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The Journal of Neuroscience, January 7, 2015 • 35(1):i • i
This Week in The Journal
Slow-Wave Sleep Rhythms May
Induce LTD
Romain Pigeat, Patrick Chausson, Fanny M.
Dreyfus, Nathalie Leresche, and Re´gis C.
Lambert
(see pages 64 –73)
As we sleep, our brains progress through
stereotypical patterns of activity that define
different sleep stages. The functions of these
activity patterns are not fully understood,
but they might contribute to memory
consolidation. Indeed, different types of
memory appear to be consolidated during
different sleep stages. Evidence suggests, for
example, that slow-wave sleep (SWS) is
particularly important for consolidating declarative memories, and it has been hypothesized that newly acquired memories are
transferred to long-term storage and integrated with older memories during this stage.
SWS is characterized by widespread synchronous oscillations between hyperpolarized down-states and depolarized up-states
that include high-frequency firing. The
oscillations are generated primarily by reciprocally connected excitatory thalamocortical (TC) neurons and inhibitory
neurons in the thalamic reticular nucleus
(NRT). High-frequency spiking in NRT
neurons causes hyperpolarization of TC
neurons, thus de-inactivating low-threshold T-type calcium channels. These channels open when IPSPs subside, resulting in
calcium elevation, depolarization, and rebound spiking in TC neurons. Feedback
from TC neurons to NRT neurons evokes
subsequent rounds of inhibition.
Note that the pattern of activity that occurs in NRT–TC pairs during SWS is similar
to that underlying synaptic plasticity
throughout the CNS: presynaptic action potentials lead to postsynaptic calcium elevation. In fact, Pigeat et al. report that
stimulating NRT fibers in rat brain slices
while depolarizing postsynaptic TC neurons from ⫺80 to ⫺30 mV—a protocol
meant to mimic the NRT bursts and TC depolarization during SWS—resulted in longterm depression of IPSCs (I-LTD).
Buffering calcium or blocking T channels
prevented the induction of I-LTD, but
blocking other calcium channels types did
not, indicating that T channels were necessary and sufficient for I-LTD induction.
Blocking metabotropic glutamate receptors
blocked I-LTD, suggesting there was a heterosynaptic component (activation of glutamatergic synapses was required to alter
GABAergic synapses), but stimulating a
subset of GABAergic inputs to a cell produced I-LTD selectively at those synapses,
indicating there was also a homosynaptic
component. Finally, I-LTD required activation of GABAA receptors and the Ca 2⫹/
calmodulin-dependent phosphatase calcineurin, which has been previously
shown to mediate LTD through interactions with GABAA receptor subunits.
When dominant-negative Fgfr1 was expressed in developing
zebrafish (bottom), SAG area (defined by neuronal marker
expression, green) was reduced compared to controls (top) in
the neurogenic region (dashed lines) of the otic placode. See
the article by Wang et al. for details.
FGF Drives Neurogenic Fate in the
Otic Placode
Jialiang Wang, Ying Wu, Feng Zhao, Yuting
Wu, Wei Dong, et al.
(see pages 234 –244)
During development, peripheral sensory
neurons and their associated structures arise
from the neural crest and cranial placodes—
specialized ectodermal regions that border the
neural plate that forms the CNS. The otic placode forms neural (VIIIth ganglion neurons),
sensory (hair cells), and nonneural structures
of the inner ear, including both auditory and
vestibular components. As in all tissues, this
development proceeds through a sequential
process of fate restriction, proliferation, and
differentiation controlled by numerous genes
and signaling pathways.
Fibroblast growth factors (FGFs) are required to specify neurogenic fate early in otic
development, and they also appear to contribute to specification of some hair cell types. In
zebrafish, knocking down Fgf8a or Fgf3
greatly reduces the size of the statoacoustic
ganglia (SAG), and knocking down both proteins prevents ear formation altogether. To
further elucidate the role of FGF signaling at
different stages of otic development, Wang et
al. used heat-activated mutants and inhibitors
of various signaling pathways.
Expressing a dominant-negative form of
the FGF receptor (Fgfr1) 10 –12 hours post
fertilization (hpf) greatly reduced SAG area,
whereas overexpressing Fgf8 at this stage
modestly increased SAG area. Importantly,
neither manipulation affected overall ear
development and neither affected SAG area
when applied after 14 hpf, suggesting that
FGF signaling selectively affects otic neurogenesis at 10 –14 hpf. But applying an FGFR
antagonist at 10 –14 hpf reduced the number of ultricular hair cells as well as reducing
SAG area, confirming that FGF signaling is
required to specify at least some hair cell
fates.
Interestingly, FGF appeared to affect
neurogenesis and hair cell development
through different downstream effectors:
inhibiting phosphoinositide 3-kinases
(PI3Ks) reduced SAG area without affecting hair cell number, whereas disrupting
ERK1/2 signaling reduced hair cell numbers without affecting SAG area. Given this
divergence, it is somewhat surprising that
Atoh1a, a transcription factor involved in hair
cell determination, was found to contribute to
SAG neurogenesis and to be regulated by
FGFR–PI3K signaling. As expected from previous research, the transcription factor Sox9a
also contributed to SAG neurogenesis downstreamofFGFR–PI3Ksignaling.Byinvestigating the shared targets of these transcription
factors, Wang et al. identified two previously
unrecognized contributors to otic neurogenesis: tlx2 and eya2.
The Journal of Neuroscience
January 7, 2015 • Volume 35 Number 1 • www.jneurosci.org
i
This Week in The Journal
Journal Club
1
Considering the Impact of Large-Scale Network Interactions on Cognitive Control
Fiona Kumfor, Nadene Dermody, and Muireann Irish
Brief Communications
366
Bridging the Gap between Perceptual and Cognitive Perspectives on Absolute Pitch
Stefan Elmer, Lars Rogenmoser, Ju¨rg Ku¨hnis, and Lutz Ja¨ncke
Articles
Cover legend: Glycine receptor ␣1 subunits (green)
are trafficked into the dendrites of hippocampal
neurons. The protein GM130 (pink) is present in the
cis-Golgi and DAPI (blue) labels the nucleus (Adobe
Photoshop filter plastic wrap was added to the
original image). For more information, see the article
by Schaefer et al. (pages 422– 437).
CELLULAR/MOLECULAR
䊉
21
Brg1-Dependent Chromatin Remodelling Is Not Essentially Required during
Oligodendroglial Differentiation
Melanie Bischof, Matthias Weider, Melanie Ku¨spert, Klaus-Armin Nave,
and Michael Wegner
64
Sleep Slow Wave-Related Homo and Heterosynaptic LTD of Intrathalamic
GABAAergic Synapses: Involvement of T-Type Ca2ⴙ Channels and Metabotropic
Glutamate Receptors
Romain Pigeat, Patrick Chausson, Fanny M. Dreyfus, Nathalie Leresche,
and Re´gis C. Lambert
112
Diversity of Glutamatergic Synaptic Strength in Lateral Prefrontal versus Primary
Visual Cortices in the Rhesus Monkey
Maria Medalla and Jennifer I. Luebke
221
Itk Signals Promote Neuroinflammation by Regulating CD4ⴙ T-Cell Activation
and Trafficking
Arun K. Kannan, Do-Geun Kim, Avery August, and Margaret S. Bynoe
325
Gene Dosage in the Dysbindin Schizophrenia Susceptibility Network Differentially
Affect Synaptic Function and Plasticity
Ariana P. Mullin, Madhumala K. Sadanandappa, Wenpei Ma, Dion K. Dickman,
Krishnaswamy VijayRaghavan, Mani Ramaswami, Subhabrata Sanyal,
and Victor Faundez
352
Chromatin Landscape Defined by Repressive Histone Methylation during
Oligodendrocyte Differentiation
Jia Liu, Laura Magri, Fan Zhang, Nidaa O. Marsh, Stefanie Albrecht,
Jimmy L. Huynh, Jasbir Kaur, Tanja Kuhlmann, Weijia Zhang, Paul A. Slesinger,
and Patrizia Casaccia
372
Combinatorial Mutagenesis of the Voltage-Sensing Domain Enables the Optical
Resolution of Action Potentials Firing at 60 Hz by a Genetically Encoded Fluorescent
Sensor of Membrane Potential
Hong Hua Piao, Dhanarajan Rajakumar, Bok Eum Kang, Eun Ha Kim,
and Bradley J. Baker
386
cJun and CREB2 in the Postsynaptic Neuron Contribute to Persistent Long-Term
Facilitation at a Behaviorally Relevant Synapse
Jiang-Yuan Hu, Amir Levine, Ying-Ju Sung, and Samuel Schacher
DEVELOPMENT/PLASTICITY/REPAIR
䊉
140
Mapping the Stability of Human Brain Asymmetry across Five Sex-Chromosome
Aneuploidies
Amy Lin, Liv Clasen, Nancy Raitano Lee, Gregory L. Wallace, Francois Lalonde,
Jonathan Blumenthal, Jay N. Giedd, and Armin Raznahan
234
Fgf-Signaling-Dependent Sox9a and Atoh1a Regulate Otic Neural Development in
