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The Journal of Neuroscience, December 16, 2009 • 29(50):i • i
This Week in The Journal
F Cellular/Molecular ΠDevelopment/Plasticity/Repair shape orientation tuning, GABA and GABA
antagonists increase or decrease orientation
NMDA Receptors Drive Bursting in Ventral Spinal Interneurons Drive selectivity of neurons, respectively. Further-
Dopaminergic Neurons Simultaneous Contralateral Activity more, visual stimuli induce GABA-dependent
gamma frequency (30–80 Hz) oscillations in
Christopher A. Deister, Mark A. Nadine Rabe, Henrik Gezelius, excitatory and inhibitory neurons in the visual
Teagarden, Charles J. Wilson Anna Vallstedt, Fatima Memic, and cortex. The frequency of gamma oscillations is
and Carlos A. Paladini Klas Kullander correlated with GABA concentration, and Ed-
(see pages 15888 –15897) den et al. now report that across individuals,
(see pages 15642–15649)
the ability of people to discriminate the orien-
Dopaminergic neurons in the substantia nigra Mammalian locomotion is controlled by spi- tation of oblique stimuli increases with in-
exhibit two firing modes. Bursting occurs nalcordcentralpatterngeneratorscomprising creased cortical GABA levels (measured with
when an animal receives an unexpected re- interneurons that drive motor neuron burst- magnetic resonance spectroscopy) and with
ward or a stimulus that is associated with re- ing. In some behaviors, e.g., walking, inhibi- the frequency of gamma oscillations (mea-
ward, while an underlying pacemaker activity tory connections across the midline cause sured via magnetoencephalography). Dis-
sets baseline dopamine levels and thus regu- alternating bursts in contralateral motor neu- crimination of vertical stimuli was not
lates burst amplitude. Last week we high- rons; in other behaviors, e.g., hopping, excita- correlated with GABA levels or gamma fre-
lighted work by Putzier et al. in which tory connections between contralateral quency, however, and it is not clear what
dynamic clamp experiments showed that the neuron pools cause synchronous bursts. Ex- causal relationships, if any, exist among the
characteristic activation voltage of Cav1.3 periments by Rabe et al. suggest that commis- three variables.
channels makes pacemaker firing possible. suralinterneuronsthatdrivealternatingbursts
Thisweek,Deisteretal.usethedynamicclamp are guided across the midline by netrin-1, Neurobiology of Disease
together with pharmacological manipulations whereas at least some commissural interneu- Haptoglobin Protects Neurons from
to investigate the channels underlying burst rons driving synchronous bursting are not. As
firing. Contrary to predictions of earlier mod-
Blood-Induced Toxicity
a result, mice lacking netrin-1 produced bilat-
els, iontophoresis of glutamate onto dendrites erally synchronous instead of alternating Xiurong Zhao, Shen Song, Guanghua
or somata was equally able to elicit bursts, bursts. Knockout of netrin-1 disrupted path- Sun, Roger Strong, Jie Zhang, James C.
which were diminished by NMDA receptor finding by both excitatory and inhibitory Grotta, and Jaroslaw Aronowski
antagonists. Injection of alternating depolariz- commissural neurons of most types, but a
ing and hyperpolarizing current, but not con- (see pages 15819 –15827)
larger fraction of inhibitory commissural ax-
stant depolarizing current, replicated the ons were lost, resulting in a shift from a pre- After intracerebral hemorrhage (ICH),
effects of glutamate, suggesting excessive so- dominance of inhibitory connections to a blood enters the brain and red blood cells
dium channel inactivation can prevent sus- predominance of excitatory connections. Fur- lyse, releasing hemoglobin. Breakdown of
tained firing. Additional results suggest that thermore, the ventral-most cluster of com- hemoglobin releases heme and iron, which
magnesium block of NMDA receptors helps missural interneurons was completely spared, cause oxidative damage leading to neuron
to limit this inactivation and extend bursts. suggesting these neurons could be the primary death. In the periphery, such damage is lim-
drivers of simultaneous bursting. ited by haptoglobin, a protein produced by
the liver that binds to extracellular hemoglo-
f Behavioral/Systems/Cognitive bin, accelerates its clearance, and prevents
the release of heme iron. Although hapto-
Orientation Discrimination globin levels are normally high in peripheral
Correlates with GABA Levels vessels, levels are normally low in the brain,
increasing only after injury. Zhao et al. show
Richard A.E. Edden, Suresh D. that haptoglobin is produced in the brain by
Muthukumaraswamy, Tom C.A. oligodendrocytes and that it limits oxidative
Freeman, and Krish D. Singh damage from blood lysates. When blood ly-
(see pages 15721–15726) sate was injected into the brain, transgenic
mice lacking haptoglobin had greater func-
Much controversy surrounds the hypothesis tional deficits and larger reductions in neuro-
that precise orientation tuning of visual corti- nal and glial proteins than controls, whereas
Iontophoresis of glutamate (shaded area) elicits a burst of action cal neurons requires GABAergic inhibition to mice overexpressing haptoglobin had less
potentials in dopaminergic neurons (top). Suprathreshold (yel- suppress activity of neurons whose preferred damage. Production of haptoglobin by cul-
low line) oscillations persist in the presence of sodium channel orientation is orthogonal to that of the stimu- tured oligodendrocytes was increased by the
blocker (middle), but are eliminated by NMDA receptor antago- lus. Although intracellular recordings have drug sulforaphane, which also reduces dam-
nist (bottom). See the article by Deister et al. for details. failed to detect inhibitory inputs that could age from experimental ICH in vivo.
The Journal of Neuroscience
December 16, 2009 • Volume 29 Number 50 • www.jneurosci.org
i This Week in The Journal
Brief Communications
f 15721 Orientation Discrimination Performance Is Predicted by GABA Concentration and
Gamma Oscillation Frequency in Human Primary Visual Cortex
Richard A. E. Edden, Suresh D. Muthukumaraswamy, Tom C. A. Freeman,
and Krish D. Singh
15756 Diminutive Digits Discern Delicate Details: Fingertip Size and the Sex Difference in
Tactile Spatial Acuity
Ryan M. Peters, Erik Hackeman, and Daniel Goldreich
Cover legend: Two superimposed focal planes of a Articles
flat-mounted retina from an adult mouse
heterozygous for activated leukocyte cell adhesion CELLULAR/MOLECULAR
molecule (ALCAM) that also harbored a transgene
expressing YFP in retinal ganglion cells (RGCs) and 15613 Activity-Dependent Anchoring of Importin at the Synapse Involves Regulated
amacrine cells. Cells within the RGC layer are shown in Binding to the Cytoplasmic Tail of the NR1-1a Subunit of the NMDA Receptor
green, and those within the amacrine cell layer have Rachel A. Jeffrey, Toh Hean Ch’ng, Thomas J. O’Dell, and Kelsey C. Martin
been pseudocolored purple. For more information, see 15735 Rescue of Motor Coordination by Purkinje Cell-Targeted Restoration of Kv3.3
the article by Buhusi et al. in this issue (pages 15630- Channels in Kcnc3-Null Mice Requires Kcnc1
15641). Edward C. Hurlock, Mitali Bose, Ganon Pierce, and Rolf H. Joho
15770 Synchronous and Asynchronous Transmitter Release at Nicotinic Synapses Are
Differentially Regulated by Postsynaptic PSD-95 Proteins
Robert A. Neff III, William G. Conroy, Jeffrey D. Schoellerman, and
Darwin K. Berg
15796 Direct Interaction of GABAB Receptors with M2 Muscarinic Receptors Enhances
Muscarinic Signaling
Stephanie B. Boyer, Sinead M. Clancy, Miho Terunuma, Raquel Revilla-Sanchez,
Steven M. Thomas, Stephen J. Moss, and Paul A. Slesinger
15836 GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta
Burst Stimulation-Induced Long-Term Potentiation
Neng Gong, Yong Li, Guo-Qiang Cai, Rui-Fang Niu, Qi Fang, Kun Wu,
Zhong Chen, Long-Nian Lin, Lin Xu, Jian Fei, and Tian-Le Xu
15851 Endolymphatic Sodium Homeostasis by Extramacular Epithelium of the Saccule
Sung Huhn Kim and Daniel C. Marcus
15878 Activity-Dependent Vesicular Monoamine Transporter-Mediated Depletion of the
Nucleus Supports Somatic Release by Serotonin Neurons
Lesley A. Colgan, Ilva Putzier, and Edwin S. Levitan
15888 An Intrinsic Neuronal Oscillator Underlies Dopaminergic Neuron Bursting
Christopher A. Deister, Mark A. Teagarden, Charles J. Wilson,
and Carlos A. Paladini
DEVELOPMENT/PLASTICITY/REPAIR
15630 ALCAM Regulates Mediolateral Retinotopic Mapping in the Superior Colliculus
Mona Buhusi, Galina P. Demyanenko, Karry M. Jannie, Jasbir Dalal,
Eli P. B. Darnell, Joshua A. Weiner, and Patricia F. Maness
Π15642 Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of
