Table of contents


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Focus

Focus on epilepsy

While the coordinated activity of neuronal circuits underlies the brain's ability to encode and store information as well as carry out cognitive and sensorimotor tasks, aberrant activity, like increased synchronization of neuronal firing, can generate seizures. Recurrent, spontaneous seizure activity is a primary characteristic of epilepsy, a chronic disorder which affects over 65 million people worldwide. Recent work examining the mechanisms which regulate neuronal excitability and those that mediate the modulation of circuit activity have begun to provide some insight into this disease of abnormal neuronal firing.

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Editorial

Focus on epilepsy p317

doi:10.1038/nn.3964

Nature Neuroscience presents a Focus issue highlighting recent advances in elucidating the mechanisms driving the onset and persistence of the epilepsies.


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Obituary

Vernon B. Mountcastle 1918–2015 p318

Solomon H Snyder

doi:10.1038/nn.3958


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Correspondence

GDNF is not required for catecholaminergic neuron survival in vivo pp319 - 322

Jaakko Kopra, Carolina Vilenius, Shane Grealish, Mari-Anne Härma, Kärt Varendi, Jesse Lindholm, Eero Castrén, Vootele Võikar, Anders Björklund, T Petteri Piepponen, Mart Saarma & Jaan-Olle Andressoo

doi:10.1038/nn.3941

Glial cell line-derived neurotrophic factor (GDNF) is in clinical trials for treating Parkinson's disease. However, endogenous GDNF function in brain catecholaminergic neurons has remained controversial. The authors utilized three complementary conditional knock-out approaches during development and adulthood and found that GDNF is not required for the maintenance of the catecholaminergic neurons in mice.


Reply to “GDNF is not required for catecholaminergic neuron survival in vivopp322 - 323

Alberto Pascual & José López-Barneo

doi:10.1038/nn.3942


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News and Views

The amygdala accountant: new tricks for an old structure pp324 - 325

Clayton P Mosher & Peter H Rudebeck

doi:10.1038/nn.3949

What drives us to pursue distant, more valuable goals over more proximate, lesser ones? Counter to what you might expect, this type of advanced goal-directed planning and foresight in primates may involve the amygdala. In a reward savings task, neurons in the amygdala track the length and subjective value of internally generated plans.

See also: Article by Hernádi et al.


Neighborly synapses help each other out pp326 - 327

J Simon Wiegert & Thomas G Oertner

doi:10.1038/nn.3955

Cortical circuits are shaped by sensory experience. These changes have now been visualized with single-synapse resolution in vivo, revealing clustered potentiation along stretches of dendrite.

See also: Article by Zhang et al.


Attention: feedback focuses a wandering mind pp327 - 328

Edward Awh & Edward K Vogel

doi:10.1038/nn.3962

Neurofeedback that tracks attentional focus in real time using fMRI and alerts subjects to impending lapses by modulating the difficulty of the task itself has been demonstrated to improve behavioral performance.

See also: Article by deBettencourt et al.


Tread softly and carry a clock's tick pp329 - 330

Joseph J Paton & Brian Lau

doi:10.1038/nn.3959

Skilled behavior is thought to rely on the dorsal striatum. A study now reports that skills depend on striatal encoding of movement kinematics, linking learned sequences of movements with temporally distributed striatal activity.

See also: Article by Rueda-Orozco & Robbe


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Perspectives

Focus on epilepsy

Beyond the hammer and the scalpel: selective circuit control for the epilepsies pp331 - 338

Esther Krook-Magnuson & Ivan Soltesz

doi:10.1038/nn.3943

Current treatment options are, for many patients with epilepsy, either insufficient or ineffective and, thus, new therapeutic methodologies are necessary. In this Perspective, Esther Krook-Magnuson and Ivan Soltesz look at recent advances in optogenetic-based modulation of circuit activity and seizures with an eye toward the prospect—and challenges—of utilizing these technologies for the treatment of epilepsy.


Focus on epilepsy

Animal models in epilepsy research: legacies and new directions pp339 - 343

Brian P Grone & Scott C Baraban

doi:10.1038/nn.3934

In this Perspective article, Brian Grone and Scott Baraban examine some of the numerous nonhuman animal models of epilepsy. The authors outline how traditional animal models have advanced our understanding of seizure initiation and epileptogenesis and also describe how the use of more 'non-traditional' model systems may further improve insight into both disease mechanisms as well as potential therapeutic avenues.


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Reviews

Focus on epilepsy

Pathway-driven discovery of epilepsy genes pp344 - 350

Jeffrey Noebels

doi:10.1038/nn.3933

In this Review, Jeff Noebels examines recent advances in the identification of new genes underlying the onset of epilepsy. Given their functional convergence on synaptic inhibition and rich interactive landscape, collective analysis of genes driving major network interactions—as performed in the cancer field—may help point the way forward toward better diagnostics and target prioritization.


