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The Journal of Neuroscience, March 18, 2015 • 35(11):i • i
This Week in The Journal
Dendritic Filtering Differs in
Pyramidal Tract and
Intratelencephalic Neurons
Nikolai C. Dembrow, Boris V. Zemelman, and
Daniel Johnston
(see pages 4501– 4514)
The prefrontal cortex (PFC) integrates inputs
from many cortical and subcortical areas to
guide decision making and executive control.
Two important afferent pathways—from the
hippocampus and the contralateral PFC—
extend through all PFC layers, but what neurons the afferents target and how the targets
process and integrate the transmitted information are poorly understood. Answering
these questions is difficult, because EPSPs
evoked by synaptic inputs to pyramidal neurons’ distal apical dendrites are greatly attenuated by the time they reach the soma, where
electrophysiological recordings are typically
made. Nevertheless, such inputs likely influence neuronal outputs by eliciting dendritic
spikes and/or integrating with other synaptic
inputs. Further complicating the quest to
understand cortical information processing,
cortical layer 5 (L5) houses two classes of pyramidal neurons: pyramidal tract (PT) neurons,
which project to the thalamus, basal ganglia,
brainstem, and spinal cord; and intratelencephalic (IT) neurons, which are the only cortical neurons to project to the contralateral
hemisphere. These neurons differ not only in
their projection patterns, but also in their gene
expression profiles and intrinsic electrophysiological properties. Thus, these two neuron
classes may process afferent input in different
ways.
ToclarifyhowL5pyramidalcellsinratmedial PFC process synaptic input, Dembrow et
al. recorded from the soma and apical dendrites of IT and PT neurons while optically
stimulating hippocampal or commissural afferents. Both afferent types provided monosynaptic input to both the apical tuft and
perisomatic regions of IT and PT neurons, but
hippocampal input to the apical tuft of PT
neurons was uncommon, occurring in only
one of five cells. In addition, although amplitude attenuated similarly as EPSPs traveled
from the apical tuft to the soma in IT and PT
neurons, the half-width and delay-to-peak at
the soma were significantly greater in IT cells.
Together, the data suggest that PT and IT neurons respond differently to hippocampal and
commissural inputs, and that while PT
neurons are driven most effectively by synchronous inputs, IT neurons can integrate information over a broader temporal window.
Thus, PFC neurons projecting to different areas may extract different information from afferent input.
Trains of simulated synaptic current (bottom) injected into
the apical dendrite of L5 pyramidal neurons produced EPSPs
in the dendrite (middle) that traveled to the soma (top). Summation of EPSPs at the soma was greater in IT neurons (red)
than in PT neurons (green). See Dembrow et al. for details.
Serotonin Increases the
Excitability of DCN Principal
Neurons
Zheng-Quan Tang and Laurence O. Trussell
(see pages 4540 – 4551)
The dorsal cochlear nucleus (DCN) is involved in localizing sounds based on spectral
characteristics, and it integrates auditory and
somatosensoryinformation—possiblytohelp
animals orient toward salient sounds and/or
to filter out auditory effects of the animal’s
own movements. The DCN is densely innervated by serotonergic fibers, which have
been proposed to mediate context-dependent
modulation of auditory responses. Serotonin
release increases when animals might benefit
from being more attentive to sound. For example, it is higher during wakefulness than
during sleep, and its levels increase in auditory
brain areas during exposure to noise, stress,
and social interactions. How DCN neurons
respond to serotonin has not previously been
elucidated, however.
Tang and Trussell now report that exogenous serotonin, as well as optical activation of
serotonergic terminals, caused a slow inward
current that increased spontaneous spiking in
fusiform neurons—the principal projection
neurons of the DCN—in mouse brainstem
slices. The serotonin-induced current was reduced by selective antagonists of 5-HT2A,
5-HT2C, and 5-HT7 receptors and was mimicked by 5-HT2A/2C receptor agonists. The
effects of serotonin were also blocked by selective blockers of hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels. Additional experiments indicated that HCN
channels were partially active in the absence of
exogenous serotonin, but serotonin caused
the channels to become activated more
quickly and at more depolarized membrane
potentials. These effects appeared to be mediated by activation of Src kinases and adenylyl
cyclase by HT2A/2C and 5-HT7 receptors,
respectively.
These data indicate that serotonin increases the excitability of DCN output neurons. The authors speculate that this may
increase acoustic responses by lowering the
acoustic threshold of fusiform cells. Looking
beyond normal DCN function, the data suggest that serotonin may have a role in tinnitus.
Tinnitus is associated with increased spontaneous activity in fusiform cells, particularly
those tuned to the frequency of the phantom
sound. This strongly implicates these neurons
in the phantom perception. Although this hyperactivity has been proposed to result from
reduced inhibitory input and/or increased excitatory input to fusiform cells, this new work
suggests that serotonin can contribute to the
phenomenon by modulating the intrinsic
electrophysiological properties of fusiform
neurons.
This Week in The Journal is written by X Teresa Esch, Ph.D.
The Journal of Neuroscience
March 18, 2015 • Volume 35 Number 11 • www.jneurosci.org
i
This Week in The Journal
Commentary
4483
Dissemination Does Not Equal Public Engagement
Bobby Heagerty
Brief Communications
Cover legend: This confocal image of a flat-mounted
retina shows retinal ganglion cell axons from wildtype (top) and Sfrp1/2 double knockout (bottom)
mouse embryos. Colors reflect the depth of the
confocal layer and reveal that mutant axons are not
constrained to the fiber layer and the optic disc, as are
wild-type axons. Axon misrouting is evident at the
optic disc (yellow-green) and in the outer layer of the
retina (pink) in the mutant, when compared to the
arrayed organization in wild-type. For more
information, see the article by Marcos et al.
(pages 4729 – 4740).
