This Week in The Journal Cellular/Molecular Hikaru genki Clusters Acetylcholine Receptors
The Journal of Neuroscience, October 15, 2014 • 34(42):i • i This Week in The Journal F Cellular/Molecular Hikaru genki Clusters Drosophila Acetylcholine Receptors Minoru Nakayama, Fumiya Matsushita, and Chihiro Hama (see pages 13872–13877) The extracellular matrix of synaptic clefts contains proteins that help cluster neurotransmitter receptors. This week we learn that Hikaru genki (Hig) is one such protein. Hig is a secreted protein localized to some synaptic clefts in Drosophila CNS, and it is required for normal locomotion and longevity. Nakayama et al. extend previous studies to show that Hig localizes specifically to cholinergic synapses, where it helps cluster acetylcholine receptors (AChRs). Expression of AChR subunits was reduced in hig mutants and as a result, the mutants were more resistant to a lethal AChR agonist. Interestingly, the longevity phenotype of hig mutants was rescued not only by expressing wild-type hig selectively cholinergic neurons, but also by expressing it selectively in glutamatergic neurons or even in glia. Regardless of its source, secreted Hig diffused and localized to cholinergic synapses. F Development/Plasticity/Repair Fezf2 Suppresses Stem Cell Proliferation and Differentiation fezf2 (green) is expressed in most neural stem cells in the subgranular zone (SGZ) and a few granule cells (red) in the granule cell layer (GCL) of mouse dentate gyrus, indicating that Fexf2 function may be conserved between fish and mice. See the article by Berberoglu et al. for details. other studies suggest that neuroimaging is sensitive to glutamate release and reflects local spiking. Lima et al. argue that previous investigations of this question were confounded by inclusion of task-related imaging components (which are not correlated with LFPs or spiking) along with stimulusrelated components and by not comparing neuroimaging and electrophysiological measures over a wide enough range of stimulus intensities. Avoiding these confounds, the authors found that the linearity and shape of intrinsic imaging responses in primary visual cortex of monkeys best matched those of spiking. F putative NSCs had high fezf2 expression levels, proliferating NSCs had low expression levels, and differentiating cells lacked detectable expression of fezf2. Loss of fezf2 function increased the proportion of proliferative relative to quiescent NSCs and increased the number of adult-born neurons in the telencephalon. Analysis of chimeric animals indicated that fezf2 acts both cell autonomously and nonautonomously to suppress NSC proliferation and differentiation. Fezf2 appeared to regulate these processes by promoting Notch signaling, that is, by regulating expression of several members of this pathway. Systems/Circuits Optical Imaging Responses Correlate with Spiking Activity F Michael A. Berberoglu, Zhiqiang Dong, Guangnan Li, Jiashun Zheng, Luz del Carmen G. Trejo Martinez, et al. Bruss Lima, Mariana M. B. Cardoso, Yevgeniy B. Sirotin, and Aniruddha Das (see pages 13911–13923) (see pages 13878 –13891) Neurons generated in adult brains can replace injured neurons, help maintain existing circuits, and/or contribute to learning. Ongoing neurogenesis requires maintenance of neural stem cell (NSC) populations in neurogenic niches, but how NSCs are kept quiescent until new neurons are needed is not fully understood. Berberoglu et al. report that the transcription factor fezf2 has a role in this process. Expressing green fluorescent protein under the control of the fezf2 promoter in zebrafish revealed that quiescent Intrinsic-signal optical imaging and bloodoxygen-level-dependent signals obtained with functional magnetic resonance imaging detect local changes in blood volume and oxygenation, from which researchers can infer changes in neuronal activity. What component of neuronal activity is best reflected by these measures remains a matter of debate, however. Some studies found that functional imaging correlates with local field potentials (LFPs) and likely reflects metabolic demand resulting from ionic currents downstream of synaptic inputs. But Behavioral/Cognitive Lateral Amygdala Neurons Store Context–Cocaine Memory Hwa-Lin (Liz) Hsiang, Jonathan R. Epp, Michel C. van den Oever, Chen Yan, Asim J. Rashid, et al. (see pages 14115–14127) With repeated exposure, cocaine users learn to associate certain cues or environments with drug use. Later re-exposure to these cues or environments induces craving and often leads to relapse. Hsiang et al. propose that these relapse-inducing associations are stored by neurons in the lateral amygdala (LA) that happen to be activated during cocaine exposure. Overexpressing CREB in ⬃10% of neurons in mouse LA made these neurons more likely than other LA neurons to be activated in a chamber associated with cocaine administration, suggesting these neurons helped form the contextual memory. Selectively ablating or silencing CREBoverexpressing neurons just before testing reduced conditioned place preference (CPP) for the cocaine-associated chamber. Furthermore, silencing CREB-overexpressing neurons immediately after training—which was expected to impair memory consolidation— eliminated CPP. Together, the data suggest that the context– cocaine association is stored in a subset of LA neurons that exhibit high CREB expression during cocaine exposure, and that reactivation of these neurons after training is required to consolidate the memory. The Journal of Neuroscience October 15, 2014 • Volume 34 Number 42 • www.jneurosci.org i This Week in The Journal Journal Club 13867 Priority Maps Explain the Roles of Value, Attention, and Salience in Goal-Oriented Behavior P. Christiaan Klink, Pia Jentgens, and Jeannette A.M. Lorteije 13870 The Temporal Dynamics of Evidence Accumulation in the Brain Martijn J. Mulder Brief Communications Cover legend: A mouse neuromuscular junction (NMJ) showing acetylcholine receptors (red), motor nerve (green), and nuclei (blue). These peripheral synapses are normally remarkably stable in adult animals, but they undergo dramatic changes in myasthenic disorders or aging. For more details, see the article by Barik et al. (pages 13892–13905). 