously proposed “patches” are rather like “mosaics” where a whole mosaic is characterized by overall
similarity in stimulus responses and pieces of the mosaic correspond to feature columns.
The Journal of Neuroscience,October 16,2013

Diverse Suppressive Influences in Area MT and Selectivity to Complex Motion Features
Yuwei Cui,
Liu D.Liu,
Farhan A.Khawaja,
Christopher C.Pack,
and Daniel A.Butts
Department of Biology and Programin Neuroscience and Cognitive Science,University of Maryland,College Park,Maryland 20742,and
Neurological Institute,McGill University,Montreal,Quebec,Canada H3A2B4
Neuronal selectivityresults frombothexcitatoryandsuppressive inputs toagivenneuron.Suppressive influences canoftensignificantlymodulate neuronal responses and
impart novel selectivity in the context of behaviorally relevant stimuli.In this work,we use a naturalistic optic flow stimulus to explore the responses of neurons in the
middle temporal area (MT) of the alert macaque monkey;these responses are interpreted using a hierarchical model that incorporates relevant nonlinear properties of
upstreamprocessing in the primary visual cortex (V1).In this stimulus context,MT neuron responses can be predicted fromdistinct excitatory and suppressive compo-
nents.Excitation is spatially localized and matches the measured preferred direction of each neuron.Suppression is typically composed of two distinct components:(1) a
directionally untuned component,which appears to play the role of surround suppression and normalization;and (2) a direction-selective component,with comparable
tuning widthas excitationanda distinct spatial footprint that is usually partially overlapping withexcitation.The directionpreference of this direction-tunedsuppression
varies widelyacross MTneurons:approximatelyone-thirdhave overlappingsuppressioninthe opposite directionas excitation,andmanyother neurons have suppression
withsimilar directionpreferences toexcitation.There is alsoa populationof MTneurons withorthogonally orientedsuppression.We demonstrate that direction-selective
suppression can impart selectivity of MT neurons to more complex velocity fields and that it can be used for improved estimation of the three-dimensional velocity of
moving objects.Thus,considering MT neurons in a complex stimulus context reveals a diverse set of computations likely relevant for visual processing in natural visual
The Journal of Neuroscience,October 16,2013

Large-Scale Brain Networks in the Awake,Truly Resting Marmoset Monkey
Annabelle M.Belcher,
Cecil C.Yen,
Haley Stepp,
Hong Gu,
Hanbing Lu,
Yihong Yang,
Afonso C.Silva,
and Elliot A.Stein
Neuroimaging Research Branch,National Institute on Drug Abuse,National Institutes of Health,Baltimore,Maryland 21224,and
Microcirculation Unit,Laboratory of Functional and Molecular Imaging,National Institute of Neurological Disorders and Stroke,National Institutes of
Health,Bethesda,Maryland 20892
Resting-state functional MRI is a powerful tool that is increasingly used as a noninvasive method for investigating whole-brain circuitry and holds great potential as a
possible diagnostic for disease.Despite this potential,fewresting-state studies have used animal models (of which nonhuman primates represent our best opportunity of
understanding complex human neuropsychiatric disease),and no work has characterized networks in awake,truly resting animals.Here we present results froma small
NewWorld monkey that allows for the characterization of resting-state networks in the awake state.Six adult common marmosets (Callithrix jacchus) were acclimated to
light,comfortable restraint using individualized helmets.Following behavioral training,resting BOLDdata were acquired during eight consecutive 10 min scans for each
conscious subject.Groupindependent component analysis revealed12 brainnetworks that overlapsubstantially withknownanatomically constrainedcircuits seeninthe
awake human.Specifically,we found eight sensory and “lower-order” networks (four visual,two somatomotor,one cerebellar,and one caudate–putamen network),and
four “higher-order” association networks (one default mode-like network,one orbitofrontal,one frontopolar,and one network resembling the human salience network).
Inadditionto their functional relevance,these network patterns bear great correspondence to those previously describedinawake humans.This first-of-its-kindreport in
an awake NewWorld nonhuman primate provides a platformfor mechanistic neurobiological examination for existing disease models established in the marmoset.
The Journal of Neuroscience,October 16,2013

