1. health and fitness
2. disease

The Journal of Neuroscience, October 8, 2014 • 34(41):i • i
This Week in The Journal
Development/Plasticity/Repair
Adult-Born Granule Cells Maintain
Olfactory Bulb Organization
F
Diana M. Cummings, Jason S. Snyder,
Michelle Brewer, Heather A. Cameron,
and Leonardo Belluscio
(see pages 13801–13810)
Olfactory sensory neurons expressing the
same odorant receptor converge onto two
isofunctional columns in the olfactory
bulb. Paired isofunctional columns are
connected by tufted cell axons, which synapse on GABAergic granule neurons. After a postnatal refinement period during
which intrabulbar projections narrow to
the width of a single glomerulus, the projection patterns remain relatively stable
throughout life, despite the continuous
addition of new granule cells in mice. In
fact, this stability requires the addition of
adult-born granule neurons, as shown by
Cummings et al. After neuronal stem cells
were ablated, intrabulbar projections
broadened. Similar broadening normally
occurs after olfactory deprivation, but the
original pattern reemerges when sensory
input is restored. Re-refinement of intrabulbar projections after sensory deprivation and restoration was prevented by
stem-cell ablation, however. Because olfactory deprivation alone causes granule
cell loss, and newborn granule cells are
added when input is restored, the authors
propose that the width of intrabulbar projections is influenced by the number of
target granule cells.
F
Systems/Circuits
Responses in Locus Ceruleus Reflect
Actions More Than Cues
Rishi M. Kalwani, Siddhartha Joshi,
and Joshua I. Gold
(see pages 13656 –13669)
The locus ceruleus (LC) and the adjacent
subceruleus nucleus (subC) are the brain’s
primary sources of norepinephrine, which
has roles in arousal, attention, and learning.
Neurons in LC respond phasically to
reward-indicating stimuli, particularly
when those stimuli elicit an abrupt behavioral response. To investigate whether this
activity is more related to the salience of the
stimulus or the decision to act, Kalwani et al.
recorded single units in LC⫹subC as monkeys performed a saccadic countermanding
task. Most neurons showed distinct responses when the saccade target (the “go”
signal) appeared and when the instructed
saccade began. In contrast, neurons did not
respond when the fixation target (the “stop”
signal) reappeared or when the saccade was
correctly aborted, even though such stops
were rewarded. Moreover, neurons showed
activity at the onset of saccades made in error after a stop signal appeared, even though
such saccades were not rewarded. Overall,
neuronal activity appeared to reflect the decision to saccade, regardless of whether the
saccade was rewarded.
F
Behavioral/Cognitive
Working Memory Deficits Can
Impair Reinforcement Learning
Anne G.E. Collins, Jaime K. Brown, James M. Gold,
James A. Waltz, and Michael J. Frank
(see pages 13747–13756)
In normal olfactory bulb (left), tufted cell axons extend approximately the width of a single glomerulus. When adult neurogenesis is prevented (right), the arbors widen. See the article by
Cummings et al. for details.
Although delusions and hallucinations are
the symptoms most commonly associated
with schizophrenia, cognitive impairment
typically emerges before the onset of other
symptoms and persists throughout the disease. Cognitive impairment involves deficits
in diverse functions, including attention,
working memory, executive control, reinforcement learning, episodic memory, and
sensory processing. Many of these deficits
might stem from an inability to maintain
representations of task-relevant information. Using a learning task that allows
dissociation of working memory and
reinforcement learning, along with a computational model that includes both components, Collins et al. found that deficits in
working memory were sufficient to explain
impairments in reinforcement learning in
schizophrenics. In particular, while the
number of items to learn (working memory
load) affected patients’ performance more
than healthy subjects’, the number of presentations of an item (amount of reinforcement) affected schizophrenic and healthy
subjects similarly. Modeling suggested that
patients had a smaller working memory
capacity, were more prone to forgetting,
and relied less on working memory than
controls.
Neurobiology of Disease
Mutant ␣-Synuclein Increases Spike
Rate of Nigral Neurons
F
Mahalakshmi Subramaniam, Daniel Althof,
Suzana Gispert, Jochen Schwenk,
Georg Auburger, et al.
(see pages 13586 –13599)
Parkinson’s disease (PD) is characterized by
loss of dopaminergic neurons selectively in
the substantia nigra (SN) and by intraneuronal inclusions containing ␣-synuclein.
PD-causing mutations in ␣-synuclein promote its accumulation, impair intracellular
degradation processes and mitochondrial
functions, and disrupt redox balance. These
effects occur ubiquitously, however: what
makes SN neurons particularly vulnerable
to degeneration remains unknown. Subramaniam et al. have found a clue to this
mystery. Overexpressing human mutant
␣-synuclein in mice caused a progressive increase in spike rate in SN dopaminergic
neurons. In contrast, firing of dopaminergic
neurons in the ventral tegmental area,
which are relatively unaffected in PD, was
not noticeably affected by the mutation. The
increased spike rate of SN neurons appeared
to stem from a reduction in the maximal
conductance of A-type Kv4.3 potassium
channels—which regulate spike frequency
in these neurons—as a result of oxidative
modification of the channel. Treatment of
brain slices with a reducing agent restored
A-type currents and reduced spike rate.
The Journal of Neuroscience
October 8, 2014 • Volume 34 Number 41 • www.jneurosci.org
i
This Week in The Journal
Journal Club
13569
The Medial Prefrontal Cortex and the Deceptiveness of Memory
Marlieke T.R. van Kesteren and Thackery I. Brown
13571
Neuroinflammation Mediates Synergy between Cerebral Ischemia and Amyloid-␤ to
Cause Synaptic Depression
Walter Swardfager, Madelaine Lynch, Sonam Dubey, and Paul M. Nagy
Articles
CELLULAR/MOLECULAR
Cover legend: The phase relationship as a function
of time between a prefrontal and a parietal local field
potential (8 –25 Hz) during a visual working memory
task. This example illustrates a flip in the phase
relationship from anti-phase to in-phase. The
background is a schematic of the phase relationships
between prefrontal and posterior parietal cortex.
For more details, see the article by Dotson et al.
(pages 13600 –13613).
