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News and Views

Helping EGFR inhibition to block cancer pp1035 - 1037

Rolf Warta & Christel Herold-Mende


Effectiveness of EGFR treatment is impaired through an early adaptive response. TNF–JNK–Axl–ERK signaling contributes to this primary resistance to EGFR inhibition and might serve as novel target to improve EGFR inhibition.

See also: Article by Guo et al.

VIP cortical conductors set the tone for chronic pain pp1037 - 1038

Erika K Harding & Michael W Salter


Loss of inhibition in a circuit in the primary somatosensory cortex that controls the activity of layer 5 neurons drives pain hypersensitivity. Restoring this inhibition resets the inhibitory–excitatory balance, producing analgesia.

See also: Article by Cichon et al.

Is the boss watching? pp1039 - 1040

Amit Etkin


A combination of computational modeling, neuroimaging and a causal manipulation of brain activity in humans reveals how the brain represents beliefs about how our choices will affect those of others we interact with.

See also: Article by Hill et al.

CREATEd viruses go global pp1041 - 1042

Keisuke Yonehara & Botond Roska


A Cre-dependent capsid selection method, CREATE, was used to produce adeno-associated viral vectors that allow gene delivery to the entire central and peripheral nervous systems, with multicolor labeling of single cells.

See also: Technical Report by Chan et al.



Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains pp1043 - 1051

Madeleine R Geisheker, Gabriel Heymann, Tianyun Wang, Bradley P Coe, Tychele N Turner, Holly A F Stessman, Kendra Hoekzema, Malin Kvarnung, Marie Shaw, Kathryn Friend, Jan Liebelt, Christopher Barnett, Elizabeth M Thompson, Eric Haan, Hui Guo, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Geert Vandeweyer, Antonino Alberti, Emanuela Avola, Mirella Vinci, Stefania Giusto, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, Jacob J Michaelson, Zdenek Sedlacek, Gijs W E Santen, Hilde Peeters, Hakon Hakonarson, Eric Courchesne, Corrado Romano, R Frank Kooy, Raphael A Bernier, Magnus Nordenskjöld, Jozef Gecz, Kun Xia, Larry S Zweifel & Evan E Eichler


This study characterizes the properties of disease-causing mutations that produce sporadic amino acid replacements in proteins of people with autism and developmental delay. The mutations tend to cluster and reoccur at specific regions important to protein function, highlighting for future follow-up ~200 candidate genes, many involved in neuronal signaling.

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease pp1052 - 1061

Kuan-lin Huang, Edoardo Marcora, Anna A Pimenova, Antonio F Di Narzo, Manav Kapoor, Sheng Chih Jin, Oscar Harari, Sarah Bertelsen, Benjamin P Fairfax, Jake Czajkowski, Vincent Chouraki, Benjamin Grenier-Boley, Céline Bellenguez, Yuetiva Deming, Andrew McKenzie, Towfique Raj, Alan E Renton, John Budde, Albert Smith, Annette Fitzpatrick, Joshua C Bis, Anita DeStefano, Hieab H H Adams, M Arfan Ikram, Sven van der Lee, Jorge L Del-Aguila, Maria Victoria Fernandez, Laura Ibañez, The International Genomics of Alzheimer's Project, The Alzheimer's Disease Neuroimaging Initiative, Rebecca Sims, Valentina Escott-Price, Richard Mayeux, Jonathan L Haines, Lindsay A Farrer, Margaret A Pericak-Vance, Jean Charles Lambert, Cornelia van Duijn, Lenore Launer, Sudha Seshadri, Julie Williams, Philippe Amouyel, Gerard D Schellenberg, Bin Zhang, Ingrid Borecki, John S K Kauwe, Carlos Cruchaga, Ke Hao & Alison M Goate


The authors identified a protective genetic allele associated with lower PU.1 (SPI1) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33, MS4A4A & MS4A6A, TYROBP) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression.

Germline Chd8 haploinsufficiency alters brain development in mouse pp1062 - 1073

Andrea L Gompers, Linda Su-Feher, Jacob Ellegood, Nycole A Copping, M Asrafuzzaman Riyadh, Tyler W Stradleigh, Michael C Pride, Melanie D Schaffler, A Ayanna Wade, Rinaldo Catta-Preta, Iva Zdilar, Shreya Louis, Gaurav Kaushik, Brandon J Mannion, Ingrid Plajzer-Frick, Veena Afzal, Axel Visel, Len A Pennacchio, Diane E Dickel, Jason P Lerch, Jacqueline N Crawley, Konstantinos S Zarbalis, Jill L Silverman & Alex S Nord


Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

A TNF–JNK–Axl–ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma pp1074 - 1084

Gao Guo, Ke Gong, Sonia Ali, Neha Ali, Shahzad Shallwani, Kimmo J Hatanpaa, Edward Pan, Bruce Mickey, Sandeep Burma, David H Wang, Santosh Kesari, Jann N Sarkaria, Dawen Zhao & Amyn A Habib


Aberrant EGFR signaling is common in glioblastoma. The authors show that inhibiting EGFR leads to increased secretion of TNF and activation of a survival pathway in cancer cells. A combined inhibition of EGFR and TNF signaling inhibits tumor growth in a mouse model, suggesting a new treatment for patients with glioblastoma.

