1. health and fitness
2. disease

The Journal of Neuroscience, November 19, 2014 • 34(47):i • i
This Week in The Journal
Cellular/Molecular
New Technique Identifies Receptors
for Specific Odors
F
Timothy S. McClintock, Kaylin Adipietro,
William B. Titlow, Patrick Breheny,
Andreas Walz, et al.
(see pages 15669 –15678)
Visual and auditory stimuli vary on continuous scales of position and wavelength,
making it easy to define the relationships between stimuli. These features are represented topographically in primary visual
and auditory cortex. In contrast, relationships between odors are generally difficult to
define objectively, and this—along with the
existence of thousands of different odorant
receptors— has hindered attempts to understand the neural mechanisms of odor
representation. Before one can begin deciphering these mechanisms, one must first
determine which odors various odor receptors respond to. McClintock et al. have developed a technique to facilitate this process.
First, specific odors were delivered intermittently to mice in which a fluorescent protein
was produced in active olfactory sensory
neurons (OSNs). Activated OSNs were then
isolated using fluorescence-activated cell
sorting. Finally, microarrays were used to
identify the odorant receptors expressed by
activated cells. The technique identified
most previously identified receptors for two
odors, along with several new receptors for
these odors.
Development/Plasticity/Repair
Loss of p27Kip148 Lets Hair Cells
Proliferate
Postnatally generated inner hair cells, marked by incorporation of EdU (white) and expression of calbindin (green), develop stereocilia, as indicated by phalloidin (actin) staining
(red). See the article by Walters et al. for details.
show that this may be possible. Conditionally knocking out p27 Kip148—a protein that
maintains cell-cycle arrest—selectively in
mouse neonatal hair cells caused the cells to
proliferate and generate new inner hair cells
that had stereocilia, expressed essential haircell proteins, and survived at least 6 weeks.
Many postnatally derived hair cells appeared to be contacted by innervating nerve
fibers. Importantly, auditory brainstem responses were normal despite the presence of
supernumerary hair cells in transgenic mice.
The next steps will be to determine whether
postnatally derived hair cells contribute to
auditory function and whether they can restore lost function.
F
Bradley J. Walters, Zhiyong Liu, Mark Crabtree,
Emily Coak, Brandon C. Cox, et al.
(see pages 15751–15763)
Hair cell degeneration causes permanent
hearing loss in mammals, but in birds, hair
cell death causes surrounding supporting
cells to re-enter the cell cycle and produce
new hair cells. Although attempts to replicate this process in mammalian supporting
cells have been somewhat successful, inducing hair cells themselves to re-enter the cell
cycle and replicate may enhance efforts to
restore hearing in humans. Walters et al.
F
Behavioral/Cognitive
TRP Channels and Serotonin Drive
Worms to Cool Locales
Takeshi Inoue, Taiga Yamashita,
and Kiyokazu Agata
(see pages 15701–15714)
Dugesia japonica is a species of nonparasitic
flatworms best known for the ability to regenerate two separate worms when cut in
half. Their relatively simple nervous system
also makes them a useful model for studying
behavioral control. Inoue et al. found that
when placed in a thermal gradient, flatworms moved toward the coolest available
temperature. This thermotaxis was also ex-
hibited by amputated head portions, but
not by headless bodies, even though these
bodies moved at normal speeds. This suggests that the brain was required to generate
thermotaxic behavior. Indeed, thermotaxis
was restored after the head and brain regenerated in decapitated worms. Furthermore,
knocking out synaptotagmin and thus preventing synaptic transmission in the regenerating brain prevented the reemergence of
thermotaxis. Of the two transient receptor
potential (TRP) channels expressed in a pattern suggestive of peripheral thermoreceptors, only one, a member of the melastatin
family, was required for thermotaxis. In addition, although GABAergic neurotransmission in the brain is required for
phototaxis, only serotonergic neurotransmission was required for thermotaxis.
F
Neurobiology of Disease
Developmental Regulators Are
Linked to Anxious Temperament
Reid S. Alisch, Pankaj Chopra, Andrew S. Fox,
Kailei Chen, Andrew T. J. White, et al.
(see pages 15548 –15556)
Anxious people are more easily distracted
by novel, potentially threatening stimuli,
and they remain focused on such stimuli
for longer than other people. These behavioral characteristics are accompanied
by greater activation of the extended
amygdala when threatening stimuli appear. Such individual differences in anxious temperament are heritable, and they
are apparent even in infants. Importantly,
toddlers who show heightened sensitivity
to and withdrawal from novel stimuli are
at increased risk for developing anxiety
disorders. Like humans, monkeys vary in
their responses to novel threatening stimuli, and anxious temperament in monkeys
is heritable, appears early in development,
and is reflected in heightened amygdalar
activation. To identify genes that might
contribute to anxious temperament, Alisch
et al. examined gene expression and DNA
methylation—an epigenetic modification
that regulates gene expression—in the
amygdala of monkeys varying in this trait.
They report that BCL11A and JAG1, two
genes involved in nervous system development, were more methylated and had lower
expression levels in more anxious monkeys.
The Journal of Neuroscience
November 19, 2014 • Volume 34 Number 47 • www.jneurosci.org
i
This Week in The Journal
Journal Club
15505
Large-Scale Network Involvement in Language Processing
Korey P. Wylie and Michael F. Regner
Articles
CELLULAR/MOLECULAR
Cover legend: A planarian, Dugesia japonica, and its
brain in the background showing serotonergic
neurons (white), GABAergic neurons (green),
dopaminergic neurons (magenta), and the other
neurons (cyan). Planaria, poikilotherms possessing a
sophisticated brain, show cryophilic thermotaxis
involving brain serotonergic neurons that process
thermosensory signals sensed by a member of the
TRPM receptor family. For more details, see the article
by Inoue et al. (pages 15701–15714).