13614
A␤ Selectively Impairs mGluR7 Modulation of NMDA Signaling in Basal Forebrain
Cholinergic Neurons: Implication in Alzheimer’s Disease
Zhenglin Gu, Jia Cheng, Ping Zhong, Luye Qin, Wenhua Liu, and Zhen Yan
13725
The Schizophrenia Susceptibility Gene Dysbindin Regulates Dendritic Spine
Dynamics
Jie-Min Jia, Zhonghua Hu, Jacob Nordman, and Zheng Li
13737
Stress Induces Pain Transition by Potentiation of AMPA Receptor Phosphorylation
Changsheng Li, Ya Yang, Sufang Liu, Huaqiang Fang, Yong Zhang,
Orion Furmanski, John Skinner, Ying Xing, Roger A. Johns, Richard L. Huganir,
and Feng Tao
DEVELOPMENT/PLASTICITY/REPAIR
䊉
13790
Ganglioside GD3 Is Required for Neurogenesis and Long-Term Maintenance of Neural
Stem Cells in the Postnatal Mouse Brain
Jing Wang, Allison Cheng, Chandramohan Wakade, and Robert K. Yu
13801
Adult Neurogenesis Is Necessary to Refine and Maintain Circuit Specificity
Diana M. Cummings, Jason S. Snyder, Michelle Brewer, Heather A. Cameron,
and Leonardo Belluscio
13840
Early Monocular Defocus Disrupts the Normal Development of Receptive-Field
Structure in V2 Neurons of Macaque Monkeys
Xiaofeng Tao, Bin Zhang, Guofu Shen, Janice Wensveen, Earl L. Smith 3rd,
Shinji Nishimoto, Izumi Ohzawa, and Yuzo M. Chino
13855
The TRIM-NHL Protein Brat Promotes Axon Maintenance by Repressing src64B
Expression
Giovanni Marchetti, Ilka Reichardt, Juergen A. Knoblich, and Florence Besse
SYSTEMS/CIRCUITS
䊉
13574
Motor Cortex Is Functionally Organized as a Set of Spatially Distinct Representations
for Complex Movements
Andrew R. Brown and G. Campbell Teskey
13656
Phasic Activation of Individual Neurons in the Locus Ceruleus/Subceruleus Complex
of Monkeys Reflects Rewarded Decisions to Go But Not Stop
Rishi M. Kalwani, Siddhartha Joshi, and Joshua I. Gold
13670
A Feedforward Inhibitory Circuit Mediates Lateral Refinement of Sensory
Representation in Upper Layer 2/3 of Mouse Primary Auditory Cortex
Ling-yun Li, Xu-ying Ji, Feixue Liang, Ya-tang Li, Zhongju Xiao,
Huizhong W. Tao, and Li I. Zhang
13701
Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced
Dendrodendritic Excitation and Inhibition
Yuguo Yu, Michele Migliore, Michael L. Hines, and Gordon M. Shepherd
13714
Presynaptic BK Channels Modulate Ethanol-Induced Enhancement of GABAergic
Transmission in the Rat Central Amygdala Nucleus
Qiang Li, Roger Madison, and Scott D. Moore
13757
The Amygdala and Basal Forebrain as a Pathway for Motivationally Guided Attention
Christopher J. Peck and C. Daniel Salzman
13819
Presynaptic Modulation of Spinal Nociceptive Transmission by Glial Cell
Line-Derived Neurotrophic Factor (GDNF)
Chiara Salio, Francesco Ferrini, Sangu Muthuraju, and Adalberto Merighi
BEHAVIORAL/COGNITIVE
䊉
13600
Frontoparietal Correlation Dynamics Reveal Interplay between Integration
and Segregation during Visual Working Memory
Nicholas M. Dotson, Rodrigo F. Salazar, and Charles M. Gray
13644
Human Muscle Spindle Sensitivity Reflects the Balance of Activity between
Antagonistic Muscles
Michael Dimitriou
13684
The Fusion of Mental Imagery and Sensation in the Temporal Association Cortex
Christopher C. Berger and H. Henrik Ehrsson
13693
Spontaneous Microsaccades Reflect Shifts in Covert Attention
Shlomit Yuval-Greenberg, Elisha P. Merriam, and David J. Heeger
13747
Working Memory Contributions to Reinforcement Learning Impairments in
Schizophrenia
Anne G.E. Collins, Jaime K. Brown, James M. Gold, James A. Waltz,
and Michael J. Frank
13768
Mirror Reversal and Visual Rotation Are Learned and Consolidated via Separate
Mechanisms: Recalibrating or Learning De Novo?
Sebastian Telgen, Darius Parvin, and Jo¨rn Diedrichsen
13811
Cortical Activation Associated with Muscle Synergies of the Human Male Pelvic Floor
Skulpan Asavasopon, Manku Rana, Daniel J. Kirages, Moheb S. Yani,
Beth E. Fisher, Darryl H. Hwang, Everett B. Lohman, Lee S. Berk,
and Jason J. Kutch
13834
Ceiling Effects Prevent Further Improvement of Transcranial Stimulation in Skilled
Musicians
Shinichi Furuya, Matthias Klaus, Michael A. Nitsche, Walter Paulus,
and Eckart Altenmu¨ller
䊉
NEUROBIOLOGY OF DISEASE
13586 Mutant ␣-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra
Neurons by Oxidative Impairment of A-Type Potassium Channels
Mahalakshmi Subramaniam, Daniel Althof, Suzana Gispert, Jochen Schwenk,
Georg Auburger, Akos Kulik, Bernd Fakler, and Jochen Roeper
13629
Alzheimer’s Disease-Like Pathology Induced by Amyloid-␤ Oligomers in Nonhuman
Primates
Leticia Forny-Germano, Natalia M. Lyra e Silva, Andre´ F. Batista,
Jordano Brito-Moreira, Matthias Gralle, Susan E. Boehnke, Brian C. Coe,
Ann Lablans, Suelen A. Marques, Ana Maria B. Martinez, William L. Klein,
Jean-Christophe Houzel, Sergio T. Ferreira, Douglas P. Munoz,
and Fernanda G. De Felice
13780
Early Alterations in Functional Connectivity and White Matter Structure in a
Transgenic Mouse Model of Cerebral Amyloidosis
Joanes Grandjean, Aileen Schroeter, Pan He, Matteo Tanadini, Ruth Keist,
Dimitrije Krstic, Uwe Konietzko, Jan Klohs, Roger M. Nitsch, and Markus Rudin
13865
Retraction: “Coordinated Regulation of Hepatic Energy Stores by Leptin and Hypothalamic
Agouti-Related Protein” by James P. Warne, Jillian M. Varonin, Sofie S. Nielsen, Louise E.
Olofsson, Christopher B. Kaelin, Streamson Chua, Jr., Gregory S. Barsh, Suneil K. Koliwad,
and Allison W. Xu appeared on pages 11972–11985 of the July 17, 2013 issue. A retraction
for this article appears on page 13865.
