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Volume 18 Issue 5, May 2015

Sequencing the exomes of patients with the motor neuron disease amyotrophic lateral sclerosis (ALS), Weishaupt and colleagues provide evidence that loss-of-function mutations in TBK1 cause familial cases of ALS and fronto-temporal dementia. The cover depicts TBK1 as yet another piece in the complex puzzle that is ALS genetics. Cover design by Erin Dewalt, concept by Alexander Arguello. Image from ThinkStock.611631

News & Views

  • Amyotrophic lateral sclerosis (ALS) is a complex and as yet untreatable neurodegenerative disorder. We discuss two examples of exome sequencing in large international collections of familial and sporadic ALS cases that are revealing new and potentially treatable pathways, such as those involving autophagy and neuroinflammation.

    • Conceição Bettencourt
    • Henry Houlden
    News & Views


  • How are quiescent adult neural stem cells (NSCs) generated during development? A study now identifies a reserve population of p57-expressing, slowly dividing embryonic neural progenitors that later give rise to adult NSCs.

    • Wieland B Huttner
    News & Views
  • Theory suggests that cerebellar granule cells combine sensory and motor signals originating from different sources. An unexpected logic governing how granule cells process different input sources may enhance computational power.

    • Nathaniel B Sawtell
    • L F Abbott
    News & Views
  • Strategic decisions can prove difficult to study. The board game shogi is used to investigate the functional neuroanatomy of strategic decisions, revealing different brain areas from those engaged by other forms of choice.

    • Nils Kolling
    • Laurence T Hunt
    News & Views
  • Insight into the mechanism by which deep brain stimulation exerts its therapeutic effects comes from recording in motor cortical regions of neurosurgical subjects undergoing subthalamic nucleus deep brain stimulation.

    • Ziv M Williams
    News & Views
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Review Article

  • In the last 25 years, explosive interest has implicated the orbitofrontal cortex in nearly every function known to cognitive neuroscience. Yet scientific progress comes as much from questioning existing ideas as proposing new ones. This review discusses major theories of orbitofrontal function and the data that invalidate these ideas.

    • Thomas A Stalnaker
    • Nisha K Cooch
    • Geoffrey Schoenbaum
    Review Article
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Brief Communication

  • Mensch et al. investigate how neuronal activity regulates CNS myelination in vivo, using zebrafish as a model. They find that blocking synaptic vesicle release reduces, and that stimulating neuronal activity increases, the number of myelin sheath made by the myelinating glia of the CNS (oligodendrocytes). These data show that neuronal activity regulates the myelinating capacity of individual oligodendrocytes.

    • Sigrid Mensch
    • Marion Baraban
    • David A Lyons
    Brief Communication
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  • The authors show that haploinsufficiency of TBK1 causes familial forms of the neurodegenerative diseases ALS and FTD. Loss of binding of a TBK1 protein interaction domain to optineurin, a protein previously linked to ALS, is sufficient to cause the disease. Both proteins regulate autophagy and inflammation.

    • Axel Freischmidt
    • Thomas Wieland
    • Jochen H Weishaupt
  • The developing human cortex contains diverse populations of neural progenitor cells, including a large proportion of outer radial glia (ORG), a progenitor type that is rare in the mouse. The authors identify a transcriptional signature of ORG characterized by markers of neuronal lineage fate and use single-cell analyses to contrast the heterogeneity of cortical progenitors across human, mouse and ferret.

    • Matthew B Johnson
    • Peter P Wang
    • Christopher A Walsh
  • The authors use developmental changes in chromatin accessibility to identify thousands of enhancer elements that are active at different postnatal developmental stages in granule neurons of the cerebellum. Zic transcription factors were found to promote gene expression patterns key for neuronal maturation by binding to late-acting enhancer elements.

    • Christopher L Frank
    • Fang Liu
    • Anne E West
  • Furutachi et al. identified a slowly dividing subpopulation of embryonic progenitors that later gives rise to most adult neural stem cells (NSCs) in the subependymal zone. Moreover, they found that p57 is responsible for the slow cell cycle of this embryonic population and acts causally in the emergence of adult NSCs.

    • Shohei Furutachi
    • Hiroaki Miya
    • Yukiko Gotoh
  • This work shows a nocoding function of Ube3a1 RNA, an alternative transcript encoded by the Angelman syndrome gene Ube3a. Valluy et al. observe that Ube3a1 RNA competes with dendritic mRNAs for microRNAs, thereby regulating dendrite arborization and spine maturation of hippocampal neurons. These findings suggest a function for competing endogenous RNAs in synaptic development.

    • Jeremy Valluy
    • Silvia Bicker
    • Gerhard Schratt
  • Using zebrafish, the authors show that neuronal activity influences which axons are selected for myelination by promoting the growth and stability of oligodendrocyte sheaths on axons. Myelination of axons in response to activity could modulate the conduction properties of specific neural circuits, thereby contributing to brain plasticity.