Relationship between the Local Structure of Orientation Map and the Strength of Orientation
Tuning of Neurons in Monkey V1:A2-Photon CalciumImaging Study
Koji Ikezoe,
Yoshiya Mori,
Kazuo Kitamura,
Hiroshi Tamura,
and Ichiro Fujita
Laboratory for Cognitive Neuroscience,Graduate School of Frontier Biosciences,Osaka University,Toyonaka,Osaka,560-8531,Japan,
Center for
Information and Neural Networks (CiNet),Osaka University and National Institute of Information and Communications Technology,Suita,Osaka,565-
Core Research for Evolutional Science and Technology (CREST),Japan Science and Technology Agency,Kawaguchi,Saitama,332-0012,
Department of Neurophysiology,Graduate School of Medicine,University of Tokyo,Bunkyo,Tokyo,113-0033,Japan
Amajority of neurons in the monkey primary visual cortex (V1) are tuned to stimulus orientations.Preferred orientations and tuning strengths vary among V1 neurons.
The preferred orientation of neurons gradually changes across the cortex with occasional failures of this organization.How V1 neurons are arranged by the strength of
orientationtuningandwhether neuronal arrangement for tuningstrengthrelates toorientationpreference maps remains controversial.Inthis study,we performedinvivo
two-photoncalciumimaginginmacaqueV1toexaminethelocal spatial organizationof orientationtuningat thelevel of singlecells.Werecordedfluorescencesignals from
individual neurons loaded with a calcium-sensitive dye in layer 2 and the uppermost tier of layer 3.The strength of orientation tuning was shared by nearby neurons,and
changedacross thecortex.Theneurons withsimilar tuningstrengthweredistributedacross at least theentirethickness of layer 2.Thetuningstrengthwas weaker inregions
where neurons exhibited heterogeneous preferred orientations,as compared with regions where neurons shared similar orientation preferences.Nearby direction-
selective neurons oftensharedtheir preferreddirections,althoughonlyafewneurons were directionselective inthe layers examined.Thus,the orientationtuningstrength
of V1 neurons is partially predictable fromthe local structure of orientation map.The weaker orientation tuning we found in regions with heterogeneous orientation
preferences suggests that orientation-independent interactions among local populations of V1 neurons play a critical role in determining their orientation tuning.
The Journal of Neuroscience,October 16,2013

Distinct Parietal and Temporal Connectivity Profiles of Ventrolateral Frontal Areas Involved in
Language Production
Daniel S.Margulies
and Michael Petrides
Max Planck Research Group:Neuroanatomy &Connectivity,Max Planck Institute for Human Cognitive and Brain Sciences,04103,Leipzig,Germany,and
Cognitive Neuroscience Unit,Montreal Neurological Institute,McGill University,Montreal,Quebec,Canada H3A2B4
Broca’s region,which in the language-dominant hemisphere of the human brain plays a major role in language production,includes two distinct cytoarchitectonic areas:
44 and 45.The unique connectivity patterns of these two areas have not been well established.In a resting-state functional connectivity study,we tested predictions about
these areas frominvasive tract-tracing studies of the connectivity of their homologs in the macaque monkey.We demonstrated their distinct connectivity profiles as well
as their differences fromthe caudally adjacent ventral parts of the premotor cortex andthe primary motor cortical regionthat represent the orofacial musculature.Area 45
is strongly connected with the superior temporal sulcus and the cortex onthe adjacent superior and middle temporal gyri.Inthe parietal region,area 45 is connected with
the angular gyrus,whereas area 44 is connected with the supramarginal gyrus.The primary motor cortical region in the caudal precentral gyrus is not connected with the
posterior parietal region,which lies outside the confines of the postcentral gyrus,whereas the ventrorostral premotor cortical area 6VR,in the most anterior part of the
precentral gyrus,has strong connections withthe rostral supramarginal gyrus.Thus,area 44,whichhas stronger connections to the posterior supramarginal gyrus,canbe
distinguishedfromboththe adjacent area 6VRandarea 45.These findings provide a major improvement inunderstandingthe connectivityof the areas inthe ventrolateral
frontal region that are involved in language production.
The Journal of Neuroscience,October 16,2013

Frontal and Parietal Cortical Interactions with Distributed Visual Representations during
Selective Attention and Action Selection
Natalie Nelissen,
Mark Stokes,
Anna C.Nobre,
and MatthewF.S.Rushworth
Action and Decision Laboratory,Department of Experimental Psychology,
Oxford Centre for Human Brain Activity,
Brain and Cognition Laboratory,
Department of Experimental Psychology,
Oxford Centre for Functional MRI of the Brain,Nuffield Department of Clinical Neurosciences,University of
Oxford,Oxford,United Kingdom,and
Cognitive Neurology Laboratory,Experimental Neurology Division,Catholic University Leuven,3000 Leuven,
Using multivoxel patternanalysis (MVPA),we studiedhowdistributedvisual representations inhumanoccipitotemporal cortex are modulatedby attentionandlinktheir
modulation to concurrent activity in frontal and parietal cortex.We detected similar occipitotemporal patterns during a simple visuoperceptual task and an attention-to-
working-memorytaskinwhichoneor twostimuli werecuedbeforebeingpresentedamongother pictures.Patternstrengthvariedfromhighest tolowest whenthestimulus
was the exclusive focus of attention,a conjoint focus,and when it was potentially distracting.Although qualitatively similar effects were seen inside regions relatively
specializedfor the stimulus categoryandoutside,the former were quantitativelystronger.Byregressingoccipitotemporal patternstrengthagainst activityelsewhere inthe
brain,we identified frontal and parietal areas exerting top-down control over,or reading information out from,distributed patterns in occipitotemporal cortex.Their
interactions withpatterns inside regions relatively specializedfor that stimulus category were higher thanthose withpatterns outside those regions andvariedinstrength
as a functionof the attentional condition.One area,the frontal operculum,was distinguishedby selectively interacting withoccipitotemporal patterns only whenthey were
the focus of attention.There was no evidence that any frontal or parietal area actively inhibited occipitotemporal representations even when they should be ignored and
were suppressed.Using MVPA to decode information within these frontal and parietal areas showed that they contained information about attentional context and/or
readout information fromoccipitotemporal cortex to guide behavior but that frontal regions lacked information about category identity.
The Journal of Neuroscience,October 16,2013