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Articles
CELLULAR/MOLECULAR
A␤ Selectively Impairs mGluR7 Modulation of NMDA Signaling in Basal Forebrain Cholinergic
Neurons: Implication in Alzheimer’s Disease
Zhenglin Gu,1 Jia Cheng,1 Ping Zhong,1,2 Luye Qin,1 Wenhua Liu,1 and Zhen Yan1,2,3
Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214,
Veterans Administration Western New York Healthcare System, Buffalo, New York 14215, and 3Department of Neurobiology, Key Laboratory for
Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing Institute for Brain Disorders, Beijing 100069, China
1
2
Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer’s disease (AD) and is thought to be responsible for the
cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of
metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR-mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving
cofilin-regulated actin dynamics. In BF cholinergic neurons, ␤-amyloid (A␤) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase
activity and decreasing cofilin-mediated actin depolymerization through a p75 NTR-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected
BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by A␤ in BF cholinergic neurons. It provides a potential basis for the A␤-induced disruption
of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD.
The Journal of Neuroscience, October 8, 2014 • 34(41):13614 –13628
The Schizophrenia Susceptibility Gene Dysbindin Regulates Dendritic Spine Dynamics
Jie-Min Jia,* Zhonghua Hu,* Jacob Nordman,* and X Zheng Li
Unit on Synapse Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3732
Dysbindin is a schizophrenia susceptibility gene required for the development of dendritic spines. The expression of dysbindin proteins is decreased in the brains of
schizophrenia patients, and neurons in mice carrying a deletion in the dysbindin gene have fewer dendritic spines. Hence, dysbindin might contribute to the spine pathology
of schizophrenia, which manifests as a decrease in the number of dendritic spines. The development of dendritic spines is a dynamic process involving formation,
retraction, and transformation of dendritic protrusions. It has yet to be determined whether dysbindin regulates the dynamics of dendritic protrusions. Here we address
this question using time-lapse imaging in hippocampal neurons. Our results show that dysbindin is required to stabilize dendritic protrusions. In dysbindin-null neurons,
dendritic protrusions are hyperactive in formation, retraction, and conversion between different types of protrusions. We further show that CaMKII␣ is required for the
stabilization of mushroom/thin spines, and that the hyperactivity of dendritic protrusions in dysbindin-null neurons is attributed in part to decreased CaMKII␣ activity
resulting from increased inhibition of CaMKII␣ by Abi1. These findings elucidate the function of dysbindin in the dynamic morphogenesis of dendritic protrusions, and
reveal the essential roles of dysbindin and CaMKII␣ in the stabilization of dendritic protrusions during neuronal development.
The Journal of Neuroscience, October 8, 2014 • 34(41):13725–13736
Stress Induces Pain Transition by Potentiation of AMPA Receptor Phosphorylation
Changsheng Li,1,5* Ya Yang,1,2* X Sufang Liu,1,5* Huaqiang Fang,3 Yong Zhang,1 X Orion Furmanski,1 John Skinner,1
Ying Xing,5,6 Roger A. Johns,1 Richard L. Huganir,3,4 and X Feng Tao1,7
Department of Anesthesiology and Critical Care Medicine, 2The Russell H. Morgan Department of Radiology and Radiological Science, 3Solomon H.
Snyder Department of Neuroscience, and 4Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,
5Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, People’s Republic of China, 6Basic Medical College, Xinxiang Medical University,
Xinxiang, Henan 453003, People’s Republic of China, and 7Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas,
Texas 75246
1
Chronic postsurgical pain is a serious issue in clinical practice. After surgery, patients experience ongoing pain or become sensitive to incident, normally nonpainful
stimulation. The intensity and duration of postsurgical pain vary. However, it is unclear how the transition from acute to chronic pain occurs. Here we showed that social
defeat stress enhanced plantar incision-induced AMPA receptor GluA1 phosphorylation at the Ser831 site in the spinal cord and greatly prolonged plantar incision-induced
pain. Interestingly, targeted mutation of the GluA1 phosphorylation site Ser831 significantly inhibited stress-induced prolongation of incisional pain. In addition, stress
hormones enhanced GluA1 phosphorylation and AMPA receptor-mediated electrical activity in the spinal cord. Subthreshold stimulation induced spinal long-term
potentiation in GluA1 phosphomimetic mutant mice, but not in wild-type mice. Therefore, spinal AMPA receptor phosphorylation contributes to the mechanisms
underlying stress-induced pain transition.
The Journal of Neuroscience, October 8, 2014 • 34(41):13737–13746
DEVELOPMENT/PLASTICITY/REPAIR
Ganglioside GD3 Is Required for Neurogenesis and Long-Term Maintenance of Neural Stem
Cells in the Postnatal Mouse Brain
Jing Wang,1,4 Allison Cheng,1 Chandramohan Wakade,3,4 and Robert K. Yu1,2,4
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 2Department of Neurology, Medical College of Georgia, and
3Department of Physical Therapy, College of Allied Health Science, Georgia Regents University, Augusta, Georgia 30912, and 4Charlie Norwood VA Medical
Center, Augusta, Georgia 30904
1
The maintenance of a neural stem cell (NSC) population in mammalian postnatal and adult life is crucial for continuous neurogenesis and neural repair. However, the
molecular mechanism of how NSC populations are maintained remains unclear. Gangliosides are important cellular membrane components in the nervous system. We
previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self-renewal capacity of NSCs in vitro. Here, we investigated its role in postnatal and
adult neurogenesis in GD3-synthase knock-out (GD3S-KO) and wild-type mice. GD3S-KO mice with deficiency in GD3 and the downstream b-series gangliosides showed a
progressive loss of NSCs both at the SVZ and the DG of the hippocampus. The decrease of NSC populations in the GD3S-KO mice resulted in impaired neurogenesis at the
granular cell layer of the olfactory bulb and the DG in the adult. In addition, defects of the self-renewal capacity and radial glia-like stem cell outgrowth of postnatal GD3S-KO
NSCs could be rescued by restoration of GD3 expression in these cells. Our study demonstrates that the b-series gangliosides, especially GD3, play a crucial role in the
long-term maintenance NSC populations in postnatal mouse brain. Moreover, the impaired neurogenesis in the adult GD3S-KO mice led to depression-like behaviors. Thus,
our results provide convincing evidence linking b-series gangliosides deficiency and neurogenesis defects to behavioral deficits, and support a crucial role of gangliosides
in the long-term maintenance of NSCs in adult mice.
