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The Journal of Neuroscience, January 21, 2015 • 35(3):i • i
This Week in The Journal
Write Protection Expands Model
of LTP
Lorric Ziegler, Friedemann Zenke,
David B. Kastner, and Wulfram Gerstner
(see pages 1319 –1334)
Glutamatergic activation of relatively depolarized postsynaptic neurons leads to
long-term synaptic potentiation (LTP).
Changes that occur early in LTP are
thought to tag activated synapses, allowing them to capture newly synthesized
plasticity-related products (PRPs), which
include scaffolding and cytoskeletal proteins. These PRPs are required to consolidate early LTP into late LTP; without
them, synaptic strength decreases to baseline within a few hours.
Ziegler et al. have developed a computational model that simulates three temporal
phases of LTP, as well as the analogous
stages of long-term depression (LTD). The
phases are represented by three bistable,
synapse-specific variables—weight, tagging,
and scaffolding—which can be in “low” or
“high” states. Depending on its strength and
frequency, simulated synaptic activity can
cause weight, tagging, and scaffolding variables to switch between low and high states
with time courses characteristic of shortterm potentiation, early-LTP, and late-LTP,
respectively. Importantly, the model extends previous models by incorporating a
two-stage write-protection mechanism that
gates the transition between phases and prevents overwriting of previously stored
memories. The first gate represents the molecular changes necessary for tagging; it determines whether the synaptic weight can
influence the tagging variable, and its state is
determined by stimulation strength. The
second gate represents the molecular
changes necessary for consolidation; it determines whether the tagging variable can
influence the scaffolding variable and its
state is determined by additional inputs that
represent reward or novelty that promote
the production of PRPs.
Model simulations reproduced many
experimental results gathered in hippocampal slices. For example, weak tetanic stimulation produced early LTP, but strong
stimulation was required to induce lateLTP. The model also replicated cross-
tagging, in which strong tetanic stimulation
of a subset of synapses not only produces
late-LTP at those synapses, but also consolidates early-LTD that was previously produced at other synapses of the same cell.
Notably, the write-protection mechanism
enabled the model to replicate results not
explained by previous models, such as “tagresetting,” in which the strength of a depotentiated tagged synapse spontaneously
recovers, and “behavioral tagging,” in which
exposure to a novel environment enables a
weak stimulus to induce plasticity.
SS firing pattern changes in one PC across reach trials with and
without external force. In trials without perturbation (below
horizontal line), firing rate (color coded) was highest around
movement onset (first vertical line). The firing pattern gradually changed in the presence of external force. After adaptation (toward top of panel), firing rate increased not only at
movement onset, but also at the onset of the force (middle
vertical line) and, to a lesser extent, after force offset (third
vertical line). See the article by Hewitt et al. for details.
Purkinje Cell Simple Spike Pattern
Changes during Adaptation
Angela L. Hewitt, Laurentiu S. Popa,
and Timothy J. Ebner
(see pages 1106 –1124)
The emergence of motor deficits after cerebellar damage indicates that the cerebellum is involved in producing smooth, continuous
movements. It is also thought to contribute to
motor learning and adaptation in response to
changing conditions, such as external forces or
muscle fatigue. More specifically, the cerebellumhasbeenhypothesizedtoprovideforward
internal models, that is, predictions about
what body movements will result from motor
commands. It has further been proposed that
discrepancies between the predicted movement and the actual movement (as assessed by
sensory feedback) produce a prediction error
that can lead to modification of the internal
model. How these hypothetical roles might be
implemented by neuronal firing remains unclear, however.
Cerebellar Purkinje cells (PCs) exhibit
two types of spiking. Simple spikes (SSs) are
driven by parallel fiber inputs, and they appear to encode eye and limb position, velocity, and acceleration during movements.
Complex spikes are triggered by climbing
fiber input, and it has been proposed that
they play a role in learning. One way to investigate cerebellar function is to examine
how firing patterns change during learning.
This has primarily been done during adaptation of eye movements. To investigate
how modulation of PC spiking might contribute to motor learning during reaching
movements, Hewitt et al. recorded PC activity as monkeys adapted such movements to
counteract externally administered forces.
Initially, the perturbation altered the kinematics of arm movements (i.e., the position,
velocity, and acceleration of the arm over
the course of the reach), but as monkeys
learned to compensate for the expected perturbation over subsequent trials, the kinematic parameters became similar to those in
the absence of perturbation. As this adaptation took place, the pattern of SSs changed
in slightly more than half of recorded PCs,
whereas complex spiking was affected in
only ⬃10% of PCs. Unlike previous findings showing that spike timing changes
alone may be sufficient for adaptation of
saccade amplitude, changes in both the sensitivity and timing of SSs relative to kinematics occurred during reach adaptation.
These differences were largest for position
and velocity encoding. Furthermore, both
increases and decreases in SSs occurred during learning, suggesting multiple plasticity
mechanisms took place.
This Week in The Journal is written by X Teresa Esch, Ph.D.
The Journal of Neuroscience
January 21, 2015 • Volume 35 Number 3 • www.jneurosci.org
i
This Week in The Journal
Editorial
867
A Message from the Editor-in-Chief
Dora Angelaki
Journal Club
Cover legend: Retroviral injections label control
neurons (green) and neurons lacking the autismassociated gene Pten (red) in the mouse dentate
gyrus. Neuronal reconstructions and images of
dendritic spines with labeled synapses demonstrate
that Pten knockout increases cell size and synapse
number, resulting in neuronal hyperactivity. Parallel
morphological and physiological analyses underscore
the tight coupling of neuronal structure to function.
For more information, see the article by Williams et al.
(pages 943–959).
868
The Functional Role of Astrocyte Calcium Signaling in Cortical Blood Flow Regulation
Kyle R. Biesecker and Anja I. Srienc
871
Friend or Foe? Perceptual Categorization across Species
Guy E. Hawkins
Brief Communications
873
Autocrine Boost of NMDAR Current in Hippocampal CA1 Pyramidal Neurons by a
PMCA-Dependent, Perisynaptic, Extracellular pH Shift
Huei-Ying Chen and Mitchell Chesler
936
The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Gene VRK1 Regulates
Neuronal Migration through an Amyloid-␤ Precursor Protein-Dependent Mechanism
Hadar Vinograd-Byk, Tamar Sapir, Lara Cantarero, Pedro A. Lazo,
Sharon Zeligson, Dorit Lev, Tally Lerman-Sagie, Paul Renbaum, Orly Reiner,
and Ephrat Levy-Lahad
1038
NLP-12 Engages Different UNC-13 Proteins to Potentiate Tonic and Evoked Release
Zhitao Hu, Amy B. Vashlishan-Murray, and Joshua M. Kaplan
1211
Patterned, But Not Tonic, Optogenetic Stimulation in Motor Thalamus Improves
Reaching in Acute Drug-Induced Parkinsonian Rats
Sonja Seeger-Armbruster, Cle´mentine Bosch-Bouju, Shane T.C. Little,
Roseanna A. Smither, Stephanie M. Hughes, Brian I. Hyland,
and Louise C. Parr-Brownlie
Articles
CELLULAR/MOLECULAR
906
Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling
Peter Go¨ttle, Jennifer K. Sabo, Andre´ Heinen, Gene Venables, Klintsy Torres,
Nevena Tzekova, Carlos M. Parras, David Kremer, Hans-Peter Hartung,
Holly S. Cate, and Patrick Ku¨ry
972
BDNF Stimulation of Protein Synthesis in Cortical Neurons Requires the MAP
Kinase-Interacting Kinase MNK1
Maja Genheden, Justin W. Kenney, Harvey E. Johnston,
Antigoni Manousopoulou, Spiros D. Garbis, and Christopher G. Proud
985
ATP Binding to Synaspsin IIa Regulates Usage and Clustering of Vesicles in Terminals
of Hippocampal Neurons
Yoav Shulman, Alexandra Stavsky, Tatiana Fedorova, Dan Mikulincer,
Merav Atias, Igal Radinsky, Joy Kahn, Inna Slutsky, and Daniel Gitler
1250
HDAC2 Selectively Regulates FOXO3a-Mediated Gene Transcription during Oxidative
Stress-Induced Neuronal Cell Death
Shengyi Peng, Siqi Zhao, Feng Yan, Jinbo Cheng, Li Huang, Hong Chen,
Qingsong Liu, Xunming Ji, and Zengqiang Yuan
1260
Dysregulation of Kv3.4 Channels in Dorsal Root Ganglia Following Spinal Cord Injury
David M. Ritter, Benjamin M. Zemel, Tamara J. Hala, Michael E. O’Leary,
Angelo C. Lepore, and Manuel Covarrubias
DEVELOPMENT/PLASTICITY/REPAIR
䊉
943
Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory
Synaptic Drive
Michael R. Williams, Tyrone DeSpenza Jr, Meijie Li, Allan T. Gulledge,
and Bryan W. Luikart
1011
Signal Transducer and Activator of Transcription-3 Maintains the Stemness of Radial
Glia at Mid-Neurogenesis