䊉
15638
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and cAMP-Dependent
Modulation of Exocytosis in Cultured Rat Lactotrophs
Ana I. Calejo, Jernej Jorgacˇevski, Bosˇtjan Rituper, Alenka Gucˇek,
Patrícia M. Pereira, Manuel A.S. Santos, Maja Potokar, Nina Vardjan,
Marko Kreft, Paula P. Gonc¸alves, and Robert Zorec
15669
In Vivo Identification of Eugenol-Responsive and Muscone-Responsive Mouse
Odorant Receptors
Timothy S. McClintock, Kaylin Adipietro, William B. Titlow, Patrick Breheny,
Andreas Walz, Peter Mombaerts, and Hiroaki Matsunami
15689
Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal
Neurons and Glia
Daniel A. Ryskamp, Andrew O. Jo, Amber M. Frye, Felix Vazquez-Chona,
Nanna MacAulay, Wallace B. Thoreson, and David Krizˇaj
15764
Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation
and Mediates mTORC1-Dependent Myelination in Brain
Yi Zou, Wanxiang Jiang, Jianqing Wang, Zhongping Li, Junyan Zhang,
Jicheng Bu, Jia Zou, Liang Zhou, Shouyang Yu, Yiyuan Cui, Weiwei Yang,
Liping Luo, Qing R. Lu, Yanhui Liu, Mina Chen, Paul F. Worley, and Bo Xiao
15779
Netrin-G/NGL Complexes Encode Functional Synaptic Diversification
Hiroshi Matsukawa, Sachiko Akiyoshi-Nishimura, Qi Zhang, Rafael Luja´n,
Kazuhiko Yamaguchi, Hiromichi Goto, Kunio Yaguchi, Tsutomu Hashikawa,
Chie Sano, Ryuichi Shigemoto, Toshiaki Nakashiba, and Shigeyoshi Itohara
DEVELOPMENT/PLASTICITY/REPAIR
䊉
15751
Auditory Hair Cell-Specific Deletion of p27Kip1 in Postnatal Mice Promotes
Cell-Autonomous Generation of New Hair Cells and Normal Hearing
Bradley J. Walters, Zhiyong Liu, Mark Crabtree, Emily Coak, Brandon C. Cox,
and Jian Zuo
15816
Prox1 Regulates Olig2 Expression to Modulate Binary Fate Decisions in Spinal Cord
Neurons
Valeria Kaltezioti, Daphne Antoniou, Athanasios Stergiopoulos, Ismini Rozani,
Hermann Rohrer, and Panagiotis K. Politis
SYSTEMS/CIRCUITS
15508
Neural Representation of Motion-In-Depth in Area MT
Takahisa M. Sanada and Gregory C. DeAngelis
15522
Area MT Encodes Three-Dimensional Motion
Thaddeus B. Czuba, Alexander C. Huk, Lawrence K. Cormack, and Adam Kohn
15534
Functional Relationships between the Hippocampus and Dorsomedial Striatum in
Learning a Visual Scene-Based Memory Task in Rats
Se´bastien Delcasso, Namjung Huh, Jung Seop Byeon, Jihyun Lee, Min Whan Jung,
and Inah Lee
15557
The Neural Circuit Mechanisms Underlying the Retinal Response to Motion Reversal
Eric Y. Chen, Janice Chou, Jeongsook Park, Greg Schwartz,
and Michael J. Berry, II
15601
Pathway-Selective Adjustment of Prefrontal-Amygdala Transmission during Fear
Encoding
Maithe Arruda-Carvalho and Roger L. Clem
15621
Learning To Minimize Efforts versus Maximizing Rewards: Computational Principles
and Neural Correlates
Vasilisa Skvortsova, Stefano Palminteri, and Mathias Pessiglione
15722
Equilibrium-Based Movement Endpoints Elicited from Primary Motor Cortex Using
Repetitive Microstimulation
Gustaf M. Van Acker, III, Sommer L. Amundsen, William G. Messamore,
Hongyu Y. Zhang, Carl W. Luchies, and Paul D. Cheney
15793
Posttraining Ablation of Adult-Generated Olfactory Granule Cells Degrades
Odor–Reward Memories
Maithe Arruda-Carvalho, Katherine G. Akers, Axel Guskjolen,
Masanori Sakaguchi, Sheena A. Josselyn, and Paul W. Frankland
15804
Long-Term Memory Stabilized by Noise-Induced Rehearsal
Yi Wei and Alexei A. Koulakov
BEHAVIORAL/COGNITIVE
15576
Dissociating Movement from Movement Timing in the Rat Primary Motor Cortex
Eric B. Knudsen, Marissa E. Powers, and Karen A. Moxon
15610
Reward Activates Stimulus-Specific and Task-Dependent Representations in Visual
Association Cortices
Anne-Marike Schiffer, Timothy Muller, Nick Yeung, and Florian Waszak
15631
Regulation of Experience-Dependent Bidirectional Chemotaxis by a Neural Circuit
Switch in Caenorhabditis elegans
Yohsuke Satoh, Hirofumi Sato, Hirofumi Kunitomo, Xianfeng Fei,
Koichi Hashimoto, and Yuichi Iino
15648
Functional Compensation in the Ventromedial Prefrontal Cortex Improves
Memory-Dependent Decisions in Older Adults
Nichole R. Lighthall, Scott A. Huettel, and Roberto Cabeza
15679
Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved
in Anxiety Regulation
Timothy J. Schoenfeld, Alexander D. Kloth, Brian Hsueh, Matthew B. Runkle,
Gary A. Kane, Samuel S.-H. Wang, and Elizabeth Gould
䊉
15701
Thermosensory Signaling by TRPM Is Processed by Brain Serotonergic Neurons to
Produce Planarian Thermotaxis
Takeshi Inoue, Taiga Yamashita, and Kiyokazu Agata
15715
Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons
during Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss
Robbert Havekes, Vibeke M. Bruinenberg, Jennifer C. Tudor, Sarah L. Ferri,
Arnd Baumann, Peter Meerlo, and Ted Abel
15735
Cholinergic Stimulation Enhances Bayesian Belief Updating in the Deployment of
Spatial Attention
Simone Vossel, Markus Bauer, Christoph Mathys, Rick A. Adams,
Raymond J. Dolan, Klaas E. Stephan, and Karl J. Friston
15743
Dopamine Transporter Genotype Is Associated with a Lateralized Resistance to
Distraction during Attention Selection
Daniel P. Newman, Tarrant D.R. Cummins, Janette H.S. Tong, Beth P. Johnson,
Hayley Pickering, Peter Fanning, Joseph Wagner, Jack T.T. Goodrich,
Ziarih Hawi, Christopher D. Chambers, and Mark A. Bellgrove
NEUROBIOLOGY OF DISEASE
䊉
15548
Differentially Methylated Plasticity Genes in the Amygdala of Young Primates Are
Linked to Anxious Temperament, an at Risk Phenotype for Anxiety and Depressive
Disorders
Reid S. Alisch, Pankaj Chopra, Andrew S. Fox, Kailei Chen, Andrew T.J. White,
Patrick H. Roseboom, Sunduz Keles, and Ned H. Kalin
15587
Delayed Disease Onset and Extended Survival in the SOD1G93A Rat Model of
Amyotrophic Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex
Gretchen M. Thomsen, Genevieve Gowing, Jessica Latter, Maximus Chen,
Jean-Philippe Vit, Kevin Staggenborg, Pablo Avalos, Mor Alkaslasi,
Laura Ferraiuolo, Shibi Likhite, Brian K. Kaspar, and Clive N. Svendsen
15658
Differential Effects of Delayed Aging on Phenotype and Striatal Pathology in a Murine
Model of Huntington Disease
Sara J. Tallaksen-Greene, Marianna Sadagurski, Li Zeng, Roseanne Mauch,
Matthew Perkins, Varuna C. Banduseela, Andrew P. Lieberman,
Richard A. Miller, Henry L. Paulson, and Roger L. Albin
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Articles
CELLULAR/MOLECULAR
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and cAMP-Dependent
Modulation of Exocytosis in Cultured Rat Lactotrophs
Ana I. Calejo,1,2* Jernej Jorgacˇevski,2,4* Bosˇtjan Rituper,2 Alenka Gucˇek,2 Patrícia M. Pereira,1 Manuel A.S. Santos,1
Maja Potokar,2,4 Nina Vardjan,2,4 Marko Kreft,2,3,4 Paula P. Gonc¸alves,1 and Robert Zorec2,4
Centre for Environmental and Marine Studies & Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro, Portugal, 2Laboratory of
Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, and 3Biotechnical Faculty, University of Ljubljana, 1000
Ljubljana, Slovenia, and 4Celica Biomedical Center, 1000 Ljubljana, Slovenia
1
Hormone and neurotransmitter release from vesicles is mediated by regulated exocytosis, where an aqueous channel-like structure, termed a fusion pore, is formed. It was
recently shown that second messenger cAMP modulates the fusion pore, but the detailed mechanisms remain elusive. In this study, we asked whether the
hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are activated by cAMP, are involved in the regulation of unitary exocytic events. By using the
Western blot technique, a real-time PCR, immunocytochemistry in combination with confocal microscopy, and voltage-clamp measurements of hyperpolarizing currents,
we show that HCN channels are present in the plasma membrane and in the membrane of secretory vesicles of isolated rat lactotrophs. Single vesicle membrane
capacitance measurements of lactotrophs, where HCN channels were either augmented by transfection or blocked with an HCN channel blocker (ZD7288), show
modulated fusion pore properties. We suggest that the changes in local cation concentration, mediated through HCN channels, which are located on or near
secretory vesicles, have an important role in modulating exocytosis.