The Journal of Neuroscience, October 8, 2014 • 34(41):13790 –13800
Adult Neurogenesis Is Necessary to Refine and Maintain Circuit Specificity
Diana M. Cummings,1 Jason S. Snyder,2 X Michelle Brewer,2 Heather A. Cameron,2 and Leonardo Belluscio1
Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, and 2Section on
Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
1
The circuitry of the olfactory bulb contains a precise anatomical map that links isofunctional regions within each olfactory bulb. This intrabulbar map forms perinatally and
undergoes activity-dependent refinement during the first postnatal weeks. Although this map retains its plasticity throughout adulthood, its organization is remarkably
stable despite the addition of millions of new neurons to this circuit. Here we show that the continuous supply of new neuroblasts from the subventricular zone is necessary
for both the restoration and maintenance of this precise central circuit. Using pharmacogenetic methods to conditionally ablate adult neurogenesis in transgenic mice, we
find that the influx of neuroblasts is required for recovery of intrabulbar map precision after disruption due to sensory block. We further demonstrate that eliminating
adult-born interneurons in naive animals leads to an expansion of tufted cell axons that is identical to the changes caused by sensory block, thus revealing an essential role
for new neurons in circuit maintenance under baseline conditions. These findings show, for the first time, that inhibiting adult neurogenesis alters the circuitry of projection
neurons in brain regions that receive new interneurons and points to a critical role for adult-born neurons in stabilizing a brain circuit that exhibits high levels of plasticity.
The Journal of Neuroscience, October 8, 2014 • 34(41):13801–13810
Early Monocular Defocus Disrupts the Normal Development of Receptive-Field Structure in V2
Neurons of Macaque Monkeys
X Xiaofeng Tao,1 Bin Zhang,1,2 Guofu Shen,1 Janice Wensveen,1 X Earl L. Smith 3rd,1 Shinji Nishimoto,3,4
Izumi Ohzawa,3,4 and Yuzo M. Chino1
College of Optometry, University of Houston, Houston, Texas 77204-2020, 2College of Optometry, NOVA Southeastern University, Fort Lauderdale, Florida
33314, 3Graduate School of Frontier Biosciences, Osaka University, Osaka 560-8531, Japan, and 4Center for Information and Neural Networks, National
Institute of Information and Communications Technology, Osaka 560-8531, Japan
1
Experiencing different quality images in the two eyes soon after birth can cause amblyopia, a developmental vision disorder. Amblyopic humans show the reduced capacity
for judging the relative position of a visual target in reference to nearby stimulus elements (position uncertainty) and often experience visual image distortion. Although
abnormal pooling of local stimulus information by neurons beyond striate cortex (V1) is often suggested as a neural basis of these deficits, extrastriate neurons in the
amblyopic brain have rarely been studied using microelectrode recording methods. The receptive field (RF) of neurons in visual area V2 in normal monkeys is made up of
multiple subfields that are thought to reflect V1 inputs and are capable of encoding the spatial relationship between local stimulus features. We created primate models of
anisometropic amblyopia and analyzed the RF subfield maps for multiple nearby V2 neurons of anesthetized monkeys by using dynamic two-dimensional noise stimuli and
reverse correlation methods. Unlike in normal monkeys, the subfield maps of V2 neurons in amblyopic monkeys were severely disorganized: subfield maps showed higher
heterogeneity within each neuron as well as across nearby neurons. Amblyopic V2 neurons exhibited robust binocular suppression and the strength of the suppression was
positively correlated with the degree of hereogeneity and the severity of amblyopia in individual monkeys. Our results suggest that the disorganized subfield maps and
robust binocular suppression of amblyopic V2 neurons are likely to adversely affect the higher stages of cortical processing resulting in position uncertainty and image
distortion.
The Journal of Neuroscience, October 8, 2014 • 34(41):13840 –13854
The TRIM-NHL Protein Brat Promotes Axon Maintenance by Repressing src64B Expression
Giovanni Marchetti,1 Ilka Reichardt,2 Juergen A. Knoblich,2 and Florence Besse1
1Institute of Biology Valrose, University of Nice Sophia Antipolis, CNRS UMR7277, INSERM U1091, 06108 Nice Cedex 2, France and 2Institute of Molecular
Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria
The morphology and the connectivity of neuronal structures formed during early development must be actively maintained as the brain matures. Although impaired axon
stability is associated with the progression of various neurological diseases, relatively little is known about the factors controlling this process. We identified Brain tumor
(Brat), a conserved member of the TRIM-NHL family of proteins, as a new regulator of axon maintenance in Drosophila CNS. Brat function is dispensable for the initial
growth of Mushroom Body axons, but is required for the stabilization of axon bundles. We found that Brat represses the translation of src64B, an upstream regulator of a
conserved Rho-dependent pathway previously shown to promote axon retraction. Furthermore, brat phenotypes are phenocopied by src64B overexpression, and partially
suppressed by reducing the levels of src64B or components of the Rho pathway, suggesting that brat promotes axon maintenance by downregulating the levels of Src64B.
Finally, Brat regulates brain connectivity via its NHL domain, but independently of its previously described partners Nanos, Pumilio, and d4EHP. Thus, our results uncover a
novel post-transcriptional regulatory mechanism that controls the maintenance of neuronal architecture by tuning the levels of a conserved rho-dependent signaling pathway.
The Journal of Neuroscience, October 8, 2014 • 34(41):13855–13864
SYSTEMS/CIRCUITS
Motor Cortex Is Functionally Organized as a Set of Spatially Distinct Representations for
Complex Movements
Andrew R. Brown1,2 and G. Campbell Teskey1,2,3,4,5
Hotchkiss Brain Institute, Departments of 2Neuroscience, 3Cell Biology and Anatomy, 4Psychology, and 5Physiology and Pharmacology, University of
Calgary, Calgary, Alberta T2N 4N1, Canada
1
There is a long-standing debate regarding the functional organization of motor cortex. Intracortical microstimulation (ICMS) studies have provided two contrasting views
depending on the duration of stimulation. In the rat, short-duration ICMS reveals two spatially distributed forelimb movement representations, the rostral forelimb area
(RFA) and caudal forelimb area (CFA), eliciting identical movements. In contrast, long-duration ICMS reveals spatially distributed, complex, multijoint movement areas,
with grasping found exclusively in the rostral area and reach-shaping movements of the arm located in the caudal area. To provide corroboration for which interpretation
is correct, we selectively inactivated the RFA/grasp area during the performance of skilled forelimb behaviors using a reversible cortical cooling deactivation technique. A
significant impairment of grasping in the single-pellet retrieval task and manipulations of pasta was observed during cooling deactivation of the RFA/grasp area, but not the
CFA/arm area. Our results indicate a movement-based, rather than a muscle-based, functional organization of motor cortex, and provide evidence for a conserved
homology of independent grasp and reach circuitry shared between primates and rats.