䊉 13872 The Matrix Protein Hikaru genki Localizes to Cholinergic Synaptic Clefts and Regulates Postsynaptic Organization in the Drosophila Brain Minoru Nakayama, Fumiya Matsushita, and Chihiro Hama 13906 Role of Glutamatergic Projections from Ventral Tegmental Area to Lateral Habenula in Aversive Conditioning David H. Root, Carlos A. Mejias-Aponte, Jia Qi, and Marisela Morales 14006 The Rac1 Inhibitor NSC23766 Suppresses CREB Signaling by Targeting NMDA Receptor Function Hailong Hou, Andre´s E. Cha´vez, Chih-Chieh Wang, Hongtian Yang, Hua Gu, Benjamin A. Siddoway, Benjamin J. Hall, Pablo E. Castillo, and Houhui Xia 14108 Goal-Congruent Default Network Activity Facilitates Cognitive Control R. Nathan Spreng, Elizabeth DuPre, Dhawal Selarka, Juliana Garcia, Stefan Gojkovic, Judith Mildner, Wen-Ming Luh, and Gary R. Turner Articles CELLULAR/MOLECULAR 13892 LRP4 Is Critical for Neuromuscular Junction Maintenance Arnab Barik, Yisheng Lu, Anupama Sathyamurthy, Andrew Bowman, Chengyong Shen, Lei Li, Wen-cheng Xiong, and Lin Mei 13948 Long-Term In Vivo Imaging of Dendritic Spines in the Hippocampus Reveals Structural Plasticity Ligang Gu, Stefanie Kleiber, Lena Schmid, Felix Nebeling, Miriam Chamoun, Julia Steffen, Jens Wagner, and Martin Fuhrmann 13976 Numb Regulates the Polarized Delivery of Cyclic Nucleotide-Gated Ion Channels in Rod Photoreceptor Cilia Vasanth Ramamurthy, Christine Jolicoeur, Demetra Koutroumbas, Johanna Mu¨hlhans, Yun-Zheng Le, William W. Hauswirth, Andreas Giessl, and Michel Cayouette 13988 KIS, a Kinase Associated with Microtubule Regulators, Enhances Translation of AMPA Receptors and Stimulates Dendritic Spine Remodeling Neus Pedraza, Rau´l Ortiz, Alba Cornado´, Artur Llobet, Martí Aldea, and Carme Gallego 14055 Multimodal Use of Calcitonin Gene-Related Peptide and Substance P in Itch and Acute Pain Uncovered by the Elimination of Vesicular Glutamate Transporter 2 from Transient Receptor Potential Cation Channel Subfamily V Member 1 Neurons Katarzyna Rogoz, Helena H. Andersen, Malin C. Lagerstro¨m, and Klas Kullander DEVELOPMENT/PLASTICITY/REPAIR 䊉 13911 Heterogeneously Expressed fezf2 Patterns Gradient Notch Activity in Balancing the Quiescence, Proliferation, and Differentiation of Adult Neural Stem Cells Michael A. Berberoglu, Zhiqiang Dong, Guangnan Li, Jiashun Zheng, Luz del Carmen G. Trejo Martinez, Jisong Peng, Mahendra Wagle, Brian Reichholf, Claudia Petritsch, Hao Li, Samuel J. Pleasure, and Su Guo 13924 Selective Activation of Ipsilateral Motor Pathways in Intact Humans Toshiki Tazoe and Monica A. Perez 14013 Characterization of Ectopic Colonies That Form in Widespread Areas of the Nervous System with Neural Stem Cell Transplants into the Site of a Severe Spinal Cord Injury Oswald Steward, Kelli G. Sharp, Kelly Matsudaira Yee, Maya N. Hatch, and Joseph F. Bonner 14022 Multifunctional Liposomes Reduce Brain -Amyloid Burden and Ameliorate Memory Impairment in Alzheimer’s Disease Mouse Models Claudia Balducci, Simona Mancini, Stefania Minniti, Pietro La Vitola, Margherita Zotti, Giulio Sancini, Mario Mauri, Alfredo Cagnotto, Laura Colombo, Fabio Fiordaliso, Emanuele Grigoli, Mario Salmona, Anniina Snellman, Merja Haaparanta-Solin, Gianluigi Forloni, Massimo Masserini, and Francesca Re 14128 Adult Neural Precursor Cells from the Subventricular Zone Contribute Significantly to Oligodendrocyte Regeneration and Remyelination Yao Lulu Xing, Philipp T. Ro¨th, Jo Anne S. Stratton, Bernard H.A. Chuang, Jill Danne, Sarah L. Ellis, Sze Woei Ng, Trevor J. Kilpatrick, and Tobias D. Merson SYSTEMS/CIRCUITS 䊉 13878 Stimulus-Related Neuroimaging in Task-Engaged Subjects Is Best Predicted by Concurrent Spiking Bruss Lima, Mariana M.B. Cardoso, Yevgeniy B. Sirotin, and Aniruddha Das 13935 Dynamic Modulation of Amygdala–Hippocampal Connectivity by Emotional Arousal Matthias Fastenrath, David Coynel, Klara Spalek, Annette Milnik, Leo Gschwind, Benno Roozendaal, Andreas Papassotiropoulos, and Dominique J.F. de Quervain 14032 Presynaptic T-Type Ca2ⴙ Channels Modulate Dendrodendritic Mitral–Mitral and Mitral–Periglomerular Connections in Mouse Olfactory Bulb Adam Fekete, Jamie Johnston, and Kerry R. Delaney 14046 Systematic Shifts in the Balance of Excitation and Inhibition Coordinate the Activity of Axial Motor Pools at Different Speeds of Locomotion Sandeep Kishore, Martha W. Bagnall, and David L. McLean BEHAVIORAL/COGNITIVE 13998 Temporal Memory Is Shaped by Encoding Stability and Intervening Item Reactivation Sarah DuBrow and Lila Davachi 䊉 14096 Large-Scale Brain Network Dynamics Supporting Adolescent Cognitive Control Dominic B. Dwyer, Ben J. Harrison, Murat Yu¨cel, Sarah Whittle, Andrew Zalesky, Christos Pantelis, Nicholas B. Allen, and Alex Fornito 14115 Manipulating a “Cocaine Engram” in Mice Hwa-Lin (Liz) Hsiang, Jonathan R. Epp, Michel C. van den Oever, Chen Yan, Asim J. Rashid, Nathan Insel, Li Ye, Yosuke Niibori, Karl Deisseroth, Paul W. Frankland, and Sheena A. Josselyn 14147 Neurons in the Nucleus Accumbens Promote Selection Bias for Nearer Objects Sara E. Morrison and Saleem M. Nicola NEUROBIOLOGY OF DISEASE 13954 Impact of RTN3 Deficiency on Expression of BACE1 and Amyloid Deposition Qi Shi, Yingying Ge, Md. Golam Sharoar, Wanxia He, Rong Xiang, Zhuohua Zhang, Xiangyou Hu, and Riqiang Yan 13963 Resting-State Functional Connectivity Changes in Aging apoE4 and apoE-KO Mice Valerio Zerbi, Maximilian Wiesmann, Tim L. Emmerzaal, Diane Jansen, Maarten Van Beek, Martina P.C. Mutsaers, Christian F. Beckmann, Arend Heerschap, and Amanda J. Kiliaan 14069 Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice Johanna Knoferle, Seo Yeon Yoon, David Walker, Laura Leung, Anna K. Gillespie, Leslie M. Tong, Nga Bien-Ly, and Yadong Huang 14079 SLC30A10 Is a Cell Surface-Localized Manganese Efflux Transporter, and Parkinsonism-Causing Mutations Block Its Intracellular Trafficking and Efflux Activity Dinorah Leyva-Illades, Pan Chen, Charles E. Zogzas, Steven Hutchens, Jonathan M. Mercado, Caleb D. Swaim, Richard A. Morrisett, Aaron B. Bowman, Michael Aschner, and Somshuvra Mukhopadhyay 14163 Correction: The article “Structural and Functional Plasticity of Astrocyte Processes and Dendritic Spine Interactions” by Alberto Perez-Alvarez, Marta Navarrete, Ana Covelo, Eduardo D. Martin, and Alfonso Araque appeared on pages 12738 –12744 of the September 17, 2014 issue. A correction for that article appears on page 14163. 14164 Erratum: The article “On the Role of Suppression in Spatial Attention: Evidence from Negative BOLD in Human Subcortical and Cortical Structures” by Andre´ D. Gouws, Ivan Alvarez, David M. Watson, Maiko Uesaki, Jessica Rogers, and Antony B. Morland appeared on pages 10347–10360 of the July 30, 2014 issue. An erratum for that article appears on page 14164. Persons interested in becoming members of the Society for Neuroscience should contact the Membership Department, Society for Neuroscience, 1121 14th St., NW, Suite 1010, Washington, DC 20005, phone 202-962-4000. 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BRIEF COMMUNICATIONS The Matrix Protein Hikaru genki Localizes to Cholinergic Synaptic Clefts and Regulates Postsynaptic Organization in the Drosophila Brain Minoru Nakayama, Fumiya Matsushita, and X Chihiro Hama Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan The synaptic cleft, a crucial space involved in neurotransmission, is filled with extracellular matrix that serves as a scaffold for synaptic differentiation. However, little is known about the proteins present in the matrix and their functions in synaptogenesis, especially in the CNS. Here, we report that Hikaru genki (Hig), a secreted protein with an Ig motif and complement control protein domains, localizes specifically to the synaptic clefts of cholinergic synapses in the Drosophila CNS. The data indicate that this specific localization is achieved by capture of secreted Hig in synaptic clefts, even when it is ectopically expressed in glia. In the absence of Hig, the cytoskeletal scaffold protein DLG accumulated abnormally in cholinergic postsynapses, and the synaptic distribution of acetylcholine receptor (AchR) subunits D␣6 and