Zebrafish
Jialiang Wang, Ying Wu, Feng Zhao, Yuting Wu, Wei Dong, Jue Zhao,
Zuoyan Zhu, and Dong Liu
409
Expanded Terminal Fields of Gustatory Nerves Accompany Embryonic BDNF
Overexpression in Mouse Oral Epithelia
Chengsan Sun, Arjun Dayal, and David L. Hill
SYSTEMS/CIRCUITS
53
Imaging the Awake Visual Cortex with a Genetically Encoded Voltage Indicator
Matteo Carandini, Daisuke Shimaoka, L. Federico Rossi, Tatsuo K. Sato,
Andrea Benucci, and Thomas Kno¨pfel
84
Temporal Plasticity Involved in Recovery from Manual Dexterity Deficit after Motor
Cortex Lesion in Macaque Monkeys
Yumi Murata, Noriyuki Higo, Takuya Hayashi, Yukio Nishimura,
Yoko Sugiyama, Takao Oishi, Hideo Tsukada, Tadashi Isa, and Hirotaka Onoe
146
Circuit Formation and Function in the Olfactory Bulb of Mice with Reduced
Spontaneous Afferent Activity
Paolo Lorenzon, Nelly Redolfi, Michael J. Podolsky, Ilaria Zamparo,
Sira Angela Franchi, Gianluca Pietra, Anna Boccaccio, Anna Menini,
Venkatesh N. Murthy, and Claudia Lodovichi
170
Cortical State Determines Global Variability and Correlations in Visual Cortex
Marieke L. Schölvinck, Aman B. Saleem, Andrea Benucci, Kenneth D. Harris,
and Matteo Carandini
198
Distinct Midbrain and Habenula Pathways Are Involved in Processing Aversive
Events in Humans
Kelly Hennigan, Kimberlee D’Ardenne, and Samuel M. McClure
299
Motor Origin of Precise Synaptic Inputs onto Forebrain Neurons Driving
a Skilled Behavior
Daniela Vallentin and Michael A. Long
BEHAVIORAL/COGNITIVE
74
128
Pharmacogenetic Excitation of Dorsomedial Prefrontal Cortex Restores Fear
Prediction Error
Joanna Oi-Yue Yau and Gavan P. McNally
Persistent CaMKII Activation Mediates Learning-Induced Long-Lasting Enhancement
of Synaptic Inhibition
Sourav Ghosh, Iris Reuveni, Raphael Lamprecht, and Edi Barkai
161
Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal
and Subcortical Limbic Mechanisms in Rats
E.J. Marijke Achterberg, Linda W.M. van Kerkhof, Ruth Damsteegt,
Viviana Trezza, and Louk J.M.J. Vanderschuren
179
Learning Modifies Odor Mixture Processing to Improve Detection of
Relevant Components
Jen-Yung Chen, Emiliano Marachlian, Collins Assisi, Ramon Huerta,
Brian H. Smith, Fernando Locatelli, and Maxim Bazhenov
209
The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex
Heather J. Gilbert, Trevor M. Shackleton, Katrin Krumbholz, and Alan R. Palmer
245
Saccade Planning Evokes Topographically Specific Activity in the Dorsal
and Ventral Streams
Golbarg T. Saber, Franco Pestilli, and Clayton E. Curtis
253
Spatial and Temporal Characteristics of Error-Related Activity in the Human Brain
Maital Neta, Francis M. Miezin, Steven M. Nelson, Joseph W. Dubis,
Nico U.F. Dosenbach, Bradley L. Schlaggar, and Steven E. Petersen
339
Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of
Behavioral Inhibition
Xuanmao Chen, Hong Cao, Amit Saraf, Larry S. Zweifel, and Daniel R. Storm
NEUROBIOLOGY OF DISEASE
4
Demyelination Causes Adult CNS Progenitors to Revert to an Immature State
and Express Immune Cues That Support Their Migration
Sarah Moyon, Anne Laure Dubessy, Marie Stephane Aigrot, Matthew Trotter,
Jeffrey K. Huang, Luce Dauphinot, Marie Claude Potier, Christophe Kerninon,
Stephane Melik Parsadaniantz, Robin J. M. Franklin, and Catherine Lubetzki
36
Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via
Regulation of NMDA Receptor 2B Subunit
Jun-Xia Yang, Lu Hua, Yan-Qiang Li, Yan-Yu Jiang, Dong Han, He Liu,
Qian-Qian Tang, Xiao-Na Yang, Cui Yin, Ling-Yun Hao, Le Yu, Peng Wu,
Cui-Jie Shao, Hai-Lei Ding, Yong-Mei Zhang, and Jun-Li Cao
96
Gene Expression Analyses Identify Narp Contribution in the Development
of L-DOPA-Induced Dyskinesia
Fanny Charbonnier-Beaupel, Marion Malerbi, Cristina Alcacer, Khadija Tahiri,
Wassila Carpentier, Chuansong Wang, Matthew During, Desheng Xu,
Paul F. Worley, Jean-Antoine Girault, Denis Herve´, and Jean-Christophe Corvol
267
Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal
Connectivity Associated with Longitudinal Change
Alan Anticevic, Xinyu Hu, Yuan Xiao, Junmei Hu, Fei Li, Feng Bi,
Michael W. Cole, Aleksandar Savic, Genevieve J. Yang, Grega Repovs,
John D. Murray, Xiao-Jing Wang, Xiaoqi Huang, Su Lui, John H. Krystal,
and Qiyong Gong
287
Altered Sensory Experience Exacerbates Stable Dendritic Spine and Synapse Loss in a
Mouse Model of Huntington’s Disease
Reena Prity Murmu, Wen Li, Zsuzsanna Szepesi, and Jia-Yi Li
308
Extracellular Glutamate Exposure Facilitates Group I mGluR-Mediated
Epileptogenesis in the Hippocampus
Wangfa Zhao, Shih-Chieh Chuang, Steven R. Young, Riccardo Bianchi,
and Robert K.S. Wong
316
Stress Induces the Danger-Associated Molecular Pattern HMGB-1 in the
Hippocampus of Male Sprague Dawley Rats: A Priming Stimulus of Microglia and the
NLRP3 Inflammasome
Michael D. Weber, Matthew G. Frank, Kevin J. Tracey, Linda R. Watkins,
and Steven F. Maier
396
PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse
Models of Fragile X Syndrome
Catherine H. Choi, Brian P. Schoenfeld, Eliana D. Weisz, Aaron J. Bell,
Daniel B. Chambers, Joseph Hinchey, Richard J. Choi, Paul Hinchey,
Maria Kollaros, Michael J. Gertner, Neal J. Ferrick, Allison M. Terlizzi,
Nicole Yohn, Eric Koenigsberg, David A. Liebelt, R. Suzanne Zukin,
Newton H. Woo, Michael R. Tranfaglia, Natalia Louneva, Steven E. Arnold,
Steven J. Siegel, Francois V. Bolduc, Thomas V. McDonald, Thomas A. Jongens,
and Sean M.J. McBride
422
Disturbed Neuronal ER-Golgi Sorting of Unassembled Glycine Receptors Suggests
Altered Subcellular Processing Is a Cause of Human Hyperekplexia
Natascha Schaefer, Christoph J. Kluck, Kerry L. Price, Heike Meiselbach,
Nadine Vornberger, Stephan Schwarzinger, Stephanie Hartmann,
Georg Langlhofer, Solveig Schulz, Nadja Schlegel, Knut Brockmann, Bryan Lynch,
Cord-Michael Becker, Sarah C.R. Lummis, and Carmen Villmann
438
Correction: The article “Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors
Can Mediate Neuroprotection Independent of HDAC Inhibition” by Sama F. Sleiman, David
E. Olson, Megan W. Bourassa, Saravanan S. Karuppagounder, Yan-Ling Zhang, Jennifer
Gale, Florence F. Wagner, Manuela Basso, Giovanni Coppola, John T. Pinto, Edward B.
Holson, and Rajiv R. Ratan appeared on pages 14328 –14337 of the October 22, 2014 issue.
A correction for that article appears on page 438.
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BRIEF COMMUNICATIONS
Bridging the Gap between Perceptual and Cognitive Perspectives on Absolute Pitch
Stefan Elmer,1* Lars Rogenmoser,1* Ju¨rg Ku¨hnis,1 and Lutz Ja¨ncke1,2,3,4,5
Division Neuropsychology, Institute of Psychology, 2Center for Integrative Human Physiology (ZIHP), 3International Normal Aging and Plasticity Imaging
Center (INAPIC), and 4University Research Priority Program (URPP) “Dynamic of Healthy Aging,” University of Zurich, CH-8050 Zurich, Switzerland and
5Department of Special Education, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
1
Absolute pitch (AP) refers to the rare ability to identify the chroma of a tone or to produce a specific pitch without reference to keyality (e.g., G or C). Previously, AP has been
proposed to rely on the distinctive functional-anatomical architecture of the left auditory-related cortex (ARC), this specific trait possibly enabling an optimized early
“categorical perception”. In contrast, currently prevailing models of AP postulate that cognitive rather than perceptual processes, namely “pitch labeling” mechanisms,
more likely constitute the bearing skeleton of AP. This associative memory component has previously been proposed to be dependent, among other mechanisms, on the
recruitment of the left dorsolateral prefrontal cortex (DLPFC) as well as on the integrity of the left arcuate fasciculus, a fiber bundle linking the posterior supratemporal
plane with the DLPFC. Here, we attempted to integrate these two apparently conflicting perspectives on AP, namely early “categorical perception” and “pitch labeling”. We
used electroencephalography and evaluated resting-state intracranial functional connectivity between the left ARC and DLPFC in a sample of musicians with and without
AP. Results demonstrate significantly increased left-hemispheric theta phase synchronization in AP compared with non-AP musicians. Within the AP group, this specific
electrophysiological marker was predictive of absolute-hearing behavior and explained ⬃30% of variance. Thus, we propose that in AP subjects the tonal inputs and the
corresponding mnemonic representations are tightly coupled in such a manner that the distinctive electrophysiological signature of AP can saliently be detected in only 3
min of resting-state measurements.