The Journal of Neuroscience, October 8, 2014 • 34(41):13574 –13585
Phasic Activation of Individual Neurons in the Locus Ceruleus/Subceruleus Complex of
Monkeys Reflects Rewarded Decisions to Go But Not Stop
Rishi M. Kalwani,1 X Siddhartha Joshi,2 and X Joshua I. Gold2
1Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and 2Department of Neuroscience, University of Pennsylvania, Philadelphia,
Pennsylvania 19104
Neurons in the brainstem nucleus locus ceruleus (LC) often exhibit phasic activation in the context of simple sensory-motor tasks. The functional role of this activation,
which leads to the release of norepinephrine throughout the brain, is not yet understood in part because the conditions under which it occurs remain in question. Early
studies focused on the relationship of LC phasic activation to salient sensory events, whereas more recent work has emphasized its timing relative to goal-directed
behavioral responses, possibly representing the end of a sensory-motor decision process. To better understand the relationship between LC phasic activation and sensory,
motor, and decision processing, we recorded spiking activity of neurons in the LC⫹ (LC and the adjacent, norepinephrine-containing subceruleus nucleus) of monkeys
performing a countermanding task. The task required the monkeys to occasionally withhold planned, saccadic eye movements to a visual target. We found that many well
isolated LC⫹ units responded to both the onset of the visual cue instructing the monkey to initiate the saccade and again after saccade onset, even when it was initiated
erroneously in the presence of a stop signal. Many of these neurons did not respond to saccades made outside of the task context. In contrast, neither the appearance of the
stop signal nor the successful withholding of the saccade elicited an LC⫹ response. Therefore, LC⫹ phasic activation encodes sensory and motor events related to decisions
to execute, but not withhold, movements, implying a functional role in goal-directed actions, but not necessarily more covert forms of processing.
The Journal of Neuroscience, October 8, 2014 • 34(41):13656 –13669
A Feedforward Inhibitory Circuit Mediates Lateral Refinement of Sensory Representation in
Upper Layer 2/3 of Mouse Primary Auditory Cortex
Ling-yun Li,1,4 Xu-ying Ji,1,5 Feixue Liang,1,5 Ya-tang Li,1,4 Zhongju Xiao,5 Huizhong W. Tao,1,3 and Li I. Zhang1,2
Zilkha Neurogenetic Institute, Departments of 2Physiology and Biophysics and 3Cell and Neurobiology, 4Neuroscience Graduate Program, Keck School of
Medicine, University of Southern California, Los Angeles, California 90089, and 5Department of Physiology, School of Basic Medical Sciences, Southern
Medical University, Guangzhou 510515, China
1
Sensory information undergoes ordered and coordinated processing across cortical layers. Whereas cortical layer (L) 4 faithfully acquires thalamic information, the
superficial layers appear well staged for more refined processing of L4-relayed signals to generate corticocortical outputs. However, the specific role of superficial layer
processing and how it is specified by local synaptic circuits remains not well understood. Here, in the mouse primary auditory cortex, we showed that upper L2/3 circuits
play a crucial role in refining functional selectivity of excitatory neurons by sharpening auditory tonal receptive fields and enhancing contrast of frequency representation.
This refinement is mediated by synaptic inhibition being more broadly recruited than excitation, with the inhibition predominantly originating from interneurons in the
same cortical layer. By comparing the onsets of synaptic inputs as well as of spiking responses of different types of neuron, we found that the broadly tuned, fast responding
inhibition observed in excitatory cells can be primarily attributed to feedforward inhibition originating from parvalbumin (PV)-positive neurons, whereas somatostatin
(SOM)-positive interneurons respond much later compared with the onset of inhibitory inputs to excitatory neurons. We propose that the feedforward circuit-mediated
inhibition from PV neurons, which has an analogous function to lateral inhibition, enables upper L2/3 excitatory neurons to rapidly refine auditory representation.
The Journal of Neuroscience, October 8, 2014 • 34(41):13670 –13683
Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic
Excitation and Inhibition
Yuguo Yu,1,2,* Michele Migliore,2,3* Michael L. Hines,2 and Gordon M. Shepherd2
Center for Computational Systems Biology, The State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, School of
Life Sciences, Shanghai, 200433, China, 2Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, and 3Institute of
Biophysics, National Research Council, 90146 Palermo, Italy
1
The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits
present in olfactory bulb is unknown. Here a scaled-up model of the mitral– granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing
of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition
(inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about
the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results
suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb.
The Journal of Neuroscience, October 8, 2014 • 34(41):13701–13713
Presynaptic BK Channels Modulate Ethanol-Induced Enhancement of GABAergic Transmission
in the Rat Central Amygdala Nucleus
Qiang Li,1,2,3 Roger Madison,2,3 and Scott D. Moore1,3
Departments of 1Psychiatry and 2Neurosurgery, Duke University Medical Center, Durham, North Carolina 27710, and 3Durham VA Medical Center,
Durham, North Carolina 27705
Large-conductance calcium-activated potassium BK channels are widely expressed in the brain and are involved in the regulation of neuronal functions such as neurotransmitter release. However, their possible role in mediating ethanol-induced GABA release is still unknown. We assessed the role of BK channels in modulating the action of
ethanol on inhibitory synaptic transmission mediated via GABAA receptors in the rat central nucleus of the amygdala (CeA). Evoked IPSCs (eIPSCs) mediated by GABAA
receptors were isolated from CeA neurons under whole-cell voltage clamp, and their response to selective BK channel antagonists, channel activators, or ethanol was
analyzed. Blocking BK channels with the specific BK channel antagonist paxilline significantly increased the mean amplitude of eIPSCs, whereas the activation of BK
channels with the channel opener NS1619 reversibly attenuated the mean amplitude of eIPSCs. Ethanol (50 mM) alone enhanced the amplitude of eIPSCs but failed to further
enhance eIPSCs in the slices pretreated with paxilline. Bath application of either BK channel blockers significantly increased the frequency of miniature IPSCs (mIPSCs).
Similarly, 50 mM ethanol alone also enhanced mIPSC frequency. Increases in mIPSC frequency by either selective BK channel antagonists or ethanol were not accompanied
with changes in the amplitude of mIPSCs. Furthermore, following bath application of BK channel blockers for 10 min, ethanol failed to further increase mIPSC frequency.
Together, these results suggest that blocking BK channels mimics the effects of ethanol on GABA release and that presynaptic BK channels could serve as a target for ethanol
effects in CeA.