D␣7 significantly decreased. hig mutant flies consistently exhibited resistance to the AchR agonist spinosad, which causes lethality by specifically activating the D␣6 subunit, suggesting that loss of Hig compromises the cholinergic synaptic activity mediated by D␣6. These results indicate that Hig is a specific component of the synaptic cleft matrix of cholinergic synapses and regulates their postsynaptic organization in the CNS. The Journal of Neuroscience, October 15, 2014 • 34(42):13872–13877 Role of Glutamatergic Projections from Ventral Tegmental Area to Lateral Habenula in Aversive Conditioning X David H. Root, Carlos A. Mejias-Aponte, Jia Qi, and Marisela Morales Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland 21224 The ventral tegmental area (VTA) plays roles in both reward and aversion. The participation of VTA in diverse behaviors likely reflects its heterogeneous neuronal phenotypes and circuits. Recent findings indicate that VTA GABAergic neurons that coexpress tyrosine hydroxylase (TH) projecting to lateral habenula (LHb) play a role in reward. In addition to these mesohabenular TH-GABAergic neurons, the VTA has many neurons expressing vesicular glutamate transporter 2 (VGluT2) that also project to LHb. To determine the behavioral role of mesohabenular VGluT2 neurons, we targeted channelrhodopsin2 to VTA VGluT2 neurons of VGluT2::Cre mice. These mice were tested in an apparatus where moving into one chamber stimulated VTA VGluT2 projections within the LHb, and exiting the chamber inactivated the stimulation. We found that mice spent significantly less time in the chamber where VGluT2 mesohabenular fiber stimulation occurred. Mice that received injections of mixed AMPA and NMDA glutamate receptor antagonists in LHb were unresponsive to VGluT2-mesohabenular fiber stimulation, demonstrating the participation of LHb glutamate receptors in mesohabenular stimulation-elicited aversion. In the absence of light stimulation, mice showed a conditioned place aversion to the chamber that was previously associated with VGluT2-mesohabenular fiber stimulation. We conclude that there is a glutamatergic signal from VTA VGluT2-mesohabenular neurons that plays a role in aversion by activating LHb glutamatergic receptors. The Journal of Neuroscience, October 15, 2014 • 34(42):13906 –13910 The Rac1 Inhibitor NSC23766 Suppresses CREB Signaling by Targeting NMDA Receptor Function Hailong Hou,1 X Andre´s E. Cha´vez,3 Chih-Chieh Wang,4 Hongtian Yang,1 Hua Gu,1 Benjamin A. Siddoway,1 Benjamin J. Hall,4,5 Pablo E. Castillo,3 and Houhui Xia1,2 Neuroscience Center and 2Department of Cell Biology and Anatomy, LSU Health Science Center, New Orleans, Louisiana 70112, 3Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and 4Neuroscience Program and 5Departments of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118 1 NMDA receptor signaling plays a complex role in CREB activation and CREB-mediated gene transcription, depending on the subcellular location of NMDA receptors, as well as how strongly they are activated. However, it is not known whether Rac1, the prototype of Rac GTPase, plays a role in neuronal CREB activation induced by NMDA receptor signaling. Here, we report that NSC23766, a widely used specific Rac1 inhibitor, inhibits basal CREB phosphorylation at S133 (pCREB) and antagonizes changes in pCREB levels induced by NMDA bath application in rat cortical neurons. Unexpectedly, we found that NSC23766 affects the levels of neuronal pCREB in a Rac1-independent manner. Instead, our results indicate that NSC23766 can directly regulate NMDA receptors as indicated by their strong effects on both exogenous and synaptically evoked NMDA receptor-mediated currents in mouse and rat neurons, respectively. Our findings strongly suggest that Rac1 does not affect pCREB signaling in cortical neurons and reveal that NSC23766 could be a novel NMDA receptor antagonist. The Journal of Neuroscience, October 15, 2014 • 34(42):14006 –14012 Goal-Congruent Default Network Activity Facilitates Cognitive Control R. Nathan Spreng,1,2 Elizabeth DuPre,1 Dhawal Selarka,4 Juliana Garcia,1 Stefan Gojkovic,4 Judith Mildner,1 X Wen-Ming Luh,3 and Gary R. Turner4 1Laboratory of Brain and Cognition, Department of Human Development, 2Human Neuroscience Institute, and 3Cornell MRI Facility, Cornell University, Ithaca, New York 14853, and 4Department of Psychology, York University, Toronto, Ontario, M3J1P3, Canada Substantial neuroimaging evidence suggests that spontaneous engagement of the default network impairs performance on tasks requiring executive control. We investigated whether this impairment depends on the congruence between executive control demands and internal mentation. We hypothesized that activation of the default network might enhance performance on an executive control task if control processes engage long-term memory representations that are supported by the default network. Using fMRI, we scanned 36 healthy young adult humans on a novel two-back task requiring working memory for famous and anonymous faces. In this task, participants (1) matched anonymous faces interleaved with anonymous face, (2) matched anonymous faces interleaved with a famous face, or (3) matched a famous faces interleaved with an anonymous face. As predicted, we observed a facilitation effect when matching famous faces, compared with anonymous faces. We also observed greater activation of the default network during these famous face-matching trials. The results suggest that activation of the default network can contribute to task performance during an externally directed executive control task. Our findings provide evidence that successful activation of the default network in a contextually relevant manner facilitates goal-directed cognition. The Journal of Neuroscience, October 15, 2014 • 34(42):14108 –14114 Articles CELLULAR/MOLECULAR LRP4 Is Critical for Neuromuscular Junction Maintenance Arnab Barik,1* Yisheng Lu,1* X Anupama Sathyamurthy,1 Andrew Bowman,1 Chengyong Shen,1 Lei Li,1 Wen-cheng Xiong,1,2,3 and Lin Mei1,2,3 Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, 2Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, and 3Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30904 1 The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. However, it remains unclear whether the agrin signaling pathway is critical for NMJ maintenance because null mutation of any of the three genes is perinatal lethal. In this study, we generated imKO mice, a mutant strain whose LRP4 gene can be deleted in muscles by doxycycline (Dox) treatment. Ablation of the LRP4 gene in adult muscle enabled studies of its role in NMJ maintenance. We demonstrate that Dox treatment of P30 mice reduced muscle strength and compound muscle action potentials. AChR clusters became fragmented with diminished junctional folds and synaptic vesicles. The amplitude and frequency of miniature endplate potentials were reduced, indicating impaired neuromuscular transmission and providing cellular mechanisms of adult LRP4 deficiency. We showed that LRP4 ablation led to the loss of synaptic agrin and the 90 kDa fragments, which occurred ahead of other prejunctional and