See also: News and Views by Warta & Herold-Mende

Sensory integration and neuromodulatory feedback facilitate Drosophila mechanonociceptive behavior pp1085 - 1095

Chun Hu, Meike Petersen, Nina Hoyer, Bettina Spitzweck, Federico Tenedini, Denan Wang, Alisa Gruschka, Lara S Burchardt, Emanuela Szpotowicz, Michaela Schweizer, Ananya R Guntur, Chung-Hui Yang & Peter Soba


Noxious thermal and mechanical stimuli have to be faithfully detected and avoided to ensure survival. In this study, the authors uncover a modality-specific circuit responsible specifically for mechanonociceptive behavior in Drosophila. They show that the escape response to mechanical but not thermal noxious stimuli requires multisensory integration by mechanosensory neurons and neuromodulatory feedback signaling.

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1 pp1096 - 1103

Thomas Rathjen, Xin Yan, Natalia L Kononenko, Min-Chi Ku, Kun Song, Leiron Ferrarese, Valentina Tarallo, Dmytro Puchkov, Gaga Kochlamazashvili, Sebastian Brachs, Luis Varela, Klara Szigeti-Buck, Chun-Xia Yi, Sonja C Schriever, Sudhir Gopal Tattikota, Anne Sophie Carlo, Mirko Moroni, Jan Siemens, Arnd Heuser, Louise van der Weyden, Andreas L Birkenfeld, Thoralf Niendorf, James F A Poulet, Tamas L Horvath, Matthias H Tschöp, Matthias Heinig, Mirko Trajkovski, Volker Haucke & Matthew N Poy


The precise mechanisms that cause human obesity remain unknown. Here the authors illustrate how increased expression of Cadm1, a mediator of synapse assembly, is relevant to weight gain. Reduction of Cadm1 in multiple brain regions promoted weight loss, and these observations provide insight into the neuronal pathways contributing to obesity.

Neural signatures of dynamic stimulus selection in Drosophila pp1104 - 1113

Yi Sun, Aljoscha Nern, Romain Franconville, Hod Dana, Eric R Schreiter, Loren L Looger, Karel Svoboda, Douglas S Kim, Ann M Hermundstad & Vivek Jayaraman


Using two-color two-photon calcium imaging, the authors identified transformations of representations across synaptically connected pairs of neurons along a visual pathway to the Drosophila central complex. Neural responses to stimuli in the ipsilateral field are modulated by stimuli in the contralateral field, an effect that depends on past stimulus history.

Active dendritic integration as a mechanism for robust and precise grid cell firing pp1114 - 1121

Christoph Schmidt-Hieber, Gabija Toleikyte, Laurence Aitchison, Arnd Roth, Beverley A Clark, Tiago Branco & Michael Häusser


Combining electrophysiology and computational modeling, the authors show that the dendrites of entorhinal cortex stellate and pyramidal cells are electrically excitable and that this improves the robustness of grid cell firing. The results suggest that active dendrites are critical for spatial navigation, a fundamental computation in the brain.

Activation of cortical somatostatin interneurons prevents the development of neuropathic pain pp1122 - 1132

Joseph Cichon, Thomas J J Blanck, Wen-Biao Gan & Guang Yang


Using in vivo calcium imaging in a mouse model of neuropathic pain, the authors found a persistent increase in the activity of somatosensory cortex pyramidal neurons following peripheral nerve injury. Repeated pharmacogenetic activation of somatostatin-expressing inhibitory neurons after injury not only corrected this abnormal cortical activity but also prevented the development of chronic pain.

See also: News and Views by Harding & Salter

Reorganization of corticospinal output during motor learning pp1133 - 1141

Andrew J Peters, Jun Lee, Nathan G Hedrick, Keelin O'Neil & Takaki Komiyama


Corticospinal cells of the motor cortex act as a direct link between the cortex and movement-generating circuits within the spinal cord. The authors demonstrate that the relationship between activity of these cells and movement changes with time and learning, indicating a flexible cortical output to drive movements.