Left-Right Alternating Locomotor Circuitry
Nadine Rabe, Henrik Gezelius, Anna Vallstedt, Fatima Memic, and Klas Kullander
15694 Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration
Ofira Einstein, Yael Friedman-Levi, Nikolaos Grigoriadis, and Tamir Ben-Hur
15859 The Small GTPase Rac1 Regulates Auditory Hair Cell Morphogenesis
¨ ´´
Cynthia M. Grimsley-Myers, Conor W. Sipe, Gwenaelle S. G. Geleoc,
and Xiaowei Lu
15923 Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine
Neurons
Banafsheh Kadkhodaei, Takehito Ito, Eliza Joodmardi, Bengt Mattsson,
Claude Rouillard, Manolo Carta, Shin-Ichi Muramatsu, Chiho Sumi-Ichinose,
Takahide Nomura, Daniel Metzger, Pierre Chambon, Eva Lindqvist,
¨ ¨
Nils-Goran Larsson, Lars Olson, Anders Bjorklund, Hiroshi Ichinose,
and Thomas Perlmann
15933 Emx1-Lineage Progenitors Differentially Contribute to Neural Diversity in the
Striatum and Amygdala
Laura A. Cocas, Goichi Miyoshi, Rosalind S. E. Carney, Vitor H. Sousa,
Tsutomu Hirata, Kevin R. Jones, Gord Fishell, Molly M. Huntsman, and
Joshua G. Corbin
BEHAVIORAL/SYSTEMS/COGNITIVE
15621 Selection and Maintenance of Spatial Information by Frontal Eye Field Neurons
Katherine M. Armstrong, Mindy H. Chang, and Tirin Moore
15650 Neural and Behavioral Discrimination of Sound Duration by Cats
Ling Qin, Yongchun Liu, JingYu Wang, ShuNan Li, and Yu Sato
15669 Serotonin Affects Association of Aversive Outcomes to Past Actions
Saori C. Tanaka, Kazuhiro Shishida, Nicolas Schweighofer, Yasumasa Okamoto,
Shigeto Yamawaki, and Kenji Doya
15675 Frontal Feedback-Related Potentials in Nonhuman Primates: Modulation during
Learning and under Haloperidol
Julien Vezoli and Emmanuel Procyk
15684 Age- and Gender-Related Differences in the Cortical Anatomical Network
Gaolang Gong, Pedro Rosa-Neto, Felix Carbonell, Zhang J. Chen, Yong He,
and Alan C. Evans
15713 Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction
of Cued But Not Contextual Fear Memory
Susan Sangha, Rajeevan T. Narayanan, Jorge R. Bergado-Acosta, Oliver Stork,
Thomas Seidenbecher, and Hans-Christian Pape
15727 Overlapping and Distinct Neural Systems Code for Subjective Value during
Intertemporal and Risky Decision Making
¨
Jan Peters and Christian Buchel
15745 Early-Life Stress Disrupts Attachment Learning: The Role of Amygdala Corticosterone,
Locus Ceruleus Corticotropin Releasing Hormone, and Olfactory Bulb Norepinephrine
Stephanie Moriceau, Kiseko Shionoya, Katherine Jakubs, and Regina M. Sullivan
15762 Electrophysiology of Object Naming in Primary Progressive Aphasia
Robert S. Hurley, Ken A. Paller, Christina A. Wieneke, Sandra Weintraub,
Cynthia K. Thompson, Kara D. Federmeier, and M.-Marsel Mesulam
15780 Cooperative and Competitive Interactions Facilitate Stereo Computations in Macaque
Primary Visual Cortex
Jason M. Samonds, Brian R. Potetz, and Tai Sing Lee
15870 Preparation to Inhibit a Response Complements Response Inhibition during
Performance of a Stop-Signal Task
Junichi Chikazoe, Koji Jimura, Satoshi Hirose, Ken-ichiro Yamashita,
Yasushi Miyashita, and Seiki Konishi
15898 Auditory Cortical Activity after Intracortical Microstimulation and Its Role for
Sensory Processing and Learning
Matthias Deliano, Henning Scheich, and Frank W. Ohl
15910 Adult Plasticity in Multisensory Neurons: Short-Term Experience-Dependent
Changes in the Superior Colliculus
Liping Yu, Barry E. Stein, and Benjamin A. Rowland
NEUROBIOLOGY OF DISEASE
15660 Amyloid Precursor Protein Regulates Cav1.2 L-type Calcium Channel Levels
and Function to Influence GABAergic Short-Term Plasticity
Li Yang, Zilai Wang, Baiping Wang, Nicholas J. Justice, and Hui Zheng
15703 Novel Mediators of Amyloid Precursor Protein Signaling
Andrzej Swistowski, Qiang Zhang, Mark E. Orcholski, Danielle Crippen,
Cathy Vitelli, Alexei Kurakin, and Dale E. Bredesen
15810 A Novel Allele of Myosin VIIa Reveals a Critical Function for the C-Terminal FERM
Domain for Melanosome Transport in Retinal Pigment Epithelial Cells
Martin Schwander, Vanda Lopes, Anna Sczaniecka, Daniel Gibbs,
Concepcion Lillo, David Delano, Lisa M. Tarantino, Tim Wiltshire,
¨
David S. Williams, and Ulrich Muller
15819 Neuroprotective Role of Haptoglobin after Intracerebral Hemorrhage
Xiurong Zhao, Shen Song, Guanghua Sun, Roger Strong, Jie Zhang,
James C. Grotta, and Jaroslaw Aronowski
15828 Sustained Morphine-Induced Sensitization and Loss of Diffuse Noxious Inhibitory
Controls in Dura-Sensitive Medullary Dorsal Horn Neurons
Akiko Okada-Ogawa, Frank Porreca, and Ian D. Meng
15846 Unexpected Lack of Hypersensitivity in LRRK2 Knock-Out Mice to MPTP
(1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine)
Eva Andres-Mateos, Rebeca Mejias, Masayuki Sasaki, Xiaojie Li, Brian M. Lin,
Saskia Biskup, Li Zhang, Rebecca Banerjee, Bobby Thomas, Lichuan Yang,
Guosheng Liu, M. Flint Beal, David L. Huso, Ted M. Dawson,
and Valina L. Dawson
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BRIEF COMMUNICATIONS
Orientation Discrimination Performance Is Predicted by GABA Concentration and Gamma
Oscillation Frequency in Human Primary Visual Cortex
Richard A. E. Edden,1,2,3* Suresh D. Muthukumaraswamy,3* Tom C. A. Freeman,3 and Krish D. Singh3
Schools of 1Biosciences and 2Chemistry, and 3Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff CF10 3AT,
United Kingdom
Neuronal orientation selectivity has been shown in animal models to require corticocortical network cooperation and to be dependent on the presence of GABAergic
inhibition. However, it is not known whether variability in these fundamental neurophysiological parameters leads to variability in behavioral performance. Here, using a
combination of magnetic resonance spectroscopy, magnetoencephalography, and visual psychophysics, we show that individual performance on a visual orientation
discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex.
Behaviorally, a strong oblique effect was found, with the mean angular threshold for oblique discrimination being five times higher than that for vertically oriented stimuli.
Similarly, we found an oblique effect for the dependency of performance on neurophysiological parameters. Orientation detection thresholds were significantly negatively
correlated with visual cortex GABA concentration for obliquely oriented patterns (r 0.65, p 0.015) but did not reach significance for vertically oriented stimuli (r
0.39, p 0.2). Similarly, thresholds for obliquely oriented stimuli were negatively correlated with gamma oscillation frequency (r 0.65, p 0.017), but thresholds for
vertical orientations were not (r 0.02, p 0.9). Gamma oscillation frequency was positively correlated with GABA concentration in primary visual cortex (r 0.67, p
0.013). These results confirm the importance of GABAergic inhibition in orientation selectivity and demonstrate, for the first time, that interindividual performance on a
simple visual task is linked to neurotransmitter concentration. The results also suggest a key role for GABAergic gamma oscillations in visual discrimination tasks.
The Journal of Neuroscience, December 16, 2009 • 29(50):15721–15726
Diminutive Digits Discern Delicate Details: Fingertip Size and the Sex Difference in Tactile
Spatial Acuity
Ryan M. Peters,1 Erik Hackeman,2 and Daniel Goldreich1,2
1Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada, and 2Department of Occupational
Therapy, Duquesne University, Pittsburgh, Pennsylvania 15282
We have observed that passive tactile spatial acuity, the ability to resolve the spatial structure of surfaces pressed upon the skin, differs subtly but consistently between the
sexes, with women able to perceive finer surface detail than men. Eschewing complex central explanations, we hypothesized that this sex difference in somatosensory
perception might result from simple physical differences between the fingers of women and men. To investigate, we tested 50 women and 50 men on a tactile grating
orientation task and measured the surface area of the participants’ index fingertips. In subsets of participants, we additionally measured finger skin compliance and
optically imaged the fingerprint microstructure to count sweat pores. We show here that tactile perception improves with decreasing finger size, and that this correlation
fully explains the better perception of women, who on average have smaller fingers than men. Indeed, when sex and finger size are both considered in statistical analyses,
only finger size predicts tactile acuity. Thus, a man and a woman with fingers of equal size will, on average, enjoy equal tactile acuity. We further show that sweat pores, and
presumably the Merkel receptors beneath them, are packed more densely in smaller fingers.
