The Journal of Neuroscience, January 14, 2015 • 35(2):i • i
This Week in The Journal
Acetylcholine May Help People
Use New Strategies
Nicola J. Ray, Claudia Metzler-Baddeley,
Mizanur R. Khondoker, Michel J. Grothe,
Stefan Teipel, et al.
(see pages 739 –747)
Cholinergic neurons in the basal forebrain
project throughout the cortex and to other
brain structures, regulating arousal, attention, learning, and working memory. Cholinergic innervation declines with age, with
initial loss of synapses followed by axonal
degeneration and cell death. These losses are
exacerbated in mild cognitive impairment
(MCI) and become still more pronounced
in Alzheimer’s disease. Cholinergic pathology likely contributes to cognitive deficits in
these diseases, and treatment with cholinesterase inhibitors slows cognitive decline.
Because attention is required for effective memory encoding, teasing apart acetylcholine’s roles in memory and attention is
difficult. Assessing the role of acetylcholine
in memory is further complicated by the fact
that degeneration of cholinergic pathways is
typically accompanied by damage to medial
temporal lobe structures that are essential
for learning and memory. Even lesion studies in monkeys have not definitively defined
acetylcholine’s role in memory, because
precisely targeting cholinergic pathways is
difficult. Nonetheless, one study (Browning
et al., 2010, Cerebral Cortex 20:282) found
that selectively damaging cholinergic basal
forebrain neurons did not by itself impair
memory, but it greatly exacerbated the effects of fornix lesions. These authors suggested that rather than enhancing memory
encoding, cholinergic projections facilitate
cognitive flexibility, enabling animals to use
alternative strategies when first-choice pathways are damaged.
Ray et al. provide support for this hypothesis with studies examining the relationship between the volume of brain
structures and performance on memory
tests in MCI patients and controls. Previous studies indicated that the fornix—a
fiber tract that connects the hippocampus
to other brain areas and is essential for
memory functions—is damaged in MCI
and that patients may engage other tracts,
including the parahippocampal cingulum
(PHC), during recall tasks. Consistent
with this, a regression model indicated
that the link between recall and fornix
structure was weaker in patients. Adding
left PHC volume into the model improved
the fit, suggesting this tract contributes to
recall performance in patients. Importantly, the PHC-linked improvement was
greatest in patients that had the greatest
basal forebrain volume, suggesting that
patients with a relatively intact cholinergic
system were better able to engage the PHC
to compensate for fornix degeneration.
Volume of the fornix (red) is reduced in MCI patients (bottom)
compared to controls (top). MCI patients may compensate for
this loss by relying on the PHC (green). See the article by Ray
et al. for details.
Neuropathic Pain Is Suppressed
in Infants
Rebecca McKelvey, Temugin Berta,
Elizabeth Old, Ru-Rong Ji, and Maria Fitzgerald
(see pages 457– 466)
Peripheral nerve injury often causes neuropathic pain, characterized by hypersensitivity to mildly noxious stimuli and pain
in the absence of stimulation. Injured
nerves release cellular components that
activate toll-like receptors on glia; activated glia, in turn, release cytokines that
alter glial glutamate uptake and increase
neuronal excitability. In adults, the increased sensitivity of neurons in nociceptive pathways causes neuropathic pain
that persists for months. Neuropathic
pain is rare in children under 6 years old,
however, and when it occurs, it resolves
more quickly than in adults. Nonetheless,
injured toddlers sometimes develop neuropathic pain as they approach adolescence, and it has been suggested that
seemingly unexplained pain syndromes
arising in adolescence may actually stem
from earlier injury. This hypothesis gains
support from animal studies of spared
nerve injury (SNI): SNI causes adult rats
to exhibit neuropathic pain behaviors
within a week, but does not produce such
behaviors in pups until 3 weeks after
injury.
Now McKelvey et al. provide evidence
that neuropathic pain is actively suppressed by anti-inflammatory cytokines
in young rodents. Like rats, adult mice exhibited cold and mechanical hypersensitivity as well as reduced weight-bearing
within 7 d of SNI; but when SNI was administered on postnatal day 10 (P10),
such hypersensitivity did not appear until
P31. In both young and adult mice, the excitability of spared wide-dynamic-range
sensory neurons and the expression of proinflammatory cytokines in the dorsal horn
of the spinal cord increased in parallel with
the appearance of behavioral hypersensitivity—within 1 week after SNI in adults, but
not until 3 weeks after SNI in pups. Pups
were unique, however, in showing increased
expression of the anti-inflammatory cytokines IL-10 and IL-4 a week after injury. Notably, the expression of these cytokines
subsided by 21 d after injury, when proinflammatory cytokine expression was elevated. Moreover, when IL-10 was blocked
starting 7 d after SNI in pups, mechanical
hypersensitivity appeared the next day.
Likewise, injecting a pro-inflammatory cytokine 7 d after SNI quickly induced mechanical hypersensitivity in pups. Together,
these data indicate that pro-inflammatory
cytokines suppress neuropathic pain in injured mouse pups.
This Week in The Journal is written by X Teresa Esch, Ph.D.
The Journal of Neuroscience
January 14, 2015 • Volume 35 Number 2 • www.jneurosci.org
i
This Week in The Journal
Journal Club
439
Guidance of Movements by Prior Experience: A Bayesian Account of Reach
Performance
Darren Rhodes and Philip J.W. Woodgate
Brief Communications
Cover legend: This composite time-lapse image
shows superecliptic-pHluorin–transferrin-receptor
fluorescence signal in a cultured hippocampal
pyramidal cell. The pH-sensitive fluorophore
conjugated to the transferrin receptor serves as an
optical reporter of recycling endosome exocytosis, a
process critical for synaptic potentiation.
Posttranslational modification of the synaptic scaffold
protein AKAP79/150 by the palmitoyl-acyltransferase
DHHC2 is crucial for the regulation of recycling
endosome exocytosis. For more information, see the
article by Woolfrey et al. (pages 442– 456).
467
Necessary, Yet Dissociable Contributions of the Insular and Ventromedial Prefrontal
Cortices to Norm Adaptation: Computational and Lesion Evidence in Humans
Xiaosi Gu, Xingchao Wang, Andreas Hula, Shiwei Wang, Shuai Xu,
Terry M. Lohrenz, Robert T. Knight, Zhixian Gao, Peter Dayan,
and P. Read Montague
544
Integration of Purkinje Cell Inhibition by Cerebellar Nucleo-Olivary Neurons
Marion Najac and Indira M. Raman
643
Motor Cortex Layer V Pyramidal Neurons Exhibit Dendritic Regression, Spine Loss,
and Increased Synaptic Excitation in the Presymptomatic hSOD1G93A Mouse Model of
Amyotrophic Lateral Sclerosis
Matthew J. Fogarty, Peter G. Noakes, and Mark C. Bellingham
Articles
CELLULAR/MOLECULAR
442
The Palmitoyl Acyltransferase DHHC2 Regulates Recycling Endosome Exocytosis
and Synaptic Potentiation through Palmitoylation of AKAP79/150
Kevin M. Woolfrey, Jennifer L. Sanderson, and Mark L. Dell’Acqua
495
Accounting for the Delay in the Transition from Acute to Chronic Pain:
Axonal and Nuclear Mechanisms
Luiz F. Ferrari, Oliver Bogen, David B. Reichling, and Jon D. Levine
571
Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor
TRPM8
Carlos A. Toro, Stephanie Eger, Luis Veliz, Pamela Sotelo-Hitschfeld,
Deny Cabezas, Maite A. Castro, Katharina Zimmermann, and Sebastian Brauchi
621
Different Patterns of Electrical Activity Lead to Long-term Potentiation by Activating
Different Intracellular Pathways
Guoqi Zhu, Yan Liu, Yubin Wang, Xiaoning Bi, and Michel Baudry
678
Inflammasome-Induced IL-1␤ Secretion in Microglia Is Characterized by Delayed
Kinetics and Is Only Partially Dependent on Inflammatory Caspases
Saskia M. Burm, Ella A. Zuiderwijk-Sick, Anke E.J. ‘t Jong, Céline van der Putten,
Jennifer Veth, Ivanela Kondova, and Jeffrey J. Bajramovic
831
Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor
Responses
Meaghan A. Paganelli and Gabriela K. Popescu
DEVELOPMENT/PLASTICITY/REPAIR
550
Appraisal of Brain Connectivity in Radiologically Isolated Syndrome by Modeling
Imaging Measures
Antonio Giorgio, Maria Laura Stromillo, Alessandro De Leucio, Francesca Rossi,
Imke Brandes, Bahia Hakiki, Emilio Portaccio, Maria Pia Amato,
and Nicola De Stefano
559
Vertebrate Epidermal Cells Are Broad-Specificity Phagocytes That Clear Sensory
Axon Debris
Jeffrey P. Rasmussen, Georgeann S. Sack, Seanna M. Martin, and Alvaro Sagasti
599
Topologically Dissociable Patterns of Development of the Human Cerebral Cortex
Simon N. Vandekar, Russell T. Shinohara, Armin Raznahan, David R. Roalf,
Michelle Ross, Nicholas DeLeo, Kosha Ruparel, Ragini Verma, Daniel H. Wolf,
Ruben C. Gur, Raquel E. Gur, and Theodore D. Satterthwaite
SYSTEMS/CIRCUITS
474
Leptin Receptor Signaling in the Hypothalamus Regulates Hepatic Autonomic Nerve
Activity via Phosphatidylinositol 3-Kinase and AMP-Activated Protein Kinase
Mamoru Tanida, Naoki Yamamoto, Donald A. Morgan, Yasutaka Kurata,
Toshishige Shibamoto, and Kamal Rahmouni
527
Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis
Tyler M. Basting, Peter G.R. Burke, Roy Kanbar, Kenneth E. Viar,
Daniel S. Stornetta, Ruth L. Stornetta, and Patrice G. Guyenet
648