The Journal of Neuroscience, November 19, 2014 • 34(47):15638 –15647
In Vivo Identification of Eugenol-Responsive and Muscone-Responsive Mouse Odorant
Receptors
Timothy S. McClintock,1 Kaylin Adipietro,5 William B. Titlow,1 Patrick Breheny,2 Andreas Walz,3† Peter Mombaerts,3,4
and Hiroaki Matsunami5,6
Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, 2Department of Biostatistics, University of Iowa, Iowa City, Iowa 52242,
Rockefeller University, New York, New York 10065, 4Max Planck Research Unit for Neurogenetics, D-60438 Frankfurt, Germany, 5Department of
Molecular Genetics and Microbiology and 6Duke Institute for Brain Sciences, Department of Neurobiology, Duke University Medical Center, Durham,
North Carolina 27710
1
3
Our understanding of mammalian olfactory coding has been impeded by the paucity of information about the odorant receptors (ORs) that respond to a given odorant
ligand in awake, freely behaving animals. Identifying the ORs that respond in vivo to a given odorant ligand from among the ⬃1100 ORs in mice is intrinsically challenging
but critical for our understanding of olfactory coding at the periphery. Here, we report an in vivo assay that is based on a novel gene-targeted mouse strain, S100a5–tauGFP,
in which a fluorescent reporter selectively marks olfactory sensory neurons that have been activated recently in vivo. Because each olfactory sensory neuron expresses a
single OR gene, multiple ORs responding to a given odorant ligand can be identified simultaneously by capturing the population of activated olfactory sensory neurons and
using expression profiling methods to screen the repertoire of mouse OR genes. We used this in vivo assay to re-identify known eugenol- and muscone-responsive mouse
ORs. We identified additional ORs responsive to eugenol or muscone. Heterologous expression assays confirmed nine eugenol-responsive ORs (Olfr73, Olfr178, Olfr432,
Olfr610, Olfr958, Olfr960, Olfr961, Olfr913, and Olfr1234) and four muscone-responsive ORs (Olfr74, Olfr235, Olfr816, and Olfr1440). We found that the human ortholog of
Olfr235 and Olfr1440 responds to macrocyclic ketone and lactone musk odorants but not to polycyclic musk odorants or a macrocyclic diester musk odorant. This novel
assay, called the Kentucky in vivo odorant ligand–receptor assay, should facilitate the in vivo identification of mouse ORs for a given odorant ligand of interest.
The Journal of Neuroscience, November 19, 2014 • 34(47):15669 –15678
Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal Neurons
and Glia
Daniel A. Ryskamp,1,2 Andrew O. Jo,1 Amber M. Frye,1 Felix Vazquez-Chona,1 Nanna MacAulay,3
Wallace B. Thoreson,4,5 and David Krizˇaj1,2,6,7
Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and 2Interdepartmental Program in Neuroscience, Salt Lake City, Utah 84132,
Department of Cellular and Molecular Medicine, University of Copenhagen, 1165 Copenhagen, Denmark, 4Department of Ophthalmology & Visual
Sciences, and 5Department of Pharmacology and Experimental Neurosciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, and
6Department of Neurobiology & Anatomy and 7Center for Translational Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132
1
3
Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain
physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume
regulation is provided by Mu¨ller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Mu¨ller cell volume
increases into physiological responses. Hypotonic stimuli induced sustained [Ca 2⫹]i elevations that were inhibited by TRPV4 antagonists and absent in TRPV4 ⫺/⫺ Mu¨ller
cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca 2⫹ waves, and, in excess, were sufficient to induce
reactive gliosis. In contrast, neurons responded to TRPV4 agonists and swelling with fast, inactivating Ca 2⫹ signals that were independent of phospholipase A2. Our results
support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with
potentially significant consequences for normal and pathological retinal function.
The Journal of Neuroscience, November 19, 2014 • 34(47):15689 –15700
Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation and Mediates
mTORC1-Dependent Myelination in Brain
Yi Zou,1* Wanxiang Jiang,1* Jianqing Wang,1 Zhongping Li,1 Junyan Zhang,1,2 Jicheng Bu,1 Jia Zou,1 Liang Zhou,1
Shouyang Yu,1 Yiyuan Cui,1 Weiwei Yang,1 Liping Luo,1,2 Qing R. Lu,3 Yanhui Liu,4 Mina Chen,1 Paul F. Worley,2
and Bo Xiao1,2,4
Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China,
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 3Department of
Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, and 4Department of Neurosurgery,
West China Hospital, Sichuan University, 610041 Chengdu, P.R. China
1
2
Rheb1 is an immediate early gene that functions to activate mammalian target of rapamycin (mTor) selectively in complex 1 (mTORC1). We have demonstrated previously
that Rheb1 is essential for myelination in the CNS using a Nestin-Cre driver line that deletes Rheb1 in all neural cell lineages, and recent studies using oligodendrocytespecific CNP-Cre have suggested a preferential role for mTORC1 is myelination in the spinal cord. Here, we examine the role of Rheb1/mTORC1 in mouse oligodendrocyte
lineage using separate Cre drivers for oligodendrocyte progenitor cells (OPCs) including Olig1-Cre and Olig2-Cre as well as differentiated and mature oligodendrocytes
including CNP-Cre and Tmem10-Cre. Deletion of Rheb1 in OPCs impairs their differentiation to mature oligodendrocytes. This is accompanied by reduced OPC cell-cycle
exit suggesting a requirement for Rheb1 in OPC differentiation. The effect of Rheb1 on OPC differentiation is mediated by mTor since Olig1-Cre deletion of mTor
phenocopies Olig1-Cre Rheb1 deletion. Deletion of Rheb1 in mature oligodendrocytes, in contrast, does not disrupt developmental myelination or myelin maintenance.
Loss of Rheb1 in OPCs or neural progenitors does not affect astrocyte formation in gray and white matter, as indicated by the pan-astrocyte marker Aldh1L1. We conclude
that OPC-intrinsic mTORC1 activity mediated by Rheb1 is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require
Rheb1 to make myelin or maintain it in the adult brain. These studies reveal mechanisms that may be relevant for both developmental myelination and impaired
remyelination in myelin disease.
The Journal of Neuroscience, November 19, 2014 • 34(47):15764 –15778
Netrin-G/NGL Complexes Encode Functional Synaptic Diversification
Hiroshi Matsukawa,1 Sachiko Akiyoshi-Nishimura,1 Qi Zhang,1 Rafael Luja´n,2 Kazuhiko Yamaguchi,1 Hiromichi Goto,1
Kunio Yaguchi,1 Tsutomu Hashikawa,3 Chie Sano,1 Ryuichi Shigemoto,4,5 Toshiaki Nakashiba,1 and Shigeyoshi Itohara1
1Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), Wako, Saitama, 351-0198, Japan, 2IDINE, Departamento de Ciencias Me
´dicas,
Facultad de Medicina, Universidad Castilla-La Mancha, 13071 Albacete, Spain, 3Research Resource Center, RIKEN BSI, Wako, Saitama, 351-0198, Japan,
4Division of Cerebral Structure, National Institute for Physiological Science, Okazaki 444-8787, Japan, and 5IST Austria, 3400 Klosterneuburg, Austria
Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic
adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific
subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and
NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1
area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to
the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through
discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic
membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain
how synaptic inputs are diversified to control neuronal activity.