The Journal of Neuroscience, December 16, 2009 • 29(50):15756 –15761
Articles
CELLULAR/MOLECULAR
Activity-Dependent Anchoring of Importin at the Synapse Involves Regulated Binding to the
Cytoplasmic Tail of the NR1-1a Subunit of the NMDA Receptor
Rachel A. Jeffrey,1 Toh Hean Ch’ng,2 Thomas J. O’Dell,3 and Kelsey C. Martin1,2,4
Departments of 1Biological Chemistry, 2Psychiatry and Biobehavioral Sciences, and 3Physiology and 4Semel Institute for Neuroscience and Human
Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1737
Synaptic plasticity, the capacity of neurons to change the strength of their connections with experience, provides a mechanism for learning and memory in the brain.
Long-term plasticity requires new transcription, indicating that synaptically generated signals must be transported to the nucleus. Previous studies have described a role
for importin nuclear transport adaptors in mediating the retrograde transport of signals from synapse to nucleus during plasticity. Here, we investigated the possibility that
stimulus-induced translocation of importins from synapse to nucleus involves activity-dependent anchoring of importins at the synapse. We show that importin binds
to a nuclear localization signal (NLS) present in the cytoplasmic tail of NR1-1a. This interaction is disrupted by activation of NMDA receptors in cultured neurons and by
stimuli that trigger late-phase, but not early-phase, long-term potentiation of CA3–CA1 synapses in acute hippocampal slices. In vitro PKC phosphorylation of GST-NR1-1a
abolishes its ability to bind importin in brain lysates, and the interaction of importin and NR1 in neurons is modulated by PKC activity. Together, our results indicate
that importin is tethered at the postsynaptic density by binding to the NLS present in NR1-1a. This interaction is activity dependent, with importin being released
following NMDA receptor activation and phosphorylation rendering it available to bind soluble cargoes and transport them to the nucleus during transcription-dependent
forms of neuronal plasticity.
The Journal of Neuroscience, December 16, 2009 • 29(50):15613–15620
Rescue of Motor Coordination by Purkinje Cell-Targeted Restoration of Kv3.3 Channels in
Kcnc3-Null Mice Requires Kcnc1
Edward C. Hurlock, Mitali Bose, Ganon Pierce, and Rolf H. Joho
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111
The role of cerebellar Kv3.1 and Kv3.3 channels in motor coordination was examined with an emphasis on the deep cerebellar nuclei (DCN). Kv3 channel subunits encoded
by Kcnc genes are distinguished by rapid activation and deactivation kinetics that support high-frequency, narrow action potential firing. Previously we reported that
increased lateral deviation while ambulating and slips while traversing a narrow beam of ataxic Kcnc3-null mice were corrected by restoration of Kv3.3 channels specifically
to Purkinje cells, whereas Kcnc3-mutant mice additionally lacking one Kcnc1 allele were partially rescued. Here, we report mice lacking all Kcnc1 and Kcnc3 alleles exhibit
no such rescue. For Purkinje cell output to reach the rest of the brain it must be conveyed by neurons of the DCN or vestibular nuclei. As Kcnc1, but not Kcnc3, alleles are lost,
mutant mice exhibit increasing gait ataxia accompanied by spike broadening and deceleration in DCN neurons, suggesting the facet of coordination rescued by Purkinje-
cell-restricted Kv3.3 restoration in mice lacking just Kcnc3 is hypermetria, while gait ataxia emerges when additionally Kcnc1 alleles are lost. Thus, fast repolarization in
Purkinje cells appears important for normal movement velocity, whereas DCN neurons are a prime candidate locus where fast repolarization is necessary for normal gait
patterning.
The Journal of Neuroscience, December 16, 2009 • 29(50):15735–15744
Synchronous and Asynchronous Transmitter Release at Nicotinic Synapses Are Differentially
Regulated by Postsynaptic PSD-95 Proteins
Robert A. Neff III, William G. Conroy, Jeffrey D. Schoellerman, and Darwin K. Berg
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0357
The rate and timing of information transfer at neuronal synapses are critical for determining synaptic efficacy and higher network function. Both synchronous and
asynchronous neurotransmitter release shape the pattern of synaptic influences on a neuron. The PSD-95 family of postsynaptic scaffolding proteins, in addition to
organizing postsynaptic components at glutamate synapses, acts transcellularly to regulate synchronous glutamate release. Here we show that PSD-95 family members at
nicotinic synapses on chick ciliary ganglion neurons in culture execute multiple functions to enhance transmission. Together, endogenous PSD-95 and SAP102 in the
postsynaptic cell appear to regulate transcellularly the synchronous release of transmitter from presynaptic terminals onto the neuron while stabilizing postsynaptic
nicotinic receptor clusters under the release sites. Endogenous SAP97, in contrast, has no effect on receptor clusters but acts transcellularly from the postsynaptic cell
through N-cadherin to enhance asynchronous release. These separate and parallel regulatory pathways allow postsynaptic scaffold proteins to dictate the pattern of
cholinergic input a neuron receives; they also require balancing of PSD-95 protein levels to avoid disruptive competition that can occur through common binding domains.
The Journal of Neuroscience, December 16, 2009 • 29(50):15770 –15779
Direct Interaction of GABAB Receptors with M2 Muscarinic Receptors Enhances Muscarinic
Signaling
Stephanie B. Boyer,1,2 Sinead M. Clancy,1 Miho Terunuma,3 Raquel Revilla-Sanchez,3 Steven M. Thomas,1
Stephen J. Moss,3 and Paul A. Slesinger1,2
1Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, 2Neurosciences Graduate Program, Department of
Neurosciences, University of California, San Diego, La Jolla, California 92093, and 3Department of Neuroscience, Tufts University School of Medicine,
Boston, Massachusetts 02030
Downregulation of G-protein-coupled receptors (GPCRs) provides an important mechanism for reducing neurotransmitter signaling during sustained stimulation.
Chronic stimulation of M2 muscarinic receptors (M2Rs) causes internalization of M2R and G-protein-activated inwardly rectifying potassium (GIRK) channels in neuronal
PC12 cells, resulting in loss of function. Here, we show that coexpression of GABAB R2 receptors (GBR2s) rescues both surface expression and function of M2R, including
M2R-induced activation of GIRKs and inhibition of cAMP production. GBR2 showed significant association with M2R at the plasma membrane but not other GPCRs (M1R,
-opioid receptor), as detected by fluorescence resonance energy transfer measured with total internal reflection fluorescence microscopy. Unique regions of the proximal
C-terminal domains of GBR2 and M2R mediate specific binding between M2R and GBR2. In the brain, GBR2, but not GBR1, biochemically coprecipitates with M2R and
overlaps with M2R expression in cortical neurons. This novel heteromeric association between M2R and GBR2 provides a possible mechanism for altering muscarinic
signaling in the brain and represents a previously unrecognized role for GBR2.
The Journal of Neuroscience, December 16, 2009 • 29(50):15796 –15809
GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst
Stimulation-Induced Long-Term Potentiation
Neng Gong,1 Yong Li,2 Guo-Qiang Cai,3 Rui-Fang Niu,4 Qi Fang,1,5 Kun Wu,1,6 Zhong Chen,5 Long-Nian Lin,4 Lin Xu,1,6
Jian Fei,3 and Tian-Le Xu1
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai
200031, China, 2Department of Neurobiology, Institutes of Medical Sciences, Shanghai Jiaotong University, Shanghai 200025, China, 3School of Life Science
and Technology, Tongji University, Shanghai 200092, China, 4Shanghai Institute of Brain Functional Genomics, East China Normal University, Shanghai
200062, 5College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China, and 6Kunming Institute of Zoology, Chinese Academy of
Sciences, Kunming 650223, China
The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity
remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically
impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP induced by high-frequency stimulation or long-term depression
induced by low-frequency stimulation. The extent of LTP impairment depended on the precise burst frequency, with significant impairment at 3–7 Hz that correlated with
the time course of elevated GABAergic inhibition caused by GAT1 disruption. Furthermore, in vivo electrophysiological recordings showed that GAT1 gene deletion reduced
the frequency of hippocampal theta oscillation. Moreover, behavioral studies showed that GAT1 knock-out mice also exhibited impaired hippocampus-dependent learning
and memory. Together, these results have highlighted the important link between GABAergic inhibition and hippocampal theta oscillation, both of which are critical for
synaptic plasticity and learning behaviors.