Seulgi Hong and Mi-Ryoung Song
1136
Stimulation of Monocytes, Macrophages, and Microglia by Amphotericin
B and Macrophage Colony-Stimulating Factor Promotes Remyelination
Axinia Do¨ring, Scott Sloka, Lorraine Lau, Manoj Mishra, Jan van Minnen,
Xu Zhang, David Kinniburgh, Serge Rivest, and V. Wee Yong
1291
Motoneurons Derived from Induced Pluripotent Stem Cells Develop Mature
Phenotypes Typical of Endogenous Spinal Motoneurons
Jeremy S. Toma, Basavaraj C. Shettar, Peter H. Chipman, Devanand M. Pinto,
Joanna P. Borowska, Justin K. Ichida, James P. Fawcett, Ying Zhang, Kevin Eggan,
and Victor F. Rafuse
1319
Synaptic Consolidation: From Synapses to Behavioral Modeling
Lorric Ziegler, Friedemann Zenke, David B. Kastner, and Wulfram Gerstner
SYSTEMS/CIRCUITS
䊉
1024
Distribution and Function of HCN Channels in the Apical Dendritic Tuft of
Neocortical Pyramidal Neurons
Mark T. Harnett, Jeffrey C. Magee, and Stephen R. Williams
1052
Role of Parafacial Nuclei in Control of Breathing in Adult Rats
Robert T.R. Huckstepp, Kathryn P. Cardoza, Lauren E. Henderson,
and Jack L. Feldman
1068
Decoding a Wide Range of Hand Configurations from Macaque Motor, Premotor,
and Parietal Cortices
Stefan Schaffelhofer, Andres Agudelo-Toro, and Hansjo¨rg Scherberger
1089
Contributions of Diverse Excitatory and Inhibitory Neurons to Recurrent Network
Activity in Cerebral Cortex
Garrett T. Neske, Saundra L. Patrick, and Barry W. Connors
1106
Changes in Purkinje Cell Simple Spike Encoding of Reach Kinematics during
Adaption to a Mechanical Perturbation
Angela L. Hewitt, Laurentiu S. Popa, and Timothy J. Ebner
1160
Functional Mapping of Face-Selective Regions in the Extrastriate Visual Cortex of the
Marmoset
Chia-Chun Hung, Cecil C. Yen, Jennifer L. Ciuchta, Daniel Papoti,
Nicholas A. Bock, David A. Leopold, and Afonso C. Silva
1181
Corticospinal Tract Development and Spinal Cord Innervation Differ between
Cervical and Lumbar Targets
Tsutomu Kamiyama, Hiroshi Kameda, Naoyuki Murabe, Satoshi Fukuda,
Noboru Yoshioka, Hiroaki Mizukami, Keiya Ozawa, and Masaki Sakurai
1217
Interplay of Inhibition and Excitation Shapes a Premotor Neural Sequence
Georg Kosche, Daniela Vallentin, and Michael A. Long
1240
Musical Training Orchestrates Coordinated Neuroplasticity in Auditory Brainstem
and Cortex to Counteract Age-Related Declines in Categorical Vowel Perception
Gavin M. Bidelman and Claude Alain
BEHAVIORAL/COGNITIVE
878
Audition-Independent Vocal Crystallization Associated with Intrinsic Developmental
Gene Expression Dynamics
Chihiro Mori and Kazuhiro Wada
920
Sex-Dependent Dissociation between Emotional Appraisal and Memory:
A Large-Scale Behavioral and fMRI Study
Klara Spalek, Matthias Fastenrath, Sandra Ackermann, Bianca Auschra,
David Coynel, Julia Frey, Leo Gschwind, Francina Hartmann,
Nadine van der Maarel, Andreas Papassotiropoulos, Dominique de Quervain,
and Annette Milnik
960
Prefrontal Neuronal Responses during Audiovisual Mnemonic Processing
Jaewon Hwang and Lizabeth M. Romanski
1082
Metacognitive Mechanisms Underlying Lucid Dreaming
Elisa Filevich, Martin Dresler, Timothy R. Brick, and Simone Ku¨hn
1125
Slack Channels Expressed in Sensory Neurons Control Neuropathic Pain in Mice
Ruirui Lu, Anne E. Bausch, Wiebke Kallenborn-Gerhardt, Carsten Stoetzer,
Natasja Debruin, Peter Ruth, Gerd Geisslinger, Andreas Leffler,
Robert Lukowski, and Achim Schmidtko
1173
Aging Impairs Protein-Synthesis-Dependent Long-Term Memory in Drosophila
Ayako Tonoki and Ronald L. Davis
1192
Vestibulo-Ocular Reflex Suppression during Head-Fixed Saccades Reveals Gaze
Feedback Control
Pierre M. Daye, Dale C. Roberts, David S. Zee, and Lance M. Optican
1228
Cerebellar Cortex and Cerebellar Nuclei Are Concomitantly Activated during Eyeblink
Conditioning: A 7T fMRI Study in Humans
Markus Thu¨rling, Fabian Kahl, Stefan Maderwald, Roxana M. Stefanescu,
Marc Schlamann, Henk-Jan Boele, Chris I. De Zeeuw, Jo¨rn Diedrichsen,
Mark E. Ladd, Sebastiaan K.E. Koekkoek, and Dagmar Timmann
1307
Neural Dynamics Underlying Attentional Orienting to Auditory Representations in
Short-Term Memory
Kristina C. Backer, Malcolm A. Binns, and Claude Alain
NEUROBIOLOGY OF DISEASE
890
A53T Human ␣-Synuclein Overexpression in Transgenic Mice Induces Pervasive
Mitochondria Macroautophagy Defects Preceding Dopamine Neuron Degeneration
Linan Chen (陈), Zhiguo Xie, Susie Turkson, and Xiaoxi Zhuang
999
Evidence for Consolidation of Neuronal Assemblies after Seizures in Humans
Mark R. Bower, Matt Stead, Regina S. Bower, Michal T. Kucewicz, Vlastimil Sulc,
Jan Cimbalnik, Benjamin H. Brinkmann, Vincent M. Vasoli, Erik K. St. Louis,
Fredric B. Meyer, W. Richard Marsh, and Gregory A. Worrell
1043
The Full-Length Form of the Drosophila Amyloid Precursor Protein Is Involved in
Memory Formation
Isabelle Bourdet, Thomas Preat, and Vale´rie Goguel
1149
Desynchronization of Fast-Spiking Interneurons Reduces ␤-Band Oscillations
and Imbalance in Firing in the Dopamine-Depleted Striatum
Sriraman Damodaran, John R. Cressman, Zbigniew Jedrzejewski-Szmek,
and Kim T. Blackwell
1199
The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A␤ Pharmacodynamic
Responses in Mice, Dogs, and Humans
Patrick C. May, Brian A. Willis, Stephen L. Lowe, Robert A. Dean, Scott A. Monk,
Patrick J. Cocke, James E. Audia, Leonard N. Boggs, Anthony R. Borders,
Richard A. Brier, David O. Calligaro, Theresa A. Day,
Larry Ereshefsky, Jon A. Erickson, Hykop Gevorkyan, Celedon R. Gonzales,
Douglas E. James, Stanford S. Jhee, Steven F. Komjathy, Linglin Li,
Terry D. Lindstrom, Brian M. Mathes, Ferenc Marte´nyi, Scott M. Sheehan,
Stephanie L. Stout, David E. Timm, Grant M. Vaught, Brian M. Watson,
Leonard L. Winneroski, Zhixiang Yang, and Dustin J. Mergott
1274
Chronic Oligodendrogenesis and Remyelination after Spinal Cord Injury in Mice
and Rats
Zoe C. Hesp, Evan A. Goldstein, Carlos J. Miranda, Brain K. Kaspar, and
Dana M. McTigue
1335
Correction: The article “Paired Related Homeobox Protein 1 is a Regulatory of Stemness in
Adult Neural Stem/Progenitor Cells” by Koji Shimozaki, Gregory D. Clemenson, Jr., and
Fred H. Gage appeared on pages 4066 – 4075 of the February 27, 2013 issue. A correction for
that article appears on page 1335.
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BRIEF COMMUNICATIONS
Autocrine Boost of NMDAR Current in Hippocampal CA1 Pyramidal Neurons by a PMCADependent, Perisynaptic, Extracellular pH Shift
Huei-Ying Chen1 and Mitchell Chesler1,2
1
Department of Neuroscience and Physiology and 2Department of Neurosurgery, New York University School of Medicine, New York, New York 10016
The plasma membrane Ca 2⫹-ATPase (PMCA) is found near postsynaptic NMDARs. This transporter is a Ca 2⫹-H ⫹ exchanger that raises cell surface pH. We tested whether
the PMCA acts in an autocrine fashion to boost pH-sensitive, postsynaptic NMDAR currents. In mouse hippocampal slices, NMDAR EPSCs in a singly activated CA1
pyramidal neuron were reduced when buffering was augmented by exogenous carbonic anhydrase (XCAR). This effect was blocked by the enzyme inhibitor benzolamide
and mimicked by the addition of HEPES buffer. Similar EPSC reduction occurred when PMCA activation was prevented by dialysis of BAPTA or the PMCA inhibitor
carboxyeosin. Using HEPES, BAPTA, or carboxyeosin, the effect of XCAR was completely occluded. XCAR similarly curtailed NMDAR EPSCs of minimal amplitude, but had
no effect on small AMPAR responses. These results indicate that a significant fraction of the postsynaptic NMDAR current is reliant on a perisynaptic extracellular alkaline
shift generated by the PMCA.
The Journal of Neuroscience, January 21, 2015 • 35(3):873– 877
The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Gene VRK1 Regulates Neuronal
Migration through an Amyloid-␤ Precursor Protein-Dependent Mechanism
Hadar Vinograd-Byk,1,2* Tamar Sapir,3* Lara Cantarero,4,5 Pedro A. Lazo,4,5 Sharon Zeligson,1 Dorit Lev,6
Tally Lerman-Sagie,7 Paul Renbaum,1# Orly Reiner,3# and Ephrat Levy-Lahad1,2#
Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel, 2Hebrew University Medical School, Jerusalem 91120, Israel,
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel, 4Instituto de Biología Molecular y Celular del Ca´ncer,
Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, 37007 Salamanca, Spain, 5Instituto de Investigacio´n Biome´dica de Salamanca,
Hospital Universitario de Salamanca, 37007 Salamanca, Spain, and 6Medical Genetics Institute, 7Pediatric Neurology Unit, Wolfson Medical Center, Holon
58100, Israel
1
3
Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We
previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews,
and additional mutations in patients of different origins have recently been identified. VRK1 is a nuclear serine/threonine protein kinase known to play multiple roles in
cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in
SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell
proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of
neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the
migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads
to downregulation of amyloid-␤ precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown,
suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism.