The Journal of Neuroscience, January 7, 2015 • 35(1):366 –371
Articles
CELLULAR/MOLECULAR
Brg1-Dependent Chromatin Remodelling Is Not Essentially Required during Oligodendroglial
Differentiation
Melanie Bischof,1 Matthias Weider,1 Melanie Ku¨spert,1 Klaus-Armin Nave,2 and Michael Wegner1
Institut fu¨r Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universita¨t Erlangen-Nu¨rnberg, D-91054 Erlangen, Germany, and 2Department of
Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany
1
Myelinating Schwann cells in the vertebrate peripheral nervous system rely on Brg1 (Smarca4) for terminal differentiation. Brg1 serves as central ATP-hydrolyzing subunit
of the chromatin remodelling BAF complexes and is recruited during myelination as part of these complexes by the transcription factor Sox10 in Schwann cells. Here, we
analyzed the role of Brg1 during development of myelinating oligodendrocytes in the CNS of the mouse. Following Brg1 deletion in oligodendrocyte precursors, these cells
showed normal survival, proliferation, and migration. A mild but significant reduction in the number of oligodendrocytes with myelin gene expression in the absence of
Brg1 points to a contribution to oligodendroglial differentiation but also shows that the role of Brg1 is much less prominent than during Schwann cell differentiation.
Additionally, we failed to obtain evidence for a genetic interaction between Brg1 and Sox10 comparable with the one in Schwann cells. This argues that similarities exist
between the regulatory networks and mechanisms in both types of myelinating glia but that the exact mode of action and the relevance of functional interactions differ,
pointing to a surprising degree of variability in the control of myelination.
The Journal of Neuroscience, January 7, 2015 • 35(1):21–35
Sleep Slow Wave-Related Homo and Heterosynaptic LTD of Intrathalamic GABAAergic
Synapses: Involvement of T-Type Ca2⫹ Channels and Metabotropic Glutamate Receptors
Romain Pigeat,1,2,3 Patrick Chausson,1,2,3 Fanny M. Dreyfus,1,2,3 Nathalie Leresche,1,2,3* and Re´gis C. Lambert1,2,3*
1Sorbonne Universite
´s, UPMC University Paris 06, UM 119, Neuroscience Paris Seine (NPS), Paris F-75005, France, 2CNRS, UMR 8246, NPS, Paris F-75005,
France, and 3INSERM, U1130, NPS, Paris F-75005, France
Slow waves of non-REM sleep are suggested to play a role in shaping synaptic connectivity to consolidate recently acquired memories and/or restore synaptic homeostasis.
During sleep slow waves, both GABAergic neurons of the nucleus reticularis thalami (NRT) and thalamocortical (TC) neurons discharge high-frequency bursts of action
potentials mediated by low-threshold calcium spikes due to T-type Ca 2⫹ channel activation. Although such activity of the intrathalamic network characterized by
high-frequency firing and calcium influx is highly suited to modify synaptic efficacy, very little is still known about its consequences on intrathalamic synapse strength.
Combining in vitro electrophysiological recordings and calcium imaging, here we show that the inhibitory GABAergic synapses between NRT and TC neurons of the rat
somatosensory nucleus develop a long-term depression (I-LTD) when challenged by a stimulation paradigm that mimics the thalamic network activity occurring during
sleep slow waves. The mechanism underlying this plasticity presents unique features as it is both heterosynaptic and homosynaptic in nature and requires Ca 2⫹ entry
selectively through T-type Ca 2⫹ channels and activation of the Ca 2⫹-activated phosphatase, calcineurin. We propose that during slow-wave sleep the tight functional
coupling between GABAA receptors, calcineurin, and T-type Ca 2⫹ channels will elicit LTD of the activated GABAergic synapses when coupled with concomitant activation
of metabotropic glutamate receptors postsynaptic to cortical afferences. This I-LTD may be a key element involved in the reshaping of the somatosensory information
pathway during sleep.
The Journal of Neuroscience, January 7, 2015 • 35(1):64 –73
Diversity of Glutamatergic Synaptic Strength in Lateral Prefrontal versus Primary Visual
Cortices in the Rhesus Monkey
Maria Medalla and Jennifer I. Luebke
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118
Understanding commonalities and differences in glutamatergic synaptic signaling is essential for understanding cortical functional diversity, especially in the highly
complex primate brain. Previously, we have shown that spontaneous EPSCs differed markedly in layer 3 pyramidal neurons of two specialized cortical areas in the rhesus
monkey, the high-order lateral prefrontal cortex (LPFC) and the primary visual cortex (V1). Here, we used patch-clamp recordings and confocal and electron microscopy
to determine whether these distinct synaptic responses are due to differences in firing rates of presynaptic neurons and/or in the features of presynaptic or postsynaptic
entities. As with spontaneous EPSCs, TTX-insensitive (action potential-independent) miniature EPSCs exhibited significantly higher frequency, greater amplitude, and
slower kinetics in LPFC compared with V1 neurons. Consistent with these physiological differences, LPFC neurons possessed higher densities of spines, and the mean width
of large spines was greater compared with those on V1 neurons. Axospinous synapses in layers 2–3 of LPFC had larger postsynaptic density surface areas and a higher
proportion of large perforated synapses compared with V1. Axonal boutons in LPFC were also larger in volume and contained ⬃1.6⫻ more vesicles than did those in V1.
Further, LPFC had a higher density of AMPA GluR2 receptor labeling than V1. The properties of spines and synaptic currents of individual layer 3 pyramidal neurons
measured here were significantly correlated, consistent with the idea that significantly more frequent and larger synaptic currents are likely due to more numerous, larger,
and more powerful synapses in LPFC compared with V1.
The Journal of Neuroscience, January 7, 2015 • 35(1):112–127
Itk Signals Promote Neuroinflammation by Regulating CD4⫹ T-Cell Activation and Trafficking
Arun K. Kannan,* Do-Geun Kim,* Avery August, and Margaret S. Bynoe
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
Here we demonstrate that interleukin-2-inducible T-cell kinase (Itk) signaling in cluster of differentiation 4-positive (CD4 ⫹) T cells promotes experimental autoimmune
encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). We show that Itk⫺/⫺ mice exhibit reduced disease severity, and transfer of Itk⫺/⫺ CD4 ⫹ T cells into
T cell-deficient recipients results in lower disease severity. We observed a significant reduction of CD4 ⫹ T cells in the CNS of Itk⫺/⫺ mice or recipients of Itk⫺/⫺ CD4 ⫹ T cells
during EAE, which is consistent with attenuated disease. Itk⫺/⫺ CD4 ⫹ T cells exhibit defective response to myelin antigen stimulation attributable to displacement of
filamentous actin from the CD4 ⫹ coreceptor. This results in inadequate transmigration of Itk⫺/⫺ CD4 ⫹ T cells into the CNS and across brain endothelial barriers in vitro.
Finally, Itk⫺/⫺ CD4 ⫹ T cells show significant reduction in production of T-helper 1 (Th1) and Th17 cytokines and exhibit skewed T effector/T regulatory cell ratios. These
results indicate that signaling by Itk promotes autoimmunity and CNS inflammation, suggesting that it may be a viable target for treatment of MS.
The Journal of Neuroscience, January 7, 2015 • 35(1):221–233
Gene Dosage in the Dysbindin Schizophrenia Susceptibility Network Differentially Affect
Synaptic Function and Plasticity
Ariana P. Mullin,1 Madhumala K. Sadanandappa,2 Wenpei Ma,3 Dion K. Dickman,3 Krishnaswamy VijayRaghavan,2
Mani Ramaswami,4 Subhabrata Sanyal,5 and Victor Faundez1,6
Department of Cell Biology, Emory University, Atlanta, Georgia 30322, 2National Centre for Biological Sciences, Bangalore 560065, India, 3Department of
Biology, Neurobiology Section, University of Southern California, Los Angeles, California 90089, 4School of Genetics and Microbiology, School of Natural
Sciences, Smurfit Institute of Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin-2, Ireland, 5Biogen-Idec, Cambridge,
Massachusetts 02142, and 6Center for Social Translational Neuroscience, Emory University, Atlanta, Georgia 30322
1
Neurodevelopmental disorders arise from single or multiple gene defects. However, the way multiple loci interact to modify phenotypic outcomes remains poorly
understood. Here, we studied phenotypes associated with mutations in the schizophrenia susceptibility gene dysbindin (dysb), in isolation or in combination with null
alleles in the dysb network component Blos1. In humans, the Blos1 ortholog Bloc1s1 encodes a polypeptide that assembles, with dysbindin, into the octameric BLOC-1
complex. We biochemically confirmed BLOC-1 presence in Drosophila neurons, and measured synaptic output and complex adaptive behavior in response to BLOC-1
perturbation. Homozygous loss-of-function alleles of dysb, Blos1, or compound heterozygotes of these alleles impaired neurotransmitter release, synapse morphology, and
homeostatic plasticity at the larval neuromuscular junction, and impaired olfactory habituation. This multiparameter assessment indicated that phenotypes were differentially sensitive to genetic dosages of loss-of-function BLOC-1 alleles. Our findings suggest that modification of a second genetic locus in a defined neurodevelopmental
regulatory network does not follow a strict additive genetic inheritance, but rather, precise stoichiometry within the network determines phenotypic outcomes.