The Journal of Neuroscience, December 16, 2009 • 29(50):15836 –15845
Endolymphatic Sodium Homeostasis by Extramacular Epithelium of the Saccule
Sung Huhn Kim and Daniel C. Marcus
Cellular Biophysics Laboratory, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506-5802
The saccule is a vestibular sensory organ that depends upon regulation of its luminal fluid, endolymph, for normal transduction of linear acceleration into afferent neural
transmission. Previous studies suggested that endolymph in the saccule was merely derived from cochlear endolymph. We developed and used a preparation of isolated
mouse saccule to measure transepithelial currents from the extramacular epithelium with a current density probe. The direction and pharmacology of transepithelial
current was consistent with Na absorption by the epithelial Na channel (ENaC) and was blocked by the ENaC-specific inhibitors benzamil and amiloride. Involvement
of Na ,K -ATPase and K channels was demonstrated by reduction of the current by ouabain and the K channel blockers Ba 2 , XE991, and 4-AP. Glucocorticoids
upregulated the current via glucocorticoid receptors. Dexamethasone stimulated the current after 24 h and the stimulation was blocked by mifepristone but not spirono-
lactone. No acute response was observed to elevated cAMP in the presence of amiloride nor to bumetanide, a blocker of Na ,K ,2Cl cotransporter. The results are
consistent with a canonical model of corticosteroid-regulated Na absorption that includes entry of luminal Na through apical membrane Na channels and active
basolateral exit of Na via a Na pump, with recycling of K at the basolateral membrane via K -permeable channels. These observations provide our first understanding
of the active role played by saccular epithelium in the local regulation of the [Na ] of endolymph for maintenance of our sense of balance.
The Journal of Neuroscience, December 16, 2009 • 29(50):15851–15858
Activity-Dependent Vesicular Monoamine Transporter-Mediated Depletion of the Nucleus
Supports Somatic Release by Serotonin Neurons
Lesley A. Colgan, Ilva Putzier, and Edwin S. Levitan
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Packaging by the vesicular monoamine transporter (VMAT) is essential for mood-controlling serotonin transmission but has not been assayed during activity. Here,
two-photon imaging of the fluorescent serotonin analog 5,7-dihydroxytryptamine and three-photon imaging of endogenous serotonin were used to study vesicular
packaging as it supports release from the soma of serotonin neurons. Glutamate receptor activation in dorsal raphe brain slice evoked somatic release that was mediated
solely by vesicle exocytosis. This release was accompanied by VMAT-mediated serotonin depletion from the nucleus, a large compartment free of monoaminergic
degradation pathways that has not been implicated in neurotransmission previously. Finally, while some monoamine packaged at rest was held in reserve, monoamine
packaged during stimulation was released completely. Hence, somatic vesicles loaded by VMAT during activity rapidly undergo exocytosis. In the absence of active zones
and with limited neurotransmitter reuptake, somatic release by serotonin neurons is supported by recruitment from a large pool of extravesicular serotonin in the nucleus
and cytoplasm, and preferential release of the newly packaged transmitter.
The Journal of Neuroscience, December 16, 2009 • 29(50):15878 –15887
An Intrinsic Neuronal Oscillator Underlies Dopaminergic Neuron Bursting
Christopher A. Deister, Mark A. Teagarden, Charles J. Wilson, and Carlos A. Paladini
Neurosciences Institute, The University of Texas at San Antonio, San Antonio, Texas 78249
Dopaminergic neurons of the ventral midbrain fire high-frequency bursts when animals are presented with unexpected rewards, or stimuli that predict reward. To identify
the afferents that can initiate bursting and establish therapeutic strategies for diseases affected by altered bursting, a mechanistic understanding of bursting is essential. Our
results show that bursting is initiated by a specific interaction between the voltage sensitivity of NMDA receptors and voltage-gated ion channels that results in the
activation of an intrinsic, action potential-independent, high-frequency membrane potential oscillation. We further show that the NMDA receptor is uniquely suited for this
because of the rapid kinetics and voltage dependence imparted to it by Mg 2 ion block and unblock. This mechanism explains the discrete nature of bursting in
dopaminergic cells and demonstrates how synaptic signals may be reshaped by local intrinsic properties of a neuron before influencing action potential generation.
The Journal of Neuroscience, December 16, 2009 • 29(50):15888 –15897
DEVELOPMENT/PLASTICITY/REPAIR
ALCAM Regulates Mediolateral Retinotopic Mapping in the Superior Colliculus
Mona Buhusi,1 Galina P. Demyanenko,1 Karry M. Jannie,2 Jasbir Dalal,1 Eli P. B. Darnell,1 Joshua A. Weiner,2 and
Patricia F. Maness1
1Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, and 2Department of
Biology, University of Iowa, Iowa City, Iowa 52242
ALCAM [activated leukocyte cell adhesion molecule (BEN/SC-1/DM-GRASP)] is a transmembrane recognition molecule of the Ig superfamily (IgSF) containing five Ig domains
(two V-type, three C2-type). Although broadly expressed in the nervous and immune systems, few of its developmental functions have been elucidated. Because ALCAM has been
suggestedtointeractwiththeIgSFadhesionmoleculeL1,adeterminantofretinocollicularmapping,wehypothesizedthatALCAMmightdirecttopographictargetingtothesuperior
colliculus (SC) by serving as a substrate within the SC for L1 on incoming retinal ganglion cell (RGC) axons. ALCAM was expressed in the SC during RGC axon targeting and on RGC
axons as they formed the optic nerve; however, it was downregulated distally on RGC axons as they entered the SC. Axon tracing with DiI revealed pronounced mistargeting of RGC
axons from the temporal retina half of ALCAM null mice to abnormally lateral sites in the contralateral SC, in which these axons formed multiple ectopic termination zones. ALCAM
null mutant axons were specifically compromised in medial orientation of interstitial branches, which is known to require the ankyrin binding function of L1. As a substrate,
ALCAM–Fc protein promoted L1-dependent attachment of acutely dissociated retinal cells and an L1-expressing, ALCAM-negative cell line, consistent with an ALCAM–L1
heterophilic molecular interaction. Together, these results suggest a model in which ALCAM in the SC interacts with L1 on RGC axons to promote medial extension of RGC axon
branches important for mediolateral axon targeting in the formation of retinocollicular maps.
The Journal of Neuroscience, December 16, 2009 • 29(50):15630 –15641
Netrin-1-Dependent Spinal Interneuron Subtypes Are Required for the Formation of Left-Right
Alternating Locomotor Circuitry
Nadine Rabe, Henrik Gezelius,* Anna Vallstedt,* Fatima Memic, and Klas Kullander
Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden
Neuronal circuits in the spinal cord that produce the rhythmic and coordinated activities necessary for limb movements are referred to as locomotor central pattern
generators (CPGs). The identities and preceding development of neurons essential for coordination between left and right limbs are not yet known. We show that the ventral
floor plate chemoattractant Netrin-1 preferentially guides dorsally originating subtypes of commissural interneurons, the majority of which are inhibitory. In contrast, the
excitatory and ventralmost V3 subtype of interneurons have a normal number of commissural fibers in Netrin-1 mutant mice, thus being entirely independent of
Netrin-1-mediated attraction. This selective loss of commissural fibers in Netrin-1 mutant mice resulted in an abnormal circuitry manifested by a complete switch from
alternating to synchronous fictive locomotor activity suggesting that the most ventral-originating excitatory commissural interneurons are an important component of a
left-right synchrony circuit in the locomotor CPG. Thus, during development, Netrin-1 plays a critical role for the establishment of a functional balanced CPG.
The Journal of Neuroscience, December 16, 2009 • 29(50):15642–15649
Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration
Ofira Einstein,1 Yael Friedman-Levi,1 Nikolaos Grigoriadis,2 and Tamir Ben-Hur1
1 Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah–Hebrew University Medical Center, Jerusalem 91120, Israel, and
2 B Department of Neurology, AHEPA University Hospital of Thessaloniki, 54636 Thessaloniki, Greece
In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural
precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which
slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In
this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and
proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any
transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice.
Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain
OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC–OPC coculture system. These experiments indicated that NPCs
induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth
factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic
effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.