The Hand Sees Visual Periphery Better Than the Eye:Motor-Dependent Visual Motion Analyses
Hiroaki Gomi,
Naotoshi Abekawa,
and Shinsuke Shimojo
NTT Communication Science Laboratories,Nippon Telegraph and Telephone Corporation,Morinosato,Atsugi,Kanagawa 243-0198,Japan,
Division of
Biology,California Institute of Technology,Pasadena,California 91125,and
CREST,Japan Science and Technology,Kawaguchi,Saitama 332-0012,Japan
Information pertaining to visual motion is used in the brain not only for conscious perception but also for various kinds of motor controls.In contrast to the increasing
amount of evidence supporting the dissociation of visual processing for action versus perception,it is less clear whether the analysis of visual input is shared for
characterizing various motor outputs,whichrequire different kinds of interactions withenvironments.Here we showthat,inhumanvisuomotor control,motionanalysis
for quickhandcontrol is distinct fromthat for quickeye control interms of spatiotemporal analysis andspatial integration.The amplitudes of implicit andquickhandand
eye responses induced by visual motion stimuli differently varied with stimulus size and pattern smoothness (e.g.,spatial frequency).Surprisingly,the hand response did
not decrease even when the visual motion with a coarse pattern was mostly occluded over the visual center,whereas the eye response markedly decreased.Since these
contrasts cannot beascribedtoanydifferenceinmotor dynamics,theyclearlyindicatedifferent spatial integrationof visual motionfor theindividual motor systems.Going
against the overly unified hierarchical view of visual analysis,our data suggest that visual motion analyses are separately tailored fromearly levels to individual motor
modalities.Namely,the hand and eyes see the external world differently.
The Journal of Neuroscience,October 16,2013

miR-9 and miR-140-5p Target FoxP2 and Are Regulated as a Function of the Social Context of
Singing Behavior in Zebra Finches
Zhimin Shi,
Guanzheng Luo,
Lijuan Fu,
Zhide Fang,
XiuJie Wang,
and XiaoChing Li
Neuroscience Center of Excellence,Louisiana State University Health Sciences Center,NewOrleans,Louisiana 70112,
Institute of Genetics and
Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China,and
Biostatistics Program,School of Public Health,Louisiana State
University Health Sciences Center,NewOrleans,Louisiana 70112
Mutations inthe FOXP2gene cause speechandlanguage impairments,accompaniedbystructural andfunctional abnormalities inbrainregions underlyingspeech-related
sensory-motor processing,including the striatumand cerebellum.The sequence and expression patterns of FOXP2 are highly conserved among higher vertebrates.In the
zebra finch brain,FoxP2 is expressed in Area X,a striatal nucleus required for vocal learning,and reduced FoxP2 expression impairs dendritic development and vocal
learning.The FoxP2 gene encodes a transcription factor that controls the expression of many downstreamgenes.However,howFOXP2 gene expression is regulated is not
clearly understood.miRNAs regulate gene expression post-transcriptionally by targeting the 3￿-untranslated regions (UTRs) of mRNAs,leading to translational suppres-
sion or mRNAdegradation.In this study,we identified miR-9 and miR-140-5p as potential regulators of the FoxP2 gene.We showthat both miR-9 and miR-140-5p target
specific sequences inthe FoxP23￿-UTRanddownregulate FoxP2proteinandmRNAexpressioninvitro.We alsoshowthat the expressionof miR-9andmiR-140-5pinArea
X of the zebra finch brain is regulated during song development in juvenile zebra finches.We further show that in adult zebra finches the expression of miR-9 and
miR-140-5p in Area X is regulated as a function of the social context of song behavior in males singing undirected songs.Our findings reveal a post-transcriptional
mechanismthat regulates FoxP2expressionandsuggest that social vocal behavior caninfluencethebasal gangliacircuit controllingvocal learningviaamiRNA-FoxP2gene
regulatory network.
The Journal of Neuroscience,October 16,2013