The Journal of Neuroscience, November 19, 2014 • 34(47):15779 –15792
DEVELOPMENT/PLASTICITY/REPAIR
Auditory Hair Cell-Specific Deletion of p27Kip1 in Postnatal Mice Promotes Cell-Autonomous
Generation of New Hair Cells and Normal Hearing
Bradley J. Walters,* Zhiyong Liu,* Mark Crabtree,* Emily Coak, Brandon C. Cox, and Jian Zuo
Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105
Hearing in mammals relies upon the transduction of sound by hair cells (HCs) in the organ of Corti within the cochlea of the inner ear. Sensorineural hearing loss is a
widespread and permanent disability due largely to a lack of HC regeneration in mammals. Recent studies suggest that targeting the retinoblastoma (Rb)/E2F pathway can
elicit proliferation of auditory HCs. However, previous attempts to induce HC proliferation in this manner have resulted in abnormal cochlear morphology, HC death, and
hearing loss. Here we show that cochlear HCs readily proliferate and survive following neonatal, HC-specific, conditional knock-out of p27 Kip1 (p27CKO), a tumor
suppressor upstream of Rb. Indeed, HC-specific p27CKO results in proliferation of these cells without the upregulation of the supporting cell or progenitor cell proteins,
Prox1 or Sox2, suggesting that they remain HCs. Furthermore, p27CKO leads to a significant addition of postnatally derived HCs that express characteristic synaptic and
stereociliary markers and survive to adulthood, although a portion of the newly derived inner HCs exhibit cytocauds and lack VGlut3 expression. Despite this, p27CKO mice
exhibit normal hearing as measured by evoked auditory brainstem responses, which suggests that the newly generated HCs may contribute to, or at least do not greatly
detract from, function. These results show that p27 Kip1 actively maintains HC quiescence in postnatal mice, and suggest that inhibition of p27 Kip1 in residual HCs represents
a potential strategy for cell-autonomous auditory HC regeneration.
The Journal of Neuroscience, November 19, 2014 • 34(47):15751–15763
Prox1 Regulates Olig2 Expression to Modulate Binary Fate Decisions in Spinal Cord Neurons
Valeria Kaltezioti,1 Daphne Antoniou,1 Athanasios Stergiopoulos,1 Ismini Rozani,1 Hermann Rohrer,2
and Panagiotis K. Politis1
Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and 2Research Group
Developmental Neurobiology, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany
1
Specification of spinal cord neurons depends on gene regulation networks that impose distinct fates in neural progenitor cells (NPCs). Olig2 is a key transcription factor in
these networks by inducing motor neuron (MN) specification and inhibiting interneuron identity. Despite the critical role of Olig2 in nervous system development and
cancer progression, the upstream molecular mechanisms that control Olig2 gene transcription are not well understood. Here we demonstrate that Prox1, a transcription
repressor and downstream target of proneural genes, suppresses Olig2 expression and therefore controls ventral spinal cord patterning. In particular, Prox1 is strongly
expressed in V2 interneuron progenitors and largely excluded from Olig2⫹ MN progenitors (pMN). Gain- and loss-of-function studies in mouse NPCs and chick neural tube
show that Prox1 is sufficient and necessary for the suppression of Olig2 expression and proper control of MN versus V2 interneuron identity. Mechanistically, Prox1
interacts with the regulatory elements of Olig2 gene locus in vivo and it is critical for proper Olig2 transcription regulation. Specifically, chromatin immunoprecipitation
analysis in the mouse neural tube showed that endogenous Prox1 directly binds to the proximal promoter of the Olig2 gene locus, as well as to the K23 enhancer, which drives
Olig2 expression in the pMN domain. Moreover, plasmid-based transcriptional assays in mouse NPCs suggest that Prox1 suppresses the activity of Olig2 gene promoter and
K23 enhancer. These observations indicate that Prox1 controls binary fate decisions between MNs and V2 interneurons in NPCs via direct repression of Olig2 gene
regulatory elements.
The Journal of Neuroscience, November 19, 2014 • 34(47):15816 –15831
SYSTEMS/CIRCUITS
Neural Representation of Motion-In-Depth in Area MT
Takahisa M. Sanada1 and Gregory C. DeAngelis2
Division of Sensory and Cognitive Information, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan and 2Department of Brain and
Cognitive Sciences, Center for Visual Science, University of Rochester, New York 14627
1
Neural processing of 2D visual motion has been studied extensively, but relatively little is known about how visual cortical neurons represent visual motion trajectories that include
a component toward or away from the observer (motion in depth). Psychophysical studies have demonstrated that humans perceive motion in depth based on both changes in
binocular disparity over time (CD cue) and interocular velocity differences (IOVD cue). However, evidence for neurons that represent motion in depth has been limited, especially
in primates, and it is unknown whether such neurons make use of CD or IOVD cues. We show that approximately one-half of neurons in macaque area MT are selective for the
direction of motion in depth, and that this selectivity is driven primarily by IOVD cues, with a small contribution from the CD cue. Our results establish that area MT, a central hub
of the primate visual motion processing system, contains a 3D representation of visual motion.
The Journal of Neuroscience, November 19, 2014 • 34(47):15508 –15521
Area MT Encodes Three-Dimensional Motion
Thaddeus B. Czuba,1 Alexander C. Huk,3,4,5 Lawrence K. Cormack,3,5 and Adam Kohn1,2
Dominick Purpura Department of Neuroscience, and 2Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New
York 10461, and 3Center for Perceptual Systems, Departments of 4Neuroscience and 5Psychology, The University of Texas at Austin, Austin, Texas 78712
1
We use visual information to determine our dynamic relationship with other objects in a three-dimensional (3D) world. Despite decades of work on visual motion
processing, it remains unclear how 3D directions—trajectories that include motion toward or away from the observer—are represented and processed in visual cortex.
Area MT is heavily implicated in processing visual motion and depth, yet previous work has found little evidence for 3D direction sensitivity per se. Here we use a rich
ensemble of binocular motion stimuli to reveal that most neurons in area MT of the anesthetized macaque encode 3D motion information. This tuning for 3D motion arises
from multiple mechanisms, including different motion preferences in the two eyes and a nonlinear interaction of these signals when both eyes are stimulated. Using a novel
method for functional binocular alignment, we were able to rule out contributions of static disparity tuning to the 3D motion tuning we observed. We propose that a primary
function of MT is to encode 3D motion, critical for judging the movement of objects in dynamic real-world environments.