Primary Afferent and Spinal Cord Expression of Gastrin-Releasing Peptide:
Message, Protein, and Antibody Concerns
Carlos Solorzano, David Villafuerte, Karuna Meda, Ferda Cevikbas, Joao Bra´z,
Reza Sharif-Naeini, Dina Juarez-Salinas, Ida J. Llewellyn-Smith, Zhonghui Guan,
and Allan I. Basbaum
666
5␣-Reduced Neurosteroids Sex-Dependently Reverse Central Prenatal Programming
of Neuroendocrine Stress Responses in Rats
Paula J. Brunton, Marcio V. Donadio, Song T. Yao, Mike Greenwood,
Jonathan R. Seckl, David Murphy, and John A. Russell
761
Cholinergic Control of Gamma Power in the Midbrain Spatial Attention Network
Astra S. Bryant, C. Alex Goddard, John R. Huguenard, and Eric I. Knudsen
776
PAR1-Activated Astrocytes in the Nucleus of the Solitary Tract Stimulate Adjacent
Neurons via NMDA Receptors
Katie M. Vance, Richard C. Rogers, and Gerlinda E. Hermann
843
Structure–Function Relationships between Aldolase C/Zebrin II Expression
and Complex Spike Synchrony in the Cerebellum
Shinichiro Tsutsumi, Maya Yamazaki, Taisuke Miyazaki, Masahiko Watanabe,
Kenji Sakimura, Masanobu Kano, and Kazuo Kitamura
853
Impact of Basal Forebrain Cholinergic Inputs on Basolateral Amygdala Neurons
Cagri T. Unal, Denis Pare, and Laszlo Zaborszky
BEHAVIORAL/COGNITIVE
485
fMRI and EEG Predictors of Dynamic Decision Parameters during Human
Reinforcement Learning
Michael J. Frank, Chris Gagne, Erika Nyhus, Sean Masters, Thomas V. Wiecki,
James F. Cavanagh, and David Badre
䊉
508
Hemisphere-Dependent Attentional Modulation of Human Parietal Visual Field
Representations
Summer L. Sheremata and Michael A. Silver
634
Distributed Neural Representations of Phonological Features during Speech
Perception
Jessica S. Arsenault and Bradley R. Buchsbaum
658
Task-Induced Modulation of Intrinsic Functional Connectivity Networks in the
Behaving Rat
Jennifer Li, Sarah Martin, Mark D. Tricklebank, Adam J. Schwarz,
and Gary Gilmour
721
Dynamics of EEG Rhythms Support Distinct Visual Selection Mechanisms in Parietal
Cortex: A Simultaneous Transcranial Magnetic Stimulation and EEG Study
Paolo Capotosto, Sara Spadone, Annalisa Tosoni, Carlo Sestieri,
Gian Luca Romani, Stefania Della Penna, and Maurizio Corbetta
731
The Causal Role of the Occipital Face Area (OFA) and Lateral Occipital (LO) Cortex in
Symmetry Perception
Silvia Bona, Zaira Cattaneo, and Juha Silvanto
739
Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White
Matter Connections to Support Residual Memory in Mild Cognitive Impairment
Nicola J. Ray, Claudia Metzler-Baddeley, Mizanur R. Khondoker,
Michel J. Grothe, Stefan Teipel, Paul Wright, Helmut Heinsen, Derek K. Jones,
John P. Aggleton, and Michael J. O’Sullivan
786
The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor
Pathway Connectivity
Charlotte L. Rae, Laura E. Hughes, Michael C. Anderson, and James B. Rowe
819
Long-Delayed Expression of the Immediate Early Gene Arc/Arg3.1 Refines Neuronal
Circuits to Perpetuate Fear Memory
Daisuke Nakayama, Hirokazu Iwata, Chie Teshirogi, Yuji Ikegaya, Norio Matsuki,
and Hiroshi Nomura
NEUROBIOLOGY OF DISEASE
䊉
457
Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory
Neuroimmune Regulation
Rebecca McKelvey, Temugin Berta, Elizabeth Old, Ru-Rong Ji,
and Maria Fitzgerald
518
Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the
Glymphatic System
Benjamin A. Plog, Matthew L. Dashnaw, Emi Hitomi, Weiguo Peng,
Yonghong Liao, Nanhong Lou, Rashid Deane, and Maiken Nedergaard
583
DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury
Arthur Liesz, Alexander Dalpke, Eva Mracsko, Daniel J. Antoine, Stefan Roth,
Wei Zhou, Huan Yang, Shin-Young Na, Mustafa Akhisaroglu, Thomas Fleming,
Tatjana Eigenbrod, Peter P. Nawroth, Kevin J. Tracey, and Roland Veltkamp
610
Rcan1 Deficiency Impairs Neuronal Migration and Causes Periventricular
Heterotopia
Yang Li, Jie Wang, Yang Zhou, Dan Li, and Zhi-Qi Xiong
688
Early and Persistent Abnormal Decoding by Glial Cells at the Neuromuscular Junction
in an ALS Model
Danielle Arbour, Elsa Tremblay, E´ric Martineau, Jean-Pierre Julien,
and Richard Robitaille
707
Homeostatic Dysregulation in Membrane Properties of Masticatory Motoneurons
Compared with Oculomotor Neurons in a Mouse Model for Amyotrophic Lateral
Sclerosis
Sharmila Venugopal, Chie-Fang Hsiao, Takuma Sonoda, Martina Wiedau-Pazos,
and Scott H. Chandler
748
CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive
Dysfunction Induced by Traumatic Brain Injury
Josh M. Morganti, Timothy D. Jopson, Sharon Liu, Lara-Kirstie Riparip,
Cristian K. Guandique, Nalin Gupta, Adam R. Ferguson, and Susanna Rosi
795
Distinguishing the Central Drive to Tremor in Parkinson’s Disease and Essential
Tremor
John-Stuart Brittain, Hayriye Cagnan, Arpan R. Mehta, Tabish A. Saifee,
Mark J. Edwards, and Peter Brown
807
SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging
and Neurodegeneration via Epigenetic Regulation of IL-1␤
Seo-Hyun Cho, Jason A. Chen, Faten Sayed, Michael E. Ward, Fuying Gao,
Thi A. Nguyen, Grietje Krabbe, Peter Dongmin Sohn, Iris Lo, Sakura Minami,
Nino Devidze, Yungui Zhou, Giovanni Coppola, and Li Gan
864
Correction: The article “An RNA-Sequencing Transcriptome and Splicing Database of Glia,
Neurons, and Vascular Cells of the Cerebral Cortex” by Ye Zhang, Kenian Chen, Steven A.
Sloan, Mariko L. Bennett, Anja R. Scholze, Sean O’Keeffe, Hemali P. Phatnani, Paolo
Guarnieri, Christine Caneda, Nadine Ruderisch, Shuyun Deng, Shane A. Liddelow, Chaolin
Zhang, Richard Daneman, Tom Maniatis, Ben A. Barres, and Jian Qian Wu appeared on
pages 11929 –11947 of the September 3, 2014 issue. A correction for that article appears on
page 864.
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BRIEF COMMUNICATIONS
Necessary, Yet Dissociable Contributions of the Insular and Ventromedial Prefrontal Cortices to
Norm Adaptation: Computational and Lesion Evidence in Humans
Xiaosi Gu,1,2* Xingchao Wang,3,4* Andreas Hula,1 Shiwei Wang,3,4 Shuai Xu,3,4 Terry M. Lohrenz,2 Robert T. Knight,5,6
Zhixian Gao,3,4 Peter Dayan,7 and P. Read Montague1,2,8
Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom WC1N 3BG, 2Human Neuroimaging Laboratory, Virginia
Tech Carilion Research Institute, Roanoke, Virginia 24016, 3Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, and 4China
National Clinical Research Center for Neurological Diseases, Beijing, China 100050, 5Helen Willis Neuroscience Institute and 6Department of Psychology,
University of California, Berkeley, California 94720, 7Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom
WC1N 3AR, and 8Department of Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061
1
Social norms and their enforcement are fundamental to human societies. The ability to detect deviations from norms and to adapt to norms in a changing environment is
therefore important to individuals’ normal social functioning. Previous neuroimaging studies have highlighted the involvement of the insular and ventromedial prefrontal
(vmPFC) cortices in representing norms. However, the necessity and dissociability of their involvement remain unclear. Using model-based computational modeling and
neuropsychological lesion approaches, we examined the contributions of the insula and vmPFC to norm adaptation in seven human patients with focal insula lesions and
six patients with focal vmPFC lesions, in comparison with forty neurologically intact controls and six brain-damaged controls. There were three computational signals of
interest as participants played a fairness game (ultimatum game): sensitivity to the fairness of offers, sensitivity to deviations from expected norms, and the speed at which
people adapt to norms. Significant group differences were assessed using bootstrapping methods. Patients with insula lesions displayed abnormally low adaptation speed
to norms, yet detected norm violations with greater sensitivity than controls. Patients with vmPFC lesions did not have such abnormalities, but displayed reduced
sensitivity to fairness and were more likely to accept the most unfair offers. These findings provide compelling computational and lesion evidence supporting the necessary,
yet dissociable roles of the insula and vmPFC in norm adaptation in humans: the insula is critical for learning to adapt when reality deviates from norm expectations, and
that the vmPFC is important for valuation of fairness during social exchange.
The Journal of Neuroscience, January 14, 2015 • 35(2):467– 473
Integration of Purkinje Cell Inhibition by Cerebellar
Nucleo-Olivary Neurons
Marion Najac and Indira M. Raman
Department of Neurobiology, Northwestern University, Evanston, Illinois 60208
Neurons in the cerebellar cortex, cerebellar nuclei, and inferior olive (IO) form a trisynaptic loop critical for motor learning. IO neurons excite Purkinje cells via climbing
fibers and depress their parallel fiber inputs. Purkinje cells inhibit diverse cells in the cerebellar nuclei, including small GABAergic nucleo-olivary neurons that project to
the IO. To investigate how these neurons integrate synaptic signals from Purkinje cells, we retrogradely labeled nucleo-olivary cells in the contralateral interpositus and
lateral nuclei with cholera toxin subunit B-Alexa Fluor 488 and recorded their electrophysiological properties in cerebellar slices from weanling mice. Nucleo-olivary cells
fired action potentials over a relatively narrow dynamic range (maximal rate, ⬃70 spikes/s), unlike large cells that project to premotor areas (maximal rate, ⬃400 spikes/s).