Modeling Fall Propensity in Parkinson’s Disease:Deficits in the Attentional Control of Complex
Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation
Aaron Kucinski,
Giovanna Paolone,
Marc Bradshaw,
Roger L.Albin,
and Martin Sarter
Department of Psychology,
Neurology Service and Geriatric Research,Education and Clinical Center,Veterans Administration Ann Arbor Healthcare
Department of Neurology,and
Neuroscience Program,University of Michigan,Ann Arbor,Michigan 48109
Cognitive symptoms,complex movement deficits,and increased propensity for falls are interrelated and levodopa-unresponsive symptoms in patients with Parkinson’s
disease (PD).We developed a test systemfor the assessment of fall propensity in rats and tested the hypothesis that interactions between loss of cortical cholinergic and
striatal dopaminergic afferents increase fall propensity.Rats were trained to traverse stationary and rotating rods,placed horizontally or at inclines,and while exposed to
distractors.Rats also performed an operant Sustained Attention Task (SAT).Partial cortical cholinergic and/or caudate dopaminergic deafferentation were produced by
bilateral infusions of 192IgG-saporin(SAP) intothebasal forebrainand/or 6-hydroxydopamine(6-OHDA) intothecaudatenucleus,respectively,modelingthelesions seen
in early PD.Rats with dual cholinergic–dopaminergic lesions (DL) fell more frequently than SAP or 6-OHDA rats.Falls in DL rats were associated with incomplete
rebalancing after slips and low traversal speed.Ladder rung walking and pasta handling performance did not indicate sensorimotor deficits.SAT performance was
impairedinDLandSAPrats;however,SATperformance andfalls were correlatedonly inDLrats.Furthermore,inDLrats,but not inrats withonly dopaminergic lesions,
the placement andsize of dopaminergic lesioncorrelatedsignificantly withfall rates.The results support the hypothesis that after dual cholinergic–dopaminergic lesions,
attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement,thereby “unmasking” impaired striatal control of
complex movements and yielding falls.
The Journal of Neuroscience,October 16,2013

Synapsin Function in GABA-ergic Interneurons Is Required for Short-TermOlfactory
Madhumala K.Sadanandappa,
Beatriz Blanco Redondo,
Birgit Michels,
Veronica Rodrigues,

Erich Buchner,
and Mani Ramaswami
National Centre for Biological Sciences,Bangalore 560065,India,
Institute for Clinical Neurobiology,University of Wu¨rzburg,97078 Wu¨rzburg,Germany,
Department of Genetics for Learning and Memory,Leibniz Institute for Neurobiology,39118 Magdeburg,Germany,
School of Genetics and Microbiology,
School of Natural Sciences,Smurfit Institute of Genetics and Trinity College Institute of Neuroscience,Trinity College Dublin,Dublin-2,Ireland
In Drosophila,short-term (STH) and long-term habituation (LTH) of olfactory avoidance behavior are believed to arise from the selective potentiation of GABAergic
synapses between multiglomerular local circuit interneurons (LNs) and projection neurons in the antennal lobe.However,the underlying mechanisms remain poorly
understood.Here,we showthat synapsin (syn) function is necessary for STHand that syn
-null mutant defects in STHcan be rescued by syn
cDNAexpression solely in
the LN1subset of GABAergic local interneurons.As synapsinis asynaptic vesicle-clusteringphosphoprotein,these observations identifyapresynaptic mechanismfor STH
as well as theinhibitoryinterneurons inwhichthis mechanismis deployed.Serineresidues 6and/or 533,potential kinasetarget sites of synapsin,arenecessaryfor synapsin
function suggesting that synapsin phosphorylation is essential for STH.Consistently,biochemical analyses using a phospho-synapsin-specific antiserum show that
synapsinis a target of Ca
calmodulin-dependent kinase II (CaMKII) phosphorylationinvivo.Additional behavioral andgenetic observations demonstrate that CaMKII
function is necessary in LNs for STH.Together,these data support a model in which CaMKII-mediated synapsin phosphorylation in LNs induces synaptic vesicle
mobilizationandtherebypresynaptic facilitationof GABArelease that underlies olfactorySTH.Finally,the strikingobservationthat LTHoccurs normallyinsyn
indicates that signaling pathways for STHand LTHdiverge upstreamof synapsin function in GABAergic interneurons.
The Journal of Neuroscience,October 16,2013