The Journal of Neuroscience, December 16, 2009 • 29(50):15694 –15702
The Small GTPase Rac1 Regulates Auditory Hair Cell Morphogenesis
¨ ´´
Cynthia M. Grimsley-Myers,1 Conor W. Sipe,1 Gwenaelle S. G. Geleoc,2,3 and Xiaowei Lu1
Departments of 1Cell Biology, 2Neuroscience, and 3Otolaryngology, University of Virginia, Charlottesville, Virginia 22908
Morphogenesis of sensory hair cells, in particular their mechanotransduction organelle, the stereociliary bundle, requires highly organized remodeling of the actin
cytoskeleton. The roles of Rho family small GTPases during this process remain unknown. Here we show that deletion of Rac1 in the otic epithelium resulted in severe
defects in cochlear epithelial morphogenesis. The mutant cochlea was severely shortened with a reduced number of auditory hair cells and cellular organization of the
auditory sensory epithelium was abnormal. Rac1 mutant hair cells also displayed defects in planar cell polarity and morphogenesis of the stereociliary bundle, including
bundle fragmentation or deformation, and mispositioning or absence of the kinocilium. We further demonstrate that a Rac–PAK (p21-activated kinase) signaling pathway
mediates kinocilium–stereocilia interactions and is required for cohesion of the stereociliary bundle. Together, these results reveal a critical function of Rac1 in morpho-
genesis of the auditory sensory epithelium and stereociliary bundle.
The Journal of Neuroscience, December 16, 2009 • 29(50):15859 –15869
Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons
Banafsheh Kadkhodaei,1 Takehito Ito,2 Eliza Joodmardi,1 Bengt Mattsson,3 Claude Rouillard,1 Manolo Carta,3
Shin-Ichi Muramatsu,4 Chiho Sumi-Ichinose,5 Takahide Nomura,5 Daniel Metzger,6 Pierre Chambon,6 Eva Lindqvist,7
¨ ¨
Nils-Goran Larsson,8,10 Lars Olson,7 Anders Bjorklund,3 Hiroshi Ichinose,2 and Thomas Perlmann1,9
1Ludwig Institute for Cancer Research, Stockholm Branch, SE-171 77 Stockholm, Sweden, 2Graduate School of Bioscience and Biotechnology, Tokyo
Institute of Technology, Yokohama 226-8501, Japan, 3Wallenberg Neuroscience Center, Lund University, SE-221 84 Lund, Sweden, 4Department of
Neurology, Jichi Medical University, Tochigi 329-0498, Japan, 5Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, Aichi
´ ´ ´
470-1192, Japan, 6Department of Functional Genomics Institut de Genetique et Biologie Moleculaire et Cellulaire, 67404 Illkirch, France, Departments of
7Neuroscience, 8Laboratory Medicine, and 9Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden, and 10Max Planck Institute for
Biology of Ageing, D-50931 Cologne, Germany
Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about
their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into
adulthood. In Parkinson’s disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance
of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA
neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus
Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast,
a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson’s disease, neurons of the substantia
nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways
play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may
contribute to neurodegenerative disease.
The Journal of Neuroscience, December 16, 2009 • 29(50):15923–15932
Emx1-Lineage Progenitors Differentially Contribute to Neural Diversity in the Striatum and
Amygdala
Laura A. Cocas,1,2 Goichi Miyoshi,3* Rosalind S. E. Carney,1* Vitor H. Sousa,3 Tsutomu Hirata,1 Kevin R. Jones,4
Gord Fishell,3 Molly M. Huntsman,1,2 and Joshua G. Corbin1
1Center for Neuroscience Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC 20010, 2Interdisciplinary Program
in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, 3Neuroscience Program and Department of Cell Biology, Smilow Research
Center, New York University School of Medicine, New York, New York 10016, and 4Department of Molecular, Cellular, and Developmental Neurobiology,
University of Colorado, Boulder, Colorado 80309
In the developing mammalian basal telencephalon, neural progenitors from the subpallium generate the majority of inhibitory medium spiny neurons (MSNs) in the
striatum, while both pallial- and subpallial-derived progenitors contribute to excitatory and inhibitory neuronal diversity in the amygdala. Using a combination of
approaches, including genetic fate mapping, cell birth dating, cell migration assays, and electrophysiology, we find that cells derived from the Emx1 lineage contribute to
two distinct neuronal populations in the mature basal forebrain: inhibitory MSNs in the striatum and functionally distinct subclasses of excitatory neurons in the amygdala.
Our cell birth-dating studies reveal that these two populations are born at different times during early neurogenesis, with the amygdala population born before the MSNs.
In the striatum, Emx1-lineage neurons represent a unique subpopulation of MSNs: they are disproportionately localized to the dorsal striatum, are found in dopamine
receiving, reelin-positive patches, and are born throughout striatal neurogenesis. In addition, our data suggest that a subpopulation of these Emx1-lineage cells originate
in the pallium and subsequently migrate to the developing striatum and amygdala. Our intersectional fate-mapping analysis further reveals that Emx1-lineage cells that
coexpress Dlx exclusively generate MSNs but do not contribute to the excitatory neurons in the amygdala. Thus, both the timing of neurogenesis and differential
combinatorial gene expression appear to be key determinants of striatal versus amygdala fate decisions of Emx1-lineage cells.
The Journal of Neuroscience, December 16, 2009 • 29(50):15933–15946
BEHAVIORAL/SYSTEMS/COGNITIVE
Selection and Maintenance of Spatial Information by Frontal Eye Field Neurons
Katherine M. Armstrong, Mindy H. Chang, and Tirin Moore
Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305
Voluntary attention is often allocated according to internally maintained goals. Recent evidence indicates that the frontal eye field (FEF) participates in the deployment of
spatial attention, even in the absence of saccadic eye movements. In addition, many FEF neurons maintain persistent representations of impending saccades. However, the
role of persistent activity in the general maintenance of spatial information, and its relationship to spatial attention, has not been explored. We recorded the responses of
single FEF neurons in monkeys trained to remember cued locations in order to detect changes in targets embedded among distracters in a task that did not involve saccades.
We found that FEF neurons persistently encoded the cued location throughout the trial during the delay period, when no visual stimuli were present, and during visual
discrimination. Furthermore, FEF activity reliably predicted whether monkeys would detect the target change. Population analyses revealed that FEF neurons with
persistent activity were more effective at selecting the target from among distracters than neurons lacking persistent activity. These results demonstrate that FEF neurons
maintain spatial information in the absence of saccade preparation and suggest that this maintenance contributes to the selection of relevant visual stimuli.
The Journal of Neuroscience, December 16, 2009 • 29(50):15621–15629
Neural and Behavioral Discrimination of Sound Duration by Cats
Ling Qin,1,2 Yongchun Liu,1 JingYu Wang,1 ShuNan Li,1 and Yu Sato1
1Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan,
and 2Department of Physiology, China Medical University, Shenyang, 110001, China
Sound duration is important for distinguishing auditory object. Previous studies on the neural representation of duration have usually lacked psychophysical data obtained
from the same species; hence, the correspondence between neural and behavioral discrimination of duration remains obscure. We addressed this issue in cats by using the
signal detection theory to investigate both neural activities in the primary auditory cortex (A1) and the cat’s behavioral performance. We found that 320 ms duration can
be well discriminated from 10 ms duration by some A1 neurons with specific response patterns: sustained response extended proportionally with the increase of stimulus
duration and the On–Off response synchronizing stimulus onset and offset. Neurons with only On response cannot discriminate duration. The discrimination performance
of both sustained and On–Off responses deteriorated as the target duration decreased from 320 to 20 ms and the percentage of discriminative neurons (correct rate 0.75)
decreased from 40 to 2%. Compared with the psychophysical results, we found that the psychometric functions of cats well matched the neurometric functions of most
sustained-response neurons and a small number of On–Off-response neurons. Pooling the spikes of multiple units improved neural discrimination, which may be
attributable to the salience (noise reduction) of the responses in pooled data. Our results suggest that the sustained and Off responses of A1 neurons underlie the duration
discrimination behavior of cats.
The Journal of Neuroscience, December 16, 2009 • 29(50):15650 –15659
Serotonin Affects Association of Aversive Outcomes to Past Actions
Saori C. Tanaka,1,2,3 Kazuhiro Shishida,3,5 Nicolas Schweighofer,2,3,4 Yasumasa Okamoto,3,5 Shigeto Yamawaki,3,5 and
Kenji Doya2,3,6
1Institute of Social and Economic Research, Osaka University, Osaka 567-0047, Japan, 2Department of Computational Neurobiology, Advanced
Telecommunication Research Institute International Computational Neuroscience Laboratories, Kyoto 619-0288, Japan, 3Core Research for Evolutional
Science and Technology, Japan Science and Technology Agency, Kyoto 619-0288, Japan, 4Department of Biokinesiology and Physical Therapy, University of
Southern California, Los Angeles, California 90089-9006, 5Department of Psychiatry and Neurosciences, Hiroshima University, Hiroshima 734-8551, Japan,
and 6Neural Computation Unit, Okinawa Institute of Science and Technology, Okinawa 904-2234, Japan
Impairment in the serotonergic system has been linked to action choices that are less advantageous in a long run. Such impulsive choices can be caused by a deficit in linking
a given reward or punishment with past actions. Here, we tested the effect of manipulation of the serotonergic system by tryptophan depletion and loading on learning the
association of current rewards and punishments with past actions. We observed slower associative learning when actions were followed by a delayed punishment in the low
serotonergic condition. Furthermore, a model-based analysis revealed a positive correlation between the length of the memory trace for aversive choices and subjects’ blood
tryptophan concentration. Our results suggest that the serotonergic system regulates the time scale of retrospective association of punishments to past actions.