The Journal of Neuroscience, January 21, 2015 • 35(3):936 –942
NLP-12 Engages Different UNC-13 Proteins to Potentiate Tonic and Evoked Release
Zhitao Hu,1,2 Amy B. Vashlishan-Murray,1,2,3 and Joshua M. Kaplan1,2
1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, 2Department of Neurobiology, Harvard Medical School,
Boston, Massachusetts 02115, and 3Department of Communication Sciences and Disorders, Emerson College, Boston, Massachusetts 02116
A neuropeptide (NLP-12) and its receptor (CKR-2) potentiate tonic and evoked ACh release at Caenorhabditis elegans neuromuscular junctions. Increased evoked release
is mediated by a presynaptic pathway (egl-30 G␣q and egl-8 PLC␤) that produces DAG, and by DAG binding to short and long UNC-13 proteins. Potentiation of tonic ACh
release persists in mutants deficient for egl-30 G␣q and egl-8 PLC␤ and requires DAG binding to UNC-13L (but not UNC-13S). Thus, NLP-12 adjusts tonic and evoked release
by distinct mechanisms.
The Journal of Neuroscience, January 21, 2015 • 35(3):1038 –1042
Patterned, But Not Tonic, Optogenetic Stimulation in Motor Thalamus Improves Reaching in
Acute Drug-Induced Parkinsonian Rats
Sonja Seeger-Armbruster,1 Cle´mentine Bosch-Bouju,2 Shane T.C. Little,2 Roseanna A. Smither,1 Stephanie M. Hughes,3
Brian I. Hyland,1 and Louise C. Parr-Brownlie2
Departments of 1Physiology, 2Anatomy, and 3Biochemistry, Otago School of Medical Science, Brain Health Research Centre, University of Otago, Dunedin
9054, New Zealand
High-frequency deep brain stimulation (DBS) in motor thalamus (Mthal) ameliorates tremor but not akinesia in Parkinson’s disease. The aim of this study was to
investigate whether there are effective methods of Mthal stimulation to treat akinesia. Glutamatergic Mthal neurons, transduced with channelrhodopsin-2 by injection of
lentiviral vector (Lenti.CaMKII.hChR2(H134R).mCherry), were selectively stimulated with blue light (473 nm) via a chronically implanted fiber-optic probe. Rats performed a reach-to-grasp task in either acute drug-induced parkinsonian akinesia (0.03– 0.07 mg/kg haloperidol, s.c.) or control (vehicle injection) conditions, and the
number of reaches was recorded for 5 min before, during, and after stimulation. We compared the effect of DBS using complex physiological patterns previously recorded
in the Mthal of a control rat during reaching or exploring behavior, with tonic DBS delivering the same number of stimuli per second (rate-control 6.2 or 1.8 Hz, respectively)
and with stimulation patterns commonly used in other brain regions to treat neurological conditions (tonic 130 Hz, theta burst (TBS), and tonic 15 Hz rate-control for TBS).
Control rats typically executed ⬎150 reaches per 5 min, which was unaffected by any of the stimulation patterns. Acute parkinsonian rats executed ⬍20 reaches, displaying
marked akinesia, which was significantly improved by stimulating with the physiological reaching pattern or TBS (both p ⬍ 0.05), whereas the exploring and all tonic
patterns failed to improve reaching. Data indicate that the Mthal may be an effective site to treat akinesia, but the pattern of stimulation is critical for improving reaching
in parkinsonian rats.
The Journal of Neuroscience, January 21, 2015 • 35(3):1211–1216
Articles
CELLULAR/MOLECULAR
Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling
Peter Go¨ttle,1 Jennifer K. Sabo,2 Andre´ Heinen,1 Gene Venables,2 Klintsy Torres,1, Nevena Tzekova,1 Carlos M. Parras,3
David Kremer,1 Hans-Peter Hartung,1 Holly S. Cate,2 and Patrick Ku¨ry1
Department of Neurology, Medical Faculty, University of Du¨sseldorf, 40225 Du¨sseldorf, Germany, 2Department of Anatomy and Neuroscience, University
of Melbourne, Parkville, 3010 Victoria, Australia, and 3Universite´ Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle
´epinie`re, Inserm U1127, 75013 Paris, France
1
Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical
insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and
remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains
inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these
cells and interfere with their cellular maturation. The p57kip2 gene encodes one such potent inhibitor of oligodendroglial differentiation and this study sheds light on the
underlying mode of action. We found that subcellular distribution of the p57kip2 protein changed during differentiation of rat, mouse, and human oligodendroglial cells
both in vivo and in vitro. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelination in vitro.
In contrast, nuclear accumulation of p57kip2 resulted in blocked oligodendroglial differentiation. Experimental evidence suggests that the inhibitory role of p57kip2
depends on specific interactions with binding proteins such as LIMK-1, CDK2, Mash1, and Hes5 either by controlling their site of action or their activity. Because functional
restoration in demyelinating diseases critically depends on the successful generation of oligodendroglial cells, a therapeutic need that is currently unmet, the regulatory
mechanism described here might be of particular interest for identifying suitable drug targets and devising novel therapeutic approaches.
The Journal of Neuroscience, January 21, 2015 • 35(3):906 –919
BDNF Stimulation of Protein Synthesis in Cortical Neurons Requires the MAP KinaseInteracting Kinase MNK1
Maja Genheden,1* Justin W. Kenney,1* Harvey E. Johnston,2,3 Antigoni Manousopoulou,2,3 Spiros D. Garbis,2,3
and Christopher G. Proud1
Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom, 2Cancer Sciences and CES Units, Faculty of
Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom, and 3Centre for Proteomic Research,
Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, United Kingdom
1
Although the MAP kinase-interacting kinases (MNKs) have been known for ⬎15 years, their roles in the regulation of protein synthesis have remained obscure. Here, we
explore the involvement of the MNKs in brain-derived neurotrophic factor (BDNF)-stimulated protein synthesis in cortical neurons from mice. Using a combination of
pharmacological and genetic approaches, we show that BDNF-induced upregulation of protein synthesis requires MEK/ERK signaling and the downstream kinase, MNK1,
which phosphorylates eukaryotic initiation factor (eIF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m 7GTP cap of mRNA and with eIF4G. The
latter interaction is inhibited by the interactions of eIF4E with partner proteins, such as CYFIP1, which acts as a translational repressor. We find that BDNF induces the
release of CYFIP1 from eIF4E, and that this depends on MNK1. Finally, using a novel combination of BONCAT and SILAC, we identify a subset of proteins whose synthesis
is upregulated by BDNF signaling via MNK1 in neurons. Interestingly, this subset of MNK1-sensitive proteins is enriched for functions involved in neurotransmission and
synaptic plasticity. Additionally, we find significant overlap between our subset of proteins whose synthesis is regulated by MNK1 and those encoded by known FMRPbinding mRNAs. Together, our data implicate MNK1 as a key component of BDNF-mediated translational regulation in neurons.
The Journal of Neuroscience, January 21, 2015 • 35(3):972–984
ATP Binding to Synaspsin IIa Regulates Usage and Clustering of Vesicles in Terminals of
Hippocampal Neurons
Yoav Shulman,1,2* Alexandra Stavsky,1,2* Tatiana Fedorova,3 Dan Mikulincer,1 Merav Atias,1 Igal Radinsky,1 Joy Kahn,1
Inna Slutsky,3 and Daniel Gitler1,2
Department of Physiology and Cell Biology, Faculty of Health Sciences, and 2Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, BeerSheva 84105, Israel, and 3Department of Physiology and Pharmacology, Sackler Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University,
69978 Tel Aviv, Israel
1
Synaptic transmission is expensive in terms of its energy demands and was recently shown to decrease the ATP concentration within presynaptic terminals transiently, an
observation that we confirm. We hypothesized that, in addition to being an energy source, ATP may modulate the synapsins directly. Synapsins are abundant neuronal
proteins that associate with the surface of synaptic vesicles and possess a well defined ATP-binding site of undetermined function. To examine our hypothesis, we produced
a mutation (K270Q) in synapsin IIa that prevents ATP binding and reintroduced the mutant into cultured mouse hippocampal neurons devoid of all synapsins. Remarkably, staining for synaptic vesicle markers was enhanced in these neurons compared with neurons expressing wild-type synapsin IIa, suggesting overly efficient clustering
of vesicles. In contrast, the mutation completely disrupted the capability of synapsin IIa to slow synaptic depression during sustained 10 Hz stimulation, indicating that it
interfered with synapsin-dependent vesicle recruitment. Finally, we found that the K270Q mutation attenuated the phosphorylation of synapsin IIa on a distant PKA/
CaMKI consensus site known to be essential for vesicle recruitment. We conclude that ATP binding to synapsin IIa plays a key role in modulating its function and in defining
its contribution to hippocampal short-term synaptic plasticity.
The Journal of Neuroscience, January 21, 2015 • 35(3):985–998
HDAC2 Selectively Regulates FOXO3a-Mediated Gene Transcription during Oxidative StressInduced Neuronal Cell Death
Shengyi Peng,1,4,5 Siqi Zhao,1 Feng Yan,2 Jinbo Cheng,1 Li Huang,1 Hong Chen,1 Qingsong Liu,3 Xunming Ji,2
and Zengqiang Yuan1,4
State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, 2The Cerebrovascular
Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China, 3High Magnetic Field Laboratory, Chinese Academy of
Sciences, Hefei, Anhui, 230031, China, 4Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China, and 5College of Life
Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
1
All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal
apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone
deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced
mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not
those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and
HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1.
Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2–FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of
HDAC2 at Ser 394 and mitigated the HDAC2–FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene
transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.