AHierarchy of Attentional Priority Signals in Human Frontoparietal Cortex
Taosheng Liu
and Youyang Hou
Department of Psychology and
Neuroscience Program,Michigan State University,East Lansing,Michigan 48824
Humans can voluntarily attend to a variety of visual attributes to serve behavioral goals.Voluntary attention is believed to be controlled by a network of dorsal frontopa-
rietal areas.However,it is unknown how neural signals representing behavioral relevance (attentional priority) for different attributes are organized in this network.
Computational studies have suggested that a hierarchical organization reflecting the similarity structure of the task demands provides an efficient and flexible neural
representation.Here we examinedthe structure of attentional priority using functional magnetic resonance imaging.Participants were cuedtoattendtolocation,color,or
motion direction within the same stimulus.We found a hierarchical structure emerging in frontoparietal areas,such that multivoxel patterns for attending to spatial
locations were most distinct fromthose for attending to features,and the latter were further clustered into different dimensions (color vs motion).These results provide
novel evidence for the organization of the attentional control signals at the level of distributed neural activity.The hierarchical organization provides a computationally
efficient scheme to support flexible top-down control.
The Journal of Neuroscience,October 16,2013

Medial and Lateral Networks in Anterior Prefrontal Cortex Support Metacognitive Ability for
Memory and Perception
Benjamin Baird,
Jonathan Smallwood,
Krzysztof J.Gorgolewski,
and Daniel S.Margulies
Department of Psychological and Brain Sciences,University of California,Santa Barbara,California 93106,
Department of Psychology,University of York,
North Yorkshire YO10 5DD,United Kingdom,and
Max Planck Research Group:Neuroanatomy &Connectivity,Max Planck Institute for Human Cognitive
and Brain Sciences,04103,Leipzig,Germany
Convergent evidence indicates that frontopolar Brodmann area 10,and more generally the anterior prefrontal cortex (aPFC),supports the human capacity to monitor and
reflect oncognitionandexperience.Animportant unansweredquestion,however,is whether aPFCis ahomogeneous regionthat supports ageneral-purposemetacognitiveability
or whether there could be regional specialization within aPFC with respect to specific types of metacognitive processes.Previous studies suggest that the lateral and medial
subdivisions within aPFCmay support metacognitive judgments of moment-to-moment perceptual processes and assessments of information frommemory stored over longer
time scales,respectively.Here we directly comparedintraindividual variability inmetacognitive capacity for perceptual decisions andmemorial judgments andusedresting-state
functional connectivity(rs-fcMRI) torelatethis variabilitytotheconnectivityof themedial andlateral regions of aPFC.Wefoundabehavioral dissociationinmetacognitiveability
for perceptual andmemorial judgments.Furthermore,functional connectivityanalysis revealeddistinct patterns of connectivitythat correlatedwithindividual differences ineach
domain.Metacognitive abilityfor perceptual decisions was associatedwithgreater connectivitybetweenlateral regions of aPFCandright dorsal anterior cingulate cortex,bilateral
putamen,right caudate,andthalamus,whereasmetacognitiveabilityformemoryretrieval predictedgreaterconnectivitybetweenmedial aPFCandtheright central precuneusand
intraparietal sulcus/inferior parietal lobule.Together,these results suggest that an individual’s capacity for accurate introspection in the domains of perception and memory is
relatedtothe functional integrity of unique neural networks anchoredinthe medial andlateral regions of the aPFC.
TheJournal of Neuroscience,October 16,2013

Saccade Modulation by Optical and Electrical Stimulation in the Macaque Frontal Eye Field
Shay Ohayon,
Piercesare Grimaldi,
Nicole Schweers,
and Doris Y.Tsao
Division of Biology and
Computation and Neural Systems,California Institute of Technology,Pasadena,California 91125
Recent studies have demonstrated that strong neural modulations can be evoked with optogenetic stimulation in macaque motor cortex without observing any evoked
movements (Hanet al.,2009,2011;Diester et al.,2011).It remains unclear whysuchperturbations donot generate movements andif conditions exist under whichtheymay
evoke movements.Inthis study,we examine the effects of five optogenetic constructs inthe macaque frontal eye fieldanduse electrical microstimulationtoassess whether
optical perturbation of the local network leads to observable motor changes during optical,electrical,and combined stimulation.We report a significant increase in the
probability of evoking saccadic eye movements whenlowcurrent electrical stimulationis coupledtooptical stimulationcomparedwithwhenelectrical stimulationis used
alone.Experiments combiningchannelrhodopsin2(ChR2) andelectrical stimulationwithsimultaneous fMRI revealednodiscerniblefMRI activityat theelectrodetipwith
optical stimulation but strong activity with electrical stimulation.Our findings suggest that stimulation with current ChR2 optogenetic constructs generates subthreshold
activity that contributes to the initiation of movements but,in most cases,is not sufficient to evoke a motor response.
The Journal of Neuroscience,October 16,2013