    • Jacob H Hines
    • Andrew M Ravanelli
    • Bruce Appel
  • Hormone-induced brain masculinization occurs during a perinatal sensitive period but endures into adulthood. Researchers explored DNA methylation as a candidate mechanism. Methylation is higher in female brain and suppresses masculinization genes, which are liberated by hormone-induced reductions in DNMT activity in males. Pharmacological inhibition of DNMTs reduces methylation, masculinizes female brain and behavior and reopens the sensitive period.

    • Bridget M Nugent
    • Christopher L Wright
    • Margaret M McCarthy
  • DISC1 is believed to be a genetic risk factor for schizophrenia, but its pathophysiological functions are not fully understood. Using proteomics, Tsuboi et al. identify several RNA-binding proteins, including HZF, as DISC1 interactors and reveal that DISC1, together with HZF, regulates the dendritic transport of ITPR1 mRNA to modulate synaptic plasticity.

    • Daisuke Tsuboi
    • Keisuke Kuroda
    • Kozo Kaibuchi
  • In this manuscript, the authors use state-of-the-art imaging methods to report the discovery of novel forms of astrocyte calcium signaling in wild-type mice and in mutant mice previously thought to lack astrocyte calcium dynamics. The findings have important implications for experimental and theoretical studies of astrocyte functions in neural circuits.

    • Rahul Srinivasan
    • Ben S Huang
    • Baljit S Khakh
  • Processing multiple sensory modalities is critical for executing complex behaviors. This study finds that single cerebellar granule cells integrate inputs from both vestibular and visual input pathways, each exhibiting characteristic synaptic strengths and plasticities. These are translated into output dynamics that enhance the network's representation of complex sensory contexts.

    • François P Chabrol
    • Alexander Arenz
    • David A DiGregorio
  • It has been suggested that hippocampal sharp-wave ripples (SWR) are important for memory consolidation. Here, the authors found that the activation of a non-serotoninergic subpopulation of median raphe neurons suppresses hippocampal sharp-wave ripples and impairs memory consolidation. These findings uncover a new brainstem influence on SWR and hippocampal memory function.

    • Dong V Wang
    • Hau-Jie Yau
    • Satoshi Ikemoto
  • The relationship between EEG oscillations and underlying neural activity is unclear. The authors find a U-shaped relationship between the two in visual cortex that is linked to visuospatial attention performance in monkeys. A neural network model indicates a critical role for selective inputs to inhibitory neurons.

    • Adam C Snyder
    • Michael J Morais
    • Matthew A Smith
  • The authors used new network-analysis algorithms to examine how distributed networks of brain areas are reorganized as humans learn a new motor skill. Using fMRI, the authors found that learning induced autonomy of sensorimotor systems and that a release of cognitive control hubs predicted individual differences in learning.

    • Danielle S Bassett
    • Muzhi Yang
    • Scott T Grafton
  • In complex environments, we first select heuristic strategies and next determine concrete responses. BOLD imaging while subjects encountered game situations (shogi) revealed that activity in rostral anterior cingulate cortex and posterior cingulate cortex is correlated with defense and attack values, respectively. The cingulate cortex plays essential roles in strategy decision.

    • Xiaohong Wan
    • Kang Cheng
    • Keiji Tanaka
  • Prolonged persistence toward delayed rewards is beneficial in some environments but counterproductive in others. Human decision makers calibrate persistence according to the statistics of their environment, and delay-period activity in ventromedial prefrontal cortex reflects a dynamic, context-sensitive valuation signal that could underlie adaptive decisions between persisting and quitting.

    • Joseph T McGuire
    • Joseph W Kable
  • Although it has been widely hypothesized that decisions can be guided by mental simulation of their likely consequences, there has not been direct evidence linking prospection to choices. Here, using fMRI, the authors show that neural representation of future outcomes is related to the choices that participants make.

    • Bradley B Doll
    • Katherine D Duncan
    • Nathaniel D Daw
  • Socioeconomic status is associated with cognitive development, but the extent to which this reflects neuroanatomical differences is unclear. In 1,099 children and adolescents, family income was nonlinearly associated with brain surface area, and this association was greatest among disadvantaged children. Further, surface area mediated links between income and executive functioning.

    • Kimberly G Noble
    • Suzanne M Houston
    • Elizabeth R Sowell
  • By examining Parkinson's disease patients undergoing deep brain stimulation (DBS) implantation surgery, this study shows that therapeutic DBS acts on the primary motor cortex to reversibly reduce excessive coupling between the phase of the beta rhythm and the amplitude of broadband activity over a similar time course as the reduction in parkinsonian motor signs.

    • Coralie de Hemptinne
    • Nicole C Swann
    • Philip A Starr
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