The Journal of Neuroscience, January 21, 2015 • 35(3):1250 –1259
Dysregulation of Kv3.4 Channels in Dorsal Root Ganglia Following Spinal Cord Injury
David M. Ritter,1,2,3 Benjamin M. Zemel,1,2,3 Tamara J. Hala,1,2 Michael E. O’Leary,4 Angelo C. Lepore,1,2,3
and Manuel Covarrubias1,2,3
Department of Neuroscience, 2Farber Institute for Neuroscience, and 3Neuroscience Graduate Program, Sidney Kimmel Medical College at Thomas
Jefferson University, Philadelphia, Pennsylvania 19107, and 4Cooper Medical School of Rowan University, Camden, New Jersey 08103
1
Spinal cord injury (SCI) patients develop chronic pain involving poorly understood central and peripheral mechanisms. Because dysregulation of the voltage-gated Kv3.4
channel has been implicated in the hyperexcitable state of dorsal root ganglion (DRG) neurons following direct injury of sensory nerves, we asked whether such a
dysregulation also plays a role in SCI. Kv3.4 channels are expressed in DRG neurons, where they help regulate action potential (AP) repolarization in a manner that depends
on the modulation of inactivation by protein kinase C (PKC)-dependent phosphorylation of the channel’s inactivation domain. Here, we report that, 2 weeks after cervical
hemicontusion SCI, injured rats exhibit contralateral hypersensitivity to stimuli accompanied by accentuated repetitive spiking in putative DRG nociceptors. Also in these
neurons at 1 week after laminectomy and SCI, Kv3.4 channel inactivation is impaired compared with naive nonsurgical controls. At 2– 6 weeks after laminectomy, however,
Kv3.4 channel inactivation returns to naive levels. Conversely, Kv3.4 currents at 2– 6 weeks post-SCI are downregulated and remain slow-inactivating. Immunohistochemistry indicated that downregulation mainly resulted from decreased surface expression of the Kv3.4 channel, as whole-DRG-protein and single-cell mRNA transcript levels
did not change. Furthermore, consistent with Kv3.4 channel dysregulation, PKC activation failed to shorten the AP duration of small-diameter DRG neurons. Finally,
re-expressing synthetic Kv3.4 currents under dynamic clamp conditions dampened repetitive spiking in the neurons from SCI rats. These results suggest a novel peripheral
mechanism of post-SCI pain sensitization implicating Kv3.4 channel dysregulation and potential Kv3.4-based therapeutic interventions.
The Journal of Neuroscience, January 21, 2015 • 35(3):1260 –1273
DEVELOPMENT/PLASTICITY/REPAIR
Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory Synaptic
Drive
Michael R. Williams, Tyrone DeSpenza Jr, Meijie Li, Allan T. Gulledge, and Bryan W. Luikart
Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth College, Lebanon, New Hampshire 03756
Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including
autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts
neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes
similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately
shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that
developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and
modeling. This was accomplished by coinjecting retroviruses to either “birthdate” or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate
gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized
membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was
due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten
knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted
neurons.
The Journal of Neuroscience, January 21, 2015 • 35(3):943–959
Signal Transducer and Activator of Transcription-3 Maintains the Stemness of Radial Glia at
Mid-Neurogenesis
Seulgi Hong and Mi-Ryoung Song
School of Life Sciences, BioImaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Oryong-dong,
Buk-gu, Gwangju 500-712, Republic of Korea
Radial glial cells are stem cell-like populations of glial nature that supply neurons either directly or indirectly via basal progenitors that give rise to neurons. Here we show
that signal transducer and activator of transcription-3 (STAT3) signaling, a cytokine signaling mediated by Janus tyrosine kinase (Jak), is active during neurogenesis in
radial glia (RG) but not in basal progenitors. Enhanced STAT3 signaling in cortical progenitors caused more RG to persist rather than become neurons. Targeted deletion
or RNAi-mediated knockdown of Stat3 resulted in fewer radial glial cells and more basal progenitors and led to premature neurogenesis. The neuronal populations affected
in Stat3 mutant mice were the late-born neurons that constitute the upper cortical layers rather than early-born neurons, thus supporting the view that the role of STAT3
at mid-neurogenesis is layer specific. Analysis of dividing RG revealed that STAT3 selectively increased the proportion of dividing RG, whereas downregulation of STAT3
reduced the proportion. Consistent with this, STAT3 activity in dividing RG was associated frequently with vertical cleavage. Pair-cell analysis showed that elevated STAT3
activity correlated with symmetric division of RG, producing more RG, whereas elimination of STAT3 generated more neurogenic cells. Together, our results suggest that
STAT3 maintains the stemness of RG and inhibits their transition to basal progenitors at mid-neurogenesis, so probably preserving a pool of RG for later neurogenesis or
gliogenesis.
The Journal of Neuroscience, January 21, 2015 • 35(3):1011–1023
Stimulation of Monocytes, Macrophages, and Microglia by Amphotericin B and Macrophage
Colony-Stimulating Factor Promotes Remyelination
Axinia Do¨ring,1 Scott Sloka,1,3 Lorraine Lau,1 Manoj Mishra,1 Jan van Minnen,1 Xu Zhang,2 David Kinniburgh,2
Serge Rivest,4 and V. Wee Yong1
Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and 2Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta T2N
4N1, Canada, 3Grand River Hospital, Kitchener, Ontario N2G 1G3, Canada, and 4Centre Hospitalier Universitaire de Que´bec, Research Center and the
Department of Molecular Medicine, Laval University, Que´bec, Que´bec G1V 4G2, Canada
1
Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with
clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and
the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated
counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling.
When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator,
macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B,
particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects
were mitigated in mice treated with clodronate liposomes to reduce circulating monocytes and tissue-infiltrated macrophages. Our results have identified candidates
among currently used medications as potential therapies for the repair of myelin.
The Journal of Neuroscience, January 21, 2015 • 35(3):1136 –1148
Motoneurons Derived from Induced Pluripotent Stem Cells Develop Mature Phenotypes Typical
of Endogenous Spinal Motoneurons
Jeremy S. Toma,1 Basavaraj C. Shettar,1 Peter H. Chipman,1 Devanand M. Pinto,8 Joanna P. Borowska,1
Justin K. Ichida,5 James P. Fawcett,3,4 Ying Zhang,1 Kevin Eggan,5,6,7 and Victor F. Rafuse1,2
1Department of Medical Neuroscience, 2Department of Medicine (Neurology), 3Department of Pharmacology, and 4Department of Surgery, Dalhousie
University, Halifax, Nova Scotia, Canada, B3H 4R2, 5Howard Hughes Medical Institute, 6Harvard Stem Cell Institute, Department of Stem Cell and
Regenerative Biology, and 7Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, and 8National Research
Council, Institute for Marine Biosciences, Nova Scotia, Canada B3H 3Z1
Induced pluripotent cell-derived motoneurons (iPSCMNs) are sought for use in cell replacement therapies and treatment strategies for motoneuron diseases such as
amyotrophic lateral sclerosis (ALS). However, much remains unknown about the physiological properties of iPSCMNs and how they compare with endogenous spinal
motoneurons or embryonic stem cell-derived motoneurons (ESCMNs). In the present study, we first used a proteomic approach and compared protein expression profiles
between iPSCMNs and ESCMNs to show that ⬍4% of the proteins identified were differentially regulated. Like ESCs, we found that mouse iPSCs treated with retinoic acid
and a smoothened agonist differentiated into motoneurons expressing the LIM homeodomain protein Lhx3. When transplanted into the neural tube of developing chick
embryos, iPSCMNs selectively targeted muscles normally innervated by Lhx3 motoneurons. In vitro studies showed that iPSCMNs form anatomically mature and functional neuromuscular junctions (NMJs) when cocultured with chick myofibers for several weeks. Electrophysiologically, iPSCMNs developed passive membrane and firing
characteristic typical of postnatal motoneurons after several weeks in culture. Finally, iPSCMNs grafted into transected mouse tibial nerve projected axons to denervated
gastrocnemius muscle fibers, where they formed functional NMJs, restored contractile force. and attenuated denervation atrophy. Together, iPSCMNs possess many of the
same cellular and physiological characteristics as ESCMNs and endogenous spinal motoneurons. These results further justify using iPSCMNs as a source of motoneurons
for cell replacement therapies and to study motoneuron diseases such as ALS.
The Journal of Neuroscience, January 21, 2015 • 35(3):1291–1306
Synaptic Consolidation: From Synapses to Behavioral Modeling
Lorric Ziegler, Friedemann Zenke, David B. Kastner, and Wulfram Gerstner
School of Computer and Communication Sciences and School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne,
1015 Lausanne EPFL, Switzerland
Synaptic plasticity, a key process for memory formation, manifests itself across different time scales ranging from a few seconds for plasticity induction up to hours or even
years for consolidation and memory retention. We developed a three-layered model of synaptic consolidation that accounts for data across a large range of experimental
conditions. Consolidation occurs in the model through the interaction of the synaptic efficacy with a scaffolding variable by a read-write process mediated by a taggingrelated variable. Plasticity-inducing stimuli modify the efficacy, but the state of tag and scaffold can only change if a write protection mechanism is overcome. Our model
makes a link from depotentiation protocols in vitro to behavioral results regarding the influence of novelty on inhibitory avoidance memory in rats.
The Journal of Neuroscience, January 21, 2015 • 35(3):1319 –1334
SYSTEMS/CIRCUITS
Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical
Pyramidal Neurons
Mark T. Harnett,1 Jeffrey C. Magee,1 and Stephen R. Williams2
Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia 20147, and 2Queensland Brain Institute, The University of
Queensland, Brisbane QLD 4072, Australia
1
The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons
receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate
synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular
distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch
recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft
sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage
compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate
uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at
proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these
compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic
arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B
pyramidal neurons.