postjunctional components, suggesting that LRP4 may regulate the stability of synaptic agrin. These observations demonstrate that LRP4 is essential for maintaining the structural and functional integrity of the NMJ and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. The Journal of Neuroscience, October 15, 2014 • 34(42):13892–13905 Long-Term In Vivo Imaging of Dendritic Spines in the Hippocampus Reveals Structural Plasticity Ligang Gu, Stefanie Kleiber, Lena Schmid, Felix Nebeling, Miriam Chamoun, Julia Steffen, Jens Wagner, and Martin Fuhrmann German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Hippocampal function is important for learning and memory. During memory processing, hippocampal CA1 neurons play a crucial role by integrating excitatory synaptic input from CA3 and the entorhinal cortex. These neurons receive excitatory input almost exclusively on dendritic spines. The formation and elimination—structural plasticity— of dendritic spines reflect wiring changes within the hippocampal network. Despite the relevance of the hippocampus in learning and memory, most in vivo data on structural plasticity derive from cortical regions. We established a chronic hippocampal window approach using two-photon microscopy to visualize dendritic spines throughout all CA1 hippocampal layers and over a time course of weeks. Moreover, even granule cells in dentate gyrus could be reliably detected. We found that the spine density in stratum radiatum (⬃1.1 per micrometer) remained stable over weeks. However, a small fraction (3.4%) of spines were formed and eliminated between imaging sessions, which demonstrated that spines of CA1 neurons exhibit structural plasticity in adult mice. In addition, we tested for possible inflammatory or behavioral side effects of hippocampal window implantation. Mice exhibited a transient increase in microgliosis and astrogliosis, which declined within a few weeks. We did not detect any difference in behavioral performance in an open-field and contextual fear-conditioning paradigm. In conclusion, hippocampal long-term two-photon imaging revealed structural plasticity of dendritic spines in CA1 pyramidal neurons. This approach may provide a powerful tool to analyze changes in neuronal network rewiring during hippocampal learning and memory processes in health and disease. The Journal of Neuroscience, October 15, 2014 • 34(42):13948 –13953 Numb Regulates the Polarized Delivery of Cyclic Nucleotide-Gated Ion Channels in Rod Photoreceptor Cilia Vasanth Ramamurthy,1,2 Christine Jolicoeur,1 X Demetra Koutroumbas,1,3 Johanna Mu¨hlhans,4 Yun-Zheng Le,5 William W. Hauswirth,6 X Andreas Giessl,4 and Michel Cayouette1,2,3,7 Institut de recherches cliniques de Montreal, Montreal, Quebec H2W 1R7, Canada, 2Division of Experimental Medicine and 3Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada, 4Department of Biology, Animal Physiology, University of Erlangen-Nuremberg, 91058 Erlangen, Germany, 5Department of Medicine and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, 6Department of Ophthalmology and Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610, and 7Department of Medicine, Universite´ de Montre´al, Montreal, Quebec, H3T 1P1 Canada 1 The development and maintenance of protein compartmentalization is essential for neuronal function. A striking example is observed in light-sensing photoreceptors, in which the apical sensory cilium is subdivided into an inner and outer segment, each containing specific proteins essential for vision. It remains unclear, however, how such polarized protein localization is regulated. We report here that the endocytic adaptor protein Numb localizes to the inner, but not the outer segment of mouse photoreceptor cilia. Rod photoreceptor-specific inactivation of numb in vivo leads to progressive photoreceptor degeneration, indicating an essential role for Numb in photoreceptor cell biology. Interestingly, we report that loss of Numb in photoreceptors does not affect the localization of outer segment disk membrane proteins, such as rhodopsin, Peripherin-rds, Rom-1, and Abca4, but significantly disrupts the localization of the rod cyclic nucleotide-gated (Cng) channels, which accumulates on the inner segment plasma membrane in addition to its normal localization to the outer segments. Mechanistically, we show that Numb interacts with both subunits of the Cng channel and promotes the trafficking of Cnga1 to the recycling endosome. These results suggest a model in which Numb prevents targeting of Cng channels to the inner segment, by promoting their trafficking through the recycling endosome, where they can be sorted for specific delivery to the outer segment. This study uncovers a novel mechanism regulating polarized protein delivery in light-sensing cilia, raising the possibility that Numb plays a part in the regulation of protein trafficking in other types of cilia. The Journal of Neuroscience, October 15, 2014 • 34(42):13976 –13987 KIS, a Kinase Associated with Microtubule Regulators, Enhances Translation of AMPA Receptors and Stimulates Dendritic Spine Remodeling X Neus Pedraza,1* X Rau´l Ortiz,1* Alba Cornado´,1 X Artur Llobet,2 Martí Aldea,1 and X Carme Gallego1 Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain and 2Laboratory of Neurobiology, Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona, 08907 L’Hospitalet de Llobregat, Spain 1 Local regulation of protein synthesis allows a neuron to rapidly alter the proteome in response to synaptic signals, an essential mechanism in synaptic plasticity that is altered in many neurological diseases. Synthesis of many synaptic proteins is under local control and much of this regulation occurs through structures termed RNA granules. KIS is a protein kinase that associates with stathmin, a modulator of the tubulin cytoskeleton. Furthermore, KIS is found in RNA granules and stimulates translation driven by the -actin 3⬘UTR in neurites. Here we explore the physiological and molecular mechanisms underlying the action of KIS on hippocampal synaptic plasticity in mice. KIS downregulation compromises spine development, alters actin dynamics, and reduces postsynaptic responsiveness. The absence of KIS results in a significant decrease of protein levels of PSD-95, a postsynaptic scaffolding protein, and the AMPAR subunits GluR1 and GluR2 in a CPEB3-dependent manner. Underlying its role in spine maturation, KIS is able to suppress the spine developmental defects caused by CPEB3 overexpression. Moreover, either by direct or indirect mechanisms, KIS counteracts the inhibitory activity of CPEB3 on the GluR2 3⬘UTR at both mRNA translation and polyadenylation levels. Our study provides insights into the mechanisms that mediate dendritic spine morphogenesis and functional synaptic maturation, and suggests KIS as a link regulating spine cytoskeleton and postsynaptic activity in memory formation. The Journal of Neuroscience, October 15, 2014 • 34(42):13988 –13997 Multimodal Use of Calcitonin Gene-Related Peptide and Substance P in Itch and Acute Pain Uncovered by the Elimination of Vesicular Glutamate Transporter 2 from Transient Receptor Potential Cation Channel Subfamily V Member 1 Neurons