GABAA receptor-mediated IPSCs evoked by electrical or optogenetic stimulation of Purkinje cells were more than 10-fold slower in nucleo-olivary cells (decay time, ⬃25
ms) than in large cells (⬃2 ms), and repetitive stimulation at 20 –150 Hz evoked greatly summating IPSCs. Nucleo-olivary firing rates varied inversely with IPSP frequency,
and the timing of Purkinje IPSPs and nucleo-olivary spikes was uncorrelated. These attributes contrast with large cells, whose brief IPSCs and rapid firing rates can permit
well timed postinhibitory spiking. Thus, the intrinsic and synaptic properties of these two projection neurons from the cerebellar nuclei tailor them for differential
integration and transmission of their Purkinje cell input.
The Journal of Neuroscience, January 14, 2015 • 35(2):544 –549
Motor Cortex Layer V Pyramidal Neurons Exhibit Dendritic Regression, Spine Loss, and
Increased Synaptic Excitation in the Presymptomatic hSOD1G93A Mouse Model of Amyotrophic
Lateral Sclerosis
Matthew J. Fogarty,1 Peter G. Noakes,1,2* and Mark C. Bellingham1*
1
School of Biomedical Sciences, 2Queensland Brain Institute, University of Queensland, St. Lucia, Queensland 4072, Australia
Motor cortex layer V pyramidal neurons (LVPNs) regulate voluntary control of motor output and selectively degenerate (along with lower motor neurons) in amyotrophic
lateral sclerosis. Using dye-filling and whole-cell patch clamping in brain slices, together with high-resolution spinning disk confocal z-stack mosaics, we characterized the
earliest presymptomatic cortical LVPN morphologic and electrophysiological perturbations in hSOD1 G93A (SOD1) mice to date. Apical dendritic regression occurred from
postnatal day (P) 28, dendritic spine loss from P21, and increased EPSC frequency from P21 in SOD1 LVPNs. These findings demonstrate extensive early changes in motor
cortex of the SOD1 mouse model, which thus recapitulates clinically relevant cortical pathophysiology more faithfully than previously thought.
The Journal of Neuroscience, January 14, 2015 • 35(2):643– 647
Articles
CELLULAR/MOLECULAR
The Palmitoyl Acyltransferase DHHC2 Regulates Recycling Endosome Exocytosis and Synaptic
Potentiation through Palmitoylation of AKAP79/150
Kevin M. Woolfrey,1 Jennifer L. Sanderson,1 and Mark L. Dell’Acqua1,2
Department of Pharmacology and 2Program in Neuroscience University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
80045
1
Phosphorylation and dephosphorylation of AMPA-type ionotropic glutamate receptors (AMPARs) by kinases and phosphatases and interactions with scaffold proteins
play essential roles in regulating channel biophysical properties and trafficking events that control synaptic strength during NMDA receptor-dependent synaptic plasticity,
such as LTP and LTD. We previously demonstrated that palmitoylation of the AMPAR-linked scaffold protein A-kinase anchoring protein (AKAP) 79/150 is required for its
targeting to recycling endosomes in dendrites, where it regulates exocytosis from these compartments that is required for LTP-stimulated enlargement of postsynaptic
dendritic spines, delivery of AMPARs to the plasma membrane, and maintenance of synaptic potentiation. Here, we report that the recycling endosome-resident palmitoyl
acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms. In particular, RNAi-mediated knockdown of
DHHC2 expression in rat hippocampal neurons disrupted stimulation of exocytosis from recycling endosomes, enlargement of dendritic spines, AKAP recruitment to
spines, and potentiation of AMPAR-mediated synaptic currents that occur during LTP. Importantly, expression of a palmitoylation-independent lipidated AKAP mutant
in DHHC2-deficient neurons largely restored normal plasticity regulation. Thus, we conclude that DHHC2-AKAP79/150 signaling is an essential regulator of dendritic
recycling endosome exocytosis that controls both structural and functional plasticity at excitatory synapses.
The Journal of Neuroscience, January 14, 2015 • 35(2):442– 456
Accounting for the Delay in the Transition from Acute to Chronic Pain: Axonal and Nuclear
Mechanisms
Luiz F. Ferrari, Oliver Bogen, David B. Reichling, and Jon D. Levine
Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143
Acute insults produce hyperalgesic priming, a neuroplastic change in nociceptors that markedly prolongs inflammatory mediator-induced hyperalgesia. After an acute
initiating insult, there is a 72 h delay to the onset of priming, for which the underlying mechanism is unknown. We hypothesized that the delay is due to the time required
for a signal to travel from the peripheral terminal to the cell body followed by a return signal to the peripheral terminal. We report that when an inducer of hyperalgesic
priming (monocyte chemotactic protein 1) is administered at the spinal cord of Sprague Dawley rats, priming is detected at the peripheral terminal with a delay significantly
shorter than when applied peripherally. Spinally induced priming is detected not only when prostaglandin E2 (PGE2 ) is presented to the peripheral nociceptor terminals,
but also when it is presented intrathecally to the central terminals in the spinal cord. Furthermore, when an inducer of priming is administered in the paw, priming can be
detected in spinal cord (as prolonged hyperalgesia induced by intrathecal PGE2 ), but only when the mechanical stimulus is presented to the paw on the side where the
priming inducer was administered. Both spinally and peripherally induced priming is prevented by intrathecal oligodeoxynucleotide antisense to the nuclear transcription
factor CREB mRNA. Finally, the inhibitor of protein translation reversed hyperalgesic priming only when injected at the site where PGE2 was administered, suggesting that
the signal transmitted from the cell body to the peripheral terminal is not a newly translated protein, but possibly a newly expressed mRNA.
The Journal of Neuroscience, January 14, 2015 • 35(2):495–507
Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8
Carlos A. Toro,1,3* Stephanie Eger,4,5* Luis Veliz,1 Pamela Sotelo-Hitschfeld,1,3 Deny Cabezas,1 Maite A. Castro,2
Katharina Zimmermann,4,5 and Sebastian Brauchi1
1Instituto de Fisiología, Facultad de Medicina, 2Instituto de Bioquimica y Microbiologia, and 3Escuela de Graduados, Facultad de Ciencias, Universidad
Austral de Chile, Valdivia, Chile, 4Klinik fu¨r Ana¨sthesiologie, Universita¨tsklinikum Erlangen, Friedrich-Alexander Universita¨t Erlangen-Nu¨rnberg,
Erlangen, Germany, and 5Institut fu¨r Physiologie und Pathophysiologie, Friedrich-Alexander Universita¨t Erlangen-Nu¨rnberg, Erlangen, Germany
The spatial and temporal distribution of receptors constitutes an important mechanism for controlling the magnitude of cellular responses. Several members of the
transient receptor potential (TRP) ion channel family can regulate their function by modulating their expression at the plasma membrane (PM) through rapid vesicular
translocation and fusion. The mechanisms underlying this regulation are not completely understood, and the contribution of vesicular trafficking to physiological function
is unknown. TRPM8 receptors are expressed in mammalian peripheral sensory neurons and are essential for the detection of cold temperatures. Previously, we showed that
TRPM8-containing vesicles are segregated into three main pools, immobile at the PM, simple diffusive and corralled-hopping. Here, we show that channel expression at the
PM is modulated by TRPM8 agonists in F11 and HEK293T cells. Our results support a model in which the activation of TRPM8 channels, located at the PM, induces a
short-lived recruitment of a TRPM8-containing vesicular pool to the cell surface causing a transitory increase in the number of functional channels, affecting intrinsic
properties of cold receptor responses. We further demonstrate the requirement of intact vesicular trafficking to support sustained cold responses in the skin of mice.
The Journal of Neuroscience, January 14, 2015 • 35(2):571–582
Different Patterns of Electrical Activity Lead to Long-term Potentiation by Activating Different
Intracellular Pathways
Guoqi Zhu,1,3* Yan Liu,1,2* Yubin Wang,1 Xiaoning Bi,2 and Michel Baudry1
Graduate College of Biomedical Sciences and 2College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California
91766, and 3Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Traditional Chinese Medicine, Hefei 230038, China
1
Deciphering and storing information coded in different firing patterns are important properties of neuronal networks, as they allow organisms to respond and adapt to
external and internal events. Here we report that hippocampal CA1 pyramidal neurons respond to brief bursts of high-frequency stimulation (HFS) and ␪ burst stimulation
(TBS) with long-lasting enhanced responses (long-term potentiation [LTP]), albeit by engaging different signaling pathways. TBS induces LTP through calpain-1-mediated
suprachiasmatic nucleus circadian oscillatory protein degradation, ERK activation, and actin polymerization, whereas HFS requires adenosine A2 receptors, PKA, and
actin polymerization. TBS- but not HFS-induced LTP is impaired in calpain-1 knock-out mice. However, TBS-induced LTP and learning impairment in knock-out mice are
restored by activating the HFS pathway. Thus, different patterns of rhythmic activities trigger potentiation by activating different pathways, and cross talks between these
can be used to restore LTP and learning when elements of the pathways are impaired.
The Journal of Neuroscience, January 14, 2015 • 35(2):621– 633
Inflammasome-Induced IL-1␤ Secretion in Microglia Is Characterized by Delayed Kinetics and
Is Only Partially Dependent on Inflammatory Caspases
Saskia M. Burm,1 Ella A. Zuiderwijk-Sick,1 Anke E.J. ‘t Jong,1 Céline van der Putten,1 Jennifer Veth,1 Ivanela Kondova,2
and Jeffrey J. Bajramovic1
1
Alternatives Unit, 2Animal Science Department, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands
Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1␤ (IL-1␤).
Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue
macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated
primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization
domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia
can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1␤
expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1␤ secretion by hematopoietic macrophages, microglial
secretion of IL-1␤ is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of
strategies to modulate innate immune responses in the brain.
The Journal of Neuroscience, January 14, 2015 • 35(2):678 – 687
Actions of Bupivacaine, a Widely Used Local Anesthetic, on NMDA Receptor Responses
Meaghan A. Paganelli1 and Gabriela K. Popescu1,2
1
Neuroscience Program and the 2Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14214
NMDA receptors mediate excitatory neurotransmission in brain and spinal cord and play a pivotal role in the neurological disease state of chronic pain, which is caused by
central sensitization. Bupivacaine is the indicated local anesthetic in caudal, epidural, and spinal anesthesia and is widely used clinically to manage acute and chronic pain.
In addition to blocking Na ⫹ channels, bupivacaine affects the activity of many other channels, including NMDA receptors. Importantly, bupivacaine inhibits NMDA
receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization. We used recombinant NMDA receptors
expressed in HEK293 cells and found that increasing concentrations of bupivacaine decreased channel open probability in GluN2 subunit- and pH-independent manner by
increasing the mean duration of closures and decreasing the mean duration of openings. Using kinetic modeling of one-channel currents, we attributed the observed
current decrease to two main mechanisms: a voltage-dependent “foot-in-the-door” pore block and an allosteric gating effect. Further, the inhibition was state-independent
because it occurred to the same degree whether the drug was applied before or after glutamate stimulation and was mediated by extracellular and intracellular inhibitory
sites, via hydrophilic and hydrophobic pathways. These results predict that clinical doses of bupivacaine would decrease the peak and accelerate the decay of synaptic
NMDA receptor currents during normal synaptic transmission. These quantitative predictions inform possible applications of bupivacaine as preventative and therapeutic
approaches in chronic pain.
The Journal of Neuroscience, January 14, 2015 • 35(2):831– 842
DEVELOPMENT/PLASTICITY/REPAIR
Appraisal of Brain Connectivity in Radiologically Isolated Syndrome by Modeling Imaging
Measures
Antonio Giorgio,1 Maria Laura Stromillo,1 Alessandro De Leucio,1 Francesca Rossi,1 Imke Brandes,1,2 Bahia Hakiki,3
Emilio Portaccio,3 Maria Pia Amato,3 and Nicola De Stefano1
1
3
Departments of Medicine, Surgery, and Neuroscience, University of Siena, 53100 Siena, Italy, 2University of Osnabru¨ck, 49076 Osnabru¨ck, Germany, and
Department of Neurology, University of Florence, 50121 Florence, Italy
We hypothesized that appraisal of brain connectivity may shed light on the substrate of the radiologically isolated syndrome (RIS), a term applied to asymptomatic subjects
with brain MRI abnormalities highly suggestive of multiple sclerosis. We thus used a multimodal MRI approach on the human brain by modeling measures of microstructural integrity of white matter (WM) tracts with those of functional connectivity (FC) at the level of resting state networks in RIS subjects, demographically matched normal
controls (NC), and relapsing-remitting (RR) MS patients, also matched with RIS for brain macrostructural damage (i.e., lesions and atrophy). Compared with NC, in both
RIS subjects and MS patients altered integrity of WM tracts was present. However, RIS subjects showed, at a less conservative threshold, lower diffusivities than RRMS
patients in distinct cerebral associative, commissural, projection, and cerebellar WM tracts, suggesting a relatively better anatomical connectivity. FC was similar in NC and
RIS subjects, even in the presence of important risk factors for MS (spinal cord lesions, oligoclonal bands, and dissemination in time on MRI) and increased in RRMS
patients in two clinically relevant networks subserving “processing” (sensorimotor) and “control” (working memory) functions. In RIS, the lack of functional reorganization in key brain networks may represent a model of “functional reserve,” which may become upregulated, with an adaptive or maladaptive role, only at a later stage in case
of occurrence of clinical deficit.
The Journal of Neuroscience, January 14, 2015 • 35(2):550 –558
Vertebrate Epidermal Cells Are Broad-Specificity Phagocytes That Clear Sensory Axon Debris
Jeffrey P. Rasmussen, Georgeann S. Sack, Seanna M. Martin, and Alvaro Sagasti
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095
Cellular debris created by developmental processes or injury must be cleared by phagocytic cells to maintain and repair tissues. Cutaneous injuries damage not only
epidermal cells but also the axonal endings of somatosensory (touch-sensing) neurons, which must be repaired to restore the sensory function of the skin. Phagocytosis of
neuronal debris is usually performed by macrophages or other blood-derived professional phagocytes, but we have found that epidermal cells phagocytose somatosensory
axon debris in zebrafish. Live imaging revealed that epidermal cells rapidly internalize debris into dynamic phosphatidylinositol 3-monophosphate-positive phagosomes
that mature into phagolysosomes using a pathway similar to that of professional phagocytes. Epidermal cells phagocytosed not only somatosensory axon debris but also
debris created by injury to other peripheral axons that were mislocalized to the skin, neighboring skin cells, and macrophages. Together, these results identify vertebrate
epidermal cells as broad-specificity phagocytes that likely contribute to neural repair and wound healing.
The Journal of Neuroscience, January 14, 2015 • 35(2):559 –570
Topologically Dissociable Patterns of Development of the Human Cerebral Cortex
Simon N. Vandekar,1,2 Russell T. Shinohara,2 Armin Raznahan,4 David R. Roalf,1 Michelle Ross,2 Nicholas DeLeo,1
Kosha Ruparel,1 Ragini Verma,3 Daniel H. Wolf,1 Ruben C. Gur,1,3,5 Raquel E. Gur,1,3 and Theodore D. Satterthwaite1
Departments of 1Psychiatry, 2Biostatistics and Epidemiology, and 3Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 4Child
Psychiatry Branch, National Institutes of Mental Health, Bethesda, Maryland 20892, and 5Philadelphia Veterans Administration Medical Center,
Philadelphia, Pennsylvania 19104
Over 90 years ago, anatomists noted the cortex is thinner in sulci than gyri, suggesting that development may occur on a fine scale driven by local topology. However, studies
of brain development in youth have focused on describing how cortical thickness varies over large-scale functional and anatomic regions. How the relationship between
thickness and local sulcal topology arises in development is still not well understood. Here, we investigated the spatial relationships between cortical thickness, folding, and
underlying white matter organization to elucidate the influence of local topology on human brain development. Our approach included using both T1-weighted imaging
and diffusion tensor imaging (DTI) in a cross-sectional sample of 932 youths ages 8 –21 studied as part of the Philadelphia Neurodevelopmental Cohort. Principal
components analysis revealed separable development-related processes of regionally specific nonlinear cortical thickening (from ages 8 –14) and widespread linear cortical
thinning that have dissociable relationships with cortical topology. Whereas cortical thinning was most prominent in the depths of the sulci, early cortical thickening was
present on the gyri. Furthermore, decline in mean diffusivity calculated from DTI in underlying white matter was correlated with cortical thinning, suggesting that cortical
thinning is spatially associated with white matter development. Spatial permutation tests were used to assess the significance of these relationships. Together, these data
demonstrate that cortical remodeling during youth occurs on a local topological scale and is associated with changes in white matter beneath the cortical surface.
The Journal of Neuroscience, January 14, 2015 • 35(2):599 – 609
SYSTEMS/CIRCUITS
Leptin Receptor Signaling in the Hypothalamus Regulates Hepatic Autonomic Nerve Activity
via Phosphatidylinositol 3-Kinase and AMP-Activated Protein Kinase
Mamoru Tanida,1,4 Naoki Yamamoto,2 Donald A. Morgan,3 Yasutaka Kurata,1 Toshishige Shibamoto,1
and Kamal Rahmouni3,4,5
Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan, 2College of Pharmacology, Hokuriku University,
Kanazawa, Ishikawa 920-1180, Japan, and 3Department of Pharmacology, 4Department of Internal Medicine, and 5Fraternal Order of Eagles Diabetes
Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
1
Leptin action in the brain has emerged as an important regulator of liver function independently from its effects on food intake and body weight. The autonomic nervous
system plays a key role in the regulation of physiological processes by leptin. Here, we used direct recording of nerve activity from sympathetic or vagal nerves subserving
the liver to investigate how brain action of leptin controls hepatic autonomic nerve activity. Intracerebroventricular (ICV) administration of leptin activated hepatic
sympathetic traffic in rats and mice in dose- and receptor-dependent manners. The hepatic sympatho-excitatory effects of leptin were also observed when leptin was
microinjected directly into the arcuate nucleus (ARC), but not into the ventromedial hypothalamus (VMH). Moreover, using pharmacological and genetic approaches, we
show that leptin-induced increase in hepatic sympathetic outflow depends on PI3K but not AMP-activated protein kinase (AMPK), STAT3, or ERK1/2. Interestingly, ICV
leptin also increased hepatic vagal nerve activity in rats. We show that this response is reproduced by intra-ARC, but not intra-VMH, leptin administration and requires
PI3K and AMPK. We conclude that central leptin signaling conveys the information to the liver through the sympathetic and parasympathetic branches of the autonomic
nervous system. Our data also provide important insight into the molecular events underlying leptin’s control of hepatic autonomic nerve activity by implicating PI3K and
AMPK pathways.
The Journal of Neuroscience, January 14, 2015 • 35(2):474 – 484
Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis
Tyler M. Basting,1* Peter G.R. Burke,1* Roy Kanbar,2 Kenneth E. Viar,1 Daniel S. Stornetta,1 Ruth L. Stornetta,1
and Patrice G. Guyenet1
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, and 2Department of Pharmaceutical Sciences, Lebanese American
University, Beyrouth, Lebanon
1
In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested
this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator.
Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch
(PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN
photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (⌬fR ) was larger in
hyperoxia (65% FiO2 ), smaller in 15% FiO2 , and absent in 12% FiO2. Tidal volume changes (⌬VT ) followed the same trend. The effect of hypoxia on ⌬fR was not
arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2 ). ⌬fR was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no
frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN
neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in
conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the
inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.