The Journal of Neuroscience, October 8, 2014 • 34(41):13714 –13724
The Amygdala and Basal Forebrain as a Pathway for Motivationally Guided Attention
Christopher J. Peck1 and X C. Daniel Salzman1,2,3,4,5
Department of Neuroscience and 2Department of Psychiatry, Columbia University, New York, New York 10027, 3Kavli Institute for Brain Sciences, New
York, New York 10032, 4W.M. Keck Center on Brain Plasticity and Cognition, New York, New York 10032, and 5New York State Psychiatric Institute, New
York, New York 10032
1
Visual stimuli associated with rewards attract spatial attention. Neurophysiological mechanisms that mediate this process must register both the motivational significance
and location of visual stimuli. Recent neurophysiological evidence indicates that the amygdala encodes information about both of these parameters. Furthermore, the firing
rate of amygdala neurons predicts the allocation of spatial attention. One neural pathway through which the amygdala might influence attention involves the intimate and
bidirectional connections between the amygdala and basal forebrain (BF), a brain area long implicated in attention. Neurons in the rhesus monkey amygdala and BF were
therefore recorded simultaneously while subjects performed a detection task in which the stimulus–reward associations of visual stimuli modulated spatial attention.
Neurons in BF were spatially selective for reward-predictive stimuli, much like the amygdala. The onset of reward-predictive signals in each brain area suggested different
routes of processing for reward-predictive stimuli appearing in the ipsilateral and contralateral fields. Moreover, neurons in the amygdala, but not BF, tracked trial-to-trial
fluctuations in spatial attention. These results suggest that the amygdala and BF could play distinct yet inter-related roles in influencing attention elicited by rewardpredictive stimuli.
The Journal of Neuroscience, October 8, 2014 • 34(41):13757–13767
Presynaptic Modulation of Spinal Nociceptive Transmission by Glial Cell Line-Derived
Neurotrophic Factor (GDNF)
Chiara Salio,1 X Francesco Ferrini,1* Sangu Muthuraju,1* and X Adalberto Merighi1,2
1
University of Turin, Department of Veterinary Sciences and 2National Institute of Neuroscience, 10095 Grugliasco, Italy
The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been
reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was
mimicked by capsaicin challenge.
Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I–II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin⫹ cells
expressing GDNF and the nonpeptidergic IB4⫹ neurons expressing the GFR␣1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid)
harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFR␣1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor
interactions.
Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin⫹ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the
glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca 2⫹ imaging and patch-clamp experiments with bath-applied
GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction
of the capsaicin-evoked [Ca 2⫹]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFR␣1. Therefore, GDNF released
from peptidergic CGRP/somatostatin⫹ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4⫹ nociceptors at glomeruli in LIIid.
These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of
pain modalities.
The Journal of Neuroscience, October 8, 2014 • 34(41):13819 –13833
BEHAVIORAL/COGNITIVE
Frontoparietal Correlation Dynamics Reveal Interplay between Integration and Segregation
during Visual Working Memory
X Nicholas M. Dotson, X Rodrigo F. Salazar, and Charles M. Gray
Cell Biology and Neuroscience, Montana State University, Bozeman, Montana 59717
Working memory requires large-scale cooperation among widespread cortical and subcortical brain regions. Importantly, these processes must achieve an appropriate
balance between functional integration and segregation, which are thought to be mediated by task-dependent spatiotemporal patterns of correlated activity. Here, we used
cross-correlation analysis to estimate the incidence, magnitude, and relative phase angle of temporally correlated activity from simultaneous local field potential recordings in a network of prefrontal and posterior parietal cortical areas in monkeys performing an oculomotor, delayed match-to-sample task. We found long-range intraparietal and frontoparietal correlations that display a bimodal distribution of relative phase values, centered near 0° and 180°, suggesting a possible basis for functional
segregation among distributed networks. Both short- and long-range correlations display striking task-dependent transitions in strength and relative phase, indicating that
cognitive events are accompanied by robust changes in the pattern of temporal coordination across the frontoparietal network.
The Journal of Neuroscience, October 8, 2014 • 34(41):13600 –13613
Human Muscle Spindle Sensitivity Reflects the Balance of Activity between Antagonistic
Muscles
Michael Dimitriou
Physiology Section, Department of Integrative Medical Biology, University of Umeå, S-901 87 Umeå, Sweden
Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The
“␣–␥ coactivation” hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal
inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording
spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of
identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from
this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist
muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle
activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent
control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle.
The Journal of Neuroscience, October 8, 2014 • 34(41):13644 –13655
The Fusion of Mental Imagery and Sensation in the Temporal Association Cortex
Christopher C. Berger and H. Henrik Ehrsson
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
It is well understood that the brain integrates information that is provided to our different senses to generate a coherent multisensory percept of the world around us (Stein
and Stanford, 2008), but how does the brain handle concurrent sensory information from our mind and the external world? Recent behavioral experiments have found that
mental imagery—the internal representation of sensory stimuli in one’s mind— can also lead to integrated multisensory perception (Berger and Ehrsson, 2013); however,
the neural mechanisms of this process have not yet been explored. Here, using functional magnetic resonance imaging and an adapted version of a well known multisensory
illusion (i.e., the ventriloquist illusion; Howard and Templeton, 1966), we investigated the neural basis of mental imagery-induced multisensory perception in humans. We
found that simultaneous visual mental imagery and auditory stimulation led to an illusory translocation of auditory stimuli and was associated with increased activity in
the left superior temporal sulcus (L. STS), a key site for the integration of real audiovisual stimuli (Beauchamp et al., 2004a, 2010; Driver and Noesselt, 2008; Ghazanfar et
al., 2008; Dahl et al., 2009). This imagery-induced ventriloquist illusion was also associated with increased effective connectivity between the L. STS and the auditory cortex.
These findings suggest an important role of the temporal association cortex in integrating imagined visual stimuli with real auditory stimuli, and further suggest that
connectivity between the STS and auditory cortex plays a modulatory role in spatially localizing auditory stimuli in the presence of imagined visual stimuli.