The Journal of Neuroscience, November 19, 2014 • 34(47):15522–15533
Functional Relationships between the Hippocampus and Dorsomedial Striatum in Learning a
Visual Scene-Based Memory Task in Rats
Se´bastien Delcasso,1 Namjung Huh,2 Jung Seop Byeon,1 Jihyun Lee,1 Min Whan Jung,2,3 and Inah Lee1
Department of Brain and Cognitive Sciences, Seoul National University, Seoul, 151-742, Korea, 2Center for Synaptic Dysfunctions, Institute for Basic
Science, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea, and 3Department of Biological Sciences, Korea Advanced Institute
of Science and Technology, Daejeon, 305-701, Korea
1
The hippocampus is important for contextual behavior, and the striatum plays key roles in decision making. When studying the functional relationships with the
hippocampus, prior studies have focused mostly on the dorsolateral striatum (DLS), emphasizing the antagonistic relationships between the hippocampus and DLS in
spatial versus response learning. By contrast, the functional relationships between the dorsomedial striatum (DMS) and hippocampus are relatively unknown. The current
study reports that lesions to both the hippocampus and DMS profoundly impaired performance of rats in a visual scene-based memory task in which the animals were
required to make a choice response by using visual scenes displayed in the background. Analysis of simultaneous recordings of local field potentials revealed that the
gamma oscillatory power was higher in the DMS, but not in CA1, when the rat performed the task using familiar scenes than novel ones. In addition, the CA1-DMS networks
increased coherence at ␥, but not at ␪, rhythm as the rat mastered the task. At the single-unit level, the neuronal populations in CA1 and DMS showed differential firing
patterns when responses were made using familiar visual scenes than novel ones. Such learning-dependent firing patterns were observed earlier in the DMS than in CA1
before the rat made choice responses. The present findings suggest that both the hippocampus and DMS process memory representations for visual scenes in parallel with
different time courses and that flexible choice action using background visual scenes requires coordinated operations of the hippocampus and DMS at ␥ frequencies.
The Journal of Neuroscience, November 19, 2014 • 34(47):15534 –15547
The Neural Circuit Mechanisms Underlying the Retinal Response to Motion Reversal
Eric Y. Chen,1,2 Janice Chou,2 Jeongsook Park,1 Greg Schwartz,3 and Michael J. Berry, II1,4
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, 2University of Medicine and Dentistry of New Jersey Robert Wood
Johnson Medical School, Piscataway, New Jersey 08854, 3Departments of Ophthalmology and Physiology, Northwestern University of Washington, Chicago,
Illinois 60611, and 4Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08544
1
Tomakeupfordelaysinvisualprocessing,retinalcircuitryeffectivelypredictsthatamovingobjectwillcontinuemovinginastraightline,allowingretinalganglioncellstoanticipate
the object’s position. However, a sudden reversal of motion triggers a synchronous burst of firing from a large group of ganglion cells, possibly signaling a violation of the retina’s
motion prediction. To investigate the neural circuitry underlying this response, we used a combination of multielectrode array and whole-cell patch recordings to measure the
responsesofindividualretinalganglioncellsinthetigersalamandertoreversingstimuli.Wefoundthatdifferentpopulationsofganglioncellswereresponsibleforrespondingtothe
reversal of different kinds of objects, such as bright versus dark objects. Using pharmacology and designed stimuli, we concluded that ON and OFF bipolar cells both contributed to
the reversal response, but that amacrine cells had, at best, a minor role. This allowed us to formulate an adaptive cascade model (ACM), similar to the one previously used to describe
ganglion cell responses to motion onset. By incorporating the ON pathway into the ACM, we were able to reproduce the time-varying firing rate of fast OFF ganglion cells for all
experimentallytestedstimuli.AnalysisoftheACMdemonstratesthatbipolarcellgaincontrolisprimarilyresponsibleforgeneratingthesynchronizedretinalresponse,asindividual
bipolar cells require a constant time delay before recovering from gain control.
The Journal of Neuroscience, November 19, 2014 • 34(47):15557–15575
Pathway-Selective Adjustment of Prefrontal-Amygdala Transmission during Fear Encoding
Maithe Arruda-Carvalho and Roger L. Clem
The Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
Conditioned fear requires neural activity in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), structures that are densely interconnected at the synaptic
level. Previous work has suggested that anatomical subdivisions of mPFC make distinct contributions to fear expression and inhibition, and that the functional output of
this processing is relayed to the BLA complex. However, it remains unknown whether synaptic plasticity in mPFC-BLA networks contributes to fear memory encoding. Here
we use optogenetics and ex vivo electrophysiology to reveal the impact of fear conditioning on BLA excitatory and feedforward inhibitory circuits formed by projections
from infralimbic (IL) and prelimbic (PL) cortices. In naive mice, these pathways recruit equivalent excitation and feedforward inhibition in BLA principal neurons.
However, fear learning leads to a selective decrease in inhibition:excitation balance in PL circuits that is attributable to a postsynaptic increase in AMPA receptor function.
These data suggest a pathway-specific mechanism for fear memory encoding by adjustment of mPFC-BLA transmission. Upon reengagement of PL by conditioned cues,
these modifications may serve to amplify emotional responses.
The Journal of Neuroscience, November 19, 2014 • 34(47):15601–15609
Learning To Minimize Efforts versus Maximizing Rewards: Computational Principles and
Neural Correlates
Vasilisa Skvortsova,1,2 Stefano Palminteri,1,2,3,4 and Mathias Pessiglione1,2
Motivation, Brain and Behavior Laboratory, Neuroimaging Research Center, Brain and Spine Institute, 2INSERM U975, CNRS UMR 7225, UPMC-P6 UMR
S 1127, 7561 Paris Cedex 13, France, 3Laboratoire de Neurosciences Cognitives, INSERM U960, and 4De´partement d’Etudes Cognitives, Ecole Normale
Supe´rieure, 7505, Paris, France
1
The mechanisms of reward maximization have been extensively studied at both the computational and neural levels. By contrast, little is known about how the brain learns
to choose the options that minimize action cost. In principle, the brain could have evolved a general mechanism that applies the same learning rule to the different
dimensions of choice options. To test this hypothesis, we scanned healthy human volunteers while they performed a probabilistic instrumental learning task that varied in
both the physical effort and the monetary outcome associated with choice options. Behavioral data showed that the same computational rule, using prediction errors to
update expectations, could account for both reward maximization and effort minimization. However, these learning-related variables were encoded in partially dissociable
brain areas. In line with previous findings, the ventromedial prefrontal cortex was found to positively represent expected and actual rewards, regardless of effort. A separate
network, encompassing the anterior insula, the dorsal anterior cingulate, and the posterior parietal cortex, correlated positively with expected and actual efforts. These
findings suggest that the same computational rule is applied by distinct brain systems, depending on the choice dimension— cost or benefit—that has to be learned.
The Journal of Neuroscience, November 19, 2014 • 34(47):15621–15630
Equilibrium-Based Movement Endpoints Elicited from Primary Motor Cortex Using Repetitive
Microstimulation
Gustaf M. Van Acker, III,1 Sommer L. Amundsen,2 William G. Messamore,1 Hongyu Y. Zhang,1 Carl W. Luchies,2,3
and Paul D. Cheney1
1University of Kansas Medical Center, Department of Molecular and Integrative Physiology, Kansas City, Kansas 66160, 2University of Kansas,
Bioengineering Graduate Program, Lawrence, Kansas 66045, and 3University of Kansas, Department of Mechanical Engineering, Lawrence, Kansas 66045
High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and
movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been
systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus
parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion
on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations
in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were
few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at
the boundary between the hand and face representation. Endpoints at the extremes of the monkey’s workspace and locations above the head were largely absent. Our
movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the
length–tension relationships of the muscles.