4582
Parabrachial Calcitonin Gene-Related Peptide Neurons Mediate Conditioned Taste
Aversion
Matthew E. Carter, Sung Han, and Richard D. Palmiter
4635
␤ Oscillations Are Linked to the Initiation of Sensory-Cued Movement Sequences
and the Internal Guidance of Regular Tapping in the Monkey
Ramo´n Bartolo and Hugo Merchant
4676
Brain-Derived Neurotrophic Factor Inhibits Calcium Channel Activation, Exocytosis,
and Endocytosis at a Central Nerve Terminal
Maryna Baydyuk, Xin-Sheng Wu, Liming He, and Ling-Gang Wu
Articles
CELLULAR/MOLECULAR
䊉
4501
Temporal Dynamics of L5 Dendrites in Medial Prefrontal Cortex Regulate Integration
Versus Coincidence Detection of Afferent Inputs
Nikolai C. Dembrow, Boris V. Zemelman, and Daniel Johnston
4706
Imbalanced Mechanistic Target of Rapamycin C1 and C2 Activity in the Cerebellum of
Angelman Syndrome Mice Impairs Motor Function
Jiandong Sun, Yan Liu, Stephanie Moreno, Michel Baudry, and Xiaoning Bi
4776
Importance of Reelin C-Terminal Region in the Development and Maintenance of the
Postnatal Cerebral Cortex and Its Regulation by Specific Proteolysis
Takao Kohno, Takao Honda, Ken-ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya,
Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima,
and Mitsuharu Hattori
DEVELOPMENT/PLASTICITY/REPAIR
4528
Regional and Stage-Specific Effects of Prospectively Purified Vascular Cells on the
Adult V-SVZ Neural Stem Cell Lineage
Elizabeth E. Crouch, Chang Liu, Violeta Silva-Vargas, and Fiona Doetsch
4552
Selective Activation of Microglia Facilitates Synaptic Strength
Anna K. Clark, Doris Gruber-Schoffnegger, Ruth Drdla-Schutting,
Katharina J. Gerhold, Marzia Malcangio, and Ju¨rgen Sandku¨hler
4691
Analogous Synaptic Plasticity Profiles Emerge from Disparate Channel Combinations
Arun Anirudhan and Rishikesh Narayanan
4719
Motor Cortex Maturation Is Associated with Reductions in Recurrent Connectivity
among Functional Subpopulations and Increases in Intrinsic Excitability
Jeremy S. Biane, Massimo Scanziani, Mark H. Tuszynski, and James M. Conner
4729
Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse
Retina Ganglion Cell Axons by Direct and Indirect Mechanisms
Se´verine Marcos, Francisco Nieto-Lopez, Africa Sandonìs, Marcos Julian Cardozo,
Fabiana Di Marco, Pilar Esteve, and Paola Bovolenta
SYSTEMS/CIRCUITS
䊉
4487
Neural and Behavioral Correlates of Extended Training during Sleep Deprivation in
Humans: Evidence for Local, Task-Specific Effects
Giulio Bernardi, Francesca Siclari, Xiaoqian Yu, Corinna Zennig, Michele Bellesi,
Emiliano Ricciardi, Chiara Cirelli, Maria Felice Ghilardi, Pietro Pietrini, and
Giulio Tononi
4515
The Olfactory Tubercle Encodes Odor Valence in Behaving Mice
Marie A. Gadziola, Kate A. Tylicki, Diana L. Christian, and Daniel W. Wesson
4540
Serotonergic Regulation of Excitability of Principal Cells of the Dorsal Cochlear
Nucleus
Zheng-Quan Tang and Laurence O. Trussell
4571
Peroxisome Proliferator-Activated Receptor ␥ Controls Ingestive Behavior,
Agouti-Related Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus
John T. Garretson, Brett J.W. Teubner, Kevin L. Grove, Almira Vazdarjanova,
Vitaly Ryu, and Timothy J. Bartness
4641
Long-Latency Reductions in Gamma Power Predict Hemodynamic Changes That
Underlie the Negative BOLD Signal
Luke Boorman, Samuel Harris, Michael Bruyns-Haylett, Aneurin Kennerley,
Ying Zheng, Chris Martin, Myles Jones, Peter Redgrave, and Jason Berwick
4657
Emergence of Complex Wave Patterns in Primate Cerebral Cortex
Rory G. Townsend, Selina S. Solomon, Spencer C. Chen, Alexander N.J. Pietersen,
Paul R. Martin, Samuel G. Solomon, and Pulin Gong
4663
Anatomical Identification of Extracellularly Recorded Cells in Large-Scale
Multielectrode Recordings
Peter H. Li, Jeffrey L. Gauthier, Max Schiff, Alexander Sher, Daniel Ahn,
Greg D. Field, Martin Greschner, Edward M. Callaway, Alan M. Litke,
and E.J. Chichilnisky
4683
The Spiral Staircase: Tonotopic Microstructure and Cochlear Tuning
Christopher A. Shera
4741
Single Granule Cells Excite Golgi Cells and Evoke Feedback Inhibition in the Cochlear
Nucleus
Daniel B. Yaeger and Laurence O. Trussell
BEHAVIORAL/COGNITIVE
4614
Nociceptor Beta II, Delta, and Epsilon Isoforms of PKC Differentially Mediate
Paclitaxel-Induced Spontaneous and Evoked Pain
Ying He and Zaijie Jim Wang
4626
Cascades and Cognitive State: Focused Attention Incurs Subcritical Dynamics
Erik D. Fagerholm, Romy Lorenz, Gregory Scott, Martin Dinov, Peter J. Hellyer,
Nazanin Mirzaei, Clare Leeson, David W. Carmichael, David J. Sharp,
Woodrow L. Shew, and Robert Leech
4751
A Trade-Off between Somatosensory and Auditory Related Brain Activity during
Object Naming But Not Reading
៮ iwi Parker Jones,
Mohamed L. Seghier, Thomas M.H. Hope, Susan Prejawa, ‘O
Melanie Vitkovitch, and Cathy J. Price
NEUROBIOLOGY OF DISEASE
4587
Mutations in the Microtubule-Associated Protein 1A (Map1a) Gene Cause Purkinje
Cell Degeneration
Ye Liu, Jeong Woong Lee, and Susan L. Ackerman
4599
Selective Breeding for High Anxiety Introduces a Synonymous SNP That Increases
Neuropeptide S Receptor Activity
David A. Slattery, Roshan R. Naik, Thomas Grund, Yi-Chun Yen,
Simone B. Sartori, Andrea Fu¨chsl, Beate C. Finger, Betina Elfving,
Uwe Nordemann, Remo Guerrini, Girolamo Calo, Gregers Wegener,
Aleksander A. Mathe´, Nicolas Singewald, Ludwig Czibere, Rainer Landgraf,
and Inga D. Neumann
4760
Proximodistal Structure of Theta Coordination in the Dorsal Hippocampus of
Epileptic Rats
Franc¸ois Laurent, Jorge R. Brotons-Mas, Elena Cid, Diego Lopez-Pigozzi,
Manuel Valero, Beatriz Gal, and Liset Menendez de la Prida
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BRIEF COMMUNICATIONS
Parabrachial Calcitonin Gene-Related Peptide Neurons Mediate Conditioned Taste Aversion
Matthew E. Carter, Sung Han, and Richard D. Palmiter
Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, Washington 98195
Conditioned taste aversion (CTA) is a phenomenon in which an individual forms an association between a novel tastant and toxin-induced gastrointestinal malaise.
Previous studies showed that the parabrachial nucleus (PBN) contains neurons that are necessary for the acquisition of CTA, but the specific neuronal populations involved
are unknown. Previously, we identified calcitonin gene-related peptide (CGRP)-expressing neurons in the external lateral subdivision of the PBN (PBel) as being sufficient
to suppress appetite and necessary for the anorexigenic effects of appetite-suppressing substances including lithium chloride (LiCl), a compound often used to induce CTA.