The Journal of Neuroscience, January 14, 2015 • 35(2):527–543
Primary Afferent and Spinal Cord Expression of Gastrin-Releasing Peptide: Message, Protein,
and Antibody Concerns
Carlos Solorzano,1 David Villafuerte,1 Karuna Meda,1 Ferda Cevikbas,1,2 Joao Bra´z,1 Reza Sharif-Naeini,1
Dina Juarez-Salinas,1 Ida J. Llewellyn-Smith,4 Zhonghui Guan,3 and Allan I. Basbaum1
Departments of 1Anatomy, 2Dermatology, and 3Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94158,
and 4Cardiovascular Medicine, Human Physiology and Centre for Neuroscience, Flinders University, Bedford Park, SA 5042, Australia
There is continuing controversy relating to the primary afferent neurotransmitter that conveys itch signals to the spinal cord. Here, we investigated the DRG and spinal cord
expression of the putative primary afferent-derived “itch” neurotransmitter, gastrin-releasing peptide (GRP). Using ISH, qPCR, and immunohistochemistry, we conclude that GRP
is expressed abundantly in spinal cord, but not in DRG neurons. Titration of the most commonly used GRP antiserum in tissues from wild-type and GRP mutant mice indicates that
the antiserum is only selective for GRP at high dilutions. Paralleling these observations, we found that a GRPeGFP transgenic reporter mouse has abundant expression in superficial
dorsal horn neurons, but not in the DRG. In contrast to previous studies, neither dorsal rhizotomy nor an intrathecal injection of capsaicin, which completely eliminated spinal cord
TRPV1-immunoreactive terminals, altered dorsal horn GRP immunoreactivity. Unexpectedly, however, peripheral nerve injury induced significant GRP expression in a heterogeneous population of DRG neurons. Finally, dual labeling and retrograde tracing studies showed that GRP-expressing neurons of the superficial dorsal horn are predominantly
interneurons, that a small number coexpress protein kinase C gamma (PKC␥), but that none coexpress the GRP receptor (GRPR). Our studies support the view that pruritogens
engage spinal cord “itch” circuits via excitatory superficial dorsal horn interneurons that express GRP and that likely target GRPR-expressing interneurons. The fact that peripheral
nerve injury induced de novo GRP expression in DRG neurons points to a novel contribution of this peptide to pruritoceptive processing in neuropathic itch conditions.
The Journal of Neuroscience, January 14, 2015 • 35(2):648 – 657
5␣-Reduced Neurosteroids Sex-Dependently Reverse Central Prenatal Programming of
Neuroendocrine Stress Responses in Rats
Paula J. Brunton,1 Marcio V. Donadio,2 Song T. Yao,3 Mike Greenwood,3 Jonathan R. Seckl,4 David Murphy,3,5
and John A. Russell6
The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, United Kingdom, 2Centro Infant, Biomedical
Research Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, 90610-000, Brazil, 3Henry Wellcome
Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY, United Kingdom, 4Endocrinology Unit, Centre for
Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom, 5Department of Physiology,
University of Malaya, Kuala Lumpur, Malaysia 50603, and 6Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh,
Edinburgh, EH8 9XD, United Kingdom
1
Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS)
offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1␤; IL-1␤) in adulthood, compared with controls. IL-1␤ acts via a noradrenergic relay
from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so
allopregnanolone and 3␤-androstanediol (3␤-diol; 5␣-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek
reversal of the “programmed” hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1␤ (500 ng/kg, i.v.) in PNS females, but not in PNS males.
However, 3␤-diol normalized HPA axis responses to IL-1␤ in PNS males. ImpairedtestosteroneandprogesteronemetabolismorincreasedsecretioninPNSratswasindicatedbygreater
plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5␣-reductase mRNA
levelsinbothmaleandfemalePNSoffspringintheNTS,andinthePVNinmales.InPNSfemales,adenovirus-mediatedgenetransferwasusedtoupregulateexpressionof5␣-reductaseand
3␣-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1␤. Thus, downregulation of neurosteroid production in the brain may
underlieHPAaxishyper-responsivenessinprenatallyprogrammedoffspring,andadministrationof5␣-reducedsteroidsacutelytoPNSratsoverridesprogrammingofhyperactiveHPAaxis
responses to immune challenge in a sex-dependent manner.
TheJournalofNeuroscience,January14,2015 • 35(2):666–677
Cholinergic Control of Gamma Power in the Midbrain Spatial Attention Network
Astra S. Bryant,1,2 C. Alex Goddard,1 John R. Huguenard,3 and Eric I. Knudsen1
1
Department of Neurobiology, 2Neurosciences Program, and 3Department of Neurology, Stanford University, Stanford, California 94305
The modulation of gamma power (25–90 Hz) is associated with attention and has been observed across species and brain areas. However, mechanisms that control these
modulations are poorly understood. The midbrain spatial attention network in birds generates high-amplitude gamma oscillations in the local field potential that are
thought to represent the highest priority location for attention. Here we explore, in midbrain slices from chickens, mechanisms that regulate the power of these oscillations,
using high-resolution techniques including intracellular recordings from neurons targeted by calcium imaging. The results identify a specific subtype of neuron, expressing
non-␣7 nicotinic acetylcholine receptors, that directly drives inhibition in the gamma-generating circuit and switches the network into a primed state capable of producing
high-amplitude oscillations. The special properties of this mechanism enable rapid, persistent changes in gamma power. The brain may employ this mechanism wherever
rapid modulations of gamma power are critical to information processing.
The Journal of Neuroscience, January 14, 2015 • 35(2):761–775
PAR1-Activated Astrocytes in the Nucleus of the Solitary Tract Stimulate Adjacent Neurons via
NMDA Receptors
Katie M. Vance, Richard C. Rogers, and Gerlinda E. Hermann
Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808
Severe autonomic dysfunction, including the loss of control of the cardiovascular, respiratory, and gastrointestinal systems, is a common comorbidity of stroke and other
bleeding head injuries. Previous studies suggest that this collapse of autonomic control may be caused by thrombin acting on astrocytic protease-activated receptors
(PAR1) in the hindbrain. Using calcium imaging and electrophysiological techniques, we evaluated the mechanisms by which astrocytic PAR1s modulate the activity of
presynaptic vagal afferent terminals and postsynaptic neurons in the rat nucleus of the solitary tract (NST). Our calcium-imaging data show that astrocytic and neuronal
calcium levels increase after brain slices are treated with the PAR1 agonist SFLLRN-NH2. This increase in activity is blocked by pretreating the slices with the glial metabolic
blocker fluorocitrate. In addition, PAR1-activated astrocytes communicate directly with NST neurons by releasing glutamate. Calcium responses to SFLLRN-NH2 in the
astrocytes and neurons significantly increase after bath application of the excitatory amino acid transporter blocker DL-threo-␤-benzyloxyaspartic acid (TBOA) and
significantly decrease after bath application of the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (DL-AP5). Furthermore, astrocytic glutamate
activates neuronal GluN2B-containing NMDA receptors. Voltage-clamp recordings of miniature EPSCs (mEPSCs) from NST neurons show that astrocytes control presynaptic vagal afferent excitability directly under resting and activated conditions. Fluorocitrate significantly decreases mEPSC frequency and SFLLRN-NH2 significantly
increases mEPSC frequency. These data show that astrocytes act within a tripartite synapse in the NST, controlling the excitability of both postsynaptic NST neurons and
presynaptic vagal afferent terminals.
The Journal of Neuroscience, January 14, 2015 • 35(2):776 –785
Structure–Function Relationships between Aldolase C/Zebrin II Expression and Complex Spike
Synchrony in the Cerebellum
Shinichiro Tsutsumi,1 Maya Yamazaki,2 Taisuke Miyazaki,3 Masahiko Watanabe,3 Kenji Sakimura,2 Masanobu Kano,1
and Kazuo Kitamura1,4
1Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan, 2Department of Cellular Neurobiology,
Brain Research Institute, Niigata University, Niigata 951-8585, Japan, 3Department of Anatomy, Hokkaido University Graduate School of Medicine,
Sapporo 060-8638, Japan, and 4PRESTO, JST, Saitama 332-0012, Japan
Simple and regular anatomical structure is a hallmark of the cerebellar cortex. Parasagittally arrayed alternate expression of aldolase C/zebrin II in Purkinje cells (PCs) has
been extensively studied, but surprisingly little is known about its functional significance. Here we found a precise structure–function relationship between aldolase C
expression and synchrony of PC complex spike activities that reflect climbing fiber inputs to PCs. We performed two-photon calcium imaging in transgenic mice in which
aldolase C compartments can be visualized in vivo, and identified highly synchronous complex spike activities among aldolase C-positive or aldolase C-negative PCs, but not
across these populations. The boundary of aldolase C compartments corresponded to that of complex spike synchrony at single-cell resolution. Sensory stimulation evoked
aldolase C compartment-specific complex spike responses and synchrony. This result further revealed the structure–function segregation. In awake animals, complex spike
synchrony both within and between PC populations across the aldolase C boundary were enhanced in response to sensory stimuli, in a way that two functionally distinct PC
ensembles are coactivated. These results suggest that PC populations characterized by aldolase C expression precisely represent distinct functional units of the cerebellar
cortex, and these functional units can cooperate to process sensory information in awake animals.
The Journal of Neuroscience, January 14, 2015 • 35(2):843– 852
Impact of Basal Forebrain Cholinergic Inputs on Basolateral Amygdala Neurons
Cagri T. Unal, Denis Pare, and Laszlo Zaborszky
Center for Molecular and Behavioral Neuroscience, Rutgers, The State University, Newark, New Jersey 07102
In addition to innervating the cerebral cortex, basal forebrain cholinergic (BFc) neurons send a dense projection to the basolateral nucleus of the amygdala (BLA). In this study, we
investigated the effect of near physiological acetylcholine release on BLA neurons using optogenetic tools and in vitro patch-clamp recordings. Adult transgenic mice expressing
cre-recombinase under the choline acetyltransferase promoter were used to selectively transduce BFc neurons with channelrhodopsin-2 and a reporter through the injection of an
adeno-associated virus. Light-induced stimulation of BFc axons produced different effects depending on the BLA cell type. In late-firing interneurons, BFc inputs elicited fast
nicotinicEPSPs.Incontrast,noresponsecouldbedetectedinfast-spikinginterneurons.InprincipalBLAneurons,twodifferenteffectswereeliciteddependingontheiractivitylevel.