The Journal of Neuroscience, January 7, 2015 • 35(1):325–338
Chromatin Landscape Defined by Repressive Histone Methylation during Oligodendrocyte
Differentiation
Jia Liu,1 Laura Magri,1 Fan Zhang,2 Nidaa O. Marsh,1 Stefanie Albrecht,3 Jimmy L. Huynh,1,4 Jasbir Kaur,1
Tanja Kuhlmann,3 Weijia Zhang,2 Paul A. Slesinger,1 and Patrizia Casaccia1,4
Department of Neuroscience, 2Bioinformatics Laboratory, Department of Medicine, and 4Department of Genetics and Genomic Sciences, Icahn School of
Medicine at Mount Sinai, New York, New York 10029, and 3Institute of Neuropathology, University Hospital Mu¨nster, D-48149 Mu¨nster, Germany
1
In many cell types, differentiation requires an interplay between extrinsic signals and transcriptional changes mediated by repressive and activating histone modifications.
Oligodendrocyte progenitors (OPCs) are electrically responsive cells receiving synaptic input. The differentiation of these cells into myelinating oligodendrocytes is
characterized by temporal waves of gene repression followed by activation of myelin genes and progressive decline of electrical responsiveness. In this study, we used
chromatin isolated from rat OPCs and immature oligodendrocytes, to characterize the genome-wide distribution of the repressive histone marks, H3K9me3 and
H3K27me3, during differentiation. Although both marks were present at the OPC stage, only H3K9me3 marks (but not H3K27me3) were found to be increased during
differentiation, at genes related to neuronal lineage and regulation of membrane excitability. Consistent with these findings, the levels and activity of H3K9 methyltransferases (H3K9 HMT), but not H3K27 HMT, increased more prominently upon exposure to oligodendrocyte differentiating stimuli and were detected in stage-specific
repressive protein complexes containing the transcription factors SOX10 or YY1. Silencing H3K9 HMT, but not H3K27 HMT, impaired oligodendrocyte differentiation and
functionally altered the response of oligodendrocytes to electrical stimulation. Together, these results identify repressive H3K9 methylation as critical for gene repression
during oligodendrocyte differentiation.
The Journal of Neuroscience, January 7, 2015 • 35(1):352–365
Combinatorial Mutagenesis of the Voltage-Sensing Domain Enables the Optical Resolution of
Action Potentials Firing at 60 Hz by a Genetically Encoded Fluorescent Sensor of Membrane
Potential
Hong Hua Piao, Dhanarajan Rajakumar, Bok Eum Kang, Eun Ha Kim, and Bradley J. Baker
Center for Functional Connectomics, Korea Institute of Science and Technology, Seongbuk-gu, Seoul, 136-791, Republic of Korea
ArcLight is a genetically encoded fluorescent voltage sensor using the voltage-sensing domain of the voltage-sensing phosphatase from Ciona intestinalis that gives a large
but slow-responding optical signal in response to changes in membrane potential (Jin et al., 2012). Fluorescent voltage sensors using the voltage-sensing domain from other
species give faster yet weaker optical signals (Baker et al., 2012; Han et al., 2013). Sequence alignment of voltage-sensing phosphatases from different species revealed
conserved polar and charged residues at 7 aa intervals in the S1–S3 transmembrane segments of the voltage-sensing domain, suggesting potential coil– coil interactions.
The contribution of these residues to the voltage-induced optical signal was tested using a cassette mutagenesis screen by flanking each transmembrane segment with
unique restriction sites to allow for the testing of individual mutations in each transmembrane segment, as well as combinations in all four transmembrane segments.
Addition of a counter charge in S2 improved the kinetics of the optical response. A double mutation in the S4 domain dramatically reduced the slow component of the optical
signal seen in ArcLight. Combining that double S4 mutant with the mutation in the S2 domain yielded a probe with kinetics ⬍10 ms. Optimization of the linker sequence
between S4 and the fluorescent protein resulted in a new ArcLight-derived probe, Bongwoori, capable of resolving action potentials in a hippocampal neuron firing at 60 Hz.
Additional manipulation of the voltage-sensing domain could potentially lead to fluorescent sensors capable of optically resolving neuronal inhibition and subthreshold
synaptic activity.
The Journal of Neuroscience, January 7, 2015 • 35(1):372–385
cJun and CREB2 in the Postsynaptic Neuron Contribute to Persistent Long-Term Facilitation at
a Behaviorally Relevant Synapse
Jiang-Yuan Hu,1 Amir Levine,1 Ying-Ju Sung,2 and Samuel Schacher1
Department of Neuroscience, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, New York 10032
and 2The Commonwealth Medical College, Department of Basic Sciences, Scranton, Pennsylvania 18509
1
Basic region leucine zipper (bZIP) transcription factors regulate gene expression critical for long-term synaptic plasticity or neuronal excitability contributing to learning
and memory. At sensorimotor synapses of Aplysia, changes in activation or expression of CREB1 and CREB2 in sensory neurons are required for long-term synaptic
plasticity. However, it is unknown whether concomitant stimulus-induced changes in expression and activation of bZIP transcription factors in the postsynaptic motor
neuron also contribute to persistent long-term facilitation (P-LTF). We overexpressed various forms of CREB1, CREB2, or cJun in the postsynaptic motor neuron L7 in cell
culture to examine whether these factors contribute to P-LTF. P-LTF is evoked by 2 consecutive days of 5-HT applications (2 5-HT), while a transient form of LTF is produced
by 1 day of 5-HT applications (1 5-HT). Significant increases in the expression of both cJun and CREB2 mRNA in L7 accompany P-LTF. Overexpressing each bZIP factor in
L7 did not alter basal synapse strength, while coexpressing cJun and CREB2 in L7 evoked persistent increases in basal synapse strength. In contrast, overexpressing cJun and
CREB2 in sensory neurons evoked persistent decreases in basal synapse strength. Overexpressing wild-type cJun or CREB2, but not CREB1, in L7 can replace the second day
of 5-HT applications in producing P-LTF. Reducing cJun activity in L7 blocked P-LTF evoked by 2 5-HT. These results suggest that expression and activation of different
bZIP factors in both presynaptic and postsynaptic neurons contribute to persistent change in synapse strength including stimulus-dependent long-term synaptic plasticity.
The Journal of Neuroscience, January 7, 2015 • 35(1):386 –395
DEVELOPMENT/PLASTICITY/REPAIR
Mapping the Stability of Human Brain Asymmetry across Five Sex-Chromosome Aneuploidies
Amy Lin,1 Liv Clasen,1 Nancy Raitano Lee,1 Gregory L. Wallace,1,2 Francois Lalonde,1 Jonathan Blumenthal,1
Jay N. Giedd,1 and Armin Raznahan1
1
2
Section on Brain Imaging, Child Psychiatry Branch, National Institute of Mental Health–National Institutes of Health, Bethesda, Maryland 20892 and
Department of Speech and Hearing Sciences, George Washington University, Washington, DC 20052
The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and
environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness
(CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five sex-chromosome aneuploidies [SCAs; XXX (n ⫽ 28), XXY (n ⫽ 58), XYY (n ⫽ 26), XXYY (n ⫽ 20), and XXXXY (n ⫽ 5)], and 169 age-matched typically developing controls (80 female). In controls,
we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly
preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT
asymmetry in controls. Specifically, X-chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-chromosome aneuploidy reversed
normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT
asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y chromosomes can exert focal, nonoverlapping and
directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental
mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of sex
chromosome dosage effects on CT asymmetry.
The Journal of Neuroscience, January 7, 2015 • 35(1):140 –145
Fgf-Signaling-Dependent Sox9a and Atoh1a Regulate Otic Neural Development in Zebrafish
Jialiang Wang,* Ying Wu,* Feng Zhao,* Yuting Wu, Wei Dong, Jue Zhao, Zuoyan Zhu, and Dong Liu
The Education Ministry Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Bio-membrane and Membrane Bioengineering, School of Life Sciences, Peking University, Beijing 100871, China
Fibroblast growth factors (Fgfs) play important roles in developmental processes of the inner ear, including the ontogeny of the statoacoustic ganglia (SAG) and hair cells.
However, the detailed genetic mechanism(s) underlying Fgf/Fgfr-dependent otic neural development remains elusive. Using conditional genetic approaches and inhibitory
small molecules, we have revealed that Fgfr-PI3K/Akt signaling is mainly responsible for zebrafish SAG development and have determined that Sox9a and Atoh1a act
downstream of Fgfr-Akt signaling to specify and/or maintain the otic neuron fate during the early segmentation stage. Sox9a and Atoh1a coregulate numerous downstream
factors identified through our ChIP-seq analyses, including Tlx2 and Eya2. Fgfr-Erk1/2 signaling contributes to ultricular hair cell development during a critical period
between 9 and 15 hours postfertilization. Our work reveals that a genetic network of the previously known sensory determinant Atoh1 and the neural crest determinant Sox9
plays critical roles in SAG development. These newly uncovered roles for Atoh1and Sox9 in zebrafish otic development may be relevant to study in other species.