Focus on epilepsy

Microcircuits and their interactions in epilepsy: is the focus out of focus? pp351 - 359

Jeanne T Paz & John R Huguenard

doi:10.1038/nn.3950

In this Review, Jeanne Paz and John Huguenard examine how recent work has informed us on the function of brain microcircuitry and how different circuit types may contribute to seizure generation and/or propagation. The authors also propose the idea that these microcircuits may regulate the spread of seizures and represent new targets for therapeutic intervention.


Focus on epilepsy

Reprogramming patient-derived cells to study the epilepsies pp360 - 366

Jack M Parent & Stewart A Anderson

doi:10.1038/nn.3944

In this Review article, Jack Parent and Stewart Anderson discuss the advantages and limitations of using patient-derived cells, such as induced pluripotent stem cells, to probe the mechanisms of epileptogenesis and disease progression. In addition, they look at potential therapeutic avenues, such as cell-replacement strategies, that may arise from this field.


Focus on epilepsy

Molecular mechanisms of epilepsy pp367 - 372

Kevin Staley

doi:10.1038/nn.3947

The term ‘seizure’ emphasizes the abrupt and unpredictable nature of the onset of epochs of pathological neuronal synchrony that define the disorder of epilepsy. Mechanisms of epilepsy should account for seizure transitions with these unique temporal properties. In this review, Kevin Staley discusses how combining insights from new genetic etiologies with seizure timing may begin to outline the mechanisms by which the brain becomes predisposed to seizures.


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Brief Communications

Manipulating circadian clock neuron firing rate resets molecular circadian rhythms and behavior pp373 - 375

Jeff R Jones, Michael C Tackenberg & Douglas G McMahon

doi:10.1038/nn.3937

Using optogenetic manipulations and bioluminescence imaging of suprachiasmatic nucleus (SCN) firing rate, this study examines the interaction between molecular, electrical and behavioral circadian rhythms in mice. The study shows that alteration of clock neuron firing can reset molecular and behavioral circadian rhythms, and this effect required neuronal network interaction within the SCN. Thus, clock neuron spiking is fundamental to circadian pacemaking as both an input to and output of the neuronal network responsible for circadian behavior.


Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula pp376 - 378

Frank J Meye, Kristina Valentinova, Salvatore Lecca, Lucile Marion-Poll, Matthieu J Maroteaux, Stefano Musardo, Imane Moutkine, Fabrizio Gardoni, Richard L Huganir, François Georges & Manuel Mameli

doi:10.1038/nn.3923

This study shows that cocaine strengthens glutamatergic transmission, reduces K+ channel function and drives hyperexcitability in lateral habenula neurons projecting to the rostromedial tegmental nucleus. The authors also show that GluA1 trafficking mediates these cellular modifications and is instrumental in a drug-mediated depressive-like phenotype.


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Articles

A neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity pp379 - 385

Pushpa Verma, George J Augustine, Mohamed-Raafet Ammar, Ayumu Tashiro & Stephen M Cohen

doi:10.1038/nn.3935

microRNAs control synaptic signaling through regulation of postsynaptic responsiveness. This study provides evidence that the conserved microRNAs miR-1000 and miR-137 act presynaptically via glutamate transporters to regulate glutamate release. miR-1000 expression is activity dependent, perhaps allowing activity to fine-tune the strength of excitatory synaptic transmission.


Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons pp386 - 392

Shiliang Zhang, Jia Qi, Xueping Li, Hui-Ling Wang, Jonathan P Britt, Alexander F Hoffman, Antonello Bonci, Carl R Lupica & Marisela Morales

doi:10.1038/nn.3945

Dopamine axons projecting from the ventral tegmental area to the nucleus accumbens (mesoaccumbens axons) play a role in motivation. Tthe authors show that there are distinct microdomains releasing either dopamine or glutamate within individual mesoaccumbens axons in rats and mice.


Sensory inputs control the integration of neurogliaform interneurons into cortical circuits pp393 - 401

Natalia V De Marco García, Rashi Priya, Sebnem N Tuncdemir, Gord Fishell & Theofanis Karayannis

doi:10.1038/nn.3946

Neurogliaform interneurons constitute an essential component of cortical circuits. This paper provides evidence that, during early development, superficial neurogliaform cells of the primary somatosensory barrel field cortex receive prominent innervation from the thalamus. These afferents also activate postsynaptic NR2B-containing NMDA receptors, which are essential for the neurons' proper cortical integration.


Visualization of NMDA receptor–dependent AMPA receptor synaptic plasticity in vivo pp402 - 407

Yong Zhang, Robert H Cudmore, Da-Ting Lin, David J Linden & Richard L Huganir

doi:10.1038/nn.3936

Insertion of AMPA receptors into the synaptic membrane is thought to be a central mechanism for controlling experience-dependent changes in synaptic strength, yet this has never been observed in real time in the intact brain. Using two-photon imaging, Zhang and colleagues were able to provide this missing piece of information by tracking the insertion of GluA1 in spines in mouse barrel cortex neurons during repetitive whisker stimulation.