When principal BLA neurons were quiescent or made to fire at low rates by depolarizing current injection, light-induced activation of BFc axons elicited muscarinic IPSPs. In
contrast, with stronger depolarizing currents, eliciting firing above ⬃6 – 8 Hz, these muscarinic IPSPs lost their efficacy because stimulation of BFc inputs prolonged current-evoked
afterdepolarizations. All the effects observed in principal neurons were dependent on muscarinic receptors type 1, engaging different intracellular mechanisms in a state-dependent
manner. Overall, our results suggest that acetylcholine enhances the signal-to-noise ratio in principal BLA neurons. Moreover, the cholinergic engagement of afterdepolarizations
may contribute to the formation of stimulus associations during fear-conditioning tasks where the timing of conditioned and unconditioned stimuli is not optimal for the induction
of synaptic plasticity.
The Journal of Neuroscience, Janurary 14, 2015 • 35(2):853– 863
BEHAVIORAL/COGNITIVE
fMRI and EEG Predictors of Dynamic Decision Parameters during Human Reinforcement
Learning
Michael J. Frank,1,2,3 Chris Gagne,1 Erika Nyhus,1,4 Sean Masters,1,2 Thomas V. Wiecki,1,2 James F. Cavanagh,1,5
and David Badre1,2
Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, Rhode Island 02912, 2Brown Institute for Brain Science,
Providence, Rhode Island 09212, 3Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island 02912, 4Department of
Psychology and Program in Neuroscience, Bowdoin College, Brunswick, Maine 04011, and 5Department of Psychology, University of New Mexico,
Albuquerque, New Mexico 87131
1
What are the neural dynamics of choice processes during reinforcement learning? Two largely separate literatures have examined dynamics of reinforcement learning (RL)
as a function of experience but assuming a static choice process, or conversely, the dynamics of choice processes in decision making but based on static decision values. Here
we show that human choice processes during RL are well described by a drift diffusion model (DDM) of decision making in which the learned trial-by-trial reward values
are sequentially sampled, with a choice made when the value signal crosses a decision threshold. Moreover, simultaneous fMRI and EEG recordings revealed that this
decision threshold is not fixed across trials but varies as a function of activity in the subthalamic nucleus (STN) and is further modulated by trial-by-trial measures of
decision conflict and activity in the dorsomedial frontal cortex (pre-SMA BOLD and mediofrontal theta in EEG). These findings provide converging multimodal evidence
for a model in which decision threshold in reward-based tasks is adjusted as a function of communication from pre-SMA to STN when choices differ subtly in reward values,
allowing more time to choose the statistically more rewarding option.
The Journal of Neuroscience, January 14, 2015 • 35(2):485– 494
Hemisphere-Dependent Attentional Modulation of Human Parietal Visual Field
Representations
Summer L. Sheremata1 and Michael A. Silver2
Department of Psychology, George Washington University, Washington, DC 20052 and 2Helen Wills Neuroscience Institute, School of Optometry, and
Vision Science Graduate Group, University of California, Berkeley, California 94720
1
Posterior parietal cortex contains several areas defined by topographically organized maps of the contralateral visual field. However, recent studies suggest that ipsilateral
stimuli can elicit larger responses in the right than left hemisphere within these areas, depending on task demands. Here we determined the effects of spatial attention on
the set of visual field locations (the population receptive field [pRF]) that evoked a response for each voxel in human topographic parietal cortex. A two-dimensional
Gaussian was used to model the pRF in each voxel, and we measured the effects of attention on not only the center (preferred visual field location) but also the size (visual
field extent) of the pRF. In both hemispheres, larger pRFs were associated with attending to the mapping stimulus compared with attending to a central fixation point. In
the left hemisphere, attending to the stimulus also resulted in more peripheral preferred locations of contralateral representations, compared with attending fixation. These
effects of attention on both pRF size and preferred location preserved contralateral representations in the left hemisphere. In contrast, attentional modulation of pRF size
but not preferred location significantly increased representation of the ipsilateral (right) visual hemifield in right parietal cortex. Thus, attention effects in topographic
parietal cortex exhibit hemispheric asymmetries similar to those seen in hemispatial neglect. Our findings suggest potential mechanisms underlying the behavioral deficits
associated with this disorder.
The Journal of Neuroscience, January 15, 2015 • 35(2):508 –517
Distributed Neural Representations of Phonological Features during Speech Perception
Jessica S. Arsenault and Bradley R. Buchsbaum
Rotman Research Institute at Baycrest, Toronto, Ontario M6A 2E1, Canada, and Department of Psychology, University of Toronto, Toronto, Ontario M5S
3G3, Canada
A fundamental goal of the human auditory system is to map complex acoustic signals onto stable internal representations of the basic sound patterns of speech. Phonemes
and the distinctive features that they comprise constitute the basic building blocks from which higher-level linguistic representations, such as words and sentences, are
formed. Although the neural structures underlying phonemic representations have been well studied, there is considerable debate regarding frontal-motor cortical
contributions to speech as well as the extent of lateralization of phonological representations within auditory cortex. Here we used functional magnetic resonance imaging
(fMRI) and multivoxel pattern analysis to investigate the distributed patterns of activation that are associated with the categorical and perceptual similarity structure of 16
consonant exemplars in the English language used in Miller and Nicely’s (1955) classic study of acoustic confusability. Participants performed an incidental task while
listening to phonemes in the MRI scanner. Neural activity in bilateral anterior superior temporal gyrus and supratemporal plane was correlated with the first two
components derived from a multidimensional scaling analysis of a behaviorally derived confusability matrix. We further showed that neural representations corresponding to the categorical features of voicing, manner of articulation, and place of articulation were widely distributed throughout bilateral primary, secondary, and association
areas of the superior temporal cortex, but not motor cortex. Although classification of phonological features was generally bilateral, we found that multivariate pattern
information was moderately stronger in the left compared with the right hemisphere for place but not for voicing or manner of articulation.
The Journal of Neuroscience, January 14, 2015 • 35(2):634 – 642
Task-Induced Modulation of Intrinsic Functional Connectivity Networks in the Behaving Rat
Jennifer Li,1 Sarah Martin,1 Mark D. Tricklebank,1 Adam J. Schwarz,2,3 and Gary Gilmour1
1Centre for Cognitive Neuroscience, Eli Lilly and Company Limited, Windlesham, Surrey GU20 6PH, United Kingdom, 2Tailored Therapeutics, Eli Lilly and
Company, Indianapolis, Indiana 46285, 3Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 46285
While resting-state functional magnetic resonance imaging can probe intrinsic network connectivity in both human and rodent brain, behavioral modulation of these
connectivity patterns has not yet been demonstrated in the rodent due to the requirements of immobilization or anesthesia for MRI scanning. To enable the effects of
behavioral tasks on functional connectivity to be measured in freely moving, awake rats, implanted carbon paste electrodes (CPEs) were used to monitor low-frequency
fluctuations of tissue oxygenation. Rats were implanted with CPEs in two nodes of the default mode network (DMN) and two nodes in a lateral cortical network, revealing
amperometric oxygen correlation patterns consistent with imaging studies. Using a block design study where rats alternated between sustained periods of instrumental
response and unscheduled spontaneous behavior, task-induced decreases in functional connectivity were observed between the DMN node pair, but not in the distinct
lateral cortical network, demonstrating network-specific modulation of functional connectivity.
The Journal of Neuroscience, January 14, 2015 • 35(2):658 – 665
Dynamics of EEG Rhythms Support Distinct Visual Selection Mechanisms in Parietal Cortex: A
Simultaneous Transcranial Magnetic Stimulation and EEG Study
Paolo Capotosto,1 Sara Spadone,1 Annalisa Tosoni,1 Carlo Sestieri,1 Gian Luca Romani,1 Stefania Della Penna,1
and Maurizio Corbetta1,2
Department of Neuroscience, Imaging and Clinical Sciences, and Institute of Advanced Biomedical Technologies, University G. D’Annunzio, 66100 Chieti,
Italy, and 2Departments of Neurology, Radiology, and Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110
1
Using repetitive transcranial magnetic stimulation (rTMS), we have recently shown a functional anatomical distinction in human parietal cortex between regions involved
in maintaining attention to a location [ventral intraparietal sulcus (vIPS)] and a region involved in shifting attention between locations [medial superior parietal lobule
(mSPL)]. In particular, while rTMS interference over vIPS impaired target discrimination at contralateral attended locations, interference over mSPL affected performance
following shifts of attention regardless of the visual field (Capotosto et al., 2013). Here, using rTMS interference in conjunction with EEG recordings of brain rhythms during
the presentation of cues that indicate to either shift or maintain spatial attention, we tested whether this functional anatomical segregation involves different mechanisms
of rhythm synchronization. The transient inactivation of vIPS reduced the amplitude of the expected parieto-occipital low-␣ (8 –10 Hz) desynchronization contralateral to
the cued location. Conversely, the transient inactivation of mSPL, compared with vIPS, reduced the high-␣ (10 –12 Hz) desynchronization induced by shifting attention into
both visual fields. Furthermore, rTMS induced a frequency-specific delay of task-related modulation of brain rhythms. Specifically, rTMS over vIPS or mSPL during
maintenance (stay cues) or shifting (shift cues) of spatial attention, respectively, caused a delay of ␣ parieto-occipital desynchronization. Moreover, rTMS over vIPS during
stay cues caused a delay of ␦ (2– 4 Hz) frontocentral synchronization. These findings further support the anatomo-functional subdivision of the dorsal attention network
in subsystems devoted to shifting or maintaining covert visuospatial attention and indicate that these mechanisms operate in different frequency channels linking frontal
to parieto-occipital visual regions.