The Journal of Neuroscience, October 8, 2014 • 34(41):13684 –13692
Spontaneous Microsaccades Reflect Shifts in Covert Attention
Shlomit Yuval-Greenberg,1 Elisha P. Merriam,2 and David J. Heeger2
School of Psychological Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel, and 2Department of Psychology and
Center for Neural Science, New York University, New York, New York 10003
1
Microsaccade rate during fixation is modulated by the presentation of a visual stimulus. When the stimulus is an endogenous attention cue, the ensuing microsaccades tend
to be directed toward the cue. This finding has been taken as evidence that microsaccades index the locus of spatial attention. But the vast majority of microsaccades that
subjects make are not triggered by visual stimuli. Under natural viewing conditions, spontaneous microsaccades occur frequently (2–3 Hz), even in the absence of a
stimulus or a task. While spontaneous microsaccades may depend on low-level visual demands, such as retinal fatigue, image fading, or fixation shifts, it is unknown
whether their occurrence corresponds to changes in the attentional state. We developed a protocol to measure whether spontaneous microsaccades reflect shifts in spatial
attention. Human subjects fixated a cross while microsaccades were detected from streaming eye-position data. Detection of a microsaccade triggered the appearance of a
peripheral ring of grating patches, which were followed by an arrow (a postcue) indicating one of them as the target. The target was either congruent or incongruent
(opposite) with respect to the direction of the microsaccade (which preceded the stimulus). Subjects reported the tilt of the target (clockwise or counterclockwise relative
to vertical). We found that accuracy was higher for congruent than for incongruent trials. We conclude that the direction of spontaneous microsaccades is inherently linked
to shifts in spatial attention.
The Journal of Neuroscience, October 8, 2014 • 34(41):13693–13700
Working Memory Contributions to Reinforcement Learning Impairments in Schizophrenia
Anne G.E. Collins,1 Jaime K. Brown,2 James M. Gold,2 James A. Waltz,2 and X Michael J. Frank1
Department of Cognitive, Linguistics, and Psychological Sciences, Brown University, Providence, Rhode Island 02912, and 2Maryland Psychiatric Research
Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201
1
Previous research has shown that patients with schizophrenia are impaired in reinforcement learning tasks. However, behavioral learning curves in such tasks originate
from the interaction of multiple neural processes, including the basal ganglia- and dopamine-dependent reinforcement learning (RL) system, but also prefrontal cortexdependent cognitive strategies involving working memory (WM). Thus, it is unclear which specific system induces impairments in schizophrenia. We recently developed
a task and computational model allowing us to separately assess the roles of RL (slow, cumulative learning) mechanisms versus WM (fast but capacity-limited) mechanisms
in healthy adult human subjects. Here, we used this task to assess patients’ specific sources of impairments in learning. In 15 separate blocks, subjects learned to pick one
of three actions for stimuli. The number of stimuli to learn in each block varied from two to six, allowing us to separate influences of capacity-limited WM from the
incremental RL system. As expected, both patients (n ⫽ 49) and healthy controls (n ⫽ 36) showed effects of set size and delay between stimulus repetitions, confirming the
presence of working memory effects. Patients performed significantly worse than controls overall, but computational model fits and behavioral analyses indicate that these
deficits could be entirely accounted for by changes in WM parameters (capacity and reliability), whereas RL processes were spared. These results suggest that the working
memory system contributes strongly to learning impairments in schizophrenia.
The Journal of Neuroscience, October 8, 2014 • 34(41):13747–13756
Mirror Reversal and Visual Rotation Are Learned and Consolidated via Separate Mechanisms:
Recalibrating or Learning De Novo?
Sebastian Telgen, Darius Parvin, and X Jo¨rn Diedrichsen
Institute of Cognitive Neuroscience, University College London, London WC1N 3AR, United Kingdom
Motor learning tasks are often classified into adaptation tasks, which involve the recalibration of an existing control policy (the mapping that determines both feedforward
and feedback commands), and skill-learning tasks, requiring the acquisition of new control policies. We show here that this distinction also applies to two different
visuomotor transformations during reaching in humans: Mirror-reversal (left-right reversal over a mid-sagittal axis) of visual feedback versus rotation of visual feedback
around the movement origin. During mirror-reversal learning, correct movement initiation (feedforward commands) and online corrections (feedback responses) were
only generated at longer latencies. The earliest responses were directed into a nonmirrored direction, even after two training sessions. In contrast, for visual rotation
learning, no dependency of directional error on reaction time emerged, and fast feedback responses to visual displacements of the cursor were immediately adapted. These
results suggest that the motor system acquires a new control policy for mirror reversal, which initially requires extra processing time, while it recalibrates an existing control
policy for visual rotations, exploiting established fast computational processes. Importantly, memory for visual rotation decayed between sessions, whereas memory for
mirror reversals showed offline gains, leading to better performance at the beginning of the second session than in the end of the first. With shifts in time-accuracy tradeoff
and offline gains, mirror-reversal learning shares common features with other skill-learning tasks. We suggest that different neuronal mechanisms underlie the recalibration of an existing versus acquisition of a new control policy and that offline gains between sessions are a characteristic of latter.
The Journal of Neuroscience, October 8, 2014 • 34(41):13768 –13779
Cortical Activation Associated with Muscle Synergies of the Human Male Pelvic Floor
Skulpan Asavasopon,1* X Manku Rana,2* Daniel J. Kirages,2 Moheb S. Yani,2 Beth E. Fisher,2,5 X Darryl H. Hwang,3
Everett B. Lohman,1 X Lee S. Berk,1,4 and X Jason J. Kutch2
Physical Therapy Department, Loma Linda University, Loma Linda, California 92350, 2Division of Biokinesiology and Physical Therapy and 3Department
of Radiology, University of Southern California, Los Angeles, California 90033, 4Department of Pathology and Human Anatomy, Loma Linda University,
Loma Linda, California 92350, and 5Department of Neurology, University of Southern California, Los Angeles, California 90033
1
Human pelvic floor muscles have been shown to operate synergistically with a wide variety of muscles, which has been suggested to be an important contributor to
continence and pelvic stability during functional tasks. However, the neural mechanism of pelvic floor muscle synergies remains unknown. Here, we test the hypothesis that
activation in motor cortical regions associated with pelvic floor activation are part of the neural substrate for such synergies. We first use electromyographic recordings to
extend previous findings and demonstrate that pelvic floor muscles activate synergistically during voluntary activation of gluteal muscles, but not during voluntary
activation of finger muscles. We then show, using functional magnetic resonance imaging (fMRI), that a region of the medial wall of the precentral gyrus consistently
activates during both voluntary pelvic floor muscle activation and voluntary gluteal activation, but not during voluntary finger activation. We finally confirm, using
transcranial magnetic stimulation, that the fMRI-identified medial wall region is likely to generate pelvic floor muscle activation. Thus, muscle synergies of the human male
pelvic floor appear to involve activation of motor cortical areas associated with pelvic floor control.