The Journal of Neuroscience, December 16, 2009 • 29(50):15669 –15674
Frontal Feedback-Related Potentials in Nonhuman Primates: Modulation during Learning and
under Haloperidol
Julien Vezoli1,2 and Emmanuel Procyk1,2
1 ´
Inserm, U846, Stem Cell and Brain Research Institute, 69500 Bron, France, and 2Universite de Lyon, Lyon 1, UMR-S 846, 69003 Lyon, France
Feedback monitoring and adaptation of performance involve a medial reward system including medial frontal cortical areas, the medial striatum, and the dopaminergic
system. A considerable amount of data has been obtained on frontal surface feedback-related potentials (FRPs) in humans and on the correlate of outcome monitoring with
single unit activity in monkeys. However, work is needed to bridge knowledge obtained in the two species. The present work describes FRPs in monkeys, using chronic
recordings, during a trial and error task. We show that frontal FRPs are differentially sensitive to successes and failures and can be observed over long-term periods. In
addition, using the dopamine antagonist haloperidol we observe a selective effect on FRP amplitude that is absent for pure sensory-related potentials. These results describe
frontal dopaminergic-dependent FRPs in monkeys and corroborate a human-monkey homology for performance monitoring signals.
The Journal of Neuroscience, December 16, 2009 • 29(50):15675–15683
Age- and Gender-Related Differences in the Cortical Anatomical Network
Gaolang Gong,1 Pedro Rosa-Neto,1 Felix Carbonell,1 Zhang J. Chen,1 Yong He,2 and Alan C. Evans1
1McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada, and 2State Key Laboratory of Cognitive
Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
Neuroanatomical differences attributable to aging and gender have been well documented, and these differences may be associated with differences in behaviors and
cognitive performance. However, little is known about the dynamic organization of anatomical connectivity within the cerebral cortex, which may underlie population
differences in brain function. In this study, we investigated age and sex effects on the anatomical connectivity patterns of 95 normal subjects ranging in age from 19 to 85
years. Using the connectivity probability derived from diffusion magnetic resonance imaging tractography, we characterized the cerebral cortex as a weighted network of
connected regions. This approach captures the underlying organization of anatomical connectivity for each subject at a regional level. Advanced graph theoretical analysis
revealed that the resulting cortical networks exhibited “small-world” character (i.e., efficient information transfer both at local and global scale). In particular, the
precuneus and posterior cingulate gyrus were consistently observed as centrally connected regions, independent of age and sex. Additional analysis revealed a reduction in
overall cortical connectivity with age. There were also changes in the underlying network organization that resulted in decreased local efficiency, and also a shift of regional
efficiency from the parietal and occipital to frontal and temporal neocortex in older brains. In addition, women showed greater overall cortical connectivity and the
underlying organization of their cortical networks was more efficient, both locally and globally. There were also distributed regional differences in efficiency between sexes.
Our results provide new insights into the substrates that underlie behavioral and cognitive differences in aging and sex.
The Journal of Neuroscience, December 16, 2009 • 29(50):15684 –15693
Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction of Cued
But Not Contextual Fear Memory
Susan Sangha,1 Rajeevan T. Narayanan,1 Jorge R. Bergado-Acosta,3 Oliver Stork,3,4 Thomas Seidenbecher,1 and
Hans-Christian Pape1,2
¨ ¨ ¨ ¨
Institute of Physiology I and 2Institute for Experimental Epilepsy Research, Westfalische Wilhelms-Universitat Munster, D-48149 Munster, Germany, and
1
¨
Department of Genetics and Molecular Neurobiology, Institute for Biology and 4Center of Behavioural Brain Sciences, Otto von Guericke Universitat
3
Magdeburg, D-39120 Magdeburg, Germany
Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala,
hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in
extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals.
Extinction of conditioned fear was examined in Gad65 / mice while recording local field potentials from the amygdala, hippocampus, and PFC simultaneously while
monitoring behavior. Gad65 / mice showed generalization of cued fear, as reported previously, and impaired extinction of cued fear, such that fear remained high across
extinction training. This endurance in cued fear was associated with theta frequency synchronization between the amygdala and hippocampus. Extinction of contextual fear,
however, was unaltered in Gad65 / mice when compared with wild-type littermates. The data imply that GAD65 plays a critical role in regulating cued fear responses during
extinction learning and that, during this process, GABAergic signaling is involved in modulating synchronized activity between the amygdala and hippocampus. In view of the more
pronounced effect on cued versus contextual fear extinction, these influences may rely more on GABAergic mechanisms in the amygdala.
The Journal of Neuroscience, December 16, 2009 • 29(50):15713–15720
Overlapping and Distinct Neural Systems Code for Subjective Value during Intertemporal and
Risky Decision Making
¨
Jan Peters and Christian Buchel
Neuroimage Nord, Department of Systems Neuroscience, University Medical Center Hamburg–Eppendorf, D-20246 Hamburg, Germany
During decision making, valuation of different types of rewards may involve partially distinct neural systems, but efficient choice behavior requires a common neural
coding of stimulus value. We addressed this issue by measuring neural activity with functional magnetic resonance imaging while volunteers processed delayed and
probabilistic decision options. Behaviorally, participants discounted both types of rewards in a hyperbolic manner, and discount rates, reflecting individual preferences,
varied considerably between participants. Ventral striatum and orbitofrontal cortex showed a domain-general coding of subjective value regardless of whether rewards
were delayed or probabilistic, strongly implicating these regions in the implementation of a common neural currency of value. In contrast, fronto-polar and lateral parietal
cortex, as well as a region in the posterior cingulate cortex only correlated with the value of delayed rewards, whereas superior parietal cortex and middle occipital areas only
represented the value of probabilistic rewards. These results suggest a mechanism for the neural coding of subjective value in the human brain that is based on the
combination of domain-general and domain-specific valuation networks.
The Journal of Neuroscience, December 16, 2009 • 29(50):15727–15734
Early-Life Stress Disrupts Attachment Learning: The Role of Amygdala Corticosterone, Locus
Ceruleus Corticotropin Releasing Hormone, and Olfactory Bulb Norepinephrine
Stephanie Moriceau,1,2,4 Kiseko Shionoya,4,5 Katherine Jakubs,4,6 and Regina M. Sullivan1,2,3,4
1Emotional Brain Institute, Nathan Kline Institute, Orangeburg, New York 10962, 2Child and Adolescent Psychiatry, Child Study Center, New York
University Langone Medical Center, New York, New York 10016, 3New York University Center for Neural Science, New York, New York 10003,
4Department of Zoology, University of Oklahoma, Norman, Oklahoma 73019, 5Laboratory Neurosciences Sensorielles, Centre National de la
Recherche Scientifique, Universite Lyon, 69007 Lyon, France, and 6National Institutes of Health, Bethesda, Maryland 20892
Infant rats require maternal odor learning to guide pups’ proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit
including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress
increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography].
Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor– 0.5 mA
shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However,
stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated
CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG.
We also assessed the neural mechanism for stressed-reared pups’ abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This
was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for
the aberrant effects of stress rearing: the amygdala–LC– olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion
supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs
attachment behavior via a unique cascade of events (amygdala–LC– olfactory bulb).
The Journal of Neuroscience, December 16, 2009 • 29(50):15745–15755
Electrophysiology of Object Naming in Primary Progressive Aphasia
Robert S. Hurley,1 Ken A. Paller,1 Christina A. Wieneke,1 Sandra Weintraub,1 Cynthia K. Thompson,1
Kara D. Federmeier,2 and M.-Marsel Mesulam1
1Cognitive Neurology & Alzheimer’s Disease Center, Northwestern University, Chicago, Illinois 60660, and 2Beckman Institute, University of Illinois,
Urbana, Illinois 61801
Primary progressive aphasia (PPA), a selective neurodegeneration of the language network, frequently causes object naming impairments. We examined the N400
event-related potential (ERP) to explore interactions between object recognition and word processing in 20 PPA patients and 15 controls. Participants viewed photographs
of objects, each followed by a word that was either a match to the object, a semantically related mismatch, or an unrelated mismatch. Patients judged whether word– object
pairs matched with high accuracy (94% PPA group; 98% control group), but they failed to exhibit the normal N400 category effect (N400c), defined as a larger N400 to
unrelated versus related mismatch words. In contrast, the N400 mismatch effect (N400m), defined as a larger N400 to mismatch than match words, was observed in both
groups. N400m magnitude was positively correlated with neuropsychological measures of word comprehension but not fluency or grammatical competence, and therefore
reflected the semantic component of naming. After ERP testing, patients were asked to name the same set of objects aloud. Trials with objects that could not be named were
found to lack an N400m, although the name had been correctly recognized at the matching stage. Even accurate overt naming did not necessarily imply normal semantic
processing, as shown by the absent N400c. The N400m was preserved in one patient with postsemantic anomia, who could write the names of objects she could not verbalize.