The Journal of Neuroscience, January 14, 2015 • 34(2):721–730
The Causal Role of the Occipital Face Area (OFA) and Lateral Occipital (LO) Cortex in Symmetry
Perception
Silvia Bona,1,2,3,8 Zaira Cattaneo,4,5,6 and Juha Silvanto1,7
Brain Research Unit, O.V. Lounasmaa Laboratory, School of Science, Aalto University, 02150 Espoo, Finland, 2Advanced Magnetic Imaging Centre, Aalto
Neuroimaging, OV Lounasmaa Laboratory, School of Science, Aalto University, 00076 Espoo, Finland, 3BioMag Laboratory, HUS Medical Imaging Center,
Helsinki University Central Hospital, 00290 Helsinki, Finland, 4Department of Psychology, University of Milano-Bicocca, 20126 Milan, Italy, 5Brain
Connectivity Center, National Neurological Institute C. Mondino, 27100 Pavia, Italy, 6Milan Center for Neuroscience, 20126 Milan, Italy, 7University of
Westminster, Faculty of Science and Technology, Department of Psychology, W1B 2HW London, United Kingdom, and 8Department of Behavioural
Sciences, University of Helsinki, 00014 Helsinki, Finland
1
Symmetry is an important cue in face and object perception. Here we used fMRI-guided transcranial magnetic stimulation (TMS) to shed light on the role of the occipital
face area (OFA), a key region in face processing, and the lateral occipital (LO) cortex, a key area in object processing, in symmetry detection. In the first experiment, we
applied TMS over the rightOFA, its left homolog (leftOFA), rightLO, and vertex (baseline) while participants were discriminating between symmetric and asymmetric dot
patterns. Stimulation of rightOFA and rightLO impaired performance, causally implicating these two regions in detection of symmetry in low-level dot configurations. TMS
over rightLO but not rightOFA also significantly impaired detection of nonsymmetric shapes defined by collinear Gabor patches, demonstrating that rightOFA responds to
symmetry but not to all cues mediating figure-ground segregation. The second experiment showed a causal role for rightOFA but not rightLO in facial symmetry detection.
Overall, our results demonstrate that both the rightOFA and rightLO are sensitive to symmetry in dot patterns, whereas only rightOFA is causally involved in facial
symmetry detection.
The Journal of Neuroscience, January 14, 2015 • 35(2):731–738
Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White Matter
Connections to Support Residual Memory in Mild Cognitive Impairment
Nicola J. Ray,1 Claudia Metzler-Baddeley,3 Mizanur R. Khondoker,2 Michel J. Grothe,5 Stefan Teipel,4 Paul Wright,1
Helmut Heinsen,6 Derek K. Jones,3 John P. Aggleton,3 and Michael J. O’Sullivan1,3
Department of 1Basic and Clinical Neuroscience and 2Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London
SE5 8AF, United Kingdom, 3Cardiff University Brain Research Imaging Centre, School of Psychology, and Neuroscience and Mental Health Research
Institute, Cardiff, CF10 3AT, United Kingdom, 4German Center for Neurodegenerative Diseases Rostock/Greifswald, D-18471 Rostock, Germany,
5Department of Psychosomatic Medicine, University Medicine Rostock, D-18147 Rostock, Germany, and 6Laboratory of Morphological Brain Research,
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Wu¨rzburg, D-97080 Wu¨rzburg, Germany
The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer’s disease. In the presence of
fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer’s disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also
compromised in Alzheimer’s disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and
volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group ⫻ fornix interaction, indicating that the association between
recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated
to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free
recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and
basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when
cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional
restoration.
The Journal of Neuroscience, January 14, 2015 • 35(2):739 –747
The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway
Connectivity
Charlotte L. Rae,1,2 Laura E. Hughes,1,2 Michael C. Anderson,1,3 and James B. Rowe1,2,3
MRC Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, United Kingdom, and 2Department of Clinical Neurosciences and 3Behavioral and Clinical
Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, United Kingdom
1
Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain
controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex
influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions
between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian
model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby
amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree
of modulation by the inferior frontal gyrus, predicted individual differences in participants’ stopping performance (stop-signal reaction time). We then used diffusionweighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the
STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract
between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures.
Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control.
The Journal of Neuroscience, January 14, 2015 • 35(2):786 –794
Long-Delayed Expression of the Immediate Early Gene Arc/Arg3.1 Refines Neuronal Circuits to
Perpetuate Fear Memory
Daisuke Nakayama,1 Hirokazu Iwata,1 Chie Teshirogi,1 Yuji Ikegaya,1,2 Norio Matsuki,1 and Hiroshi Nomura1
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan, and 2Center for
Information and Neural Networks, Suita City, Osaka 565-0871, Japan
1
Fear memories typically persist for long time periods, and persistent fear memories contribute to post-traumatic stress disorder. However, little is known about the cellular
and synaptic mechanisms that perpetuate long-term memories. Here, we find that mouse hippocampal CA1 neurons exhibit biphasic Arc (also known as Arg3.1) elevations
after fear experience and that the late Arc expression regulates the perpetuation of fear memoires. An early Arc increase returned to the baseline after 6 h, followed by a
second Arc increase after 12 h in the same neuronal subpopulation; these elevations occurred via distinct mechanisms. Antisense-induced blockade of late Arc expression
disrupted memory persistence but not formation. Moreover, prolonged fear memories were associated with the delayed, specific elimination of dendritic spines and the
reactivation of neuronal ensembles formed during fear experience, both of which required late Arc expression. We propose that late Arc expression refines functional
circuits in a delayed fashion to prolong fear memory.
The Journal of Neuroscience, January 14, 2015 • 35(2):819 – 830
NEUROBIOLOGY OF DISEASE
Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory
Neuroimmune Regulation
Rebecca McKelvey,1 Temugin Berta,2 Elizabeth Old,3 Ru-Rong Ji,2 and Maria Fitzgerald1
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, 2Departments of
Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, and 3Wolfson Centre for Age Related Diseases, King’s
College London, London WC2R 2LS, United Kingdom
1
Peripheral nerve injury can trigger neuropathic pain in adults but not in infants; indeed, for unknown reasons, neuropathic pain is rare before adolescence. We show here
that the absence of neuropathic pain response in infant male rats and mice following nerve injury is due to an active, constitutive immune suppression of dorsal horn pain
activity. In contrast to adult nerve injury, which triggers a proinflammatory immune response in the spinal dorsal horn, infant nerve injury triggers an anti-inflammatory
immune response, characterized by significant increases in IL-4 and IL-10. This immediate anti-inflammatory response can also be evoked by direct C-fiber nerve
stimulation in infant, but not adult, mice. Blockade of the anti-inflammatory activity with intrathecal anti-IL10 unmasks neuropathic pain behavior in infant nerve injured
mice, showing that pain hypersensitivity in young mice is actively suppressed by a dominant anti-inflammatory neuroimmune response. As infant nerve injured mice reach
adolescence (postnatal day 25–30), the dorsal horn immune profile switches from an anti-inflammatory to a proinflammatory response characterized by significant
increases in TNF and BDNF, and this is accompanied by a late onset neuropathic pain behavior and increased dorsal horn cell sensitivity to cutaneous mechanical and cold
stimuli. These findings show that neuropathic pain following early life nerve injury is not absent but suppressed by neuroimmune activity and that “latent” pain can still
emerge at adolescence, when the neuroimmune profile changes. The data may explain why neuropathic pain is rare in young children and also why it can emerge, for no
observable reason, in adolescent patients.
The Journal of Neuroscience, January 14, 2015 • 35(2):457– 466
Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the Glymphatic
System
Benjamin A. Plog,1,2* Matthew L. Dashnaw,1* Emi Hitomi,1 Weiguo Peng,1 Yonghong Liao,1 Nanhong Lou,1
Rashid Deane,1 and Maiken Nedergaard1
1Center for Translational Neuromedicine, Department of Neurosurgery and 2Department of Pathology, University of Rochester Medical Center, Rochester,
New York 14642
The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the
severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model
that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of
glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100␤, GFAP, and neuron specific enolase.
We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic
activity.
The Journal of Neuroscience, January 14, 2015 • 35(2):518 –526
DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury
Arthur Liesz,1,2,3 Alexander Dalpke,4 Eva Mracsko,1 Daniel J. Antoine,5 Stefan Roth,2,3 Wei Zhou,1 Huan Yang,6
Shin-Young Na,1 Mustafa Akhisaroglu,1,7 Thomas Fleming,8 Tatjana Eigenbrod,4 Peter P. Nawroth,8 Kevin J. Tracey,6
and Roland Veltkamp1,9
Department of Neurology, University Heidelberg, 69120 Heidelberg, Germany, 2Institute for Stroke and Dementia Research, Klinikum der Universita¨t
Mu¨nchen, 81377 Munich, Germany, 3Munich Cluster for Systems Neurology, 80336 Munich, Germany, 4Department of Infectious Diseases, Medical
Microbiology and Hygiene, University Heidelberg, 69120 Heidelberg, Germany, 5MRC Centre for Drug Safety Science, Molecular & Clinical Pharmacology,
University of Liverpool, Liverpool L69 3GE, United Kingdom, 6Laboratory of Biomedical Sciences, Feinstein Institute for Medical Research, Manhasset,
New York 11030, 7Department of Physiology, School of Medicine, Dokuz Eylul University, Inciralti, Izmir, 35340, Turkey, 8Department of Internal
Medicine, University Heidelberg, 69120 Heidelberg, Germany, and 9Division of Brain Sciences, Imperial College London, London SW7 2AZ, United
Kingdom
1
Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent
immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a
paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and
investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior
syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and
by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute
phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of
the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrowderived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature
monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key
mechanism explaining the complex postischemic brain-immune interactions.