The Journal of Neuroscience, October 8, 2014 • 34(41):13811–13818
Ceiling Effects Prevent Further Improvement of Transcranial Stimulation in Skilled Musicians
Shinichi Furuya,1* Matthias Klaus,1* Michael A. Nitsche,2 Walter Paulus,2 and Eckart Altenmu¨ller1
Institute for Music Physiology and Musicians’ Medicine, Hanover University of Music, Drama and Media, Hanover 30175, Germany, and 2Department of
Clinical Neurophysiology, University Medical Center Go¨ttingen, Georg-August-University, Go¨ttingen 37075, Germany
1
The roles of the motor cortex in the acquisition and performance of skilled finger movements have been extensively investigated over decades. Yet it is still not known
whether these roles of motor cortex are expertise-dependent. The present study addresses this issue by comparing the effects of noninvasive transcranial direction current
stimulation (tDCS) on the fine control of sequential finger movements in highly trained pianists and musically untrained individuals. Thirteen pianists and 13 untrained
controls performed timed-sequence finger movements with each of the right and left hands before and after receiving bilateral tDCS over the primary motor cortices. The
results demonstrate an improvement of fine motor control in both hands in musically untrained controls, but deterioration in pianists following anodal tDCS over the
contralateral cortex and cathodal tDCS over the ipsilateral cortex compared with the sham stimulation. However, this change in motor performance was not evident after
stimulating with the opposite montage. These findings support the notion that changes in dexterous finger movements induced by bihemispheric tDCS are
expertise-dependent.
The Journal of Neuroscience, October 8, 2014 • 34(41):13834 –13839
NEUROBIOLOGY OF DISEASE
Mutant ␣-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra Neurons by
Oxidative Impairment of A-Type Potassium Channels
Mahalakshmi Subramaniam,1 X Daniel Althof,3 Suzana Gispert,2 Jochen Schwenk,3 Georg Auburger,2 Akos Kulik,3,4
Bernd Fakler,3 and Jochen Roeper1
1Institute of Neurophysiology, Neuroscience Center, 2Department of Neurology, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and 3Institute of
Physiology II, 4BIOSS Centre for Biological Signaling Studies, University of Freiburg, D-79104 Freiburg, Germany
Parkinson disease (PD) is an ␣-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T)
in the ␣-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on vulnerable DA SN neurons is unknown. In a mouse model
overexpressing mutant ␣-synuclein (A53T-SNCA), we identified a SN-selective increase of in vivo firing frequencies in DA midbrain neurons, which was not observed in DA
neurons in the ventral tegmental area. The selective and age-dependent gain-of-function phenotype of A53T-SCNA overexpressing DA SN neurons was in part mediated by
an increase of their intrinsic pacemaker frequency caused by a redox-dependent impairment of A-type Kv4.3 potassium channels. This selective enhancement of “stressful
pacemaking” of DA SN neurons in vivo defines a functional response to mutant ␣-synuclein that might be useful as a novel biomarker for the “DA system at risk” before the
onset of neurodegeneration in PD.
The Journal of Neuroscience, October 8, 2014 • 34(41):13586 –13599
Alzheimer’s Disease-Like Pathology Induced by Amyloid-␤ Oligomers in Nonhuman Primates
Leticia Forny-Germano,1,2 Natalia M. Lyra e Silva,1* Andre´ F. Batista,1* Jordano Brito-Moreira,1 X Matthias Gralle,1
Susan E. Boehnke,3 Brian C. Coe,3 Ann Lablans,3 Suelen A. Marques,4 Ana Maria B. Martinez,2 William L. Klein,5
X Jean-Christophe Houzel,2 Sergio T. Ferreira,1 Douglas P. Munoz,3† and Fernanda G. De Felice1†
Institute of Medical Biochemistry Leopoldo de Meis and 2Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944590, Brazil, 3Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario K7L 3N6, Canada, 4Departament of Neurobiology, Institute of Biology,
Fluminense Federal University, Nitero´i, RJ, 24020-140 Brazil, and 5Department of Neurobiology and Physiology, Northwestern University, Evanston,
Illinois 60208
1
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-␤ (A␤) oligomers,
AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble A␤ oligomers are known to accumulate in the brains of AD
patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, A␤ oligomers diffused into the brain and
accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation,
astrocyte and microglial activation, were observed in regions of the macaque brain where A␤ oligomers were abundantly detected. Most importantly, oligomer injections
induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with A␤ oligomers, as fibrillar amyloid deposits were
not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus,
generation of a macaque model of AD that links A␤ oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally
implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work
in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.
The Journal of Neuroscience, October 8, 2014 • 34(41):13629 –13643
Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse
Model of Cerebral Amyloidosis
Joanes Grandjean,1,2 Aileen Schroeter,1 Pan He,3 Matteo Tanadini,4 Ruth Keist,5 Dimitrije Krstic,5 Uwe Konietzko,2,6
Jan Klohs,1,2 Roger M. Nitsch,2,6 and Markus Rudin1,2,5
1Institute for Biomedical Engineering, and 2Center for Neuroscience Research, University and ETH Zurich, 8093 Zurich, Switzerland, 3Department of
Information Technology and Electrical Engineering, and 4Seminar for Statistics, ETH Zurich, 8092 Zurich, Switzerland, and 5Institute of Pharmacology and
Toxicology and 6Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland
Impairment of brain functional connectivity (FC) is thought to be an early event occurring in diseases with cerebral amyloidosis, such as Alzheimer’s disease. Regions
sustaining altered functional networks have been shown to colocalize with regions marked with amyloid plaques burden suggesting a strong link between FC and
amyloidosis. Whether the decline in FC precedes amyloid plaque deposition or is a consequence thereof is currently unknown. The sequence of events during early stages
of the disease is difficult to capture in humans due to the difficulties in providing an early diagnosis and also in view of the heterogeneity among patients. Transgenic mouse
lines overexpressing amyloid precursor proteins develop cerebral amyloidosis and constitute an attractive model system for studying the relationship between plaque and
functional changes. In this study, ArcA␤ transgenic and wild-type mice were imaged using resting-state fMRI methods across their life-span in a cross-sectional design to
analyze changes in FC in relation to the pathology. Transgenic mice show compromised development of FC during the first months of postnatal life compared with wild-type
animals, resulting in functional impairments that affect in particular the sensory-motor cortex already in preplaque stage. These functional alterations were accompanied
by structural changes as reflected by reduced fractional anisotropy values, as derived from diffusion tensor imaging. Our results suggest cerebral amyloidosis in mice is
preceded by impairment of neuronal networks and white matter structures. FC analysis in mice is an attractive tool for studying the implications of impaired neuronal
networks in models of cerebral amyloid pathology.
The Journal of Neuroscience, October 8, 2014 • 34(41):13780 –13789