Here, we test the hypothesis that PBel CGRP neurons are sufficient and necessary for CTA acquisition in mice. We show that optogenetic activation of these neurons is
sufficient to induce CTA in the absence of anorexigenic substances, whereas genetically induced silencing of these neurons attenuates acquisition of CTA upon exposure to
LiCl. Together, these results demonstrate that PBel CGRP neurons mediate a gastrointestinal distress signal required to establish CTA.
The Journal of Neuroscience, March 18, 2015 • 35(11):4582– 4586
␤ Oscillations Are Linked to the Initiation of Sensory-Cued Movement Sequences and the
Internal Guidance of Regular Tapping in the Monkey
Ramo´n Bartolo and Hugo Merchant
Instituto de Neurobiología, Universidad Nacional Auto´noma de Me´xico, Quere´taro, Quere´taro. 76230, Me´xico
␤ oscillations in the basal ganglia have been associated with interval timing. We recorded the putaminal local field potentials (LFPs) from monkeys performing a
synchronization-continuation task (SCT) and a serial reaction-time task (RTT), where the animals produced regularly and irregularly paced tapping sequences, respectively. We compared the activation profile of ␤ oscillations between tasks and found transient bursts of ␤ activity in both the RTT and SCT. During the RTT, ␤ power was
higher at the beginning of the task, especially when LFPs were aligned to the stimuli. During the SCT, ␤ was higher during the internally driven continuation phase,
especially for tap-aligned LFPs. Interestingly, a set of LFPs showed an initial burst of ␤ at the beginning of the SCT, similar to the RTT, followed by a decrease in ␤ oscillations
during the synchronization phase, to finally rebound during the continuation phase. The rebound during the continuation phase of the SCT suggests that the corticostriatal
circuit is involved in the control of internally driven motor sequences. In turn, the transient bursts of ␤ activity at the beginning of both tasks suggest that the basal ganglia
produce a general initiation signal that engages the motor system in different sequential behaviors.
The Journal of Neuroscience, March 18, 2015 • 35(11):4635– 4640
Brain-Derived Neurotrophic Factor Inhibits Calcium Channel Activation, Exocytosis, and
Endocytosis at a Central Nerve Terminal
Maryna Baydyuk,* Xin-Sheng Wu,* Liming He, and Ling-Gang Wu
National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival,
and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains
unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for
the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action
potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the
important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential
mechanisms by which neurotrophins achieve diverse neuronal functions.
The Journal of Neuroscience, March 18, 2015 • 35(11):4676 – 4682
Articles
CELLULAR/MOLECULAR
Temporal Dynamics of L5 Dendrites in Medial Prefrontal Cortex Regulate Integration Versus
Coincidence Detection of Afferent Inputs
Nikolai C. Dembrow, Boris V. Zemelman, and Daniel Johnston
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712
Distinct brain regions are highly interconnected via long-range projections. How this inter-regional communication occurs depends not only upon which subsets of
postsynaptic neurons receive input, but also, and equally importantly, upon what cellular subcompartments the projections target. Neocortical pyramidal neurons receive
input onto their apical dendrites. However, physiological characterization of these inputs thus far has been exclusively somatocentric, leaving how the dendrites respond
to spatial and temporal patterns of input unexplored. Here we used a combination of optogenetics with multisite electrode recordings to simultaneously measure dendritic
and somatic responses to afferent fiber activation in two different populations of layer 5 (L5) pyramidal neurons in the rat medial prefrontal cortex (mPFC). We found that
commissural inputs evoked monosynaptic responses in both intratelencephalic (IT) and pyramidal tract (PT) dendrites, whereas monosynaptic hippocampal input
primarily targeted IT, but not PT, dendrites. To understand the role of dendritic integration in the processing of long-range inputs, we used dynamic clamp to simulate
synaptic currents in the dendrites. IT dendrites functioned as temporal integrators that were particularly responsive to dendritic inputs within the gamma frequency range
(40 –140 Hz). In contrast, PT dendrites acted as coincidence detectors by responding to spatially distributed signals within a narrow time window. Thus, the PFC extracts
information from different brain regions through the combination of selective dendritic targeting and the distinct dendritic physiological properties of L5 pyramidal
dendrites.
The Journal of Neuroscience, March 18, 2015 • 35(11):4501– 4514
Imbalanced Mechanistic Target of Rapamycin C1 and C2 Activity in the Cerebellum of
Angelman Syndrome Mice Impairs Motor Function
Jiandong Sun,1 Yan Liu,1,2 Stephanie Moreno,1 Michel Baudry,2 and Xiaoning Bi1
Basic Medical Sciences, College of Osteopathic Medicine of the Pacific and 2Graduate College of Biomedical Sciences, Western University of Health
Sciences, Pomona, California 91766
1
Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific
proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The
present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS
mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS
mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated
1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi-chronic treatment of AS mice with rapamycin not only improved their motor
performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2
complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1–S6K1
pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic
spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our
results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS.
The Journal of Neuroscience, March 18, 2015 • 35(11):4706 – 4718
Importance of Reelin C-Terminal Region in the Development and Maintenance of the Postnatal
Cerebral Cortex and Its Regulation by Specific Proteolysis
Takao Kohno,1* Takao Honda,2* Ken-ichiro Kubo,2* Yoshimi Nakano,1 Ayaka Tsuchiya,1 Tatsuro Murakami,1
Hideyuki Banno,1 Kazunori Nakajima,2† and Mitsuharu Hattori1†
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and 2Department of
Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan
1
During brain development, Reelin exerts a variety of effects in a context-dependent manner, whereas its underlying molecular mechanisms remain poorly understood. We
previously showed that the C-terminal region (CTR) of Reelin is required for efficient induction of phosphorylation of Dab1, an essential adaptor protein for canonical
Reelin signaling. However, the physiological significance of the Reelin CTR in vivo remains unexplored. To dissect out Reelin functions, we made a knock-in (KI) mouse in
which the Reelin CTR is deleted. The amount of Dab1, an indication of canonical Reelin signaling strength, is increased in the KI mouse, indicating that the CTR is necessary
for efficient induction of Dab1 phosphorylation in vivo. Formation of layer structures during embryonic development is normal in the KI mouse. Intriguingly, the marginal
zone (MZ) of the cerebral cortex becomes narrower at postnatal stages because upper-layer neurons invade the MZ and their apical dendrites are misoriented and poorly
branched. Furthermore, Reelin undergoes proteolytic cleavage by proprotein convertases at a site located 6 residues from the C terminus, and it was suggested that this
cleavage abrogates the Reelin binding to the neuronal cell membrane. Results from ectopic expression of mutant Reelin proteins in utero suggest that the dendrite
development and maintenance of the MZ require Reelin protein with an intact CTR. These results provide a novel model regarding Reelin functions involving its CTR, which
is not required for neuronal migration during embryonic stages but is required for the development and maintenance of the MZ in the postnatal cerebral cortex.