The Journal of Neuroscience, January 14, 2015 • 35(2):583–598
Rcan1 Deficiency Impairs Neuronal Migration and Causes Periventricular Heterotopia
Yang Li,1,2 Jie Wang,1,2 Yang Zhou,1 Dan Li,1,2 and Zhi-Qi Xiong1
1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences. Shanghai 200031, People’s Republic of China, and 2University of Chinese Academy of Sciences, Shanghai 200031, People’s
Republic of China
Periventricular heterotopia (PH) is a cortical malformation characterized by aggregation of neurons lining the lateral ventricles due to abnormal neuronal migration. The
molecular mechanism underlying the pathogenesis of PH is unclear. Here we show that Regulators of calcineurin 1 (Rcan1), a Down syndrome-related gene, plays an
important role in radial migration of rat cortical neurons. Downregulation of Rcan1 by expressing shRNA impaired neural progenitor proliferation and led to defects in
radial migration and PH. Two isoforms of Rcan1 (Rcan1–1 and Rcan1– 4) are expressed in the rat brain. Migration defects due to downregulation of Rcan1 could be
prevented by shRNA-resistant expression of Rcan1–1 but not Rcan1– 4. Furthermore, we found that Rcan1 knockdown significantly decreased the expression level of Flna,
an F-actin cross-linking protein essential for cytoskeleton rearrangement and cell migration, mutation of which causes the most common form of bilateral PH in humans.
Finally, overexpression of FLNA in Rcan1 knockdown neurons prevented migration abnormalities. Together, these findings demonstrate that Rcan1 acts upstream from
Flna in regulating radial migration and suggest that impairment of Rcan1-Flna pathway may underlie PH pathogenesis.
The Journal of Neuroscience, January 14, 2015 • 35(2):610 – 620
Early and Persistent Abnormal Decoding by Glial Cells at the Neuromuscular Junction in an ALS
Model
Danielle Arbour,1,2 Elsa Tremblay,1,2 E´ric Martineau,1,2 Jean-Pierre Julien,3 and Richard Robitaille1,2
De´partement de neurosciences, Universite´ de Montre´al, Montre´al, Que´bec H3C 3J7, Canada, 2Groupe de recherche sur le syste`me nerveux central,
Universite´ de Montre´al, Station centre-ville, Montre´al, Que´bec H3C 3J7, Canada, and 3De´partement de psychiatrie et de neurosciences, Universite´ Laval,
Que´bec G1V 0A6, Canada
1
Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease characterized by progressive loss of motor neurons (MNs) preceded by neuromuscular junction
(NMJ) denervation. Despite the importance of NMJ denervation in ALS, the mechanisms involved remain unexplored and ill defined. The contribution of glial cells in the
disease has been highlighted, including axonal Schwann cell activation that precedes the decline of motor function and the onset of hindlimb paralysis. Because NMJ
denervation occurs early in the process and that perisynaptic Schwann cells (PSCs), glial cells at the NMJ, regulate morphological stability, integrity, and repair of the NMJ,
one could predict that PSC functions would be altered even before denervation, contributing to NMJ malfunctions. We tested this possibility using a slowly progressive
model of ALS (SOD1 G37R mice). We observed a normal NMJ organization at a presymptomatic stage of ALS (120 d), but PSC detection of endogenous synaptic activity
revealed by intracellular Ca 2⫹ changes was enhanced compared with their wild-type littermates. This inappropriate PSC decoding ability was associated with an increased
level of neurotransmitter release and dependent on intrinsic glial properties related to enhanced muscarinic receptor activation. The alteration of PSC muscarinic receptor
functions also persists during the preonset stage of the disease and became dependent on MN vulnerability with age. Together, these results suggest that PSC properties are
altered in the disease process in a manner that would be detrimental for NMJ repair. The impairments of PSC functions may contribute to NMJ dysfunction and ALS
pathogenesis.
The Journal of Neuroscience, January 14, 2015 • 35(2):688 –706
Homeostatic Dysregulation in Membrane Properties of Masticatory Motoneurons Compared
with Oculomotor Neurons in a Mouse Model for Amyotrophic Lateral Sclerosis
Sharmila Venugopal,1 Chie-Fang Hsiao,1 Takuma Sonoda,1 Martina Wiedau-Pazos,2 and Scott H. Chandler1
1Departments of Integrative Biology and Physiology, and 2Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles,
California 90095
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motoneuron disease with presently no cure. Motoneuron (MN) hyperexcitability is commonly
observed in ALS and is suggested to be a precursor for excitotoxic cell death. However, it is unknown whether hyperexcitability also occurs in MNs that are resistant to
degeneration. Second, it is unclear whether all the MNs within homogeneous motor pools would present similar susceptibility to excitability changes since high-threshold
MNs innervating fast fatigable muscle fibers selectively degenerate compared with low-threshold MNs innervating fatigue resistant slow muscle fibers. Therefore, we
concurrently examined the excitability of ALS-vulnerable trigeminal motoneurons (TMNs) controlling jaw musculature and ALS-resistant oculomotor neurons (OMNs)
controlling eye musculature in a well studied SOD1 G93A ALS mouse model using in vitro patch-clamp electrophysiology at presymptomatic ages P8 –P12. Our results show
that hyperexcitability is not a global change among all the MNs, although mutant SOD1 is ubiquitously expressed. Instead, complex changes occur in ALS-vulnerable TMNs
based on motor unit type and discharge characteristics. Firing threshold decreases among high-threshold TMNs and increases in a subpopulation of low-threshold TMNs.
The latter group was identified based on their linear frequency– current responses to triangular ramp current injections. Such complex changes in MN recruitment were
absent in ALS-resistant OMNs. We simulated the observed complex changes in TMN excitability using a computer-based jaw closer motor pool model. Model results suggest
that hypoexcitability may indeed represent emerging disease symptomology that causes resistance in muscle force initiation. Identifying the cellular and molecular
properties of these hypoexcitable cells may guide effective therapeutic strategies in ALS.
The Journal of Neuroscience, January 14, 2015 • 35(2):707–720
CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive
Dysfunction Induced by Traumatic Brain Injury
Josh M. Morganti,1,2 Timothy D. Jopson,1 Sharon Liu,3 Lara-Kirstie Riparip,1 Cristian K. Guandique,1 Nalin Gupta,3
Adam R. Ferguson,1,3 and Susanna Rosi1,2,3
Brain and Spinal Injury Center, 2Departments of Physical Therapy and Rehabilitation Science, and 3Neurological Surgery, University of California, San
Francisco, California 94110
1
Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new
therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key
mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2 ⫹ macrophages play
in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1GFP/⫹CCR2RFP/⫹ reporter mice, we show that TBI initiated a temporally
restricted accumulation of peripherally derived CCR2 ⫹ macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and
memory. Multivariate analysis delineated CCR2 ⫹ macrophages’ neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of
concept, targeting CCR2 ⫹ macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus,
therapeutically targeting the CCR2 ⫹ subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI.
The Journal of Neuroscience, January 14, 2015 • 35(2):748 –760
Distinguishing the Central Drive to Tremor in Parkinson’s Disease and Essential Tremor
John-Stuart Brittain,1 Hayriye Cagnan,1 Arpan R. Mehta,1 Tabish A. Saifee,2 Mark J. Edwards,2 and Peter Brown1
Experimental Neurology Group, Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of
Oxford, Oxford OX3 9DU, United Kingdom, and 2Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute
of Neurology, London WC1N 3BG, United Kingdom
1
Parkinson’s disease (PD) and essential tremor (ET) are the two most common movement disorders. Both have been associated with similar patterns of network activation
leading to the suggestion that they may result from similar network dysfunction, specifically involving the cerebellum. Here, we demonstrate that parkinsonian tremors and
ETs result from distinct patterns of interactions between neural oscillators. These patterns are reflected in the tremors’ derived frequency tolerance, a novel measure readily
attainable from bedside accelerometry. Frequency tolerance characterizes the temporal evolution of tremor by quantifying the range of frequencies over which the tremor
may be considered stable. We found that patients with PD (N ⫽ 24) and ET (N ⫽ 21) were separable based on their frequency tolerance, with PD associated with a broad
range of stable frequencies whereas ET displayed characteristics consistent with a more finely tuned oscillatory drive. Furthermore, tremor was selectively entrained by
transcranial alternating current stimulation applied over cerebellum. Narrow frequency tolerances predicted stronger entrainment of tremor by stimulation, providing
good evidence that the cerebellum plays an important role in pacing those tremors. The different patterns of frequency tolerance could be captured with a simple model
based on a broadly coupled set of neural oscillators for PD, but a more finely tuned set of oscillators in ET. Together, these results reveal a potential organizational principle
of the human motor system, whose disruption in PD and ET dictates how patients respond to empirical, and potentially therapeutic, interventions that interact with their
underlying pathophysiology.
The Journal of Neuroscience, January 14, 2015 • 35(2):795– 806
SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and
Neurodegeneration via Epigenetic Regulation of IL-1␤
Seo-Hyun Cho,1,3 Jason A. Chen,5 Faten Sayed,1,3,4 Michael E. Ward,1,3 Fuying Gao,5 Thi A. Nguyen,2 Grietje Krabbe,1,3
Peter Dongmin Sohn,1,3,4 Iris Lo,1 Sakura Minami,1,3 Nino Devidze,1 Yungui Zhou,1 Giovanni Coppola,5 and Li Gan1,3,4
Gladstone Institutes of Neurological Disease, 2Gladstone Institutes of Cardiovascular Disease, 3Department of Neurology, 4Neuroscience Graduate
Program, University of California, San Francisco, California 94158, and 5Departments of Psychiatry, and Biobehavioral Sciences and Neurology, Semel
Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095
1
Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by
proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal
role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and
a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency
has a causative role in aging- or tau-mediated memory deficits via IL-1␤ upregulation in mice. Interestingly, the selective activation of IL-1␤ transcription by SIRT1
deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1␤ proximal promoter. In humans, hypomethylation of IL-1␤ is strongly associated with
chronological age and with elevated IL-1␤ transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging
and neurodegenerative diseases.
The Journal of Neuroscience, January 14, 2015 • 35(2):807– 818

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