Musical Training Enhances Neural Processing of Binaural Sounds
Alexandra Parbery-Clark,
Dana L.Strait,
Emily Hittner,
and Nina Kraus
Auditory Neuroscience Laboratory,
Institute for Neuroscience,
Department of Communication Sciences,
Weinberg College of Arts and Sciences,
Department of Neurobiology and Physiology,and
Department of Otolaryngology,Northwestern University,Evanston,Illinois 60208
While hearing innoise is a complex task,eveninhighlevels of noise humans demonstrate remarkable hearing ability.Binaural hearing,whichinvolves the integrationand
analysis of incoming sounds fromboth ears,is an important mechanismthat promotes hearing in complex listening environments.Analyzing inter-ear differences helps
differentiate between sound sources–a key mechanism that facilitates hearing in noise.Even when both ears receive the same input,known as diotic hearing,speech
intelligibility in noise is improved.Although musicians have better speech-in-noise perception compared with non-musicians,we do not know to what extent binaural
processing contributes to this advantage.Musicians often demonstrate enhanced neural responses to sound,however,which may undergird their speech-in-noise
perceptual enhancements.Here,we recorded auditory brainstemresponses in young adult musicians and non-musicians to a speech stimulus for which there was no
musician advantage when presented monaurally.When presented diotically,musicians demonstrated faster neural timing and greater intertrial response consistency
relative to non-musicians.Furthermore,musicians’ enhancements to the diotically presented stimulus correlated with speech-in-noise perception.These data provide
evidence for musical training’s impact on biological processes and suggest binaural processing as a possible contributor to more proficient hearing in noise.
The Journal of Neuroscience,October 16,2013

Functional Subdomains within Human FFA
Tolga C¸ukur,
Alexander G.Huth,
Shinji Nishimoto,
and Jack L.Gallant
Helen Wills Neuroscience Institute,
Programin Bioengineering,and
Department of Psychology,University of California,Berkeley,California 94720,and
Department of Electrical and Electronics Engineering,Bilkent University,TR-06800 Ankara,Turkey
The fusiform face area (FFA) is a well-studied human brain region that shows strong activation for faces.In functional MRI studies,FFA is often assumed to be a
homogeneous collection of voxels with similar visual tuning.To test this assumption,we used natural movies and a quantitative voxelwise modeling and decoding
frameworktoestimate category tuning profiles for individual voxels withinFFA.We findthat the responses inmost FFAvoxels are strongly enhancedby faces,as reported
in previous studies.However,we also find that responses of individual voxels are selectively enhanced or suppressed by a wide variety of other categories and that these
broader tuning profiles differ across FFAvoxels.Cluster analysis of category tuning profiles across voxels reveals three spatially segregated functional subdomains within
FFA.These subdomains differ primarily intheir responses for nonface categories,suchas animals,vehicles,andcommunicationverbs.Furthermore,this segregationdoes
not depend on the statistical threshold used to define FFA fromresponses to functional localizers.These results suggest that voxels within FFA represent more diverse
information about object and action categories than generally assumed.
The Journal of Neuroscience,October 16,2013

￿-1 Gene Deletion Affects Somatosensory Neuron Function and Delays Mechanical
Hypersensitivity in Response to Peripheral Nerve Damage
Ryan Patel,
* Claudia S.Bauer,
* Manuela Nieto-Rostro,
* Wojciech Margas,
Laurent Ferron,
Kanchan Chaggar,
Kasumi Crews,
Juan D.Ramirez,
David L.H.Bennett,
Arnold Schwartz,
Anthony H.Dickenson,
and Annette C.Dolphin
Department of Neuroscience,Physiology and Pharmacology,University College London,London,WC1E 6BT,United Kingdom,
Nuffield Department of
Clinical Neurosciences,John Radcliffe Hospital,University of Oxford,Oxford,OX1 2JD,United Kingdom,and
University of Cincinnati,College of
Medicine,Cincinnati,Ohio 45229
￿-1subunit of voltage-gatedcalciumchannels is upregulatedafter sensorynerve injuryandis alsothe therapeutic target of gabapentinoiddrugs.It is therefore likely
to play a key role in the development of neuropathic pain.In this study,we have examined mice in which￿
￿-1 gene expression is disrupted,to determine whether ￿
is involved in various modalities of nociception,and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL).We find that naive
mice showa marked behavioral deficit in mechanical and cold sensitivity,but no change in thermal nociception threshold.The lower mechanical sensitivity is
mirroredbyareducedinvivoelectrophysiological response of dorsal hornwide dynamic range neurons.The Ca
2.2level is reducedinbrainandspinal cordsynaptosomes
DRGneurons exhibit lower calciumchannel current density.Furthermore,a significantly smaller number of DRGneurons respondto
the TRPM8 agonist menthol.After PSNL,￿
mice show delayed mechanical hypersensitivity,which only develops at 11 d after surgery,whereas in wild-type
littermates it is maximal at the earliest time point measured (3 d).There is no compensatory upregulation of ￿
￿-2 or ￿
￿-3 after PSNL in ￿
mice,and other
transcripts,including neuropeptide Y and activating transcription factor-3,are upregulated normally.Furthermore,the ability of pregabalin to alleviate mechanical
hypersensitivity is lost inPSNL￿
￿-1 is essential for rapiddevelopment of mechanical hypersensitivity ina nerve injury model of neuropathic pain.
The Journal of Neuroscience,October 16,2013