The Journal of Neuroscience, January 21, 2015 • 35(3):1024 –1037
Role of Parafacial Nuclei in Control of Breathing in Adult Rats
Robert T.R. Huckstepp, Kathryn P. Cardoza, Lauren E. Henderson, and Jack L. Feldman
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angles, Los Angeles, California 90095-1763
Contiguous brain regions associated with a given behavior are increasingly being divided into subregions associated with distinct aspects of that behavior. Using recently
developed neuronal hyperpolarizing technologies, we functionally dissect the parafacial region in the medulla, which contains key elements of the central pattern generator
for breathing that are important in central CO2-chemoreception and for gating active expiration. By transfecting different populations of neighboring neurons with
allatostatin or HM4D Gi/o-coupled receptors, we analyzed the effect of their hyperpolarization on respiration in spontaneously breathing vagotomized urethaneanesthetized rats. We identify two functionally separate parafacial nuclei: ventral (pFV ) and lateral (pFL ). Disinhibition of the pFL with bicuculline and strychnine led to
active expiration. Hyperpolarizing pFL neurons had no effect on breathing at rest, or changes in inspiratory activity induced by hypoxia and hypercapnia; however,
hyperpolarizing pFL neurons attenuated active expiration when it was induced by hypercapnia, hypoxia, or disinhibition of the pFL. In contrast, hyperpolarizing pFV
neurons affected breathing at rest by decreasing inspiratory-related activity, attenuating the hypoxia- and hypercapnia-induced increase in inspiratory activity, and when
present, reducing expiratory-related abdominal activity. Together with previous observations, we conclude that the pFV provides a generic excitatory drive to breathe, even
at rest, whereas the pFL is a conditional oscillator quiet at rest that, when activated, e.g., during exercise, drives active expiration.
The Journal of Neuroscience, January 21, 2015 • 35(3):1052–1067
Decoding a Wide Range of Hand Configurations from Macaque Motor, Premotor, and Parietal
Cortices
Stefan Schaffelhofer,1 Andres Agudelo-Toro,1 and Hansjo¨rg Scherberger1,2
1
German Primate Center, D-37077 Go¨ttingen, Germany, and 2Department of Biology, University of Go¨ttingen, D-37077 Go¨ttingen, Germany
Despite recent advances in decoding cortical activity for motor control, the development of hand prosthetics remains a major challenge. To reduce the complexity of such
applications, higher cortical areas that also represent motor plans rather than just the individual movements might be advantageous. We investigated the decoding of many
grip types using spiking activity from the anterior intraparietal (AIP), ventral premotor (F5), and primary motor (M1) cortices. Two rhesus monkeys were trained to grasp
50 objects in a delayed task while hand kinematics and spiking activity from six implanted electrode arrays (total of 192 electrodes) were recorded. Offline, we determined
20 grip types from the kinematic data and decoded these hand configurations and the grasped objects with a simple Bayesian classifier. When decoding from AIP, F5, and
M1 combined, the mean accuracy was 50% (using planning activity) and 62% (during motor execution) for predicting the 50 objects (chance level, 2%) and substantially
larger when predicting the 20 grip types (planning, 74%; execution, 86%; chance level, 5%). When decoding from individual arrays, objects and grip types could be predicted
well during movement planning from AIP (medial array) and F5 (lateral array), whereas M1 predictions were poor. In contrast, predictions during movement execution
were best from M1, whereas F5 performed only slightly worse. These results demonstrate for the first time that a large number of grip types can be decoded from higher
cortical areas during movement preparation and execution, which could be relevant for future neuroprosthetic devices that decode motor plans.
The Journal of Neuroscience, January 21, 2015 • 35(3):1068 –1081
Contributions of Diverse Excitatory and Inhibitory Neurons to Recurrent Network Activity in
Cerebral Cortex
Garrett T. Neske, Saundra L. Patrick, and Barry W. Connors
Department of Neuroscience, Brown University, Providence, Rhode Island 02912
The recurrent synaptic architecture of neocortex allows for self-generated network activity. One form of such activity is the Up state, in which neurons transiently receive
barrages of excitatory and inhibitory synaptic inputs that depolarize many neurons to spike threshold before returning to a relatively quiescent Down state. The extent to
which different cell types participate in Up states is still unclear. Inhibitory interneurons have particularly diverse intrinsic properties and synaptic connections with the
local network, suggesting that different interneurons might play different roles in activated network states. We have studied the firing, subthreshold behavior, and synaptic
conductances of identified cell types during Up and Down states in layers 5 and 2/3 in mouse barrel cortex in vitro. We recorded from pyramidal cells and interneurons
expressing parvalbumin (PV), somatostatin (SOM), vasoactive intestinal peptide (VIP), or neuropeptide Y. PV cells were the most active interneuron subtype during the Up
state, yet the other subtypes also received substantial synaptic conductances and often generated spikes. In all cell types except PV cells, the beginning of the Up state was
dominated by synaptic inhibition, which decreased thereafter; excitation was more persistent, suggesting that inhibition is not the dominant force in terminating Up states.
Compared with barrel cortex, SOM and VIP cells were much less active in entorhinal cortex during Up states. Our results provide a measure of functional connectivity of
various neuron types in barrel cortex and suggest differential roles for interneuron types in the generation and control of persistent network activity.
The Journal of Neuroscience, January 21, 2015 • 35(3):1089 –1105
Changes in Purkinje Cell Simple Spike Encoding of Reach Kinematics during Adaption to a
Mechanical Perturbation
Angela L. Hewitt, Laurentiu S. Popa, and Timothy J. Ebner
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
The cerebellum is essential in motor learning. At the cellular level, changes occur in both the simple spike and complex spike firing of Purkinje cells. Because simple spike
discharge reflects the main output of the cerebellar cortex, changes in simple spike firing likely reflect the contribution of the cerebellum to the adapted behavior. Therefore,
we investigated in Rhesus monkeys how the representation of arm kinematics in Purkinje cell simple spike discharge changed during adaptation to mechanical perturbations of reach movements. Monkeys rapidly adapted to a novel assistive or resistive perturbation along the direction of the reach. Adaptation consisted of matching the
amplitude and timing of the perturbation to minimize its effect on the reach. In a majority of Purkinje cells, simple spike firing recorded before and during adaptation
demonstrated significant changes in position, velocity, and acceleration sensitivity. The timing of the simple spike representations change within individual cells, including
shifts in predictive versus feedback signals. At the population level, feedback-based encoding of position increases early in learning and velocity decreases. Both timing
changes reverse later in learning. The complex spike discharge was only weakly modulated by the perturbations, demonstrating that the changes in simple spike firing can
be independent of climbing fiber input. In summary, we observed extensive alterations in individual Purkinje cell encoding of reach kinematics, although the movements
were nearly identical in the baseline and adapted states. Therefore, adaption to mechanical perturbation of a reaching movement is accompanied by widespread modifications in the simple spike encoding.
The Journal of Neuroscience, January 21, 2015 • 35(3):1106 –1124
Functional Mapping of Face-Selective Regions in the Extrastriate Visual Cortex of the Marmoset
Chia-Chun Hung,1,2 Cecil C. Yen,1 Jennifer L. Ciuchta,1 Daniel Papoti,1 Nicholas A. Bock,3 David A. Leopold,2,4
and Afonso C. Silva1
Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National
Institutes of Health, Bethesda, Maryland 20892, 2Section on Cognitive Neurophysiology and Imaging, Laboratory of Neuropsychology, National Institute of
Mental Health, National Institutes of Health, Bethesda, Maryland 20892, 3Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton,
Ontario L8S 4K1, Canada, and 4Neurophysiology Imaging Facility, National Institute of Mental Health, National Institute of Neurological Disorders and
Stroke, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20182
1
The cerebral cortex of humans and macaques has specialized regions for processing faces and other visual stimulus categories. It is unknown whether a similar functional
organization exists in New World monkeys, such as the common marmoset (Callithrix jacchus), a species of growing interest as a primate model in neuroscience. To address
this question, we measured selective neural responses in the brain of four awake marmosets trained to fix their gaze upon images of faces, bodies, objects, and control
patterns. In two of the subjects, we measured high gamma-range field potentials from electrocorticography arrays implanted over a large portion of the occipital and
inferotemporal cortex. In the other two subjects, we measured BOLD fMRI responses across the entire brain. Both techniques revealed robust, regionally specific patterns
of category-selective neural responses. We report that at least six face-selective patches mark the occipitotemporal pathway of the marmoset, with the most anterior patches
showing the strongest preference for faces over other stimuli. The similar appearance of these patches to previous findings in macaques and humans, including their
apparent arrangement in two parallel pathways, suggests that core elements of the face processing network were present in the common anthropoid primate ancestor living
⬃35 million years ago. The findings also identify the marmoset as a viable animal model system for studying specialized neural mechanisms related to high-level social
visual perception in humans.
The Journal of Neuroscience, January 21, 2015 • 35(3):1160 –1172
Corticospinal Tract Development and Spinal Cord Innervation Differ between Cervical and
Lumbar Targets
Tsutomu Kamiyama,1* Hiroshi Kameda,1* Naoyuki Murabe,1 Satoshi Fukuda,1 Noboru Yoshioka,1 Hiroaki Mizukami,2
Keiya Ozawa,2 and Masaki Sakurai1
Department of Physiology, Teikyo University School of Medicine, Tokyo 173-8605, Japan, and 2Division of Genetic Therapeutics, Jichi Medical University,
Tochigi 329-0498, Japan
1
The corticospinal (CS) tract is essential for voluntary movement, but what we know about the organization and development of the CS tract remains limited. To determine
the total cortical area innervating the seventh cervical spinal cord segment (C7), which controls forelimb movement, we injected a retrograde tracer (fluorescent microspheres) into C7 such that it would spread widely within the unilateral gray matter (to ⬎80%), but not to the CS tract. Subsequent detection of the tracer showed that, in both
juvenile and adult mice, neurons distributed over an unexpectedly broad portion of the rostral two-thirds of the cerebral cortex converge to C7. This even included cortical
areas controlling the hindlimbs (the fourth lumbar segment, L4). With aging, cell densities greatly declined, mainly due to axon branch elimination. Whole-cell recordings
from spinal cord cells upon selective optogenetic stimulation of CS axons, and labeling of axons (DsRed) and presynaptic structures (synaptophysin) through cotransfection using exo utero electroporation, showed that overgrowing CS axons make synaptic connections with spinal cells in juveniles. This suggests that neuronal circuits
involved in the CS tract to C7 are largely reorganized during development. By contrast, the cortical areas innervating L4 are limited to the conventional hindlimb area, and
the cell distribution and density do not change during development. These findings call for an update of the traditional notion of somatotopic CS projection and imply that
there are substantial developmental differences in the cortical control of forelimb and hindlimb movements, at least in rodents.