Katarzyna Rogoz, Helena H. Andersen, Malin C. Lagerstro¨m,* and Klas Kullander* Department of Neuroscience, Uppsala University, 751 24, Uppsala, Sweden Primary afferents are known to use glutamate as their principal fast neurotransmitter. However, it has become increasingly clear that peptides have an influential role in both mediating and modulating sensory transmission. Here we describe the transmission accounting for different acute pain states and itch transmitted via the transient receptor potential cation channel subfamily V member 1 (TRPV1) population by either ablating Trpv1–Cre-expressing neurons or inducing vesicular glutamate transporter 2 (VGLUT2) deficiency in Trpv1–Cre-expressing neurons. Furthermore, by pharmacological inhibition of substance P or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we evaluated the contribution of substance P or CGRP to these sensory modulations, with or without the presence of VGLUT2-mediated glutamatergic transmission in Trpv1–Cre neurons. This examination, together with c-Fos analyses, showed that glutamate via VGLUT2 in the Trpv1–Cre population together with substance P mediate acute cold pain, whereas glutamate together with CGRP mediate noxious heat. Moreover, we demonstrate that glutamate together with both substance P and CGRP mediate tissue-injury associated pain. We further show that itch, regulated by the VGLUT2-mediated transmission via the Trpv1–Cre population, depends on CGRP and gastrin-releasing peptide receptor (GRPR) transmission because pharmacological blockade of the CGRP or GRPR pathway, or genetic ablation of Grpr, led to a drastically attenuated itch. Our study reveals how different neurotransmitters combined can cooperate with each other to transmit or regulate various acute sensations, including itch. The Journal of Neuroscience, October 15, 2014 • 34(42):14055–14068 DEVELOPMENT/PLASTICITY/REPAIR Heterogeneously Expressed fezf2 Patterns Gradient Notch Activity in Balancing the Quiescence, Proliferation, and Differentiation of Adult Neural Stem Cells Michael A. Berberoglu,1,2,3,4,9* X Zhiqiang Dong,1,2,4* Guangnan Li,2,5 Jiashun Zheng,6 Luz del Carmen G. Trejo Martinez,1,2,4,11 Jisong Peng,1,2,4 Mahendra Wagle,1,2,4 Brian Reichholf,7 Claudia Petritsch,7,8 Hao Li,6 X Samuel J. Pleasure,2,3,5 and X Su Guo1,2,3,4,10 Department of Bioengineering and Therapeutic Sciences, 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, 3Graduate Program in Neuroscience, 4Institute of Human Genetics, 5Department of Neurology, 6Department of Biochemistry and Biophysics, 7Department of Neurological Surgery, and 8Brain Tumor Research Center, University of California, San Francisco, California 94143-2811, 9Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, 10State Key Laboratory of Genetic Engineering and the Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China, and 11Graduate Program in Cell and Molecular Biology, Department of Biology, San Francisco State University, San Francisco, California 94132 1 Balancing quiescence, self-renewal, and differentiation in adult stem cells is critical for tissue homeostasis. The underlying mechanisms, however, remain incompletely understood. Here we identify Fezf2 as a novel regulator of fate balance in adult zebrafish dorsal telencephalic neural stem cells (NSCs). Transgenic reporters show intermingled fezf2-GFP hi quiescent and fezf2-GFP lo proliferative NSCs. Constitutive or conditional impairment of fezf2 activity demonstrates its requirement for maintaining quiescence. Analyses of genetic chimeras reveal a dose-dependent role of fezf2 in NSC activation, suggesting that the difference in fezf2 levels directionally biases fate. Single NSC profiling coupled with genetic analysis further uncovers a fezf2-dependent gradient Notch activity that is high in quiescent and low in proliferative NSCs. Finally, fezf2-GFP hi quiescent and fezf2-GFP lo proliferative NSCs are observed in postnatal mouse hippocampus, suggesting possible evolutionary conservation. Our results support a model in which fezf2 heterogeneity patterns gradient Notch activity among neighbors that is critical to balance NSC fate. The Journal of Neuroscience, October 15, 2014 • 34(42):13911–13923 Selective Activation of Ipsilateral Motor Pathways in Intact Humans Toshiki Tazoe and Monica A. Perez Department of Physical Medicine and Rehabilitation, Center for the Neural Basis of Cognition, Systems Neuroscience Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 It has been proposed that ipsilateral motor pathways play a role in the control of ipsilateral movements and recovery of function after injury. However, the extent to which ipsilateral motor pathways are engaged in voluntary activity in intact humans remains largely unknown. Using transcranial magnetic stimulation over the arm representation of the primary motor cortex, we examined ipsilateral motor-evoked potentials (iMEPs) in a proximal arm muscle during increasing levels of unilateral and bilateral isometric force in a sitting position. We demonstrate that iMEP area and amplitude decreased during bilateral contraction of homonymous (elbow flexor) muscles and increased during bilateral contraction of heteronymous (elbow flexor and extensor) muscles compared with a unilateral contraction, regardless of the level of force tested. To further understand the neuronal inputs involved in the bilateral effects, we examined the contribution from neck afferents projecting onto ipsilateral motor pathways. Medial (away from the muscle tested) and lateral (toward the muscle tested) rotation of the head enhanced bilateral iMEP effects from homonymous and heteronymous muscles, respectively. In contrast, head flexion and extension exerted nonspecific bilateral effects on iMEPs. Intracortical inhibition, in the motor cortex where iMEPs originated, showed modulation compatible with the changes in iMEPs. We conclude that ipsilateral projections to proximal arm muscles can be selectively modulated by voluntary contraction of contralateral arm muscles, likely involving circuits mediating asymmetric tonic neck reflexes acting, at least in part, at the cortical level. The pattern of bilateral actions may represent a strategy to engage ipsilateral motor pathways in a motor behavior. The Journal of Neuroscience, October 15, 2014 • 34(42):13924 –13934 Characterization of Ectopic Colonies That Form in Widespread Areas of the Nervous System with Neural Stem Cell Transplants into the Site of a Severe Spinal Cord Injury Oswald Steward,1,2,3,4 Kelli G. Sharp,1 Kelly Matsudaira Yee,1 Maya N. Hatch,1 and Joseph F. Bonner1 Reeve–Irvine Research Center, Departments of 2Anatomy and Neurobiology, 3Neurobiology and Behavior, and 4Neurosurgery, University of California at Irvine School of Medicine, Irvine, California 92697-4265 1 We reported previously the formation of ectopic colonies in widespread areas of the nervous system after transplantation of fetal neural stem cells (NSCs) into spinal cord transection sites. Here, we characterize the incidence, distribution, and cellular composition of the colonies. NSCs harvested from E14 spinal cords from rats that express GFP were treated with a growth factor cocktail and