The Prion Protein Ligand,Stress-Inducible Phosphoprotein 1,Regulates Amyloid-￿Oligomer
Valeriy G.Ostapchenko,
Flavio H.Beraldo,
Amro H.Mohammad,
Yu-Feng Xie,
Pedro H.F.Hirata,
Ana C.Magalhaes,
Guillaume Lamour,
Hongbin Li,
Andrzej Maciejewski,
Jillian C.Belrose,
Bianca L.Teixeira,
Margaret Fahnestock,
Sergio T.Ferreira,
Neil R.Cashman,
Glaucia N.M.Hajj,
Michael F.Jackson,
Wing-Yiu Choy,
John F.MacDonald,
Vilma R.Martins,
Vania F.Prado,
and Marco A.M.Prado
Robarts Research Institute,Departments of
Physiology and Pharmacology,
Anatomy and Cell Biology,and
Biochemistry,The University of Western
Ontario,London,Ontario,Canada N6A5K8,
Department of Molecular and Cell Biology,International Research Center,A.C.Camargo Cancer Center and
National Institute for Translational Neuroscience,Sa˜o Paulo,Sa˜o Paulo,Brazil,01508-010,
Chemistry Department and
Brain Research Center,University
of British Columbia,Vancouver,British Columbia,Canada V6T 1Z4,
Department of Psychiatry and Behavioural Neurosciences,McMaster University,
Hamilton,Ontario,Canada L8S 4K1,
Institute of Medical Biochemistry,Federal University of Rio de Janeiro,Rio de Janeiro,Rio de Janeiro,Brazil,
In Alzheimer’s disease (AD),soluble amyloid-￿oligomers (A￿Os) trigger neurotoxic signaling,at least partially,via the cellular prion protein (PrP
).However,it is
unknown whether other ligands of PrP
can regulate this potentially toxic interaction.Stress-inducible phosphoprotein 1 (STI1),an Hsp90 cochaperone secreted by
astrocytes,binds to PrP
in the vicinity of the A￿Obinding site to protect neurons against toxic stimuli.Here,we investigated a potential role of STI1 in A￿Otoxicity.We
confirmedthe specific bindingof A￿Os andSTI1tothe PrPandshowedthat STI1efficientlyinhibitedA￿ObindingtoPrPinvitro(IC
of ￿70n
) andalsodecreasedA￿O
binding to culturedmouse primary hippocampal neurons.Treatment withSTI1 preventedA￿O-inducedsynaptic loss andneuronal deathinmouse culturedneurons and
long-termpotentiationinhibitioninmouse hippocampal slices.Interestingly,STI1-haploinsufficient neurons were more sensitive toA￿O-inducedcell deathandcouldbe
rescued by treatment with recombinant STI1.Noteworthy,both A￿O binding to PrP
and PrP
-dependent A￿O toxicity were inhibited by TPR2A,the PrP
domainof STI1.Additionally,PrP
–STI1 engagement activated￿7 nicotinic acetylcholine receptors,whichparticipatedinneuroprotectionagainst A￿O-inducedtoxicity.
We found an age-dependent upregulation of cortical STI1 in the APPswe/PS1dE9 mouse model of ADand in the brains of AD-affected individuals,suggesting a compen-
satory response.Our findings reveal a previously unrecognizedrole of the PrP
ligandSTI1inprotectingneurons inADandsuggest a novel pathway that may helptooffset
A￿O-induced toxicity.
The Journal of Neuroscience,October 16,2013

Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/AutismMutation
Kv10.2–R327HDemonstrate the Role of This Residue in Stabilizing the Channel Closed State
Yang Yang,
* Dmytro V.Vasylyev,
* Fadia Dib-Hajj,
Krishna R.Veeramah,
Michael F.Hammer,
Sulayman D.Dib-Hajj,
and Stephen G.Waxman
Department of Neurology and
Center for Neuroscience and Regeneration Research,Yale University School of Medicine,NewHaven,Connecticut 06510,
Rehabilitation Research Center,Veterans Affairs Connecticut Healthcare System,West Haven,Connecticut 06516,and
Arizona Research Laboratories
Division of Biotechnology,University of Arizona,Tucson,Arizona 85721
Voltage-gated potassiumchannel Kv10.2 (KCNH5) is expressed in the nervous system,but its functions and involvement in human disease are poorly understood.We
studieda humanKv10.2 channel mutation(R327H) recently identifiedina childwithepileptic encephalopathy andautistic features.Using multistate structural modeling,
we demonstrate that the Arg327 residue inthe S4 helix of voltage-sensing domainhas strong ionic interactions withnegatively chargedresidues withinthe S1–S3 helices in
the resting (closed) and early-activation state but not in the late-activation and fully-activated (open) state.The R327H mutation weakens ionic interactions between
residue 327 and these negatively charged residues,thus favoring channel opening.Voltage-clamp analysis showed a strong hyperpolarizing (￿70 mV) shift of voltage
dependence of activation and an acceleration of activation.Our results demonstrate the critical role of the Arg327 residue in stabilizing the channel closed state and
explicate for the first time the structural and functional change of a Kv10.2 channel mutation associated with neurological disease.
The Journal of Neuroscience,October 16,2013

Long-Lasting Spinal Oxytocin Analgesia Is Ensured by the Stimulation of Allopregnanolone
Synthesis Which Potentiates GABA
Receptor-Mediated Synaptic Inhibition
Pierre-Eric Juif,* Jean-Didier Breton,* Mathieu Rajalu,Alexandre Charlet,Yannick Goumon,and Pierrick Poisbeau
Centre National de la Recherche Scientifique and University of Strasbourg,Institut des Neurosciences Cellulaires et Inte´gratives,F-67084 Strasbourg,
Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in
inflammatoryandneuropathicconditions.However,cellular andmolecular mechanisms underlyingOTspinal antinociceptionarestill poorlyunderstood.Inthis study,we
usedbiochemical,electrophysiological,andbehavioral approaches todemonstrate that OTlevels are elevatedinthe spinal cordof rats exhibitingpainsymptoms,24hafter
the induction of inflammation with an intraplantar injection of ￿-carrageenan.Using a selective OT receptor antagonist,we demonstrate that this elevated OT content is
responsible for a tonic analgesia exertedonbothmechanical andthermal modalities.This phenomenonappearedto be mediatedby anOTreceptor-mediatedstimulation
of neurosteroidogenesis,which leads to an increase in GABA
receptor-mediated synaptic inhibition in lamina II spinal cord neurons.We also provide evidence that this
novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases,ERK1/2,after OT receptor activation.The
oxytocinergic inhibitorycontrol of spinal painprocessingis emergingas aninterestingtarget for future therapies since it recruits several molecular mechanisms,whichare
likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.
The Journal of Neuroscience,October 16,2013

Shared Vulnerability of Two Synaptically-Connected Medial Temporal Lobe Areas to Age and
Cognitive Decline:ASeven Tesla Magnetic Resonance Imaging Study
Geoffrey A.Kerchner,
Jeffrey D.Bernstein,
Michelle C.Fenesy,
Gayle K.Deutsch,
Manojkumar Saranathan,
Michael M.Zeineh,
and Brian K.Rutt
Stanford Center for Memory Disorders,Department of Neurology and Neurological Sciences and
Department of Radiology,Stanford University School of
Medicine,Stanford,California 94110
The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimer’s disease (AD).Postmortemhuman tissue evaluation
suggests that this pathology propagates in an ordered manner,with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare
(CA1–SRLM)—twomonosynaptically connectedstructures—exhibitingselective damage.Here,we hypothesizedthat,if ERCandCA1–SRLMshare anearly vulnerability
to ADpathology,then atrophy should occur in a proportional manner between the two structures.We tested this hypothesis in living humans,using ultra-high field 7.0 T
MRI to make fine measurements of MTL microstructure.Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild
AD,we found a significant correlation between ERC and CA1–SRLMsize that could not be explained by global atrophy affecting the MTL.Of the various structures that
contribute axons or dendrites intothe CA1–SRLMneuropil,onlyERCemergedas asignificant predictor of CA1–SRLMsize inalinear regressionanalysis.Incontrast,other
synaptically connectedelements of the MTLdidnot exhibit size correlations.CA1–SRLMandERCstructural covariance was significant for older controls andnot patients,
whereas the opposite pattern emerged for a correlation between CA1–SRLMand episodic memory performance.Interestingly,CA1–SRLMand ERC were the only MTL
structures to atrophy in older controls relative to a younger comparison group.Together,these findings suggest that ERC and CA1–SRLMshare vulnerability to both age
and AD-associated atrophy.
The Journal of Neuroscience,October 16,2013