The Journal of Neuroscience, January 21, 2015 • 35(3):1181–1191
Interplay of Inhibition and Excitation Shapes a Premotor Neural Sequence
Georg Kosche,1,2* Daniela Vallentin,1,2* and Michael A. Long1,2
1Neuroscience Institute and Department of Otolaryngology, New York University Langone Medical Center, New York, New York 10016, and 2Center for
Neural Science, New York University, New York, New York 10003
In the zebra finch, singing behavior is driven by a sequence of bursts within premotor neurons located in the forebrain nucleus HVC (proper name). In addition to these
excitatory projection neurons, HVC also contains inhibitory interneurons with a role in premotor patterning that is unclear. Here, we used a range of electrophysiological
and behavioral observations to test previously described models suggesting discrete functional roles for inhibitory interneurons in song production. We show that single
HVC premotor neuron bursts are sufficient to drive structured activity within the interneuron network because of pervasive and facilitating synaptic connections. We
characterize interneuron activity during singing and describe reliable pauses in the firing of those neurons. We then demonstrate that these gaps in inhibition are likely to
be necessary for driving normal bursting behavior in HVC premotor neurons and suggest that structured inhibition and excitation may be a general mechanism enabling
sequence generation in other circuits.
The Journal of Neuroscience, January 21, 2015 • 35(3):1217–1227
Musical Training Orchestrates Coordinated Neuroplasticity in Auditory Brainstem and Cortex
to Counteract Age-Related Declines in Categorical Vowel Perception
Gavin M. Bidelman1,2 and Claude Alain3,4,5
1Institute for Intelligent Systems, University of Memphis, Memphis, Tennessee 38152, 2School of Communication Sciences & Disorders, University of
Memphis, Memphis, Tennessee 38105, 3Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, Ontario M6A 2E1, Canada, 4Department of
Psychology, University of Toronto, Toronto, Ontario M5S 2J7, Canada, and 5Institute of Medical Sciences, University of Toronto M5S 2J7, Ontario, Canada
Musicianship in early life is associated with pervasive changes in brain function and enhanced speech-language skills. Whether these neuroplastic benefits extend to older
individuals more susceptible to cognitive decline, and for whom plasticity is weaker, has yet to be established. Here, we show that musical training offsets declines in
auditory brain processing that accompanying normal aging in humans, preserving robust speech recognition late into life. We recorded both brainstem and cortical
neuroelectric responses in older adults with and without modest musical training as they classified speech sounds along an acoustic–phonetic continuum. Results reveal
higher temporal precision in speech-evoked responses at multiple levels of the auditory system in older musicians who were also better at differentiating phonetic
categories. Older musicians also showed a closer correspondence between neural activity and perceptual performance. This suggests that musicianship strengthens
brain-behavior coupling in the aging auditory system. Last, “neurometric” functions derived from unsupervised classification of neural activity established that early
cortical responses could accurately predict listeners’ psychometric speech identification and, more critically, that neurometric profiles were organized more categorically
in older musicians. We propose that musicianship offsets age-related declines in speech listening by refining the hierarchical interplay between subcortical/cortical
auditory brain representations, allowing more behaviorally relevant information carried within the neural code, and supplying more faithful templates to the brain
mechanisms subserving phonetic computations. Our findings imply that robust neuroplasticity conferred by musical training is not restricted by age and may serve as an
effective means to bolster speech listening skills that decline across the lifespan.
The Journal of Neuroscience, January 21, 2015 • 35(3):1240 –1249
BEHAVIORAL/COGNITIVE
Audition-Independent Vocal Crystallization Associated with Intrinsic Developmental Gene
Expression Dynamics
Chihiro Mori1 and Kazuhiro Wada1,2,3
1
Graduate School of Life Science, 2Department of Biological Sciences, and 3Faculty of Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan
Complex learned behavior is influenced throughout development by both genetic and environmental factors. Birdsong, like human speech, is a complex vocal behavior
acquired through sensorimotor learning and is based on coordinated auditory input and vocal output to mimic tutor song. Song is primarily learned during a specific
developmental stage called the critical period. Although auditory input is crucial for acquiring complex vocal patterns, its exact role in neural circuit maturation for vocal
learning and production is not well understood. Using audition-deprived songbirds, we examined whether auditory experience affects developmental gene expression in
the major elements of neural circuits that mediate vocal learning and production. Compared with intact zebra finches, early-deafened zebra finches showed excessively
delayed vocal development, but their songs eventually crystallized. In contrast to the different rates of song development between the intact and deafened birds, developmental gene expression in the motor circuit is conserved in an age-dependent manner from the juvenile stage until the older adult stage, even in the deafened birds, which
indicates the audition-independent robustness of gene expression dynamics during development. Furthermore, even after adult deafening, which degrades crystallized
song, the deteriorated songs ultimately restabilized at the same point when the early-deafened birds stabilized their songs. These results indicate a genetic programassociated inevitable termination of vocal plasticity that results in audition-independent vocal crystallization.
The Journal of Neuroscience, January 21, 2015 • 35(3):878 – 889
Sex-Dependent Dissociation between Emotional Appraisal and Memory: A Large-Scale
Behavioral and fMRI Study
Klara Spalek,1 Matthias Fastenrath,1 Sandra Ackermann,2 Bianca Auschra,2 David Coynel,1 Julia Frey,1 Leo Gschwind,1
Francina Hartmann,2 Nadine van der Maarel,1 Andreas Papassotiropoulos,2,3,4 Dominique de Quervain,1,4 and
Annette Milnik2,4
Department of Psychology, 1Division of Cognitive Neuroscience and 2Division of Molecular Neuroscience, 3Life Sciences Training Facility, and 4University
Psychiatric Clinics, University of Basel, 4009 Basel, Switzerland
Extensive evidence indicates that women outperform men in episodic memory tasks. Furthermore, women are known to evaluate emotional stimuli as more arousing than
men. Because emotional arousal typically increases episodic memory formation, the females’ memory advantage might be more pronounced for emotionally arousing
information than for neutral information. Here, we report behavioral data from 3398 subjects, who performed picture rating and memory tasks, and corresponding fMRI
data from up to 696 subjects. We were interested in the interaction between sex and valence category on emotional appraisal, memory performances, and fMRI activity. The
behavioral results showed that females evaluate in particular negative (p ⬍ 10 ⫺16) and positive (p ⫽ 2 ⫻ 10 ⫺4), but not neutral pictures, as emotionally more arousing
(pinteraction ⬍ 10 ⫺16) than males. However, in the free recall females outperformed males not only in positive (p ⬍ 10 ⫺16) and negative (p ⬍ 5 ⫻ 10 ⫺5), but also in neutral
picture recall (p ⬍ 3.4 ⫻ 10 ⫺8), with a particular advantage for positive pictures (pinteraction ⬍ 4.4 ⫻ 10 ⫺10). Importantly, females’ memory advantage during free recall was
absent in a recognition setting. We identified activation differences in fMRI, which corresponded to the females’ stronger appraisal of especially negative pictures, but no
activation differences that reflected the interaction effect in the free recall memory task. In conclusion, females’ valence-category-specific memory advantage is only
observed in a free recall, but not a recognition setting and does not depend on females’ higher emotional appraisal.
The Journal of Neuroscience, January 21, 2015 • 35(3):920 –935
Prefrontal Neuronal Responses during Audiovisual Mnemonic Processing
Jaewon Hwang1 and Lizabeth M. Romanski2
Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland 21218 and 2Department of Neurobiology and Anatomy, University of
Rochester School of Medicine, Rochester, New York 14642
1
During communication we combine auditory and visual information. Neurophysiological research in nonhuman primates has shown that single neurons in ventrolateral
prefrontal cortex (VLPFC) exhibit multisensory responses to faces and vocalizations presented simultaneously. However, whether VLPFC is also involved in maintaining
those communication stimuli in working memory or combining stored information across different modalities is unknown, although its human homolog, the inferior
frontal gyrus, is known to be important in integrating verbal information from auditory and visual working memory. To address this question, we recorded from VLPFC
while rhesus macaques (Macaca mulatta) performed an audiovisual working memory task. Unlike traditional match-to-sample/nonmatch-to-sample paradigms, which
use unimodal memoranda, our nonmatch-to-sample task used dynamic movies consisting of both facial gestures and the accompanying vocalizations. For the nonmatch
conditions, a change in the auditory component (vocalization), the visual component (face), or both components was detected. Our results show that VLPFC neurons are
activated by stimulus and task factors: while some neurons simply responded to a particular face or a vocalization regardless of the task period, others exhibited activity
patterns typically related to working memory such as sustained delay activity and match enhancement/suppression. In addition, we found neurons that detected the
component change during the nonmatch period. Interestingly, some of these neurons were sensitive to the change of both components and therefore combined information
from auditory and visual working memory. These results suggest that VLPFC is not only involved in the perceptual processing of faces and vocalizations but also in their
mnemonic processing.
The Journal of Neuroscience, January 21, 2015 • 35(3):960 –971
Metacognitive Mechanisms Underlying Lucid Dreaming
Elisa Filevich,1 Martin Dresler,2 Timothy R. Brick,1,3 and Simone Ku¨hn1
Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany, 2Radboud University Nijmegen Medical Centre,
Donders Institute for Brain, Cognition and Behaviour, 6525 EZ Nijmegen, The Netherlands and 3Department of Human Development and Family Studies,
Pennsylvania State University, University Park, Pennsylvania
1
Lucid dreaming is a state of awareness that one is dreaming, without leaving the sleep state. Dream reports show that self-reflection and volitional control are more
pronounced in lucid compared with nonlucid dreams. Mostly on these grounds, lucid dreaming has been associated with metacognition. However, the link to lucid
dreaming at the neural level has not yet been explored. We sought for relationships between the neural correlates of lucid dreaming and thought monitoring.