The Journal of Neuroscience, March 18, 2015 • 35(11):4776 – 4787
DEVELOPMENT/PLASTICITY/REPAIR
Regional and Stage-Specific Effects of Prospectively Purified Vascular Cells on the Adult V-SVZ
Neural Stem Cell Lineage
Elizabeth E. Crouch,1,5 Chang Liu,2,5 Violeta Silva-Vargas,2,5,6 and Fiona Doetsch1,2,3,4,5,6
1Department of Neuroscience, 2Department of Pathology and Cell Biology, 3Department of Neurology, 4Department of Rehabilitation and Regenerative
Medicine, and 5Columbia Stem Cell Initiative, Columbia University, College of Physicians and Surgeons, New York, New York 10032, and 6Biozentrum,
University of Basel, Basel CH-4056, Switzerland
Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and
generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural
stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of
pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and
pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic
(V-SVZ) and non-neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions differentially
promote the proliferation and neuronal differentiation of qNSCs, aNSCs, and TACs. Unexpectedly, diffusible cortical signals had the most potent effects on V-SVZ
proliferation and neurogenesis, highlighting the intrinsic capacity of non-neurogenic vasculature to support stem cell behavior. Finally, we identify PlGF-2 as an
endothelial-derived mitogen that promotes V-SVZ cell proliferation. This purification strategy provides a platform to define the functional and molecular contribution of
vascular cells to stem cell niches and other brain regions under different physiological and pathological states.
The Journal of Neuroscience, March 18, 2015 • 35(11):4528 – 4539
Selective Activation of Microglia Facilitates Synaptic Strength
Anna K. Clark,1,2 Doris Gruber-Schoffnegger,1 Ruth Drdla-Schutting,1 Katharina J. Gerhold,1 Marzia Malcangio,2 and
Ju¨rgen Sandku¨hler1
Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, and 2Wolfson Centre for Age Related
Diseases, King’s College London, London SE1 1UL, United Kingdom
1
Synaptic plasticity is thought to be initiated by neurons only, with the prevailing view assigning glial cells mere specify supportive functions for synaptic transmission and
plasticity. We now demonstrate that glial cells can control synaptic strength independent of neuronal activity. Here we show that selective activation of microglia in the rat
is sufficient to rapidly facilitate synaptic strength between primary afferent C-fibers and lamina I neurons, the first synaptic relay in the nociceptive pathway. Specifically,
the activation of the CX3CR1 receptor by fractalkine induces the release of interleukin-1␤ from microglia, which modulates NMDA signaling in postsynaptic neurons,
leading to the release of an eicosanoid messenger, which ultimately enhances presynaptic neurotransmitter release. In contrast to the conventional view, this form of
plasticity does not require enhanced neuronal activity to trigger the events leading to synaptic facilitation. Augmentation of synaptic strength in nociceptive pathways
represents a cellular model of pain amplification. The present data thus suggest that, under chronic pain states, CX3CR1-mediated activation of microglia drives the
facilitation of excitatory synaptic transmission in the dorsal horn, which contributes to pain hypersensitivity in chronic pain states.
The Journal of Neuroscience, March 18, 2015 • 35(11):4552– 4570
Analogous Synaptic Plasticity Profiles Emerge from Disparate Channel Combinations
Arun Anirudhan1,2,3 and Rishikesh Narayanan1
Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India, 2School of Biotechnology, National
Institute of Technology, Calicut 637 601, India, and 3Bio-Medical Technology Wing, Sree Chitra Thirunal Institute for Medical Science & Technology,
Trivandrum 695 012, India
1
An open question within the Bienenstock-Cooper-Munro theory for synaptic modification concerns the specific mechanism that is responsible for regulating the sliding
modification threshold (SMT). In this conductance-based modeling study on hippocampal pyramidal neurons, we quantitatively assessed the impact of seven ion channels
(R- and T-type calcium, fast sodium, delayed rectifier, A-type, and small-conductance calcium-activated (SK) potassium and HCN) and two receptors (AMPAR and
NMDAR) on a calcium-dependent Bienenstock-Cooper-Munro-like plasticity rule. Our analysis with R- and T-type calcium channels revealed that differences in their
activation-inactivation profiles resulted in differential impacts on how they altered the SMT. Further, we found that the impact of SK channels on the SMT critically
depended on the voltage dependence and kinetics of the calcium sources with which they interacted. Next, we considered interactions among all the seven channels and the
two receptors through global sensitivity analysis on 11 model parameters. We constructed 20,000 models through uniform randomization of these parameters and found
360 valid models based on experimental constraints on their plasticity profiles. Analyzing these 360 models, we found that similar plasticity profiles could emerge with
several nonunique parametric combinations and that parameters exhibited weak pairwise correlations. Finally, we used seven sets of virtual knock-outs on these 360
models and found that the impact of different channels on the SMT was variable and differential. These results suggest that there are several nonunique routes to regulate
the SMT, and call for a systematic analysis of the variability and state dependence of the mechanisms underlying metaplasticity during behavior and pathology.
The Journal of Neuroscience, March 18, 2015 • 35(11):4691– 4705
Motor Cortex Maturation Is Associated with Reductions in Recurrent Connectivity among
Functional Subpopulations and Increases in Intrinsic Excitability
Jeremy S. Biane,1 Massimo Scanziani,1,2,3 Mark H. Tuszynski,1,4 and James M. Conner1
Departments of 1Neurosciences and 2Neurobiology, University of California San Diego, La Jolla, California 92093, 3Howard Hughes Medical Institute, San
Diego, California 92093, and 4Veterans Administration Medical Center, San Diego, California 92161
Behavior is derived from the configuration of synaptic connectivity among functionally diverse neurons. Fine motor behavior is absent at birth in most mammals but
gradually emerges during subsequent postnatal corticospinal system maturation; the nature of circuit development and reorganization during this period has been largely
unexplored. We investigated connectivity and synaptic signaling among functionally distinct corticospinal populations in Fischer 344 rats from postnatal day 18 through
75 using retrograde tracer injections into specific spinal cord segments associated with distinct aspects of forelimb function. Primary motor cortex slices were prepared
enabling simultaneous patch-clamp recordings of up to four labeled corticospinal neurons and testing of 3489 potential synaptic connections. We find that, in immature
animals, local connectivity is biased toward corticospinal neurons projecting to the same spinal cord segment; this within-population connectivity significantly decreases
through maturation until connection frequency is similar between neurons projecting to the same (within-population) or different (across-population) spinal segments.