The Journal of Neuroscience, January 7, 2015 • 35(1):234 –244
Expanded Terminal Fields of Gustatory Nerves Accompany Embryonic BDNF Overexpression in
Mouse Oral Epithelia
Chengsan Sun,1 Arjun Dayal,2 and David L. Hill1
Department of Psychology, University of Virginia, Charlottesville, Virginia 22904, and 2Pritzker School of Medicine, University of Chicago, Chicago, Illinois
60637
1
Brain-derived neurotrophic factor (BDNF) is expressed in gustatory epithelia and is required for gustatory neurons to locate and innervate their correct target during
development. When BDNF is overexpressed throughout the lingual epithelium, beginning embryonically, chorda tympani fibers are misdirected and innervate inappropriate targets, leading to a loss of taste buds. The remaining taste buds are hyperinnervated, demonstrating a disruption of nerve/target matching in the tongue. We tested
the hypothesis here that overexpression of BDNF peripherally leads to a disrupted terminal field organization of nerves that carry taste information to the brainstem. The
chorda tympani, greater superficial petrosal, and glossopharyngeal nerves were labeled in adult wild-type (WT) mice and in adult mice in which BDNF was overexpressed
(OE) to examine the volume and density of their central projections in the nucleus of the solitary tract. We found that the terminal fields of the chorda tympani and greater
superficial petrosal nerves and overlapping fields that included these nerves in OE mice were at least 80% greater than the respective field volumes in WT mice. The shapes
of terminal fields were similar between the two groups; however, the density and spread of labels were greater in OE mice. Unexpectedly, there were also group-related
differences in chorda tympani nerve function, with OE mice showing a greater relative taste response to a concentration series of sucrose. Overall, our results show that
disruption in peripheral innervation patterns of sensory neurons have significant effects on peripheral nerve function and central organization of their terminal fields.
The Journal of Neuroscience, January 7, 2015 • 35(1):409 – 421
SYSTEMS/CIRCUITS
Imaging the Awake Visual Cortex with a Genetically Encoded Voltage Indicator
Matteo Carandini,1 Daisuke Shimaoka,1,2 L. Federico Rossi,1 Tatsuo K. Sato,1 Andrea Benucci,1,2*
and Thomas Kno¨pfel2,3*
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom, 2RIKEN Brain Science Institute, Wako City 351-0198,
Japan, and 3Division of Brain Sciences, Imperial College London, London SW7 2AZ, United Kingdom
1
Genetically encoded voltage indicators (GEVIs) promise to reveal the membrane potential of genetically targeted neuronal populations through noninvasive, chronic
imaging of large portions of cortical space. Here we test a promising GEVI in mouse cortex during wakefulness, a challenging condition due to large hemodynamic activity,
and we introduce a straightforward projection method to separate a signal dominated by membrane voltage from a signal dominated by hemodynamic activity. We
expressed VSFP-Butterfly 1.2 plasmid in layer 2/3 pyramidal cells of visual cortex through electroporation in utero. We then used wide-field imaging with two cameras to
measure both fluorophores of the indicator in response to visual stimuli. By taking weighted sums and differences of the two measurements, we obtained clear separation
of hemodynamic and voltage signals. The hemodynamic signal showed strong heartbeat oscillations, superimposed on slow dynamics similar to blood oxygen leveldependent (BOLD) or “intrinsic” signals. The voltage signal had fast dynamics similar to neural responses measured electrically, and showed an orderly retinotopic
mapping. We compared this voltage signal with calcium signals imaged in transgenic mice that express a calcium indicator (GCaMP3) throughout cortex. The voltage signal
from VSFP had similar signal-to-noise ratios as the calcium signal, it was more immune to vascular artifacts, and it integrated over larger regions of visual space, which was
consistent with its reporting mostly subthreshold activity rather than the spiking activity revealed by calcium signals. These results demonstrate that GEVIs provide a
powerful tool to study the dynamics of neural populations at mesoscopic spatial scales in the awake cortex.
The Journal of Neuroscience, January 7, 2015 • 35(1):53– 63
Temporal Plasticity Involved in Recovery from Manual Dexterity Deficit after Motor Cortex
Lesion in Macaque Monkeys
Yumi Murata,1,2 Noriyuki Higo,1,3,4 Takuya Hayashi,5 Yukio Nishimura,4,6 Yoko Sugiyama,1,7 Takao Oishi,1,3,8
Hideo Tsukada,3,9 Tadashi Isa,3,6 and Hirotaka Onoe3,5
Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 3058568, Japan,
Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, 1020083, Japan, 3Core Research for Evolutional Science and
Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, 3320012, Japan, 4Precursory Research for Embryonic Science and Technology,
Japan Science and Technology Agency, Kawaguchi, Saitama, 3320012, Japan, 5Division of Bio-Function Dynamics Imaging, Center for Life Science
Technologies, RIKEN, Kobe, Hyogo, 6500047, Japan, 6Department of Developmental Physiology, National Institute for Physiological Sciences, National
Institutes of Natural Sciences, Okazaki, Aichi, 4448585, Japan, 7Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba,
Ibaraki, 3058577, Japan, 8Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University, Inuyama, Aichi, 4848506, Japan, and
9Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, 4348601, Japan
1
2
The question of how intensive motor training restores motor function after brain damage or stroke remains unresolved. Here we show that the ipsilesional ventral premotor cortex
(PMv) and perilesional primary motor cortex (M1) of rhesus macaque monkeys are involved in the recovery of manual dexterity after a lesion of M1. A focal lesion of the hand digit
area in M1 was made by means of ibotenic acid injection. This lesion initially caused flaccid paralysis in the contralateral hand but was followed by functional recovery of hand
movements, including precision grip, during the course of daily postlesion motor training. Brain imaging of regional cerebral blood flow by means of H2 15O-positron emission
tomography revealed enhanced activity of the PMv during the early postrecovery period and increased functional connectivity within M1 during the late postrecovery period. The
causalroleoftheseareasinmotorrecoverywasconfirmedbymeansofpharmacologicalinactivationbymuscimolduringthedifferentrecoveryperiods.Thesefindingsindicatethat,
in both the remaining primary motor and premotor cortical areas, time-dependent plastic changes in neural activity and connectivity are involved in functional recovery from the
motor deficit caused by the M1 lesion. Therefore, it is likely that the PMv, an area distant from the core of the lesion, plays an important role during the early postrecovery period,
whereas the perilesional M1 contributes to functional recovery especially during the late postrecovery period.
The Journal of Neuroscience, January 7, 2015 • 35(1):84 –95
Circuit Formation and Function in the Olfactory Bulb of Mice with Reduced Spontaneous
Afferent Activity
Paolo Lorenzon,1* Nelly Redolfi,1* Michael J. Podolsky,2 Ilaria Zamparo,1 Sira Angela Franchi,1 Gianluca Pietra,3
Anna Boccaccio,4 Anna Menini,3 Venkatesh N. Murthy,5 and Claudia Lodovichi 1,6
1Venetian Institute of Molecular Medicine (VIMM), 35129 Padua, Italy, 2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
02114, 3Neurobiology Group, SISSA, International School for Advanced Studies, 34136 Trieste, Italy, 4Biophysics Institute, CNR, 16149 Genova, Italy,
5Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, and 6Neuroscience
Institute, CNR, 35129 Padua, Italy
The type of neuronal activity required for circuit development is a matter of significant debate. We addressed this issue by analyzing the topographic organization of the
olfactory bulb in transgenic mice engineered to have very little afferent spontaneous activity due to the overexpression of the inwardly rectifying potassium channel Kir2.1
in the olfactory sensory neurons (Kir2.1 mice). In these conditions, the topography of the olfactory bulb was unrefined. Odor-evoked responses were readily recorded in
glomeruli with reduced spontaneous afferent activity, although the functional maps were coarser than in controls and contributed to altered olfactory discrimination
behavior. In addition, overexpression of Kir2.1 in adults induced a regression of the already refined connectivity to an immature (i.e., coarser) status. Our data suggest that
spontaneous activity plays a critical role not only in the development but also in the maintenance of the topography of the olfactory bulb and in sensory information
processing.
The Journal of Neuroscience, January 7, 2015 • 35(1):146 –160
Cortical State Determines Global Variability and Correlations in Visual Cortex
Marieke L. Schölvinck,1 Aman B. Saleem,1 Andrea Benucci,1 Kenneth D. Harris,1,2 and Matteo Carandini1
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom, and 2UCL Institute of Neurology and UCL Department
of Neuroscience, Physiology & Pharmacology, London WC1E 6DE, United Kingdom
1
Theresponseofneuronsinsensorycortextorepeatedstimuluspresentationsishighlyvariable.Toinvestigatethenatureofthisvariability,wecomparedthespikeactivityofneurons
in the primary visual cortex (V1) of cats with that of their afferents from lateral geniculate nucleus (LGN), in response to similar stimuli. We found variability to be much higher in
V1 than in LGN. To investigate the sources of the additional variability, we measured the spiking activity of large V1 populations and found that much of the variability was shared
across neurons: the variable portion of the responses of one neuron could be well predicted from the summed activity of the rest of the neurons. Variability thus mostly reflected
global fluctuations affecting all neurons. The size and prevalence of these fluctuations, both in responses to stimuli and in ongoing activity, depended on cortical state, being larger
in synchronized states than in more desynchronized states. Contrary to previous reports, these fluctuations invested the overall population, regardless of preferred orientation. The
global fluctuations substantially increased variability in single neurons and correlations among pairs of neurons. Once this effect was removed, pairwise correlations were reduced
and were similar regardless of cortical state. These results highlight the importance of cortical state in controlling cortical operation and can help reconcile previous studies, which
differed widely in their estimate of neuronal variability and pairwise correlations.