Human participants completed a questionnaire assessing lucid dreaming ability, and underwent structural and functional MRI. We split participants based on their
reported dream lucidity. Participants in the high-lucidity group showed greater gray matter volume in the frontopolar cortex (BA9/10) compared with those in the
low-lucidity group. Further, differences in brain structure were mirrored by differences in brain function. The BA9/10 regions identified through structural analyses
showed increases in blood oxygen level-dependent signal during thought monitoring in both groups, and more strongly in the high-lucidity group.
Our results reveal shared neural systems between lucid dreaming and metacognitive function, in particular in the domain of thought monitoring. This finding
contributes to our understanding of the mechanisms enabling higher-order consciousness in dreams.
The Journal of Neuroscience, January 21, 2015 • 35(3):1082–1088
Slack Channels Expressed in Sensory Neurons Control Neuropathic Pain in Mice
Ruirui Lu,1,2* Anne E. Bausch,3* Wiebke Kallenborn-Gerhardt,2 Carsten Stoetzer,4 Natasja Debruin,5 Peter Ruth,3
Gerd Geisslinger,2,5 Andreas Leffler,4 Robert Lukowski,3* and Achim Schmidtko1,2*
1Institut fu
¨ r Pharmakologie und Toxikologie, Universita¨t Witten/Herdecke, Zentrum fu¨r Biomedizinische Ausbildung und Forschung, 58453 Witten,
Germany, 2Pharmazentrum Frankfurt/Zentrum fu¨r Arzneimittelforschung, Entwicklung und Sicherheit, Institut fu¨r Klinische Pharmakologie,
Universita¨tsklinikum Frankfurt, 60590 Frankfurt am Main, Germany, 3Pharmakologie, Toxikologie und Klinische Pharmazie, Institut fu¨r Pharmazie, 72076
Tu¨bingen, Germany, 4Klinik fu¨r Ana¨sthesiologie und Intensivmedizin, Medizinische Hochschule Hannover, 30625 Hannover, Germany, and 5Fraunhofer
Institute for Molecular Biology and Applied Ecology IME, 60590 Frankfurt am Main, Germany
Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its
contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in
various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and
acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener
loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that
modulating its activity might represent a novel strategy for management of neuropathic pain.
The Journal of Neuroscience, January 21, 2015 • 35(3):1125–1135
Aging Impairs Protein-Synthesis-Dependent Long-Term Memory in Drosophila
Ayako Tonoki1,2 and Ronald L. Davis1
Department of Neuroscience, Scripps Research Institute Florida, Jupiter, Florida 33458, and 2Graduate School of Pharmaceutical Sciences, Chiba
University, Chuo-ku, Chiba 260-8675, Japan
1
Although aging is known to impair intermediate-term memory in Drosophila, its effect on protein-synthesis-dependent long-term memory (LTM) is unknown. We show
here that LTM is impaired with age, not due to functional defects in synaptic output of mushroom body (MB) neurons, but due to connectivity defects of dorsal paired medial
(DPM) neurons with their postsynaptic MB neurons. GFP reconstitution across synaptic partners (GRASP) experiments revealed structural connectivity defects in aged
animals of DPM neurons with MB axons in the ␣ lobe neuropil. As a consequence, a protein-synthesis-dependent LTM trace in the ␣/␤ MB neurons fails to form. Aging thus
impairs protein-synthesis-dependent LTM along with the ␣/␤ MB neuron LTM trace by lessening the connectivity of DPM and ␣/␤ MB neurons.
The Journal of Neuroscience, January 21, 2015 • 35(3):1173–1180
Vestibulo-Ocular Reflex Suppression during Head-Fixed Saccades Reveals Gaze Feedback
Control
Pierre M. Daye,1,6 Dale C. Roberts,2 David S. Zee,2,3,4,5 and Lance M. Optican6
Pierre et Marie Curie Paris-6 Universite´, INSERM UMRS 975, CNRS 7225, Paris, France, Departments of 2Neurology, 3Otolaryngology, 4Ophthalmology,
and 5Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287, and 6Laboratory of Sensorimotor Research, National
Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-4435
1
Previous experiments have shown that the vestibulo-ocular reflex (VOR) is partially suppressed during large head-free gaze (gaze ⫽ eye-in-head ⫹ head-in-space) shifts
when both the eyes and head are moving actively, on a fixed body, or when the eyes are moving actively and the head passively on a fixed body. We tested, in human subjects,
the hypothesis that the VOR is also suppressed during gaze saccades made with en bloc, head and body together, rotations. Subjects made saccades by following a target light.
During some trials, the chair rotated so as to move the entire body passively before, during, or after a saccade. The modulation of the VOR was a function of both saccade
amplitude and the time of the head perturbation relative to saccade onset. Despite the perturbation, gaze remained accurate. Thus, VOR modulation is similar when gaze
changes are programmed for the eyes alone or for the eyes and head moving together. We propose that the brain always programs a change in gaze using feedback based on
gaze and head signals, rather than on separate eye and head trajectories.
The Journal of Neuroscience, January 21, 2015 • 35(3):1192–1198
Cerebellar Cortex and Cerebellar Nuclei Are Concomitantly Activated during Eyeblink
Conditioning: A 7T fMRI Study in Humans
Markus Thu¨rling,1,2 Fabian Kahl,1 Stefan Maderwald,2 Roxana M. Stefanescu,1,2 Marc Schlamann,3 Henk-Jan Boele,4
Chris I. De Zeeuw,4,5 Jo¨rn Diedrichsen,6 Mark E. Ladd,2,7 Sebastiaan K. E. Koekkoek,4 and Dagmar Timmann1
Departments of 1Neurology, University Clinic Essen, 2Erwin L. Hahn Institute for MRI, and 3Diagnostic and Interventional Radiology and Neuroradiology,
University Clinic Essen, University of Duisburg-Essen, 45147 Essen, Germany, 4Department of Neuroscience, Erasmus University Medical Center, 3000 DR
Rotterdam, The Netherlands, 5The Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands,
6Institute of Cognitive Neuroscience, University College London, WC1N 3AR London, United Kingdom, and 7Division of Medical Physics in Radiology
(E020), German Cancer Research Center, 69120 Heidelberg, Germany
There are controversies whether learning of conditioned eyeblink responses primarily takes place within the cerebellar cortex, the interposed nuclei, or both. It has also
been suggested that the cerebellar cortex may be important during early stages of learning, and that there is a shift to the cerebellar nuclei during later stages. As yet, human
studies have provided little to resolve this question. In the present study, we established a setup that allows ultra-high-field 7T functional magnetic resonance imaging
(fMRI) of the cerebellar cortex and interposed cerebellar nuclei simultaneously during delay eyeblink conditioning in humans. Event-related fMRI signals increased
concomitantly in the cerebellar cortex and nuclei during early acquisition of conditioned eyeblink responses in 20 healthy human subjects. ANOVAs with repeatedmeasures showed significant effects of time across five blocks of 20 conditioning trials in the cortex and nuclei (p ⬍ 0.05, permutation corrected). Activations were most
pronounced in, but not limited to, lobules VI and interposed nuclei. Increased activations were most prominent at the first time the maximum number of conditioned
responses was achieved. Our data are consistent with a simultaneous and synergistic two-site model of learning during acquisition of classically conditioned eyeblinks.
Because increased MRI signal reflects synaptic activity, concomitantly increased signals in the cerebellar nuclei and cortex are consistent with findings of learning related
potentiation at the mossy fiber to nuclear cell synapse and mossy fiber to granule cell synapse. Activity related to the expression of conditioned responses, however, cannot
be excluded.
The Journal of Neuroscience, January 21, 2015 • 35(3):1228 –1239
Neural Dynamics Underlying Attentional Orienting to Auditory Representations in Short-Term
Memory
Kristina C. Backer,1,2 Malcolm A. Binns,1,3 and Claude Alain1,2
Rotman Research Institute at Baycrest Centre, Toronto, Ontario, M6A 2E1, Canada, and 2Department of Psychology and 3Dalla Lana School of Public
Health, University of Toronto, Toronto, Ontario, M5S 1A1, Canada
1
Sounds are ephemeral. Thus, coherent auditory perception depends on “hearing” back in time: retrospectively attending that which was lost externally but preserved in
short-term memory (STM). Current theories of auditory attention assume that sound features are integrated into a perceptual object, that multiple objects can coexist in
STM, and that attention can be deployed to an object in STM. Recording electroencephalography from humans, we tested these assumptions, elucidating feature-general
and feature-specific neural correlates of auditory attention to STM. Alpha/beta oscillations and frontal and posterior event-related potentials indexed feature-general
top-down attentional control to one of several coexisting auditory representations in STM. Particularly, task performance during attentional orienting was correlated with
alpha/low-beta desynchronization (i.e., power suppression). However, attention to one feature could occur without simultaneous processing of the second feature of the
representation. Therefore, auditory attention to memory relies on both feature-specific and feature-general neural dynamics.
The Journal of Neuroscience, January 21, 2015 • 35(3):1307–1318
NEUROBIOLOGY OF DISEASE
A53T Human ␣-Synuclein Overexpression in Transgenic Mice Induces Pervasive Mitochondria
Macroautophagy Defects Preceding Dopamine Neuron Degeneration
Linan Chen (陈), Zhiguo Xie, Susie Turkson, and Xiaoxi Zhuang
Department of Neurobiology, University of Chicago, Chicago, Illinois 60637
In vitro evidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson’s disease (PD). Using a tissue-specific gene
amplification strategy, we generated a transgenic mouse line with human ␣-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice
showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial
remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial
pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of ␣-synuclein and
their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic
removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration
in an in vivo model based on known PD genetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have
set the stage and direction of emphasis for future studies.