Concomitantly, postnatal maturation is associated with a significant reduction in synaptic efficacy over time and an increase in intrinsic neuronal excitability, altering how
excitation is effectively transmitted across recurrent corticospinal networks. Collectively, the postnatal emergence of fine motor control is associated with a relative
broadening of connectivity between functionally diverse cortical motor neurons and changes in synaptic properties that could enable the emergence of smaller independent
networks, enabling fine motor movement. These changes in synaptic patterning and physiological function provide a basis for the increased capabilities of the mature
versus developing brain.
The Journal of Neuroscience, March 18, 2015 • 35(11):4719 – 4728
Secreted Frizzled Related Proteins Modulate Pathfinding and Fasciculation of Mouse Retina
Ganglion Cell Axons by Direct and Indirect Mechanisms
Se´verine Marcos,1,2,3 Francisco Nieto-Lopez,1,2,3 Africa Sandonìs,1,2,3 Marcos Julian Cardozo,1,2,3 Fabiana Di Marco,1
Pilar Esteve,1,2,3 and Paola Bovolenta1,2,3
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Auto´noma de Madrid, Madrid 28049, Spain,
Centro de Investigacio´n Biome´dica en Red de Enfermedades Raras, Madrid 28049, Spain, and 3Instituto Cajal, Consejo Superior de Investigaciones
Científicas, 28002 Madrid, Spain
1
2
Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing
proper eye– brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant
mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second
messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well
explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes
during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2
normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase
activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is
reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two
ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly
signaling at the growth cone and by regulating the processing of other relevant cues.
The Journal of Neuroscience, March 18, 2015 • 35(11):4729 – 4740
SYSTEMS/CIRCUITS
Neural and Behavioral Correlates of Extended Training during Sleep Deprivation in Humans:
Evidence for Local, Task-Specific Effects
Giulio Bernardi,1,2,3 Francesca Siclari,1 Xiaoqian Yu,1 Corinna Zennig,1 Michele Bellesi,1 Emiliano Ricciardi,2,3
Chiara Cirelli,1 Maria Felice Ghilardi,4 Pietro Pietrini,2,3 and Giulio Tononi1
Department of Psychiatry, University of Wisconsin, Madison, Wisconsin 53519, 2Laboratory of Clinical Biochemistry and Molecular Biology, and 3Clinical
Psychology Branch, University of Pisa, AOUP Santa Chiara, 56126 Pisa, Italy, and 4Department of Physiology and Pharmacology, City University of New
York Medical School, New York, New York 10017
1
Recent work has demonstrated that behavioral manipulations targeting specific cortical areas during prolonged wakefulness lead to a region-specific homeostatic increase
in theta activity (5–9 Hz), suggesting that theta waves could represent transient neuronal OFF periods (local sleep). In awake rats, the occurrence of an OFF period in a brain
area relevant for behavior results in performance errors. Here we investigated the potential relationship between local sleep events and negative behavioral outcomes in
humans.
Volunteers participated in two prolonged wakefulness experiments (24 h), each including 12 h of practice with either a driving simulation (DS) game or a battery of tasks
based on executive functions (EFs). Multiple high-density EEG recordings were obtained during each experiment, both in quiet rest conditions and during execution of two
behavioral tests, a response inhibition test and a motor test, aimed at assessing changes in impulse control and visuomotor performance, respectively. In addition, fMRI
examinations obtained at 12 h intervals were used to investigate changes in inter-regional connectivity.
The EF experiment was associated with a reduced efficiency in impulse control, whereas DS led to a relative impairment in visuomotor control. A specific spatial and
temporal correlation was observed between EEG theta waves occurring in task-related areas and deterioration of behavioral performance. The fMRI connectivity analysis
indicated that performance impairment might partially depend on a breakdown in connectivity determined by a “network overload.”
Present results demonstrate the existence of an association between theta waves during wakefulness and performance errors and may contribute explaining behavioral
impairments under conditions of sleep deprivation/restriction.
The Journal of Neuroscience, March 18, 2015 • 35(11):4487– 4500
The Olfactory Tubercle Encodes Odor Valence in Behaving Mice
Marie A. Gadziola,1 Kate A. Tylicki,2 Diana L. Christian,1 and Daniel W. Wesson1,2
1
Department of Neurosciences, School of Medicine, and 2Department of Biology, Case Western Reserve University, Cleveland, Ohio 44106
Sensory information acquires meaning to adaptively guide behaviors. Despite odors mediating a number of vital behaviors, the components of the olfactory system
responsible for assigning meaning to odors remain unclear. The olfactory tubercle (OT), a ventral striatum structure that receives monosynaptic input from the olfactory
bulb, is uniquely positioned to transform odor information into behaviorally relevant neural codes. No information is available, however, on the coding of odors among OT
neurons in behaving animals. In recordings from mice engaged in an odor discrimination task, we report that the firing rate of OT neurons robustly and flexibly encodes the
valence of conditioned odors over identity, with rewarded odors evoking greater firing rates. This coding of rewarded odors occurs before behavioral decisions and
represents subsequent behavioral responses. We predict that the OT is an essential region whereby odor valence is encoded in the mammalian brain to guide goal-directed
behaviors.
The Journal of Neuroscience, March 18, 2015 • 35(11):4515– 4527
Serotonergic Regulation of Excitability of Principal Cells of the Dorsal Cochlear Nucleus
Zheng-Quan Tang and Laurence O. Trussell
Oregon Hearing Research Center and Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239
The dorsal cochlear nucleus (DCN) is one of the first stations within the central auditory pathway where the basic computations underlying sound localization are initiated
and heightened activity in the DCN may underlie central tinnitus. The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), is associated with many distinct behavioral or cognitive states, and serotonergic fibers are concentrated in the DCN. However, it remains unclear what is the function of this dense input. Using a combination of
in vitro electrophysiology and optogenetics in mouse brain slices, we found that 5-HT directly enhances the excitability of fusiform principal cells via activation of two
distinct 5-HT receptor subfamilies, 5-HT2A/2CR (5-HT2A/2C receptor) and 5-HT7R (5-HT7 receptor). This excitatory effect results from an augmentation of
hyperpolarization-activated cyclic nucleotide-gated channels (Ih or HCN channels). The serotonergic regulation of excitability is G-protein-dependent and involves cAMP
and Src kinase signaling pathways. Moreover, optogenetic activation of serotonergic axon terminals increased excitability of fusiform cells. Our findings reveal that 5-HT
exerts a potent influence on fusiform cells by altering their intrinsic properties, which may enhance the sensitivity of the DCN to sensory input.