A causal account of the brain network computations underlying strategic social behavior pp1142 - 1149

Christopher A Hill, Shinsuke Suzuki, Rafael Polania, Marius Moisa, John P O'Doherty & Christian C Ruff


The authors show that transcranial magnetic disruption of the right temporoparietal junction decreases strategic behavior during competitive interactions. The altered behavior relates to neural activity changes both locally and in interconnected prefrontal areas. These brain networks may causally underlie the ability to predict the behavior of other agents.

See also: News and Views by Etkin



Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders pp1150 - 1161

Jing Li, Wangshu Zhang, Hui Yang, Daniel P Howrigan, Brent Wilkinson, Tade Souaiaia, Oleg V Evgrafov, Giulio Genovese, Veronica A Clementel, Jennifer C Tudor, Ted Abel, James A Knowles, Benjamin M Neale, Kai Wang, Fengzhu Sun & Marcelo P Coba


Using large-scale analysis of protein interactions and bioinformatics, Li et al. describe the organization of the core-scaffold machinery of the postsynaptic density and its assembly in protein-interaction networks. The authors show how mutations associated with complex brain disorders are distributed along spatiotemporal protein complexes and modulate their protein interactions.

Transcriptomic analysis of purified human cortical microglia reveals age-associated changes pp1162 - 1171

Thais F Galatro, Inge R Holtman, Antonio M Lerario, Ilia D Vainchtein, Nieske Brouwer, Paula R Sola, Mariana M Veras, Tulio F Pereira, Renata E P Leite, Thomas Möller, Paul D Wes, Mari C Sogayar, Jon D Laman, Wilfred den Dunnen, Carlos A Pasqualucci, Sueli M Oba-Shinjo, Erik W G M Boddeke, Suely K N Marie & Bart J L Eggen


Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice.


Technical Reports

Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems pp1172 - 1179

Ken Y Chan, Min J Jang, Bryan B Yoo, Alon Greenbaum, Namita Ravi, Wei-Li Wu, Luis Sánchez-Guardado, Carlos Lois, Sarkis K Mazmanian, Benjamin E Deverman & Viviana Gradinaru


The authors report two new engineered AAV capsids that efficiently deliver genes throughout the adult central and peripheral nervous systems after intravenous administration. Complementing these capsids is an AAV toolbox that enables cell morphology and genetic manipulation studies of defined neural cell types in transgenic or wild-type animals.

See also: News and Views by Yonehara & Roska

Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber pp1180 - 1188

Ferruccio Pisanello, Gil Mandelbaum, Marco Pisanello, Ian A Oldenburg, Leonardo Sileo, Jeffrey E Markowitz, Ralph E Peterson, Andrea Della Patria, Trevor M Haynes, Mohamed S Emara, Barbara Spagnolo, Sandeep Robert Datta, Massimo De Vittorio & Bernardo L Sabatini


The authors demonstrate that optical fibers with tapered tips can homogenously illuminate either elongated brain structures or dynamically selected subregions. Tapered fibers achieve efficient optogenetic stimulation in vivo with minimal tissue damage. In addition, a single fiber can deliver light of multiple wavelengths to independently controlled regions.



Corrigendum: Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles p1189

Anusha Mishra, James P Reynolds, Yang Chen, Alexander V Gourine, Dmitri A Rusakov & David Attwell


Corrigendum: A rapidly acting glutamatergic ARCright arrowPVH satiety circuit postsynaptically regulated by α-MSH p1189

Henning Fenselau, John N Campbell, Anne M J Verstegen, Joseph C Madara, Jie Xu, Bhavik P Shah, Jon M Resch, Zongfang Yang, Yael Mandelblat-Cerf, Yoav Livneh & Bradford B Lowell


Corrigendum: Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior p1189

Nicholas J Edwards, Hugo A Tejeda, Marco Pignatelli, Shiliang Zhang, Ross A McDevitt, Jocelyn Wu, Caroline E Bass, Bernhard Bettler, Marisela Morales & Antonello Bonci


Corrigendum: Dopamine transients are sufficient and necessary for acquisition of model-based associations p1189

Melissa J Sharpe, Chun Yun Chang, Melissa A Liu, Hannah M Batchelor, Lauren E Mueller, Joshua L Jones, Yael Niv & Geoffrey Schoenbaum




Erratum: Persistently active neurons in human medial frontal and medial temporal lobe support working memory p1189

Jan Kamiński, Shannon Sullivan, Jeffrey M Chung, Ian B Ross, Adam N Mamelak & Ueli Rutishauser