The Journal of Neuroscience, November 19, 2014 • 34(47):15722–15734
Posttraining Ablation of Adult-Generated Olfactory Granule Cells Degrades Odor–Reward
Memories
Maithe Arruda-Carvalho,1,2 Katherine G. Akers,1 Axel Guskjolen,1,3 Masanori Sakaguchi,1 Sheena A. Josselyn,1,2,3,4 and
Paul W. Frankland1,2,3,4
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8, and 2Institute of Medical Science and
Departments of 3Physiology and 4Psychology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
1
Proliferation of neural progenitor cells in the subventricular zone leads to the continuous generation of new olfactory granule cells (OGCs) throughout life. These cells
synaptically integrate into olfactory bulb circuits after ⬃2 weeks and transiently exhibit heightened plasticity and responses to novel odors. Although these observations
suggest that adult-generated OGCs play important roles in olfactory-related memories, global suppression of olfactory neurogenesis does not typically prevent the
formation of odor–reward memories, perhaps because residual OGCs can compensate. Here, we used a transgenic strategy to selectively ablate large numbers of adultgenerated OGCs either before or after learning in mice. Consistent with previous studies, pretraining ablation of adult-generated OGCs did not prevent the formation of an
odor–reward memory, presumably because existing OGCs can support memory formation in their absence. However, ablation of a similar cohort of adult-generated OGCs
after training impaired subsequent memory expression, indicating that if these cells are available at the time of training, they play an essential role in subsequent expression
of odor–reward memories. Memory impairment was associated with the loss of adult-generated OGCs that were ⬎10 d in age and did not depend on the developmental
stage in which they were generated, suggesting that, once sufficiently mature, OGCs generated during juvenility and adulthood play similar roles in the expression of
odor–reward memories. Finally, ablation of adult-generated OGCs 1 month after training did not produce amnesia, indicating that adult-generated OGCs play a timelimited role in the expression of odor–reward memories.
The Journal of Neuroscience, November 19, 2014 • 34(47):15793–15803
Long-Term Memory Stabilized by Noise-Induced Rehearsal
Yi Wei and Alexei A. Koulakov
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
Cortical networks can maintain memories for decades despite the short lifetime of synaptic strengths. Can a neural network store long-lasting memories in unstable
synapses? Here, we study the effects of ongoing spike-timing-dependent plasticity (STDP) on the stability of memory patterns stored in synapses of an attractor neural
network. We show that certain classes of STDP rules can stabilize all stored memory patterns despite a short lifetime of synapses. In our model, unstructured neural noise,
after passing through the recurrent network connections, carries the imprint of all memory patterns in temporal correlations. STDP, combined with these correlations,
leads to reinforcement of all stored patterns, even those that are never explicitly visited. Our findings may provide the functional reason for irregular spiking displayed by
cortical neurons and justify models of system memory consolidation. Therefore, we propose that irregular neural activity is the feature that helps cortical networks
maintain stable connections.
The Journal of Neuroscience, November 19, 2014 • 34(47):15804 –15815
BEHAVIORAL/COGNITIVE
Dissociating Movement from Movement Timing in the Rat Primary Motor Cortex
Eric B. Knudsen,1 Marissa E. Powers,1 and Karen A. Moxon1,2
1Drexel University School of Biomedical Engineering and Health Sciences and 2Drexel University College of Medicine Departments of Neurobiology and
Anatomy, Philadelphia, Pennsylvania 19104
Neural encoding of the passage of time to produce temporally precise movements remains an open question. Neurons in several brain regions across different experimental
contexts encode estimates of temporal intervals by scaling their activity in proportion to the interval duration. In motor cortex the degree to which this scaled activity relies
upon afferent feedback and is guided by motor output remains unclear. Using a neural reward paradigm to dissociate neural activity from motor output before and after
complete spinal transection, we show that temporally scaled activity occurs in the rat hindlimb motor cortex in the absence of motor output and after transection.
Context-dependent changes in the encoding are plastic, reversible, and re-established following injury. Therefore, in the absence of motor output and despite a loss of
afferent feedback, thought necessary for timed movements, the rat motor cortex displays scaled activity during a broad range of temporally demanding tasks similar to that
identified in other brain regions.
The Journal of Neuroscience, November 19, 2014 • 34(47):15576 –15586
Reward Activates Stimulus-Specific and Task-Dependent Representations in Visual Association
Cortices
Anne-Marike Schiffer,1 Timothy Muller,1 Nick Yeung,1 and Florian Waszak2,3
Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom, 2Universite´ Paris Descartes, Sorbonne Paris Cite´, 75270
Paris, France, and 3CNRS Laboratoire Psychologie de la Perception, Unite´ Mixte de Recherche 8242, 75006 Paris, France
1
Humans reliably learn which actions lead to rewards. One prominent question is how credit is assigned to environmental stimuli that are acted upon. Recent functional
magnetic resonance imaging (fMRI) studies have provided evidence that representations of rewarded stimuli are activated upon reward delivery, providing possible
eligibility traces for credit assignment. Our study sought evidence of postreward activation in sensory cortices satisfying two conditions of instrumental learning:
postreward activity should reflect the stimulus category that preceded reward (stimulus specificity), and should occur only if the stimulus was acted on to obtain reward
(task dependency). Our experiment implemented two tasks in the fMRI scanner. The first was a perceptual decision-making task on degraded face and house stimuli.
Stimulus specificity was evident as rewards activated the sensory cortices associated with face versus house perception more strongly after face versus house decisions,
respectively, particularly in the fusiform face area. Stimulus specificity was further evident in a psychophysiological interaction analysis wherein face-sensitive areas
correlated with nucleus accumbens activity after face-decision rewards, whereas house-sensitive areas correlated with nucleus accumbens activity after house-decision
rewards. The second task required participants to make an instructed response. The criterion of task dependency was fulfilled as rewards after face versus house responses
activated the respective association cortices to a larger degree when faces and houses were relevant to the performed task. Our study is the first to show that postreward
sensory cortex activity meets these two key criteria of credit assignment, and does so independently from bottom-up perceptual processing.
The Journal of Neuroscience, November 19, 2014 • 34(47):15610 –15620
Regulation of Experience-Dependent Bidirectional Chemotaxis by a Neural Circuit Switch in
Caenorhabditis elegans
Yohsuke Satoh,1 Hirofumi Sato,1 Hirofumi Kunitomo,1 Xianfeng Fei,2 Koichi Hashimoto,3 and Yuichi Iino1,4
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, 2Department of Intelligent
Information Systems, Faculty of Science and Technology, Tohoku Bunka Gakuen University, Aoba-ku, Sendai 980-8579, Japan, 3Department of System
Information Sciences, Graduate School of Information Sciences, Tohoku University, Aoba-ku, Sendai 980-8579, Japan, and 4CREST, Japan Science and
Technology Agency, Kawaguchi, Saitama 332-0012, Japan
1
The nematode Caenorhabditis elegans changes its chemotaxis to NaCl depending on previous experience. At the behavioral level, this chemotactic plasticity is generated by
reversing the elementary behaviors for chemotaxis, klinotaxis, and klinokinesis. Here, we report that bidirectional klinotaxis is achieved by the proper use of at least two
different neural subcircuits. We simulated an NaCl concentration change by activating an NaCl-sensitive chemosensory neuron in phase with head swing and successfully
induced klinotaxis-like curving. The curving direction reversed depending on preconditioning, which was consistent with klinotaxis plasticity under a real concentration
gradient. Cell-specific ablation and activation of downstream interneurons revealed that ASER-evoked curving toward lower concentration was mediated by AIY interneurons, whereas curving to the opposite direction was not. These results suggest that the experience-dependent bidirectionality of klinotaxis is generated by a switch between
different neural subcircuits downstream of the chemosensory neuron.