The Journal of Neuroscience, March 18, 2015 • 35(11):4540 – 4551
Peroxisome Proliferator-Activated Receptor ␥ Controls Ingestive Behavior, Agouti-Related
Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus
John T. Garretson,1,3 Brett J.W. Teubner,2 Kevin L. Grove,4 Almira Vazdarjanova,5,6 Vitaly Ryu,2,3 and
Timothy J. Bartness1,2,3
Neuroscience Institute, 2Department of Biology, and 3Center for Obesity Reversal, Georgia State University, Atlanta, Georgia 30303, 4Oregon National
Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, 5Department of Pharmacology and Toxicology, Georgia Regents
University, Augusta, Georgia 30912, and 6Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30901
1
Peroxisome proliferator-activated receptor ␥ (PPAR␥) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPAR␥ agonist, increases food
intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPAR␥ in feeding are not understood. Therefore, we tested this role in Siberian
hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPAR␥
antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agoutirelated protein (AgRP) and PPAR␥ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad
libitum-fed animals; (4) whether intraperitoneally administered PPAR␥ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPAR␥ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an
effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus
with concomitant increases in PPAR␥ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases
in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPAR␥ activation is sufficient to trigger food hoarding/
intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases
in AgRP/NPY may be a direct PPAR␥-dependent process that controls ingestive behaviors.
The Journal of Neuroscience, March 18, 2015 • 35(11):4571– 4581
Long-Latency Reductions in Gamma Power Predict Hemodynamic Changes That Underlie the
Negative BOLD Signal
Luke Boorman,1 Samuel Harris,1 Michael Bruyns-Haylett,1 Aneurin Kennerley,1 Ying Zheng,2 Chris Martin,1
Myles Jones,1 Peter Redgrave,1 and Jason Berwick1
Department of Psychology, University of Sheffield, Sheffield S10 2TP, United Kingdom, and 2School of Systems Engineering, University of Reading,
Reading RG6 6AY, United Kingdom
1
Studies that use prolonged periods of sensory stimulation report associations between regional reductions in neural activity and negative blood oxygenation leveldependent (BOLD) signaling. However, the neural generators of the negative BOLD response remain to be characterized. Here, we use single-impulse electrical stimulation
of the whisker pad in the anesthetized rat to identify components of the neural response that are related to “negative” hemodynamic changes in the brain. Laminar multiunit
activity and local field potential recordings of neural activity were performed concurrently with two-dimensional optical imaging spectroscopy measuring hemodynamic
changes. Repeated measurements over multiple stimulation trials revealed significant variations in neural responses across session and animal datasets. Within this
variation, we found robust long-latency decreases (300 and 2000 ms after stimulus presentation) in gamma-band power (30 – 80 Hz) in the middle-superficial cortical layers
in regions surrounding the activated whisker barrel cortex. This reduction in gamma frequency activity was associated with corresponding decreases in the hemodynamic
responses that drive the negative BOLD signal. These findings suggest a close relationship between BOLD responses and neural events that operate over time scales that outlast the
initiating sensory stimulus, and provide important insights into the neurophysiological basis of negative neuroimaging signals.
The Journal of Neuroscience, March 18, 2015 • 35(11):4641– 4656
Emergence of Complex Wave Patterns in Primate Cerebral Cortex
Rory G. Townsend,1,2 Selina S. Solomon,2,3 Spencer C. Chen,2,3 Alexander N.J. Pietersen,2,3 Paul R. Martin,2,3,4
Samuel G. Solomon,3,5 and Pulin Gong1,2
1School of Physics, University of Sydney, New South Wales 2006, Australia, 2ARC Centre of Excellence for Integrative Brain Function, University of Sydney,
New South Wales 2001, Australia, 3Discipline of Physiology, University of Sydney, Sydney, New South Wales 2006, Australia, 4Save Sight Institute,
University of Sydney, Sydney, New South Wales 2001, Australia, and 5Department of Experimental Psychology, University College London, WC1P 0AH,
London, United Kingdom
Slow brain rhythms are attributed to near-simultaneous (synchronous) changes in activity in neuron populations in the brain. Because they are slow and widespread,
synchronous rhythms have not been considered crucial for information processing in the waking state. Here we adapted methods from turbulence physics to analyze
␦-band (1– 4 Hz) rhythms in local field potential (LFP) activity, in multielectrode recordings from cerebral cortex in anesthetized marmoset monkeys. We found that
synchrony contributes only a small fraction (less than one-fourth) to the local spatiotemporal structure of ␦-band signals. Rather, ␦-band activity is dominated by
propagating plane waves and spatiotemporal structures, which we call complex waves. Complex waves are manifest at submillimeter spatial scales, and millisecond-range
temporal scales. We show that complex waves can be characterized by their relation to phase singularities within local nerve cell networks. We validate the biological
relevance of complex waves by showing that nerve cell spike rates are higher in presence of complex waves than in the presence of synchrony and that there are nonrandom
patterns of evolution from one type of complex wave to another. We conclude that slow brain rhythms predominantly indicate spatiotemporally organized activity in local
nerve cell circuits, not synchronous activity within and across brain regions.
The Journal of Neuroscience, March 18, 2015 • 35(11):4657– 4662
Anatomical Identification of Extracellularly Recorded Cells in Large-Scale Multielectrode
Recordings
Peter H. Li,1,2,3 Jeffrey L. Gauthier,2 Max Schiff,2 Alexander Sher,4 Daniel Ahn,2 Greg D. Field,2,5 Martin Greschner,2,6
Edward M. Callaway,2 Alan M. Litke,4 and E.J. Chichilnisky1,2
Departments of Neurosurgery and Ophthalmology, and Hansen Experimental Physics Laboratory, Stanford University, Stanford, California 94305,
Systems Neurobiology, The Salk Institute for Biological Studies, La Jolla, California 92037, 3Google Inc, Mountain View, California 94043, 4Santa Cruz
Institute for Particle Physics, University of California, Santa Cruz, California 95064, 5Department of Neurobiology, Duke University School of Medicine,
Durham, North Carolina 27710, and 6Department of Neuroscience, Carl von Ossietzky University, Oldenburg 26129, Germany
1
2
This study combines for the first time two major approaches to understanding the function and structure of neural circuits: large-scale multielectrode recordings, and
confocal imaging of labeled neurons. To achieve this end, we develop a novel approach to the central problem of anatomically identifying recorded cells, based on the
electrical image: the spatiotemporal pattern of voltage deflections induced by spikes on a large-scale, high-density multielectrode array. Recordings were performed from
identified ganglion cell types in the macaque retina. Anatomical images of cells in the same preparation were obtained using virally transfected fluorescent labeling or by
immunolabeling after fixation. The electrical image was then used to locate recorded cell somas, axon initial segments, and axon trajectories, and these signatures were used
to identify recorded cells. Comparison of anatomical and physiological measurements permitted visualization and physiological characterization of numerically dominant
ganglion cell types with high efficiency in a single preparation.