grafted into the site of a complete spinal cord transection. Two months after transplant, spinal cord and brain tissue were analyzed histologically. Ectopic colonies were found at long distances from the transplant in the central canal of the spinal cord, the surface of the brainstem and spinal cord, and in the fourth ventricle. Colonies were present in 50% of the rats, and most rats had multiple colonies. Axons extended from the colonies into the host CNS. Colonies were strongly positive for nestin, a marker for neural precursors, and contained NeuN-positive cells with processes resembling dendrites, GFAP-positive astrocytes, APC/CC1positive oligodendrocytes, and Ki-67-positive cells, indicating ongoing proliferation. Stereological analyses revealed an estimated 21,818 cells in a colony in the fourth ventricle, of which 1005 (5%) were Ki-67 positive. Immunostaining for synaptic markers (synaptophysin and VGluT-1) revealed large numbers of synaptophysin-positive puncta within the colonies but fewer VGluT-1 puncta. Continuing expansion of NSC-derived cell masses in confined spaces in the spinal cord and brain could produce symptoms attributable to compression of nearby tissue. It remains to be determined whether other cell types with self-renewing potential can also form colonies. The Journal of Neuroscience, October 15, 2014 • 34(42):14013–14021 Multifunctional Liposomes Reduce Brain -Amyloid Burden and Ameliorate Memory Impairment in Alzheimer’s Disease Mouse Models Claudia Balducci,1 X Simona Mancini,4 Stefania Minniti,4 X Pietro La Vitola,1 Margherita Zotti,1 Giulio Sancini,4 Mario Mauri,4 Alfredo Cagnotto,2 X Laura Colombo,2 Fabio Fiordaliso,3 X Emanuele Grigoli,1 Mario Salmona,2 Anniina Snellman,5 Merja Haaparanta-Solin,5 Gianluigi Forloni,1 Massimo Masserini,4 and Francesca Re4 Departments of 1Neuroscience, 2Molecular Biochemistry and Pharmacology, and 3Cardiovascular Research, Institute for Istituto di Ricovero e Cura a Carattere Scientifico/Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy, 4Department of Health Sciences, University of Milano-Bicocca, 20900 Monza, Italy, and 5MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, 20520 Turku, Finland Alzheimer’s disease is characterized by the accumulation and deposition of plaques of -amyloid (A) peptide in the brain. Given its pivotal role, new therapies targeting A are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A assemblies and evaluated their efficiency in reducing the A burden in Alzheimer’s disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood– brain barrier targeting and with phosphatidic acid for A binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble A1– 42 (⫺33%), assessed by ELISA, and the number and total area of plaques (⫺34%) detected histologically. Also, brain A oligomers were reduced (⫺70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [ 11C]Pittsburgh compound B (PIB). The reduction of brain A was associated with its increase in liver (⫹18%) and spleen (⫹20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain A aggregates and promote peptide removal across the blood– brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer’s disease. The Journal of Neuroscience, October 15, 2014 • 34(42):14022–14031 Adult Neural Precursor Cells from the Subventricular Zone Contribute Significantly to Oligodendrocyte Regeneration and Remyelination Yao Lulu Xing,1,2 Philipp T. Ro¨th,1,2 Jo Anne S. Stratton,1,3 Bernard H.A. Chuang,1 Jill Danne,4,6 Sarah L. Ellis,4,6 Sze Woei Ng,1 Trevor J. Kilpatrick,1,3,5 and Tobias D. Merson1,2,5 The Florey Institute of Neuroscience and Mental Health, and 2Florey Department of Neuroscience and Mental Health, and 3Department of Anatomy and Neuroscience, 4Sir Peter MacCallum Department of Oncology, and 5Melbourne Neuroscience Institute, The University of Melbourne, Parkville 3010, Victoria, Australia, and 6Peter MacCallum Cancer Centre, East Melbourne 3006, Victoria, Australia 1 Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis and remyelinaton in demyelinating diseases. Recent studies have demonstrated that neural precursor cells (NPCs) from the adult subventricular zone (SVZ) can also generate new oligodendrocytes after demyelination. However, the relative contribution of NPCs versus pOPCs to remyelination is unknown. We used in vivo genetic fate mapping to assess the behavior of each progenitor type within the corpus callosi (CCs) of mice subjected to cuprizone-induced demyelination. Nestin-CreERT2 and Pdgfra-CreERT2 transgenic mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and pOPCs respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and contributed to oligodendrogenesis. This capacity was most prominent in rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes significantly outnumbered those generated from pOPCs. Sixty-two percent of all nodes of Ranvier in this region were flanked by at least one paranode generated from an NPC-derived oligodendrocyte. Remarkably, g-ratios (ratio of the axon diameter to the diameter of the axon plus myelin sheath) of myelinated axons in regions subject to significant NPC-derived remyelination were equivalent to those of unchallenged controls, and immunoelectron microscopy revealed that NPC-derived myelin was significantly thicker than that generated by pOPCs, regardless of axonal caliber. We also demonstrate that a reduced efficiency of remyelination in the caudal CC was associated with long-term impairment in the maturation of oligodendrogenic NPCs but only transient delay in pOPC differentiation. Collectively, our data define a major distinct role for NPCs in remyelination, identifying them as a key target for enhancing myelin repair in demyelinating diseases. The Journal of Neuroscience, October 15, 2014 • 34(42):14128 –14146 SYSTEMS/CIRCUITS Stimulus-Related Neuroimaging in Task-Engaged Subjects Is Best Predicted by Concurrent Spiking X Bruss Lima,1,2 Mariana M.B. Cardoso,1,3 Yevgeniy B. Sirotin,4 and X Aniruddha Das1 Department of Neuroscience, Columbia University, New York, New York 10032, 2The Italian Academy for Advanced Studies in America, Columbia University, New York, New York 10027, 3Champalimaud Neuroscience Programme, Champalimaud Foundation, 1400-038 Lisboa, Portugal, and 4Rockefeller University, New York, New York 10065 1 The implicit goal of functional magnetic resonance imaging is to infer local neural activity. There is considerable debate, however, as to whether imaging correlates most linearly with local spiking or some local field potential (LFP) measurement. Through simultaneous neuroimaging (intrinsic-signal optical imaging) and electrode recordings from alert, task-engaged macaque monkeys, we showed previously that local electrophysiology correlates with only a specific stimulus-related imaging component. Here we show that this stimulus-related component— obtained by subtracting a substantial task-related component—is particularly linear with local spiking over a comprehensive range of response strengths. Matches to concurrent LFP measurements are, to varying degrees, poorer. As a control, we also tried matching the full imaging signal to local electrophysiology without subtracting