The Journal of Neuroscience, November 19, 2014 • 34(47):15631–15637
Functional Compensation in the Ventromedial Prefrontal Cortex Improves Memory-Dependent
Decisions in Older Adults
Nichole R. Lighthall,1 Scott A. Huettel,1,2,3 and Roberto Cabeza1
Center for Cognitive Neuroscience, 2Department of Psychology and Neuroscience, and 3Brain Imaging and Analysis Center, Duke University, Durham,
North Carolina 27708
1
Everyday consumer choices frequently involve memory, as when we retrieve information about consumer products when making purchasing decisions. In this context,
poor memory may affect decision quality, particularly in individuals with memory decline, such as older adults. However, age differences in choice behavior may be reduced
if older adults can recruit additional neural resources that support task performance. Although such functional compensation is well documented in other cognitive
domains, it is presently unclear whether it can support memory-guided decision making and, if so, which brain regions play a role in compensation. The current study
engaged younger and older humans in a memory-dependent choice task in which pairs of consumer products from a popular online-shopping site were evaluated with
different delays between the first and second product. Using functional imaging (fMRI), we found that the ventromedial prefrontal cortex (vmPFC) supports compensation
as defined by three a priori criteria: (1) increased vmPFC activation was observed in older versus younger adults; (2) age-related increases in vmPFC activity were associated
with increased retrieval demands; and (3) increased vmPFC activity was positively associated with performance in older adults— evidence of successful compensation.
Extending these results, we observed evidence for compensation in connectivity between vmPFC and the dorsolateral PFC during memory-dependent choice. In contrast,
we found no evidence for age differences in value-related processing or age-related compensation for choices without delayed retrieval. Together, these results converge on
the conclusion that age-related decline in memory-dependent choice performance can be minimized via functional compensation in vmPFC.
The Journal of Neuroscience, November 19, 2014 • 34(47):15648 –15657
Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved in Anxiety
Regulation
Timothy J. Schoenfeld,1 Alexander D. Kloth,2 Brian Hsueh,1 Matthew B. Runkle,1 Gary A. Kane,1 Samuel S.-H. Wang,2
and Elizabeth Gould1
Departments of 1Psychology and 2Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08544
Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the
ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with
electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into
the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP
combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal
HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among
inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these
findings suggest that neuronal gap junctions in the vHIP–mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional
mechanisms are likely involved in running-induced reduction in anxiety.
The Journal of Neuroscience, November 19, 2014 • 34(47):15679 –15688
Thermosensory Signaling by TRPM Is Processed by Brain Serotonergic Neurons to Produce
Planarian Thermotaxis
Takeshi Inoue,* Taiga Yamashita,* and Kiyokazu Agata
Department of Biophysics, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo-ku, Kyoto 606-8502, Japan
For most organisms, sensitive recognition of even slight changes in environmental temperature is essential for adjusting their behavioral strategies to ensure homeostasis
and survival. However, much remains to be understood about the molecular and cellular processes that regulate thermosensation and the corresponding behavioral
responses. Planarians display clear thermotaxis, although they have a relatively simple brain. Here, we devised a quantitative thermotaxis assay and unraveled a neural
pathway involved in planarian thermotaxis by combinatory behavioral assays and RNAi analysis. We found that thermosensory neurons that expressed a planarian Dugesia
japonica homolog of the Transient Receptor Potential Melastatin family a (DjTRPMa) gene were required for the thermotaxis. Interestingly, although these thermosensory
neurons are distributed throughout their body, planarians with a dysfunctional brain due to regeneration-dependent conditional gene knockdown (Readyknock) of the
synaptotagmin gene completely lost their thermotactic behavior. These results suggest that brain function is required as a central processor for the thermosensory response.
Therefore, we investigated the type(s) of brain neurons involved in processing the thermal signals by gene knockdown of limiting enzymes for neurotransmitter biosynthesis in the brain. We found that serotonergic neurons with dendrites that were elongated toward DjTRPMa-expressing thermosensory neurons might be required for the
processing of signals from thermosensory neurons that results in thermotaxis. These results suggest that serotonergic neurons in the brain may interact with thermosensory neurons activated by TRPM ion channels to produce thermotaxis in planarians.
The Journal of Neuroscience, November 19, 2014 • 34(47):15701–15714
Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during
Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss
Robbert Havekes,1 Vibeke M. Bruinenberg,1,2 Jennifer C. Tudor,1 Sarah L. Ferri,1 Arnd Baumann,3 Peter Meerlo,2
and Ted Abel1
1Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 2Center for Behavior and Neurosciences, University of Groningen,
Groningen, The Netherlands, and 3Forschungszentrum Ju¨lich, Institute of Complex Systems, Zellula¨re Biophysik (ICS-4), D-52425 Ju¨lich, Germany
The hippocampus is particularly sensitive to sleep loss. Although previous work has indicated that sleep deprivation impairs hippocampal cAMP signaling, it remains to be
determined whether the cognitive deficits associated with sleep deprivation are caused by attenuated cAMP signaling in the hippocampus. Further, it is unclear which cell
types are responsible for the memory impairments associated with sleep deprivation. Transgenic approaches lack the spatial resolution to manipulate specific signaling
pathways selectively in the hippocampus, while pharmacological strategies are limited in terms of cell-type specificity. Therefore, we used a pharmacogenetic approach
based on a virus-mediated expression of a G␣s-coupled Drosophila octopamine receptor selectively in mouse hippocampal excitatory neurons in vivo. With this approach,
a systemic injection with the receptor ligand octopamine leads to increased cAMP levels in this specific set of hippocampal neurons. We assessed whether transiently
increasing cAMP levels during sleep deprivation prevents memory consolidation deficits associated with sleep loss in an object–location task. Five hours of total sleep
deprivation directly following training impaired the formation of object–location memories. Transiently increasing cAMP levels in hippocampal neurons during the course
of sleep deprivation prevented these memory consolidation deficits. These findings demonstrate that attenuated cAMP signaling in hippocampal excitatory neurons is a
critical component underlying the memory deficits in hippocampus-dependent learning tasks associated with sleep deprivation.
The Journal of Neuroscience, November 19, 2014 • 34(47):15715–15721
Cholinergic Stimulation Enhances Bayesian Belief Updating in the Deployment of Spatial
Attention
Simone Vossel,1,2 Markus Bauer,1,3 Christoph Mathys,1,4,5 Rick A. Adams,1 Raymond J. Dolan,1 Klaas E. Stephan,1,5,6 and
Karl J. Friston1
Wellcome Trust Centre for Neuroimaging, University College London, WC1N 3BG London, United Kingdom, 2Cognitive Neuroscience, Institute of
Neuroscience and Medicine (INM-3), Research Centre Juelich, 52425 Juelich Germany, 3School of Psychology, University of Nottingham, University Park,
Nottingham NG7 2RD, United Kingdom, 4Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, United Kingdom,
5Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and ETH Zurich, 8032 Zurich, Switzerland, and 6Laboratory
for Social and Neural Systems Research, University of Zurich, 8006 Zurich, Switzerland
1
The exact mechanisms whereby the cholinergic neurotransmitter system contributes to attentional processing remain poorly understood. Here, we applied computational
modeling to psychophysical data (obtained from a spatial attention task) under a psychopharmacological challenge with the cholinesterase inhibitor galantamine (Reminyl). This allowed us to characterize the cholinergic modulation of selective attention formally, in terms of hierarchical Bayesian inference. In a placebo-controlled,
within-subject, crossover design, 16 healthy human subjects performed a modified version of Posner’s location-cueing task in which the proportion of validly and invalidly
cued targets (percentage of cue validity, % CV) changed over time. Saccadic response speeds were used to estimate the parameters of a hierarchical Bayesian model to test
whether cholinergic stimulation affected the trial-wise updating of probabilistic beliefs that underlie the allocation of attention or whether galantamine changed the
mapping from those beliefs to subsequent eye movements. Behaviorally, galantamine led to a greater influence of probabilistic context (% CV) on response speed than
placebo. Crucially, computational modeling suggested this effect was due to an increase in the rate of belief updating about cue validity (as opposed to the increased
sensitivity of behavioral responses to those beliefs). We discuss these findings with respect to cholinergic effects on hierarchical cortical processing and in relation to the
encoding of expected uncertainty or precision.