The Journal of Neuroscience, March 18, 2015 • 35(11):4663– 4675
The Spiral Staircase: Tonotopic Microstructure and Cochlear Tuning
Christopher A. Shera
Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts 02114
Although usually assumed to be smooth and continuous, mammalian cochlear frequency-position maps are predicted to manifest a staircase-like structure comprising
plateaus of nearly constant characteristic frequency separated by abrupt discontinuities. The height and width of the stair steps are determined by parameters of cochlear
frequency tuning and vary with location in the cochlea. The step height is approximately equal to the bandwidth of the auditory filter (critical band), and the step width
matches that of the spatial excitation pattern produced by a low-level pure tone. Stepwise tonotopy is an emergent property arising from wave reflection and interference
within the cochlea, the same mechanisms responsible for the microstructure of the hearing threshold. Possible relationships between the microstructure of the cochlear
map and the tiered tonotopy observed in the inferior colliculus are explored.
The Journal of Neuroscience, March 18, 2015 • 35(11):4683– 4690
Single Granule Cells Excite Golgi Cells and Evoke Feedback Inhibition in the Cochlear Nucleus
Daniel B. Yaeger1 and Laurence O. Trussell2
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, and 2Vollum Institute and Oregon Hearing
Research Center, Oregon Health and Science University, Portland, Oregon 97239
1
In cerebellum-like circuits, synapses from thousands of granule cells converge onto principal cells. This fact, combined with theoretical considerations, has led to the
concept that granule cells encode afferent input as a population and that spiking in individual granule cells is relatively unimportant. However, granule cells also provide
excitatory input to Golgi cells, each of which provide inhibition to hundreds of granule cells. We investigated whether spiking in individual granule cells could recruit Golgi
cells and thereby trigger widespread inhibition in slices of mouse cochlear nucleus. Using paired whole-cell patch-clamp recordings, trains of action potentials at 100 Hz in
single granule cells was sufficient to evoke spikes in Golgi cells in ⬃40% of paired granule-to-Golgi cell recordings. High-frequency spiking in single granule cells evoked
IPSCs in ⬃5% of neighboring granule cells, indicating that bursts of activity in single granule cells can recruit feedback inhibition from Golgi cells. Moreover, IPSPs
mediated by single Golgi cell action potentials paused granule cell firing, suggesting that inhibitory events recruited by activity in single granule cells were able to control
granule cell firing. These results suggest a previously unappreciated relationship between population coding and bursting in single granule cells by which spiking in a small
number of granule cells may have an impact on the activity of a much larger number of granule cells.
The Journal of Neuroscience, March 18, 2015 • 35(11):4741– 4750
BEHAVIORAL/COGNITIVE
Nociceptor Beta II, Delta, and Epsilon Isoforms of PKC Differentially Mediate PaclitaxelInduced Spontaneous and Evoked Pain
Ying He and Zaijie Jim Wang
Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, Illinois 60612
As one of the most effective and frequently used chemotherapeutic agents, paclitaxel produces peripheral neuropathy (paclitaxel-induced peripheral neuropathy or PIPN)
that negatively affects chemotherapy and persists after cancer therapy. The mechanisms underlying this dose-limiting side effect remain to be fully elucidated. This study
aimed to investigate the role of nociceptor protein kinase C (PKC) isoforms in PIPN. Employing multiple complementary approaches, we have identified a subset of PKC
isoforms, namely ␤II, ␦, and ⑀, were activated by paclitaxel in the isolated primary afferent sensory neurons. Persistent activation of PKC␤II, PKC␦, and PKC⑀ was also
observed in the dorsal root ganglion neurons after chronic treatment with paclitaxel in a mouse model of PIPN. Isoform-selective inhibitors of PKC␤II, PKC␦, and PKC⑀
given intrathecally dose-dependently attenuated paclitaxel-induced mechanical allodynia and heat hyperalgesia. Surprisingly, spinal inhibition of PKC␤II and PKC␦, but
not PKC⑀, blocked the spontaneous pain induced by paclitaxel. These data suggest that a subset of nociceptor PKC isoforms differentially contribute to spontaneous and
evoked pain in PIPN, although it is not clear whether PKC⑀ in other regions regulates spontaneous pain in PIPN. The findings can potentially offer new selective targets for
pharmacological intervention of PIPN.
The Journal of Neuroscience, March 18, 2015 • 35(11):4614 – 4625
Cascades and Cognitive State: Focused Attention Incurs Subcritical Dynamics
Erik D. Fagerholm,1 Romy Lorenz,1 Gregory Scott,1 Martin Dinov,1 Peter J. Hellyer,1 Nazanin Mirzaei,1 Clare Leeson,1
David W. Carmichael,2 David J. Sharp,1 Woodrow L. Shew,3 and Robert Leech1
The Computational, Cognitive and Clinical Neuroimaging Laboratory, The Centre for Neuroscience, The Division of Brain Sciences, Imperial College
London, Hammersmith Hospital Campus, London W12 0NN, United Kingdom, 2Imaging and Biophysics, UCL Institute of Child Health, London WC1N
1EH, United Kingdom, and 3University of Arkansas, Department of Physics, Fayetteville, Arkansas 72701
1
The analysis of neuronal avalanches supports the hypothesis that the human cortex operates with critical neural dynamics. Here, we investigate the relationship between
cascades of activity in electroencephalogram data, cognitive state, and reaction time in humans using a multimodal approach. We recruited 18 healthy volunteers for the
acquisitionofsimultaneouselectroencephalogramandfunctionalmagneticresonanceimagingduringbothrestandduringavisuomotorcognitivetask.Wecompareddistributions
of electroencephalogram-derived cascades to reference power laws for task and rest conditions. We then explored the large-scale spatial correspondence of these cascades in the
simultaneously acquired functional magnetic resonance imaging data. Furthermore, we investigated whether individual variability in reaction times is associated with the amount
of deviation from power law form. We found that while resting state cascades are associated with approximate power law form, the task state is associated with subcritical dynamics.
Furthermore, we found that electroencephalogram cascades are related to blood oxygen level-dependent activation, predominantly in sensorimotorbrain regions. Finally, we found
that decreased reaction times during the task condition are associated with increased proximity to power law form of cascade distributions. These findings suggest that the resting
stateisassociatedwithnear-criticaldynamics,inwhichahighdynamicrangeandalargerepertoireofbrainstatesmaybeadvantageous.Incontrast,afocusedcognitivetaskinduces
subcritical dynamics, which is associated with a lower dynamic range, which in turn may reduce elements of interference affecting task performance.