task-related components. These control matches were consistently worse; they were, however, slightly better for gamma LFP than spiking, potentially resolving discrepancies between our findings and earlier reports favoring LFP. The Journal of Neuroscience, October 15, 2014 • 34(42):13878 –13891 Dynamic Modulation of Amygdala–Hippocampal Connectivity by Emotional Arousal Matthias Fastenrath,1,2 David Coynel,1,2 Klara Spalek,1,2 X Annette Milnik,2,4 Leo Gschwind,1,2 Benno Roozendaal,3 Andreas Papassotiropoulos,2,4,5,6 and Dominique J.F. de Quervain1,4,6 Division of Cognitive Neuroscience, Department of Psychology, University of Basel, 4055 Basel, Switzerland, 2Division of Molecular Neuroscience, Department of Psychology, University of Basel, 4055 Basel, Switzerland, 3Radboud University Nijmegen, Department of Cognitive Neuroscience and Donders Institute for Brain, Cognition and Behaviour, 6525 EZ Nijmegen, The Netherlands, 4Psychiatric University Clinics, University of Basel, 4012 Basel, Switzerland, 5Department Biozentrum, Life Sciences Training Facility, University of Basel, 4056 Basel, Switzerland, and 6Transfaculty Research Platform, University of Basel, 4055 Basel, Switzerland 1 Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence. The Journal of Neuroscience, October 15, 2014 • 34(42):13935–13947 Presynaptic T-Type Ca2⫹ Channels Modulate Dendrodendritic Mitral–Mitral and Mitral–Periglomerular Connections in Mouse Olfactory Bulb Adam Fekete,1,2 Jamie Johnston,1,3 and Kerry R. Delaney1 Department of Biology, University of Victoria, Victoria, British Columbia, V8W 2Y2, Canada, 2Program in Neurosciences and Mental Health, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada, and 3Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom 1 Mitral cells express low-voltage activated Cav3.3 channels on their distal apical tuft dendrites (McKay et al., 2006; Johnston and Delaney, 2010). They also discharge Na ⫹-dependent dendritic action potentials and release glutamate from these dendrites. Around resting membrane potentials, between ⫺65 and ⫺50 mV, Cav3.x channels are a primary determinant of cytoplasmic [Ca 2⫹]. In this study using C57 mice, we present evidence that subthreshold Cav3.x-mediated Ca 2⫹ influx modulates action potential evoked transmitter release and directly drives asynchronous release from distal tuft dendrites. Presynaptic hyperpolarization and selective block of Cav3.x channels with Z941 (Tringham et al., 2012) reduce mitral-to-mitral EPSP amplitude, increase the coefficient of variation of EPSPs, and increase paired-pulse ratios, consistent with a reduced probability of transmitter release. Both hyperpolarization and Cav3.x channel blockade reduce steady-state cytoplasmic [Ca 2⫹] in the tuft dendrite without reducing action potential evoked Ca 2⫹ influx, suggesting that background [Ca 2⫹] modulates evoked release. We demonstrate that Cav3.x-mediated Ca 2⫹ influx from even one mitral cell at membrane potentials between ⫺65 and ⫺50 mV is sufficient to produce feedback inhibition from periglomerular neurons. Deinactivation of Cav3.x channels by hyperpolarization increases T-type Ca 2⫹ influx upon repolarization and increases feedback inhibition to produce subthreshold modulation of the mitral–periglomerular reciprocal circuit. The Journal of Neuroscience, October 15, 2014 • 34(42):14032–14045 Systematic Shifts in the Balance of Excitation and Inhibition Coordinate the Activity of Axial Motor Pools at Different Speeds of Locomotion Sandeep Kishore, Martha W. Bagnall, and David L. McLean Department of Neurobiology, Northwestern University, Evanston, Illinois 60625 An emerging consensus from studies of axial and limb networks is that different premotor populations are required for different speeds of locomotion. An important but unresolved issue is why this occurs. Here, we perform voltage-clamp recordings from axial motoneurons in larval zebrafish during “fictive” swimming to test the idea that systematic differences in the biophysical properties of axial motoneurons are associated with differential tuning in the weight and timing of synaptic drive, which would help explain premotor population shifts. We find that increases in swimming speed are accompanied by increases in excitation preferentially to lower input resistance (Rin) motoneurons, whereas inhibition uniformly increases with speed to all motoneurons regardless of Rin. Additionally, while the timing of rhythmic excitatory drive sharpens within the pool as speed increases, there are shifts in the dominant source of inhibition related to Rin. At slow speeds, anti-phase inhibition is larger throughout the pool. However, as swimming speeds up, inhibition arriving in-phase with local motor activity increases, particularly in higher Rin motoneurons. Thus, in addition to systematic differences in the weight and timing of excitation related to Rin and speed, there are also speed-dependent shifts in the balance of different sources of inhibition, which is most obvious in more excitable motor pools. We conclude that synaptic drive is differentially tuned to the biophysical properties of motoneurons and argue that differences in premotor circuits exist to simplify the coordination of activity within spinal motor pools during changes in locomotor speed. The Journal of Neuroscience, October 15, 2014 • 34(42):14046 –14054 BEHAVIORAL/COGNITIVE Temporal Memory Is Shaped by Encoding Stability and Intervening Item Reactivation Sarah DuBrow1 and Lila Davachi1,2 1 Department of Psychology and 2Center for Neural Science, New York University, New York, New York 10003 Making sense of previous experience requires remembering the order in which events unfolded in time. Prior work has implicated the hippocampus and medial temporal lobe cortex in memory for temporal information associated with individual episodes. However, the processes involved in encoding and retrieving temporal information across extended sequences is relatively poorly understood. Here we used fMRI during the encoding and retrieval of extended sequences to test specific predictions about the type of information used to resolve temporal order and the role of the hippocampus in this process. Participants studied sequences of images of celebrity faces and common objects followed by a recency discrimination test. The main conditions of interest were pairs of items that had been presented with three intervening items, half of which included an intervening category shift. During encoding, hippocampal pattern similarity across intervening items was associated with subsequent successful order memory. To test for evidence of associative retrieval, we trained a classifier to discriminate encoding patterns associated with faces versus objects and applied the classifier on fMRI patterns during recency discrimination. We found evidence that the category content of intervening items was reactivated during recency judgments, and this was related to hippocampal encoding-retrieval similarity. A follow-up behavioral priming experiment revealed additional evidence for intervening item reinstatement during temporal order judgments. Reinstatement did not differ according to whether the items occurred