The Journal of Neuroscience, January 21, 2015 • 35(3):890 –905
Evidence for Consolidation of Neuronal Assemblies after Seizures in Humans
Mark R. Bower,1,3 Matt Stead,1,3 Regina S. Bower,2,3 Michal T. Kucewicz,1,3 Vlastimil Sulc,1,3,5 Jan Cimbalnik,1,3,5
Benjamin H. Brinkmann,1,3 Vincent M. Vasoli,1,3 Erik K. St. Louis,4 Fredric B. Meyer,2 W. Richard Marsh,2
and Gregory A. Worrell1,3
Department of Neurology, 2Department of Neurologic Surgery, 3Division of Clinical Neurophysiology and Epilepsy, Mayo Systems Electrophysiology
Laboratory, and 4Departments of Medicine and Neurology, Cognitive Neurophysiology Laboratory and Center for Sleep Medicine, Mayo Clinic, Rochester,
Minnesota 55905, and 5St. Anne’s Hospital, International Center for Research Consortium, 656 91 Brno, Czech Republic
1
The establishment of memories involves reactivation of waking neuronal activity patterns and strengthening of associated neural circuits during slow-wave sleep (SWS), a
process known as “cellular consolidation” (Dudai and Morris, 2013). Reactivation of neural activity patterns during waking behaviors that occurs on a timescale of seconds
to minutes is thought to constitute memory recall (O’Keefe and Nadel, 1978), whereas consolidation of memory traces may be revealed and served by correlated firing
(reactivation) that appears during sleep under conditions suitable for synaptic modification (Buhry et al., 2011). Although reactivation has been observed in human
neuronal recordings (Gelbard-Sagiv et al., 2008; Miller et al., 2013), reactivation during sleep has not, likely because data are difficult to obtain and the effect is subtle.
Seizures, however, provide intense and synchronous, yet sparse activation (Bower et al., 2012) that could produce a stronger consolidation effect if seizures activate
learning-related mechanisms similar to those activated by learned tasks. Continuous wide-bandwidth recordings from patients undergoing intracranial monitoring for
drug-resistant epilepsy revealed reactivation of seizure-related neuronal activity during subsequent SWS, but not wakefulness. Those neuronal assemblies that were most
strongly activated during seizures showed the largest correlation changes, suggesting that consolidation selectively strengthened neuronal circuits activated by seizures.
These results suggest that seizures “hijack” physiological learning mechanisms and also suggest a novel epilepsy therapy targeting neuronal dynamics during post-seizure
sleep.
The Journal of Neuroscience, January 21, 2015 • 35(3):999 –1010
The Full-Length Form of the Drosophila Amyloid Precursor Protein Is Involved in Memory
Formation
Isabelle Bourdet, Thomas Preat, and Vale´rie Goguel
Genes and Dynamics of Memory Systems, Brain Plasticity Unit, CNRS, ESPCI-ParisTech, PSL Research University, 75005 Paris, France
The APP plays a central role in AD, a pathology that first manifests as a memory decline. Understanding the role of APP in normal cognition is fundamental in understanding the progression of AD, and mammalian studies have pointed to a role of secreted APP␣ in memory. In Drosophila, we recently showed that APPL, the fly APP ortholog,
is required for associative memory. In the present study, we aimed to characterize which form of APPL is involved in this process. We show that expression of a
secreted-APPL form in the mushroom bodies, the center for olfactory memory, is able to rescue the memory deficit caused by APPL partial loss of function. We next assessed
the impact on memory of the Drosophila ␣-secretase kuzbanian (KUZ), the enzyme initiating the nonamyloidogenic pathway that produces secreted APPL␣. Strikingly,
KUZ overexpression not only failed to rescue the memory deficit caused by APPL loss of function, it exacerbated this deficit. We further show that in addition to an increase
in secreted-APPL forms, KUZ overexpression caused a decrease of membrane-bound full-length species that could explain the memory deficit. Indeed, we observed that
transient expression of a constitutive membrane-bound mutant APPL form is sufficient to rescue the memory deficit caused by APPL reduction, revealing for the first time
a role of full-length APPL in memory formation. Our data demonstrate that, in addition to secreted APPL, the noncleaved form is involved in memory, raising the possibility
that secreted and full-length APPL act together in memory processes.
The Journal of Neuroscience, January 21, 2015 • 35(3):1043–1051
Desynchronization of Fast-Spiking Interneurons Reduces ␤-Band Oscillations and Imbalance in
Firing in the Dopamine-Depleted Striatum
Sriraman Damodaran, John R. Cressman, Zbigniew Jedrzejewski-Szmek, and Kim T. Blackwell
Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030
Oscillations in the ␤-band (8 –30 Hz) that emerge in the output nuclei of the basal ganglia during Parkinson’s disease, along with an imbalanced activation of the direct and
indirect pathways, have been linked to the hypokinetic motor output associated with the disease. Although dopamine depletion causes a change in cellular and network
properties in the striatum, it is unclear whether abnormal activity measured in the globus pallidus and substantia nigra pars reticulata is caused by abnormal striatal
activity. Here we use a computational network model of medium spiny neurons (MSNs)—fast-spiking interneurons (FSIs), based on data from several mammalian species,
and find that robust ␤-band oscillations and imbalanced firing emerge from implementation of changes to cellular and circuit properties caused by dopamine depletion.
These changes include a reduction in connections between MSNs, a doubling of FSI inhibition to D2 MSNs, an increase in D2 MSN dendritic excitability, and a reduction in
D2 MSN somatic excitability. The model reveals that the reduced decorrelation between MSNs attributable to weakened lateral inhibition enables the strong influence of
synchronous FSIs on MSN firing and oscillations. Weakened lateral inhibition also produces an increased sensitivity of MSN output to cortical correlation, a condition
relevant to the parkinsonian striatum. The oscillations of FSIs, in turn, are strongly modulated by fast electrical transmission between FSIs through gap junctions. These
results suggest that pharmaceuticals that desynchronize FSI activity may provide a novel treatment for the enhanced ␤-band oscillations, imbalanced firing, and motor
dysfunction in Parkinson’s disease.
The Journal of Neuroscience, January 21, 2015 • 35(3):1149 –1159
The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A␤ Pharmacodynamic
Responses in Mice, Dogs, and Humans
Patrick C. May,1 Brian A. Willis,1 Stephen L. Lowe,2 Robert A. Dean,1 Scott A. Monk,1 Patrick J. Cocke,1 James E. Audia,1
Leonard N. Boggs,1 Anthony R. Borders,1 Richard A. Brier,1 David O. Calligaro,1 Theresa A. Day,1 Larry Ereshefsky,3*
Jon A. Erickson,1 Hykop Gevorkyan,4 Celedon R. Gonzales,1 Douglas E. James,1 Stanford S. Jhee,3 Steven F. Komjathy,1
Linglin Li,1 Terry D. Lindstrom,1† Brian M. Mathes,1 Ferenc Marte´nyi,1 Scott M. Sheehan,1 Stephanie L. Stout,1
David E. Timm,1 Grant M. Vaught,1 Brian M. Watson,1 Leonard L. Winneroski,1 Zhixiang Yang,1 and Dustin J. Mergott1
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, 2National University of Singapore Centre for Clinical
Pharmacology, Singapore 117597, Singapore, 3PAREXEL International, Glendale, California 91206, and 4California Clinical Trials Medical Group,
Inc., Glendale, California 91206
1
BACE1 is a key protease controlling the formation of amyloid ␤, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer’s disease (AD). Therefore, the
developmentofpotentandselectiveinhibitorsofBACE1hasbeenafocusofmanydrugdiscoveryeffortsinacademiaandindustry.Herein,wereportthenonclinicalandearlyclinical
development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently
translates in vitro activity into robustin vivo amyloid ␤ lowering in nonclinical animal models. Similar potent and persistent amyloid ␤ lowering was observed in plasma and lumbar
CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of
amyloid lowering and as an attractive target for potential disease modification therapy in AD.
The Journal of Neuroscience, January 21, 2015 • 35(3):1199 –1210
Chronic Oligodendrogenesis and Remyelination after Spinal Cord Injury in Mice and Rats
Zoe C. Hesp,1 Evan A. Goldstein,1 Carlos J. Miranda,4 Brain K. Kaspar,3,4 and Dana M. McTigue2,3
1Neuroscience Graduate Studies Program, 2Department of Neuroscience, and 3Center for Brain and Spinal Cord Repair, The Ohio State University,
Columbus, Ohio 43210, and 4Nationwide Children’s Hospital, Columbus, Ohio 43205
Adult progenitor cells proliferate in the acutely injured spinal cord and their progeny differentiate into new oligodendrocytes (OLs) that remyelinate spared axons. Whether
this endogenous repair continues beyond the first week postinjury (wpi), however, is unknown. Identifying the duration of this response is essential for guiding therapies
targeting improved recovery from spinal cord injury (SCI) by enhancing OL survival and/or remyelination. Here, we used two PDGFR␣-reporter mouse lines and rats
injected with a GFP-retrovirus to assess progenitor fate through 80 d after injury. Surprisingly, new OLs were generated as late as 3 months after injury and their processes
ensheathed axons near and distal to the lesion, colocalized with MBP, and abutted Caspr⫹ profiles, suggesting newly formed myelin. Semithin sections confirmed
stereotypical thin OL remyelination and few bare axons at 10 wpi, indicating that demyelination is relatively rare. Astrocytes in chronic tissue expressed the pro-OL
differentiation and survival factors CNTF and FGF-2. In addition, pSTAT3⫹ NG2 cells were present through at least 5 wpi, revealing active signaling of the Jak/STAT
pathway in these cells. The progenitor cell fate genes Sox11, Hes5, Id2, Id4, BMP2, and BMP4 were dynamically regulated for at least 4 wpi. Collectively, these data verify that
the chronically injured spinal cord is highly dynamic. Endogenous repair, including oligodendrogenesis and remyelination, continues for several months after SCI,
potentially in response to growth factors and/or transcription factor changes. Identifying and understanding spontaneous repair processes such as these is important so
that beneficial plasticity is not inadvertently interrupted and effort is not exerted to needlessly duplicate ongoing spontaneous repair.
The Journal of Neuroscience, January 21, 2015 • 35(3):1274 –1290