The Journal of Neuroscience, January 7, 2015 • 35(1):170 –178
Distinct Midbrain and Habenula Pathways Are Involved in Processing Aversive Events in
Humans
Kelly Hennigan,1 Kimberlee D’Ardenne,2 and Samuel M. McClure1
1
Department of Psychology, Stanford University, Stanford, California 94305, and 2Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016
Emerging evidence implicates the midbrain dopamine system and its interactions with the lateral habenula in processing aversive information and learning to avoid
negative outcomes. We examined neural responses to unexpected, aversive events using methods specialized for imaging the midbrain and habenula in humans. Robust
activation to aversive relative to neutral events was observed in the habenula and two regions within the ventral midbrain: one located within the ventral tegmental area
(VTA) and the other in the substantia nigra (SN). Aversive processing increased functional connectivity between the VTA and the habenula, putamen, and medial prefrontal
cortex, whereas the SN exhibited a different pattern of functional connectivity. Our findings provide evidence for a network comprising the VTA and SN, the habenula, and
mesocorticolimbic structures that supports processing aversive events in humans.
The Journal of Neuroscience, January 7, 2015 • 35(1):198 –208
Motor Origin of Precise Synaptic Inputs onto Forebrain Neurons Driving a Skilled Behavior
Daniela Vallentin1,2 and Michael A. Long1,2
NYU Neuroscience 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
1
Sensory feedback is crucial for learning and performing many behaviors, but its role in the execution of complex motor sequences is poorly understood. To address this, we
consider the forebrain nucleus HVC in the songbird, which contains the premotor circuitry for song production and receives multiple convergent sensory inputs. During
singing, projection neurons within HVC exhibit precisely timed synaptic events that may represent the ongoing motor program or song-related sensory feedback. To
distinguish between these possibilities, we recorded the membrane potential from identified HVC projection neurons in singing zebra finches. External auditory perturbations during song production did not affect synaptic inputs in these neurons. Furthermore, the systematic removal of three sensory feedback streams (auditory,
proprioceptive, and vagal) did not alter the frequency or temporal precision of synaptic activity observed. These findings support a motor origin for song-related synaptic
events and suggest an updated circuit model for generating behavioral sequences.
The Journal of Neuroscience, January 7, 2015 • 35(1):299 –307
BEHAVIORAL/COGNITIVE
Pharmacogenetic Excitation of Dorsomedial Prefrontal Cortex Restores Fear Prediction Error
Joanna Oi-Yue Yau and Gavan P. McNally
School of Psychology, The University of New South Wales, Sydney 2052, New South Wales, Australia
Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and
learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex
(dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and
isolated actions of prediction error by using an associative blocking design. Rats were trained to fear the visual CS (CSA) in stage I via pairings with footshock. Then in stage
II, rats received compound presentations of visual CSA and auditory CS (CSB) with footshock. This prior fear conditioning of CSA reduced the prediction error during stage
II to block fear learning to CSB. The group of rats that received AAV– hSYN– eYFP vector that was treated with clozapine-N-oxide (CNO; 3 mg/kg, i.p.) before stage II showed
blocking when tested in the absence of CNO the next day. In contrast, the groups that received AAV– hSYN– hM3Dq and AAV–CaMKII␣– hM3Dq that were treated with
CNO before stage II training did not show blocking; learning toward CSB was restored. This restoration of prediction error and fear learning was specific to the injection of
CNO because groups that received AAV– hSYN– hM3Dq and AAV–CaMKII␣– hM3Dq that were injected with vehicle before stage II training did show blocking. These
effects were not attributable to the DREADD manipulation enhancing learning or arousal, increasing fear memory strength or asymptotic levels of fear learning, or altering
fear memory retrieval. Together, these results identify a causal role for dmPFC in a signature of adaptive behavior: using the past to predict future danger and learning from
errors in these predictions.
The Journal of Neuroscience, January 7, 2015 • 35(1):74 – 83
Persistent CaMKII Activation Mediates Learning-Induced Long-Lasting Enhancement of
Synaptic Inhibition
Sourav Ghosh, Iris Reuveni, Raphael Lamprecht, and Edi Barkai
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel
Training rats in a particularly difficult olfactory-discrimination task results in acquisition of high skill to perform the task superbly, termed “rule learning” or “learning
set.” Such complex learning results in enhanced intrinsic neuronal excitability of piriform cortex pyramidal neurons, and in their excitatory synaptic interconnections.
These changes, while subserving memory maintenance, must be counterbalanced by modifications that prevent overspreading of activity and uncontrolled synaptic
strengthening. Indeed, we have previously shown that the average amplitude of GABAA-mediated miniature IPSCs (mIPSCs) in these neurons is enhanced for several days
after learning, an enhancement mediated via a postsynaptic mechanism. To unravel the molecular mechanism of this long-term inhibition enhancement, we tested the role
of key second-messenger systems in maintaining such long-lasting modulation. The calcium/calmodulin-dependent kinase II (CaMKII) blocker, KN93, significantly
reduced the average mIPSC amplitude in neurons from trained rats only to the average pretraining level. A similar effect was obtained by the CaMKII peptide inhibitor,
tatCN21. Such reduction resulted from decreased single-channel conductance and not in the number of activated channels. The PKC inhibitor, GF109203X, reduced the
average mIPSC amplitude in neurons from naive, pseudo-trained, and trained animals, and the difference between the trained and control groups remained. Such reduction
resulted from a decrease in the number of activated channels. The PKA inhibitor H89 dihydrochloride did not affect the average mIPSC amplitude in neurons from any of
the three groups. We conclude that learning-induced enhancement of GABAA-mediated synaptic inhibition is maintained by persistent CaMKII activation.
The Journal of Neuroscience, January 7, 2015 • 35(1):128 –139
Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and
Subcortical Limbic Mechanisms in Rats
E.J. Marijke Achterberg,1* Linda W.M. van Kerkhof,2* Ruth Damsteegt,2 Viviana Trezza,3
and Louk J.M.J. Vanderschuren1,2
Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CM
Utrecht, The Netherlands, 2Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht,
The Netherlands, and 3Department of Science, Section of Biomedical Sciences and Technologies, University “Roma Tre,” 00146 Rome, Italy
1
Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development.
However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely
used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to
identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic
corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated
in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social
exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor
atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social
play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings
increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used
treatments for ADHD.
The Journal of Neuroscience, January 7, 2015 • 35(1):161–169
Learning Modifies Odor Mixture Processing to Improve Detection of Relevant Components
Jen-Yung Chen,1* Emiliano Marachlian,2,3* Collins Assisi,1 Ramon Huerta,4 Brian H. Smith,5 Fernando Locatelli,2†
and Maxim Bazhenov1†
Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, 2Laboratorio de Neurobiología de la Memoria,
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFIByNE-CONICET,
Buenos Aires 1428, Argentina, 3Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428,
Argentina, 4Biocircuits Institute, University of California, San Diego, La Jolla 92093, and 5School of Life Sciences, Arizona State University, Tempe, Arizona
85287
1
Honey bees have a rich repertoire of olfactory learning behaviors, and they therefore are an excellent model to study plasticity in olfactory circuits. Recent behavioral,
physiological, and molecular evidence suggested that the antennal lobe, the first relay of the olfactory system in insects and analog to the olfactory bulb in vertebrates, is
involved in associative and nonassociative olfactory learning. Here we use calcium imaging to reveal how responses across antennal lobe projection neurons change after
association of an input odor with appetitive reinforcement. After appetitive conditioning to 1-hexanol, the representation of an odor mixture containing 1-hexanol becomes
more similar to this odor and less similar to the background odor acetophenone. We then apply computational modeling to investigate how changes in synaptic connectivity
can account for the observed plasticity. Our study suggests that experience-dependent modulation of inhibitory interactions in the antennal lobe aids perception of salient
odor components mixed with behaviorally irrelevant background odors.
The Journal of Neuroscience, January 7, 2015 • 35(1):179 –197
The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex
Heather J. Gilbert, Trevor M. Shackleton, Katrin Krumbholz, and Alan R. Palmer
MRC Institute of Hearing Research, University Park, Nottingham, NG7 2RD, United Kingdom
The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can
be made 12–15 dB more detectable by inverting the waveform of either the tone or noise at one ear (S␲, N␲). Single-cell responses to BMLD stimuli were measured in the
primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise.
Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either
increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all
stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As
in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons’ selectivity for interaural time difference. Our results suggest
that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and
that the psychophysical detection threshold is based on the lowest neural thresholds across the population.
The Journal of Neuroscience, January 7, 2015 • 35(1):209 –220
Saccade Planning Evokes Topographically Specific Activity in the Dorsal and Ventral Streams
Golbarg T. Saber,1* Franco Pestilli,3* and Clayton E. Curtis1,2
Center for Neural Science, and 2Department of Psychology, New York University, New York, New York 10003, and 3Department of Psychological and Brain
Sciences, Indiana University, Bloomington, Indiana 47405
1
Saccade planning may invoke spatially-specific feedback signals that bias early visual activity in favor of top-down goals. We tested this hypothesis by measuring cortical
activity at the early stages of the dorsal and ventral visual processing streams. Human subjects maintained saccade plans to (prosaccade) or away (antisaccade) from a
spatial location over long memory-delays. Results show that cortical activity persists in early visual cortex at the retinotopic location of upcoming saccade goals. Topographically specific activity persists as early as V1, and activity increases along both dorsal (V3A/B, IPS0) and ventral (hV4, VO1) visual areas. Importantly, activity persists
when saccade goals are available only via working memory and when visual targets and saccade goals are spatially disassociated. We conclude that top-down signals elicit
retinotopically specific activity in visual cortex both in the dorsal and ventral streams. Such activity may underlie mechanisms that prioritize locations of task-relevant
objects.