N400 analyses can thus help dissect the multiple cognitive mechanisms that contribute to object naming failures in PPA.
The Journal of Neuroscience, December 16, 2009 • 29(50):15762–15769
Cooperative and Competitive Interactions Facilitate Stereo Computations in Macaque Primary
Visual Cortex
Jason M. Samonds,1 Brian R. Potetz,2 and Tai Sing Lee1
1 Center for the Neural Basis of Cognition and Computer Science Department, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, and
2 Department of Electrical Engineering and Computer Science, Kansas University, Lawrence, Kansas 66045
Inferring depth from binocular disparities is a difficult problem for the visual system because local features in the left- and right-eye images must be matched correctly to
solve this “stereo correspondence problem.” Cortical architecture and computational studies suggest that lateral interactions among neurons could help resolve local
uncertainty about disparity encoded in individual neurons by incorporating contextual constraints. We found that correlated activity among pairs of neurons in primary
visual cortex depended both on disparity-tuning relationships and the stimuli displayed within the receptive fields of the neurons. Nearby pairs of neurons with distinct
disparity tuning exhibited a decrease in spike correlation at competing disparities soon after response onset. Distant neuronal pairs of similar disparity tuning exhibited an
increase in spike correlation at mutually preferred disparities. The observed correlated activity and response dynamics suggests that local competitive and distant
cooperative interactions improve disparity tuning of individual neurons over time. Such interactions could represent a neural substrate for the principal constraints
underlying cooperative stereo algorithms.
The Journal of Neuroscience, December 16, 2009 • 29(50):15780 –15795
Preparation to Inhibit a Response Complements Response Inhibition during Performance of a
Stop-Signal Task
Junichi Chikazoe, Koji Jimura, Satoshi Hirose, Ken-ichiro Yamashita, Yasushi Miyashita, and Seiki Konishi
Department of Physiology, The University of Tokyo School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan
Inhibition of inappropriate responses is an essential executive function needed for adaptation to changing environments. In stop-signal tasks, which are often used to
investigate response inhibition, subjects make “go” responses while they prepare to stop at a suddenly given “stop” signal. However, the preparatory processes ongoing
before response inhibition have rarely been investigated, and it remains unclear how the preparation contributes to response inhibition. In the present study, a stop-signal
task was designed so that the extent of the preparation could be estimated using behavioral and neuroimaging measures. Specifically, in addition to the conventional go
trials where preparation to stop was required (“uncertain-go” trials), another type of go trial was introduced where a stop-signal was never given and such preparation was
unnecessary (“certain-go” trials). An index reflecting the “preparation cost” was then calculated by subtracting the reaction times in the certain-go trials from those in the
uncertain-go trials. It was revealed that the stop signal reaction time, a common index used to evaluate the efficiency of response inhibition, decreased as the preparation
cost increased, indicating greater preparation supports more efficient inhibition. In addition, imaging data showed that response inhibition recruited frontoparietal
regions (the contrast “stop vs uncertain-go”) and that preparation recruited most of the inhibition-related frontoparietal regions (the contrast “uncertain-go vs certain-
go”). It was also revealed that the inhibition-related activity declined as the preparation cost increased. These behavioral and imaging results suggest preparation makes a
complementary contribution to response inhibition during performance of a stop-signal task.
The Journal of Neuroscience, December 16, 2009 • 29(50):15870 –15877
Auditory Cortical Activity after Intracortical Microstimulation and Its Role for Sensory
Processing and Learning
Matthias Deliano,1 Henning Scheich,1 and Frank W. Ohl1,2
1Leibniz-Institute for Neurobiology, D-39118 Magdeburg, Germany, and 2Institute of Biology, Otto-von-Guericke-University, D-39118 Magdeburg,
Germany
Several studies have shown that animals can learn to make specific use of intracortical microstimulation (ICMS) of sensory cortex within behavioral tasks. Here, we
investigate how the focal, artificial activation by ICMS leads to a meaningful, behaviorally interpretable signal. In natural learning, this involves large-scale activity patterns
in widespread brain-networks. We therefore trained gerbils to discriminate closely neighboring ICMS sites within primary auditory cortex producing evoked responses
largely overlapping in space. In parallel, during training, we recorded electrocorticograms (ECoGs) at high spatial resolution. Applying a multivariate classification
procedure, we identified late spatial patterns that emerged with discrimination learning from the ongoing poststimulus ECoG. These patterns contained information about
the preceding conditioned stimulus, and were associated with a subsequent correct behavioral response by the animal. Thereby, relevant pattern information was mainly
carried by neuron populations outside the range of the lateral spatial spread of ICMS-evoked cortical activation ( 1.2 mm). This demonstrates that the stimulated cortical
area not only encoded information about the stimulation sites by its focal, stimulus-driven activation, but also provided meaningful signals in its ongoing activity related
to the interpretation of ICMS learned by the animal. This involved the stimulated area as a whole, and apparently required large-scale integration in the brain. However,
ICMS locally interfered with the ongoing cortical dynamics by suppressing pattern formation near the stimulation sites. The interaction between ICMS and ongoing cortical
activity has several implications for the design of ICMS protocols and cortical neuroprostheses, since the meaningful interpretation of ICMS depends on this interaction.
The Journal of Neuroscience, December 16, 2009 • 29(50):15898 –15909
Adult Plasticity in Multisensory Neurons: Short-Term Experience-Dependent Changes in the
Superior Colliculus
Liping Yu,1 Barry E. Stein,2 and Benjamin A. Rowland2
1East China Normal University, School of Life Sciences, Institute of Cognitive Neuroscience, Shanghai, China, and 2Department of Neurobiology and
Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1010
Multisensory neurons in the superior colliculus (SC) have the capability to integrate signals that belong to the same event, despite being conveyed by different senses. They
develop this capability during early life as experience is gained with the statistics of cross-modal events. These adaptations prepare the SC to deal with the cross-modal
events that are likely to be encountered throughout life. Here, we found that neurons in the adult SC can also adapt to experience with sequentially ordered cross-modal
(visual-auditory or auditory-visual) cues, and that they do so over short periods of time (minutes), as if adapting to a particular stimulus configuration. This short-term
plasticity was evident as a rapid increase in the magnitude and duration of responses to the first stimulus, and a shortening of the latency and increase in magnitude of the
responses to the second stimulus when they are presented in sequence. The result was that the two responses appeared to merge. These changes were stable in the absence
of experience with competing stimulus configurations, outlasted the exposure period, and could not be induced by equivalent experience with sequential within-modal
(visual-visual or auditory-auditory) stimuli. A parsimonious interpretation is that the additional SC activity provided by the second stimulus became associated with, and
increased the potency of, the afferents responding to the preceding stimulus. This interpretation is consistent with the principle of spike-timing-dependent plasticity, which
may provide the basic mechanism for short term or long term plasticity and be operative in both the adult and neonatal SC.
The Journal of Neuroscience, December 16, 2009 • 29(50):15910 –15922
NEUROBIOLOGY OF DISEASE
Amyloid Precursor Protein Regulates Cav1.2 L-type Calcium Channel Levels and Function to
Influence GABAergic Short-Term Plasticity
Li Yang,1* Zilai Wang,1,2* Baiping Wang,1 Nicholas J. Justice,1 and Hui Zheng1,2,3
1Huffington Center on Aging, 2Department of Molecular and Human Genetics, and 3Departments of Molecular and Cellular Biology and Neuroscience,
Baylor College of Medicine, Houston, Texas 77030
Amyloid precursor protein (APP) has been strongly implicated in the pathogenesis of Alzheimer’s disease (AD). Although impaired synaptic function is believed to be an
early and causative event in AD, how APP physiologically regulates synaptic properties remains poorly understood. Here, we report a critical role for APP in the regulation
of L-type calcium channels (LTCC) in GABAergic inhibitory neurons in striatum and hippocampus. APP deletion in mice leads to an increase in the levels of Cav1.2, the
pore-forming subunit of LTCCs, and subsequent increases in GABAergic calcium currents (ICa 2 ) that can be reversed by reintroduction of APP. Upregulated levels of Cav1.2
result in reduced GABAergic paired-pulse inhibition and increased GABAergic post-tetanic potentiation in both striatal and hippocampal neurons, indicating that APP
modulates synaptic properties of GABAergic neurons by regulating Cav1.2. Furthermore, APP physically interacts with Cav1.2, suggesting a mechanism in which loss of APP
leads to an inappropriate accumulation and aberrant activity of Cav1.2. These results provide a direct link between APP and calcium signaling and might help explain how
altered APP regulation leads to changes in synaptic function that occur with AD.