The Journal of Neuroscience, November 19, 2014 • 34(47):15735–15742
Dopamine Transporter Genotype Is Associated with a Lateralized Resistance to Distraction
during Attention Selection
Daniel P. Newman,1 Tarrant D.R. Cummins,1 Janette H.S. Tong,1 Beth P. Johnson,1 Hayley Pickering,1 Peter Fanning,1
Joseph Wagner,2 Jack T.T. Goodrich,2 Ziarih Hawi,1 Christopher D. Chambers,3 and Mark A. Bellgrove1,2
Monash University, School of Psychological Sciences, Clayton, Victoria 3800, Australia, 2The University of Queensland, Queensland Brain Institute and
School of Psychology, Brisbane, Queensland 4072, Australia, and 3Cardiff University, School of Psychology, Cardiff CF10 3AT, United Kingdom
1
Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative
contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional
versus response selection. A sample of nonclinical adult humans (N ⫽ 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker
tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively
functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and
confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and
spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele
demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were
presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None
of these significant effects could be explained by speed–accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.
The Journal of Neuroscience, November 19, 2014 • 34(47):15743–15750
NEUROBIOLOGY OF DISEASE
Differentially Methylated Plasticity Genes in the Amygdala of Young Primates Are Linked to
Anxious Temperament, an at Risk Phenotype for Anxiety and Depressive Disorders
Reid S. Alisch,1 Pankaj Chopra,5 Andrew S. Fox,2,4,6 Kailei Chen,3 Andrew T.J. White,1 Patrick H. Roseboom,1
Sunduz Keles,3 and Ned H. Kalin1,2,4,6
Departments of 1Psychiatry, 2Psychology, 3Statistics, and the 4Health Emotion Research Institute, University of Wisconsin, Madison, Wisconsin 53719,
5Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and 6Waisman Laboratory for Brain Imaging and Behavior,
University of Wisconsin, Madison, Wisconsin 53705
Children with an anxious temperament (AT) are at a substantially increased risk to develop anxiety and depression. The young rhesus monkey is ideal for studying the
origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. Heritability, functional
imaging, and gene expression studies of AT in young monkeys revealed that the central nucleus of the amygdala (Ce) is a key environmentally sensitive substrate of this at
risk phenotype. Because epigenetic marks (e.g., DNA methylation) can be modulated by environmental stimuli, these data led us to hypothesize a role for DNA methylation
in the development of AT. To test this hypothesis, we used reduced representation bisulfite sequencing to examine the cross-sectional genome-wide methylation levels in
the Ce of 23 age-matched monkeys (1.3 ⫾ 0.2 years) phenotyped for AT. Because AT reflects a continuous trait-like variable, we used an analytical approach that is
consistent with this biology to identify genes in the Ce with methylation patterns that predict AT. Expression data from the Ce of these same monkeys were then used to find
differentially methylated candidates linked to altered gene regulation. Two genes particularly relevant to the AT phenotype were BCL11A and JAG1. These transcripts have
well-defined roles in neurodevelopmental processes, including neurite arborization and the regulation of neurogenesis. Together, these findings represent a critical step
toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety and depressive disorders.
The Journal of Neuroscience, November 19, 2014 • 34(47):15548 –15556
Delayed Disease Onset and Extended Survival in the SOD1G93A Rat Model of Amyotrophic
Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex
Gretchen M. Thomsen,1 Genevieve Gowing,1 Jessica Latter,1 Maximus Chen,1 Jean-Philippe Vit,2,3 Kevin Staggenborg,1
Pablo Avalos,1 Mor Alkaslasi,1 Laura Ferraiuolo,4 Shibi Likhite,4 Brian K. Kaspar,4,5
and Clive N. Svendsen1,2
Board of Governors Regenerative Medicine Institute, 2Department of Biomedical Sciences, and 3Biobehavioral Research Core, Cedars-Sinai Medical
Center, Los Angeles, California 90048, 4Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, and
5Department of Neuroscience, Ohio State University, Columbus, Ohio 43210
1
Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death
typically within 3–5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to
cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical
changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord
and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that,
in the SOD1 G93A rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although
overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role
in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1 G93A rats through targeted delivery of AAV9 –SOD1–
shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an
early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.
The Journal of Neuroscience, November 19, 2014 • 34(47):15587–15600
Differential Effects of Delayed Aging on Phenotype and Striatal Pathology in a Murine Model of
Huntington Disease
Sara J. Tallaksen-Greene,1 Marianna Sadagurski,2 Li Zeng,1 Roseanne Mauch,1 Matthew Perkins,1
Varuna C. Banduseela,3 Andrew P. Lieberman,3 Richard A. Miller,3 Henry L. Paulson,1,4 and Roger L. Albin1,4,5
Departments of 1Neurology, 2Internal Medicine, 3Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109, 4Michigan
Alzheimer Disease Center, Ann Arbor, Michigan 48105, and 5Neurology Service and Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann
Arbor, Michigan 48105
The common neurodegenerative syndromes exhibit age-related incidence, and many Mendelian neurodegenerative diseases exhibit age-related penetrance. Mutations
slowing aging retard age related pathologies. To assess whether delayed aging retards the effects of a mutant allele causing a Huntington’s disease (HD)-like syndrome, we
generated compound mutant mice, placing a dominant HD knock-in polyglutamine allele onto the slow-aging Snell dwarf genotype. The Snell genotype did not affect
mutant huntingtin protein expression. Bigenic and control mice were evaluated prospectively from 10 to 100 weeks of age. Adult HD knock-in allele mice lost weight
progressively with weight loss blunted significantly in male bigenic HD knock-in/Snell dwarf mice. Impaired balance beam performance developed significantly more
slowly in bigenic HD knock-in/Snell dwarf mice. Striatal dopamine receptor expression was diminished significantly and similarly in all HD-like mice, regardless of the Snell
genotype. Striatal neuronal intranuclear inclusion burden was similar between HD knock-in mice with and without the Snell genotype, whereas nigral neuropil aggregates
were diminished in bigenic HD knock-in/Snell dwarf mice. Compared with control mice, Snell dwarf mice exhibited differences in regional benzodiazepine and cannabinoid
receptor binding site expression. These results indicate that delaying aging delayed behavioral decline with little effect on the development of striatal pathology in this
model of HD but may have altered synaptic pathology. These results indicate that mutations prolonging lifespan in mice delay onset of significant phenotypic features of this
model and also demonstrate dissociation between striatal pathology and a commonly used behavioral measure of disease burden in HD models.
The Journal of Neuroscience, November 19, 2014 • 34(47):15658 –15668