The Journal of Neuroscience, March 18, 2015 • 35(11):4626 – 4634
A Trade-Off between Somatosensory and Auditory Related Brain Activity during Object Naming
But Not Reading
Mohamed L. Seghier,1 Thomas M.H. Hope,1 Susan Prejawa,1 ‘O៮ iwi Parker Jones,1,2 Melanie Vitkovitch,3 and
Cathy J. Price1
Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London WC1N 3BG, United Kingdom, 2Wolfson College, University of Oxford,
Oxford OX2 6UD, United Kingdom, and 3School of Psychology, University of East London, Water Lane, London E15 4LZ, United Kingdom
1
The parietal operculum, particularly the cytoarchitectonic area OP1 of the secondary somatosensory area (SII), is involved in somatosensory feedback. Using fMRI with 58
human subjects, we investigated task-dependent differences in SII/OP1 activity during three familiar speech production tasks: object naming, reading and repeatedly
saying “1-2-3.” Bilateral SII/OP1 was significantly suppressed (relative to rest) during object naming, to a lesser extent when repeatedly saying “1-2-3” and not at all during
reading. These results cannot be explained by task difficulty but the contrasting difference between naming and reading illustrates how the demands on somatosensory
activity change with task, even when motor output (i.e., production of object names) is matched. To investigate what determined SII/OP1 deactivation during object
naming, we searched the whole brain for areas where activity increased as that in SII/OP1 decreased. This across subject covariance analysis revealed a region in the right
superior temporal sulcus (STS) that lies within the auditory cortex, and is activated by auditory feedback during speech production. The tradeoff between activity in SII/OP1
and STS was not observed during reading, which showed significantly more activation than naming in both SII/OP1 and STS bilaterally. These findings suggest that,
although object naming is more error prone than reading, subjects can afford to rely more or less on somatosensory or auditory feedback during naming. In contrast, fast
and efficient error-free reading places more consistent demands on both types of feedback, perhaps because of the potential for increased competition between lexical and
sublexical codes at the articulatory level.
The Journal of Neuroscience, March 18, 2015 • 35(11):4751– 4759
NEUROBIOLOGY OF DISEASE
Mutations in the Microtubule-Associated Protein 1A (Map1a) Gene Cause Purkinje Cell
Degeneration
Ye Liu, Jeong Woong Lee, and Susan L. Ackerman
Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine 04609
The structural microtubule-associated proteins (MAPs) are critical for the organization of neuronal microtubules (MTs). Microtubule-associated protein 1A (MAP1A) is
one of the most abundantly expressed MAPs in the mammalian brain. However, its in vivo function remains largely unknown. Here we describe a spontaneous mouse
mutation, nm2719, which causes tremors, ataxia, and loss of cerebellar Purkinje neurons in aged homozygous mice. The nm2719 mutation disrupts the Map1a gene. We
show that targeted deletion of mouse Map1a gene leads to similar neurodegenerative defects. Before neuron death, Map1a mutant Purkinje cells exhibited abnormal focal
swellings of dendritic shafts and disruptions in axon initial segment (AIS) morphology. Furthermore, the MT network was reduced in the somatodendritic and AIS
compartments, and both the heavy and light chains of MAP1B, another brain-enriched MAP, was aberrantly distributed in the soma and dendrites of mutant Purkinje cells.
MAP1A has been reported to bind to the membrane-associated guanylate kinase (MAGUK) scaffolding proteins, as well as to MTs. Indeed, PSD-93, the MAGUK specifically
enriched in Purkinje cells, was reduced in Map1a ⫺/ ⫺ Purkinje cells. These results demonstrate that MAP1A functions to maintain both the neuronal MT network and the
level of PSD-93 in neurons of the mammalian brain.
The Journal of Neuroscience, March 18, 2015 • 35(11):4587– 4598
Selective Breeding for High Anxiety Introduces a Synonymous SNP That Increases
Neuropeptide S Receptor Activity
David A. Slattery,1* Roshan R. Naik,1,3* Thomas Grund,1 Yi-Chun Yen,3 Simone B. Sartori,4 Andrea Fu¨chsl,1
Beate C. Finger,1 Betina Elfving,5 Uwe Nordemann,2 Remo Guerrini,6 Girolamo Calo,7 Gregers Wegener,5,9
Aleksander A. Mathe´,8 Nicolas Singewald,4 Ludwig Czibere,3 Rainer Landgraf,3 and Inga D. Neumann1
Department of Behavioral and Molecular Neurobiology, and 2Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany,
Max Planck Institute of Psychiatry, 80804 Munich, Germany, 4Department of Pharmacology and Toxicology, University of Innsbruck, 6020 Innsbruck,
Austria, 5Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8000 Aarhus, Denmark, 6Department of Chemistry
and Pharmaceutical Sciences and Laboratorio per le Tecnologie delle Terapie Avanzate, University of Ferrara, 44100 Ferrara, Italy, 7Department of Medical
Sciences, Section of Pharmacology, National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy, 8Clinical Neuroscience, Karolinska
Institutet, SE-171 77 Stockholm, Sweden, and 9Pharmaceutical Centre of Excellence, School of Pharmacy, North West University, Potchefstroom, 2520,
South Africa
1
3
Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism
associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into
this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined
the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which
we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a
glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity—an effect that was
prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of
HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice,
respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents
are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.
The Journal of Neuroscience, March 18, 2015 • 35(11):4599 – 4613
Proximodistal Structure of Theta Coordination in the Dorsal Hippocampus of Epileptic Rats
Franc¸ois Laurent,1* Jorge R. Brotons-Mas,1* Elena Cid,1* Diego Lopez-Pigozzi,1 Manuel Valero,1 Beatriz Gal,1,2 and
Liset Menendez de la Prida1
1
Instituto Cajal, CSIC, Madrid 28002, Spain and 2Universidad Europea de Madrid, Villaviciosa de Odo´n, Madrid 28670, Spain
Coherent neuronal activity in the hippocampal– entorhinal circuit is a critical mechanism for episodic memory function, which is typically impaired in temporal lobe
epilepsy. To better understand how this mechanism is implemented and degraded in this condition, we used normal and epileptic rats to examine theta activity accompanying active exploration. Assisted by multisite recordings of local field potentials (LFPs) and layer-specific profiling of input pathways, we provide detailed quantification
of the proximodistal coherence of theta activity in the dorsal hippocampus of these animals. Normal rats showed stronger coordination between the temporoammonic and
perforant entorhinal inputs (measured from lamina-specific current source density signals) at proximal locations, i.e., closer to CA3; while epileptic rats exhibited stronger
interactions at distal locations, i.e., closer to subiculum. This opposing trend in epileptic rats was associated with the reorganization of the temporoammonic and perforant
pathways that accompany hippocampal sclerosis, the pathological hallmark of this disease. In addition to this connectivity constraint, we discovered that the appropriate
timing between entorhinal inputs arriving over several theta cycles at the proximal and distal ends of the dorsal hippocampus was impaired in epileptic rats. Computational
reconstruction of LFP signals predicted that restoring timing variability has a major impact on repairing theta coherence. This manipulation, when tested pharmacologically via systemic administration of group III mGluR antagonists, successfully re-established theta coordination of LFPs in epileptic rats. Thus, proximodistal organization
of entorhinal inputs is instrumental in temporal lobe physiology and a candidate mechanism to study cognitive comorbidities of temporal lobe epilepsy.
The Journal of Neuroscience, March 18, 2015 • 35(11):4760 – 4775