The Journal of Neuroscience, December 16, 2009 • 29(50):15660 –15668
Novel Mediators of Amyloid Precursor Protein Signaling
Andrzej Swistowski,1* Qiang Zhang,1* Mark E. Orcholski,1 Danielle Crippen,1 Cathy Vitelli,1 Alexei Kurakin,1 and
Dale E. Bredesen1,2
1Buck Institute for Age Research, Novato, California 94945, and 2Department of Neurology, University of California, San Francisco, San Francisco,
California 94143
Multiple recent reports implicate amyloid precursor protein (APP) signaling in the pathogenesis of Alzheimer’s disease, but the APP-dependent signaling network involved
has not been defined. Here, we report a novel consensus sequence for interaction with the PDZ-1 and PDZ-2 domains of the APP-interacting proteins Mint1, Mint2, and
Mint3 (X11 , X11 , and X11 ), and multiple novel interactors for these proteins, with the finding that transcriptional coactivators are highly represented among these
interactors. Furthermore, we show that Mint3 interaction with a set of the transcriptional coactivators leads to nuclear localization and transactivation, whereas interaction
of the same set with Mint1 or Mint2 prevents nuclear localization and transactivation. These results define new mediators of the signal transduction network mediated by
APP.
The Journal of Neuroscience, December 16, 2009 • 29(50):15703–15712
A Novel Allele of Myosin VIIa Reveals a Critical Function for the C-Terminal FERM Domain for
Melanosome Transport in Retinal Pigment Epithelial Cells
Martin Schwander,1 Vanda Lopes,2,3 Anna Sczaniecka,1 Daniel Gibbs,2 Concepcion Lillo,2 David Delano,4
¨
Lisa M. Tarantino,5 Tim Wiltshire,5 David S. Williams,2,3 and Ulrich Muller1
1Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, 2Departments of
Pharmacology and Neuroscience, School of Medicine, University of California at San Diego, La Jolla, California 92093, 3Departments of Ophthalmology and
Neurobiology, Jules Stein Eye Institute, School of Medicine, University of California Los Angeles, Los Angeles, California 90095, 4Genomics Institute of the
Novartis Research Foundation, San Diego, California 92121, and 5Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27516
Mutations in the head and tail domains of the motor protein myosin VIIA (MYO7A) cause deaf-blindness (Usher syndrome type 1B, USH1B) and nonsyndromic deafness
(DFNB2, DFNA11). The head domain binds to F-actin and serves as the MYO7A motor domain, but little is known about the function of the tail domain. In a genetic screen,
we have identified polka mice, which carry a mutation (c.5742 5G A) that affects splicing of the MYO7A transcript and truncates the MYO7A tail domain at the
C-terminal FERM domain. In the inner ear, expression of the truncated MYO7A protein is severely reduced, leading to defects in hair cell development. In retinal pigment
epithelial (RPE) cells, the truncated MYO7A protein is expressed at comparative levels to wild-type protein but fails to associate with and transport melanosomes. We
conclude that the C-terminal FERM domain of MYO7A is critical for melanosome transport in RPE cells. Our findings also suggest that MYO7A mutations can lead to
tissue-specific effects on protein levels, which may explain why some mutations in MYO7A lead to deafness without retinal impairment.
The Journal of Neuroscience, December 16, 2009 • 29(50):15810 –15818
Neuroprotective Role of Haptoglobin after Intracerebral Hemorrhage
Xiurong Zhao, Shen Song, Guanghua Sun, Roger Strong, Jie Zhang, James C. Grotta, and Jaroslaw Aronowski
Stroke Program, Department of Neurology, University of Texas Health Science Center, Medical School at Houston, Houston, Texas 77030
After intracerebral hemorrhage (ICH), the brain parenchyma is exposed to blood containing red blood cells (RBCs) and consequently to its lysis products. Iron-rich
hemoglobin (Hb) is the most abundant protein in RBCs. When released into the brain parenchyma during hemolysis, Hb becomes a central mediator of cytotoxicity. Our
study indicates that haptoglobin (Hp), an acute-phase response protein primarily synthesized in the liver and known to bind and neutralize Hb in the bloodstream, is also
expressed in brain in which it plays an important role in defending neurons from damage induced by hemolytic products after ICH. We demonstrate that the Hb-induced
hypohaptoglobinemia aggravates ICH-induced brain damage while pharmacologic intervention with sulforaphane to induce brain Hp is linked to a reduction in brain
damage. In agreement with these findings, Hp deficiency worsens whereas Hp overexpression alleviates ICH-mediated brain injury. We also identified that oligodendroglia
are the primary source of brain-derived Hp among brain cells and that oligodendroglia-released Hp plays protective roles against Hb-mediated toxicity to neurons and
oligodendrocytes. We conclude that Hp, particularly the brain-derived Hp, plays cytoprotective roles and represents a potential therapeutic target for ICH treatment.
The Journal of Neuroscience, December 16, 2009 • 29(50):15819 –15827
Sustained Morphine-Induced Sensitization and Loss of Diffuse Noxious Inhibitory Controls in
Dura-Sensitive Medullary Dorsal Horn Neurons
Akiko Okada-Ogawa,1 Frank Porreca,2 and Ian D. Meng3
1Department of Oral Diagnosis, School of Dentistry, Nihon University, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan, 2Department of
Pharmacology, College of Medicine, University of Arizona, Health Sciences Center, Tucson, Arizona 85724, and 3Department of Physiology, College of
Osteopathic Medicine, University of New England, Biddeford, Maine 04005
Overuse of medications used to treat migraine headache can produce a chronic daily headache, termed medication overuse headache (MOH). Although “overuse” of
opioids, triptans, and over-the-counter analgesics can all produce MOH, the neuronal mechanisms remain unknown. Headache pain is likely to be produced by stimulation
of primary afferent neurons that innervate the intracranial vasculature and the resulting activation of medullary dorsal horn (MDH) neurons. The present study compared
the receptive field properties of MDH dura-sensitive neurons in rats treated with morphine to those given vehicle. Animals were implanted with osmotic minipumps or
pellets for sustained subcutaneous administration of morphine or vehicle 6 –7 d before recording from dura-sensitive neurons. Electrical and mechanical activation
thresholds from the dura were significantly lower in chronic morphine-treated animals when compared to vehicle controls. In addition, sustained morphine increased the
cutaneous receptive field sizes. The presence of diffuse noxious inhibitory controls (DNICs) was examined by placing the tail in 55°C water during concomitant noxious
thermal stimulation of the cutaneous receptive field, usually located in the ophthalmic region. The DNIC stimulus produced significant inhibition of heat-evoked activity
in vehicle- but not chronic morphine-treated animals. Inactivation of the rostral ventromedial medulla with 4% lidocaine reinstated DNICs in chronic morphine-treated
animals. These results are consistent with studies demonstrating a loss of DNICs in patients that suffer from chronic daily headache and may partially explain why overuse
of medication used to treat migraine can induce headaches.
The Journal of Neuroscience, December 16, 2009 • 29(50):15828 –15835
Unexpected Lack of Hypersensitivity in LRRK2 Knock-Out Mice to MPTP (1-Methyl-4-Phenyl-
1,2,3,6-Tetrahydropyridine)
Eva Andres-Mateos,1* Rebeca Mejias,1* Masayuki Sasaki,1 Xiaojie Li,1 Brian M. Lin,1 Saskia Biskup,1 Li Zhang,1
Rebecca Banerjee,6 Bobby Thomas,6 Lichuan Yang,6 Guosheng Liu,5 M. Flint Beal,6 David L. Huso,5 Ted M. Dawson,1,2,3
and Valina L. Dawson1,2,3,4
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, 2Department of Neurology, 3Solomon H. Snyder Department of Neuroscience,
1
Department of Physiology, and 5Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore,
4
Maryland 21205, and 6Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of Parkinson’s disease (PD). Whether loss of LRRK2 function accounts for
neurodegeneration of dopamine neurons in PD is not known, nor is it known whether LRRK2 kinase activity modulates the susceptibility of dopamine (DA) neurons to the
selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To better understand the role of LRRK2 in DA neuronal survival and its role in the
susceptibility of DA neurons to MPTP, we generated LRRK2 knock-out (KO) mice lacking the kinase domain of LRRK2. Here, we show that LRRK2 KO mice are viable and
have no major abnormalities and live to adulthood. The dopaminergic system is normal in LRRK2 KO mice as assessed via HPLC for DA and its metabolites and via
stereologic assessment of DA neuron number in young and aged mice. Importantly, there is no significant difference in the susceptibility of LRRK2 KO and wild-type mice
to MPTP. These results suggest that LRRK2 plays little if any role in the development and survival of DA neurons under physiologic conditions. Thus, PD due to LRRK2
mutations are likely not due to a loss of function. Moreover, LRRK2 is not required for the susceptibility of DA neurons to MPTP.
The Journal of Neuroscience, December 16, 2009 • 29(50):15846 –15850
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