See also: News and Views by Wiegert & Oertner


Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern pp408 - 414

David Sherman, Jason W Worrell, Yan Cui & Jack L Feldman

doi:10.1038/nn.3938

The authors investigated the role of glycinergic preBötC neurons in respiratory rhythmogenesis in mice using viral delivery of Channelrhodopsin-2 (ChR2) or Archaerhodopsin (Arch) genes. They conclude that glycinergic preBötC neurons modulate inspiratory pattern and are important for reflex apneas but that the rhythm can persist after significant dampening of their activity.


Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area pp415 - 422

Ja Wook Koo, Michelle S Mazei-Robison, Quincey LaPlant, Gabor Egervari, Kevin M Braunscheidel, Danielle N Adank, Deveroux Ferguson, Jian Feng, Haosheng Sun, Kimberly N Scobie, Diane M Damez-Werno, Efrain Ribeiro, Catherine Jensen Peña, Deena Walker, Rosemary C Bagot, Michael E Cahill, Sarah Ann R Anderson, Benoit Labonté, Georgia E Hodes, Heidi Browne, Benjamin Chadwick, Alfred J Robison, Vincent F Vialou, Caroline Dias, Zachary Lorsch, Ezekiell Mouzon, Mary Kay Lobo, David M Dietz, Scott J Russo, Rachael L Neve, Yasmin L Hurd & Eric J Nestler

doi:10.1038/nn.3932

Comprehensive analysis of epigenetic regulation demonstrates a series of complex, interacting chromatin mechanisms by which chronic exposure to opiates downregulates Bdnf gene transcription in the ventral tegmental area. This regulatory cascade is also shown to play a role in controlling opiate-induced behavioral plasticity.


Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory pp423 - 434

Anna G Orr, Edward C Hsiao, Max M Wang, Kaitlyn Ho, Daniel H Kim, Xin Wang, Weikun Guo, Jing Kang, Gui-Qiu Yu, Anthony Adame, Nino Devidze, Dena B Dubal, Eliezer Masliah, Bruce R Conklin & Lennart Mucke

doi:10.1038/nn.3930

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders.


Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression pp435 - 443

Woosuk Chung, Su Yeon Choi, Eunee Lee, Haram Park, Jaeseung Kang, Hanwool Park, Yeonsoo Choi, Dongsoo Lee, Sae-Geun Park, Ryunhee Kim, Yi Sul Cho, Jeonghoon Choi, Myoung-Hwan Kim, Jong Won Lee, Seungjoon Lee, Issac Rhim, Min Whan Jung, Daesoo Kim, Yong Chul Bae & Eunjoon Kim

doi:10.1038/nn.3927

Enhanced NMDA receptor function and social interaction deficits are observed in mice lacking the excitatory postsynaptic scaffolding protein IRSp53. Reducing NMDAR activity by pharmacological methods rescues the impaired social interaction observed in these mice. This suggests that enhanced NMDA receptor function may be associated with social deficits.


In vivo coincidence detection in mammalian sound localization generates phase delays pp444 - 452

Tom P Franken, Michael T Roberts, Liting Wei, Nace L Golding & Philip X Joris

doi:10.1038/nn.3948

Coincidence detection is a fundamental neural operation, developed to an extreme in the computation of interaural time differences for sound localization. This study utilizes intracellular in vivo recordings and pharmacological manipulations in the medial superior olive of Mongolian gerbil to reveal that maximal coincidence is not just determined by the timing of synaptic inputs, but also by intrinsic neural properties.


The striatum multiplexes contextual and kinematic information to constrain motor habits execution pp453 - 460

Pavel E Rueda-Orozco & David Robbe

doi:10.1038/nn.3924

The authors recorded spiking activity in the sensorimotor striatum of rats performing a motor sequence in an automatic manner. They report continuous and integrative representation of contextual and kinematic information. Reversible perturbation of these representation increased execution variability, suggesting a strong contribution in constraining the execution motor habits.

See also: News and Views by Paton & Lau


Planning activity for internally generated reward goals in monkey amygdala neurons pp461 - 469

István Hernádi, Fabian Grabenhorst & Wolfram Schultz

doi:10.1038/nn.3925

Combining single-neuron recordings and a multistep economic choice task in monkeys, the authors find activity in amygdala neurons that predicts the value and length of an internally planned choice sequence leading to future reward. Prospective amygdala activity appears to encode components of an internal plan and guide behavior over several steps towards self-defined, distant goals.

See also: News and Views by Mosher & Rudebeck


Closed-loop training of attention with real-time brain imaging pp470 - 475

Megan T deBettencourt, Jonathan D Cohen, Ray F Lee, Kenneth A Norman & Nicholas B Turk-Browne

doi:10.1038/nn.3940

Lapses of attention are commonplace, potentially because they are detected too late to be prevented. The authors use real-time fMRI to provide participants continuous access to their attentional state. Real-time feedback, particularly from frontoparietal cortex, improved sustained attention abilities and modified representations in visual cortex and basal ganglia.

See also: News and Views by Awh & Vogel


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