The Journal of Neuroscience, January 7, 2015 • 35(1):245–252
Spatial and Temporal Characteristics of Error-Related Activity in the Human Brain
Maital Neta,1 Francis M. Miezin,2,3,7 Steven M. Nelson,9 Joseph W. Dubis,2 Nico U.F. Dosenbach,2
Bradley L. Schlaggar,2,3,4,5 and Steven E. Petersen2,3,5,6,7,8
Department of Psychology, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, Departments of 2Neurology, 3Radiology, 4Pediatrics, 5Anatomy and
Neurobiology, and 6Neurosurgery, Washington University School of Medicine, Departments of 7Psychology and 8Biomedical Engineering, Washington
University, St Louis, Missouri 63110, and 9VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, Texas 76711
1
A number of studies have focused on the role of specific brain regions, such as the dorsal anterior cingulate cortex during trials on which participants make errors, whereas
others have implicated a host of more widely distributed regions in the human brain. Previous work has proposed that there are multiple cognitive control networks, raising
the question of whether error-related activity can be found in each of these networks. Thus, to examine error-related activity broadly, we conducted a meta-analysis
consisting of 12 tasks that included both error and correct trials. These tasks varied by stimulus input (visual, auditory), response output (button press, speech), stimulus
category (words, pictures), and task type (e.g., recognition memory, mental rotation). We identified 41 brain regions that showed a differential fMRI BOLD response to error
and correct trials across a majority of tasks. These regions displayed three unique response profiles: (1) fast, (2) prolonged, and (3) a delayed response to errors, as well as
a more canonical response to correct trials. These regions were found mostly in several control networks, each network predominantly displaying one response profile. The
one exception to this “one network, one response profile” observation is the frontoparietal network, which showed prolonged response profiles (all in the right hemisphere),
and fast profiles (all but one in the left hemisphere). We suggest that, in the place of a single localized error mechanism, these findings point to a large-scale set of
error-related regions across multiple systems that likely subserve different functions.
The Journal of Neuroscience, January 7, 2015 • 35(1):253–266
Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral
Inhibition
Xuanmao Chen,1 Hong Cao,1,2 Amit Saraf,1 Larry S. Zweifel,1 and Daniel R. Storm1
Department of Pharmacology, School of Medicine, University of Washington, Seattle, Washington 98195, 2Institute of Neurobiology, Institute of Brain
Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
1
The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation.
We examined the locomotor activity, and impulsive and social behaviors of AC1⫹ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that
AC1⫹ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive,
and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1⫹ mice can be corrected by valproate, a mood-stabilizing drug. These data
indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition.
The Journal of Neuroscience, January 7, 2015 • 35(1):339 –351
NEUROBIOLOGY OF DISEASE
Demyelination Causes Adult CNS Progenitors to Revert to an Immature State and Express
Immune Cues That Support Their Migration
Sarah Moyon,1,2,3 Anne Laure Dubessy,1,2,3 Marie Stephane Aigrot,1,2,3 Matthew Trotter,7 Jeffrey K. Huang,6
Luce Dauphinot,1,2,3 Marie Claude Potier,1,2,3 Christophe Kerninon,4 Stephane Melik Parsadaniantz,8
Robin J. M. Franklin,6 and Catherine Lubetzki1,2,3,5
Universite´ Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle E´pinie`re, 75013 Paris, France, 2Institut National de la
Sante´ et de la Recherche Me´dicale, U 1127, 75013 Paris, France, 3CNRS, Unite Mixte de Recherche 7225, 75013 Paris, France, 4Institut Hospitalo
Universitaire-A-Institut du Cerveau et de la Moelle E´pinie`re, 75013 Paris, France, 5Groupe Hospitalier Pitie´-Salpeˆtrie`re, 75013 Paris, France, 6Department of
Clinical Neuroscience, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB3 0ES, United
Kingdom, 7Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Forvie Site, Cambridge CB2 0SZ, United Kingdom, and 8Institut
de la Vision, UMRS 968, UMR 7210 CNRS, Universite´ Pierre et Marie Curie-Paris 6, 75012 Paris, France
1
The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here
we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive
picture of how they become activated after demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more
similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased
expression of two genes of the innate immune system, IL1␤ and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate
immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their
repopulation of areas of demyelination and hence their ability to contribute to remyelination.
The Journal of Neuroscience, January 7, 2015 • 35(1):4 –20
Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via Regulation
of NMDA Receptor 2B Subunit
Jun-Xia Yang,1,2* Lu Hua,1,2* Yan-Qiang Li,1,2* Yan-Yu Jiang,1,2 Dong Han,1,2 He Liu,1,2 Qian-Qian Tang,1,2
Xiao-Na Yang,1,2 Cui Yin,1,2 Ling-Yun Hao,1,2 Le Yu,1,2 Peng Wu,1,2 Cui-Jie Shao,1,2 Hai-Lei Ding,1,2 Yong-Mei Zhang,1,2
and Jun-Li Cao1,2,3
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221004, China, 2Jiangsu Province Key Laboratory of Anesthesia and
Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221004, China, and 3Department of Anesthesiology, The Affiliated Hospital of Xuzhou
Medical College, Xuzhou 221002, China
1
Chronic pain is still a basic science and clinical challenge. Unraveling of the neurobiological mechanisms involved in chronic pain will offer novel targets for the development of therapeutic strategies. It is well known that central sensitization in the anterior cingulate cortex (ACC) plays a critical role in initiation, development, and
maintenance of chronic pain. However, the underlying mechanisms still remain elusive. Here, we reported that caveolin-1 (Cav-1), a scaffolding protein in membrane rafts,
was persistently upregulated and activated in the ACC neurons after chronic constriction injury (CCI) in mice. Knockdown or blocking of Cav-1 in the contralateral ACC to
the injury side reversed CCI-induced pain behavioral and neuronal sensitization and overexpression of Cav-1 in the ipsilateral ACC-induced pain behavior in the unaffected
hindpaw. Furthermore, we found that Cav-1 directly binding with NMDA receptor 2B subunit (NR2B) and promotion of NR2B surface levels in the ACC contributed to
modulation of chronic neuropathic pain. Disrupting the interaction of Cav-1 and NR2B through microinjection of a short peptide derived from the C-terminal of NR2B into
the ACC exhibited a significant anti-nociception effect associated with decrease of surface NR2B expression. Moreover, Cav-1 increased intracellular Ca 2⫹ concentration
and activated the ERK/CREB signaling pathway in an NR2B-dependent manner in the ACC. Our findings implicate that Cav-1 in the ACC neurons modulates chronic
neuropathic pain via regulation of NR2B and subsequent activation of ERK/CREB signaling, suggesting a possible caveolin-mediated process would participate in neuronal
transmission pathways implicated in pain modulation.
The Journal of Neuroscience, January 7, 2015 • 35(1):36 –52
Gene Expression Analyses Identify Narp Contribution in the Development of L-DOPA-Induced
Dyskinesia
Fanny Charbonnier-Beaupel,1,2,3,4* Marion Malerbi,1,2,3,5,6* Cristina Alcacer,1,5,6* Khadija Tahiri,1,2,3 Wassila Carpentier,7
Chuansong Wang,8 Matthew During,8 Desheng Xu,9 Paul F. Worley,9 Jean-Antoine Girault,1,5,6 Denis Herve´,1,5,6* and
Jean-Christophe Corvol1,2,3,10*
Sorbonne Universite´s, UPMC Univ Paris 06, Paris, France, 2Inserm, UMR-S 1127, ICM, Pitie´-Salpeˆtrie`re Hospital, 75013 Paris, France, 3CNRS, UMR 7225,
75013 Paris, France, 4Assistance Publique Hoˆpitaux de Paris, Department of Pharmacy, Pitie´-Salpeˆtrie`re Hospital, 75013 Paris, France, 5Inserm UMR-S 839,
75005 Paris, France, 6Institut du Fer a` Moulin, 75005 Paris, France, 7UPMC Univ Paris 06, Post genomic platform P3S, 75013 Paris, France, 8Departments of
Molecular Virology, Immunology and Medical Genetics, Neuroscience and Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, 9Johns
Hopkins University School of Medicine, Solomon H. Snyder Department of Neuroscience, Baltimore, Maryland 21205, and 10Assistance Publique Hoˆpitaux
de Paris, Inserm, Clinical Investigation Center, CIC-1422, Pitie´-Salpeˆtrie`re Hospital, 75013 Paris, France
1
In Parkinson’s disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results
from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome
analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 – 6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which
genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by L-DOPA. L-DOPA-dependent deregulation of 28
genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic
animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal
activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by
SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared
with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature
induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes,
Nptx2, in the development of LID.
The Journal of Neuroscience, January 7, 2015 • 35(1):96 –111
Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity
Associated with Longitudinal Change
Alan Anticevic,1,2,3,4,5,6* Xinyu Hu,1* Yuan Xiao,1 Junmei Hu,3 Fei Li,1 Feng Bi,3 Michael W. Cole,7 Aleksandar Savic,8
Genevieve J. Yang,2,5 Grega Repovs,9 John D. Murray,10 Xiao-Jing Wang,10 Xiaoqi Huang,1 Su Lui,1* John H. Krystal,2
and Qiyong Gong1,2
Huaxi MR Research Center (HMRRC), Departments of Radiology, Psychiatry, and Psychology,West China Hospital and Schools of Clinical Medicine and Public
Administration, Sichuan University, Chengdu, Sichuan, 610041 China, 2Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
06511, 3Departments of Psychiatry and Oncology, Stat Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041 China,
4Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut 06519, 5Interdepartmental Neuroscience Program, Yale
University, New Haven, Connecticut 06520, 6Department of Psychology, Yale University, New Haven, Connecticut 06520, 7Center for Molecular and Behavioral
Neuroscience, Rutgers University, Newark, New Jersey 07102, 8University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb 10000, Croatia, 9Department of
Psychology, University of Ljubljana, 1000 Ljubljana, Slovenia, and 10Center for Neural Science, New York University, New York, New York 06510
1
Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia
studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs
in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence
suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129
non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesisdriven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less
evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with
PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n ⫽ 25), which also predicted immediate symptom
improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may
decrease longitudinally, could have prognostic and therapeutic implications.
The Journal of Neuroscience, January 7, 2015 • 35(1):267–286
Altered Sensory Experience Exacerbates Stable Dendritic Spine and Synapse Loss in a Mouse
Model of Huntington’s Disease
Reena Prity Murmu,1 Wen Li,1 Zsuzsanna Szepesi,1 and Jia-Yi Li1,2
Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A10, 22184
Lund, Sweden, and 2Neuroscience Institute, College of Life and Health Sciences, Northeastern University, Shenyang 110015, People’s Republic of China
1
A key question in Huntington’s disease (HD) is what underlies the early cognitive deficits that precede the motor symptoms and the characteristic neuronal death observed
in HD. The mechanisms underlying cognitive symptoms in HD remain unknown. Postmortem HD brain and animal model studies demonstrate pathologies in dendritic
spines and abnormal synaptic plasticity before motor symptoms and neurodegeneration. Experience-dependent synaptic plasticity caused by mechanisms such as LTP or
novel sensory experience potentiates synaptic strength, enhances new dendritic spine formation and stabilization, and may contribute to normal cognitive processes, such
as learning and memory. We have previously reported that under baseline conditions (without any sensory manipulation) neuronal circuitry in HD (R6/2 mouse model)
was highly unstable, which led to a progressive loss of persistent spines in these mice, and that mutant huntingtin was directly involved in the process. Here, we investigated
whether pathological processes of HD interfere with the normal experience-dependent plasticity of dendritic spines in the R6/2 model. Six weeks of two-photon in vivo
imaging before and after whisker trimming revealed that sensory deprivation exacerbates loss of persistent-type, stable spines in R6/2 mice compared with wild-type
littermates. In addition, sensory deprivation leads to impaired transformation of newly generated spines into persistent spines in R6/2 mice. As a consequence, reduced
synaptic density and decreased PSD-95 protein levels are evident in their barrel cortical neurons. These data suggest that mutant huntingtin is implicated in maladaptive
synaptic plasticity, which could be one of the plausible mechanisms underlying early cognitive deficits in HD.
The Journal of Neuroscience, January 7, 2015 • 35(1):287–298
Extracellular Glutamate Exposure Facilitates Group I mGluR-Mediated Epileptogenesis in the
Hippocampus
Wangfa Zhao, Shih-Chieh Chuang, Steven R. Young, Riccardo Bianchi, and Robert K.S. Wong
The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York
Downstate Medical Center, Brooklyn, New York 11203
Stimulation of group I mGluRs elicits several forms of translation-dependent neuronal plasticity including epileptogenesis. The translation process underlying plasticity
induction is controlled by repressors including the fragile X mental retardation protein (FMRP). In the absence of FMRP-mediated repression, a condition that occurs in a
mouse model (Fmr1⫺/⫺) of fragile X syndrome, group I mGluR-activated translation is exaggerated causing enhanced seizure propensity. We now show that glutamate
exposure (10 ␮M for 30 min) reduced FMRP levels in wild-type mouse hippocampal slices. Downregulation of FMRP was dependent on group I mGluR activation and was
blocked by a proteasome inhibitor (MG-132). Following glutamate exposure, synaptic stimulation induced prolonged epileptiform discharges with properties similar to
those observed in Fmr1⫺/⫺ preparations. In both cases, prolonged epileptiform discharges were blocked by group I mGluR antagonists (LY367385 ⫹ MPEP) and their
induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis
of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated
prolonged epileptiform discharges.
The Journal of Neuroscience, January 7, 2015 • 35(1):308 –315
Stress Induces the Danger-Associated Molecular Pattern HMGB-1 in the Hippocampus of Male
Sprague Dawley Rats: A Priming Stimulus of Microglia and the NLRP3 Inflammasome
Michael D. Weber,1* Matthew G. Frank,1* Kevin J. Tracey,2 Linda R. Watkins,1 and Steven F. Maier1
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Colorado 80309, and 2Laboratory of Biomedical
Science, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York 11030
1
Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which
stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming
and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100
inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether
HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the HMGB-1 antagonist BoxA was injected into the cisterna magna before IS. Hippocampal
microglia were isolated 24 h later and stimulated with LPS ex vivo to probe for stress-induced sensitization of proinflammatory responses. Previous IS potentiated gene
expression of NLRP3 and proinflammatory cytokines to LPS, that is, microglia were sensitized. Treatment with BoxA abolished this effect. To determine whether HMGB-1
is sufficient to prime microglia, IS was replaced with intracerebral administration of disulfide or fully reduced HMGB-1. Intracerebral disulfide HMGB-1 mimicked the
effect of the stressor, because microglia isolated from HMGB-1-treated rats expressed exaggerated NLRP3 and proinflammatory cytokine expression after LPS treatment, whereas
fully reduced HMGB-1 had no effect. The present results suggest that the CNS innate immune system can respond to an acute stressor as if it were cellular damage, thereby releasing
the danger signal HMGB-1 in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for a later immune challenge.
The Journal of Neuroscience, January 7, 2015 • 35(1):316 –324
PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of
Fragile X Syndrome
Catherine H. Choi,1,2,3 Brian P. Schoenfeld,1,4* Eliana D. Weisz,4* Aaron J. Bell,1,4 Daniel B. Chambers,5 Joseph Hinchey,1
Richard J. Choi,1 Paul Hinchey,1 Maria Kollaros,1 Michael J. Gertner,6 Neal J. Ferrick,1,4 Allison M. Terlizzi,1
Nicole Yohn,4 Eric Koenigsberg,1 David A. Liebelt,1 R. Suzanne Zukin,6 Newton H. Woo,7 Michael R. Tranfaglia,8
Natalia Louneva,9 Steven E. Arnold,9 Steven J. Siegel,9 Francois V. Bolduc,5 Thomas V. McDonald,1 Thomas A. Jongens,4
and Sean M. J. McBride1,4,9
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461,
Department of Medicine, Lehigh Valley Health System, Allentown, Pennsylvania 18103, 3Department of Dermatology, Drexel University College of
Medicine, Philadelphia, Pennsylvania 19107, 4Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,
5Department of Pediatrics, Center for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2N8, Canada, 6Dominick P. Purpura Department of
Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, 7Division of Anesthesia, Analgesia and Addiction Products, Office of Drug
Evaluation II, OND/CDER/FDA, Silver Spring, Maryland 20993, 8FRAXA Research Foundation, Newburyport, Massachusetts 01950, and 9Department of
Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
1
2
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive
impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate
receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels
can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects
in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate
that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating
the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates
PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
The Journal of Neuroscience, January 7, 2015 • 35(1):396 – 408
Disturbed Neuronal ER-Golgi Sorting of Unassembled Glycine Receptors Suggests Altered
Subcellular Processing Is a Cause of Human Hyperekplexia
Natascha Schaefer,1* Christoph J. Kluck,2* Kerry L. Price,3 Heike Meiselbach,4 Nadine Vornberger,1
Stephan Schwarzinger,5 Stephanie Hartmann,2 Georg Langlhofer,1 Solveig Schulz,6 Nadja Schlegel,7 Knut Brockmann,8
Bryan Lynch,9 Cord-Michael Becker,2 Sarah C.R. Lummis,3 and Carmen Villmann1
Institute for Clinical Neurobiology, Julius-Maximilians-University of Wu¨rzburg, 97078 Wu¨rzburg, Germany, 2Institute of Biochemistry, Department of
Biochemistry and Molecular Medicine, Friedrich-Alexander-University Erlangen-Nu¨rnberg, 91054 Erlangen, Germany, 3Department of Biochemistry,
University of Cambridge, Cambridge CB2 1QW, United Kingdom, 4Institute of Biochemistry, Bioinformatics Department, Friedrich-Alexander-University
Erlangen-Nu¨rnberg, 91054 Erlangen, Germany, 5Research Center for Bio-Macromolecules and Department of Biopolymers, University Bayreuth, 95447
Bayreuth, Germany, 6Center of Human Genetics and 7Department of Neuropediatrics, Jena University Hospital, 07743 Jena, Germany, 8Interdisciplinary
Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, 37075
Go¨ttingen, Germany, and 9Temple Street Children’s University Hospital, Dublin, Dublin1, Ireland
1
Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) ␣1 biogenesis. Here, we examine the properties
of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel
mutants localized in the large extracellular domain of the GlyR ␣1 have reduced cell surface expression with a high proportion of receptors being retained in the ER,
although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed
that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but
none of those in loop D/␤2–3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that
a proportion of GlyR ␣1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/␤2–3 is an
important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in
ligand binding.
The Journal of Neuroscience, January 7, 2015 • 35(1):422– 437