within a single context or across context boundaries. Thus, these data suggest that inter-item associative encoding and retrieval mediated by the hippocampus contribute to temporal order memory. The Journal of Neuroscience, October 15, 2014 • 34(42):13998 –14005 Large-Scale Brain Network Dynamics Supporting Adolescent Cognitive Control Dominic B. Dwyer,1 Ben J. Harrison,1 Murat Yu¨cel,1,2 Sarah Whittle,1,4 Andrew Zalesky,1,3 Christos Pantelis,1 Nicholas B. Allen,4,5 and Alex Fornito1,2 Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia 3053, 2Monash Clinical and Imaging Neuroscience, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia 3168, and 3Melbourne School of Engineering, The University of Melbourne, Victoria, Australia 3010, 4Melbourne School of Psychological Sciences, The University of Melbourne, Victoria, Australia 3010, and 5Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne, Victoria, Australia 3010 1 Adolescence is a time when the ability to engage cognitive control is linked to crucial life outcomes. Despite a historical focus on prefrontal cortex functioning, recent evidence suggests that differences between individuals may relate to interactions between distributed brain regions that collectively form a cognitive control network (CCN). Other research points to a spatially distinct and functionally antagonistic system—the default-mode network (DMN)—which typically deactivates during performance of control tasks. This literature implies that individual differences in cognitive control are determined either by activation or functional connectivity of CCN regions, deactivation or functional connectivity of DMN regions, or some combination of both. We tested between these possibilities using a multilevel fMRI characterization of CCN and DMN dynamics, measured during performance of a cognitive control task and during a task-free resting state, in 73 human adolescents. Better cognitive control performance was associated with (1) reduced activation of CCN regions, but not deactivation of the DMN; (2) variations in task-related, but not resting-state, functional connectivity within a distributed network involving both the CCN and DMN; (3) functional segregation of core elements of these two systems; and (4) task-dependent functional integration of a set of peripheral nodes into either one network or the other in response to prevailing stimulus conditions. These results indicate that individual differences in adolescent cognitive control are not solely attributable to the functioning of any single region or network, but are instead dependent on a dynamic and context-dependent interplay between the CCN and DMN. The Journal of Neuroscience, October 15, 2014 • 34(42):14096 –14107 Manipulating a “Cocaine Engram” in Mice Hwa-Lin (Liz) Hsiang,1,2,3 Jonathan R. Epp,1,2,3 Michel C. van den Oever,1,2,3 Chen Yan,1,2,3 Asim J. Rashid,1,2,3 Nathan Insel,1,2,3 Li Ye,4 Yosuke Niibori,1,2,3 Karl Deisseroth,4 Paul W. Frankland,1,2,3 and Sheena A. Josselyn1,2,3 Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada, 2Institute of Medical Sciences, and 3Department of Psychology, Physiology, University of Toronto, Toronto, ON, M5G 1X8, Canada, and 4Department of Bioengineering and Psychiatry, Stanford University, Stanford, California 94305 1 Experience with drugs of abuse (such as cocaine) produces powerful, long-lasting memories that may be important in the development and persistence of drug addiction. The neural mechanisms that mediate how and where these cocaine memories are encoded, consolidated and stored are unknown. Here we used conditioned place preference in mice to examine the precise neural circuits that support the memory of a cocaine-cue association (the “cocaine memory trace” or “cocaine engram”). We found that a small population of neurons (⬃10%) in the lateral nucleus of amygdala (LA) were recruited at the time of cocaine-conditioning to become part of this cocaine engram. Neurons with increased levels of the transcription factor CREB were preferentially recruited or allocated to the cocaine engram. Ablating or silencing neurons overexpressing CREB (but not a similar number of random LA neurons) before testing disrupted the expression of a previously acquired cocaine memory, suggesting that neurons overexpressing CREB become a critical hub in what is likely a larger cocaine memory engram. Consistent with theories that coordinated postencoding reactivation of neurons within an engram or cell assembly is crucial for memory consolidation (Marr, 1971; Buzsa´ki, 1989; Wilson and McNaughton, 1994; McClelland et al., 1995; Girardeau et al., 2009; Dupret et al., 2010; Carr et al., 2011), we also found that post-training suppression, or nondiscriminate activation, of CREB overexpressing neurons impaired consolidation of the cocaine memory. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. The Journal of Neuroscience, October 15, 2014 • 34(42):14115–14127 Neurons in the Nucleus Accumbens Promote Selection Bias for Nearer Objects Sara E. Morrison1 and Saleem M. Nicola1,2 1Department of Psychiatry and Behavioral Science and 2Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461 Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level. The Journal of Neuroscience, October 15, 2014 • 34(42):14147–14162 NEUROBIOLOGY OF DISEASE Impact of RTN3 Deficiency on Expression of BACE1 and Amyloid Deposition Qi Shi,1* Yingying Ge,1* X Md. Golam Sharoar,1 Wanxia He,1 Rong Xiang,2 Zhuohua Zhang,2 Xiangyou Hu,1 and Riqiang Yan1 Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and 2Department of Cell Biology, School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, 410083 Changsha, People’s Republic of China 1 Reticulon 3 (RTN3) has previously been shown to interact with BACE1 and negatively regulate BACE1 activity. To what extent RTN3 deficiency affects BACE1 activity is an intriguing question. In this study, we aimed to address this by generating RTN3-null mice. Mice with complete deficiency of RTN3 grow normally and have no obviously discernible phenotypes. Morphological analyses of RTN3-null mice showed no significant alterations in cellular structure, although RTN3 is recognized as a protein contributing to the shaping of tubular endoplasmic reticulum. Biochemical analysis revealed that RTN3 deficiency increased protein levels of BACE1. This elevation of BACE1 levels correlated with enhanced processing of amyloid precursor protein at the -secretase site. We also demonstrated that RTN3 deficiency in Alzheimer’s mouse models facilitates amyloid deposition, further supporting an in vivo role of RTN3 in the regulation of BACE1 activity. Since it has been shown that RTN3 monomer is reduced in brains of Alzheimer’s patients, our results suggest that long-lasting reduction of RTN3 levels has adverse effects on BACE1 activity and may contribute to Alzheimer’s pathogenesis. The Journal of Neuroscience, October 15, 2014 • 34(42):13954 –13962 Resting-State Functional Connectivity Changes in Aging apoE4 and apoE-KO Mice Valerio Zerbi,1,2 Maximilian Wiesmann,1,3 Tim L. Emmerzaal,1 Diane Jansen,1 Maarten Van Beek,1 X Martina P.C. Mutsaers,1 Christian F. Beckmann,4,5 Arend Heerschap,2 and Amanda J. Kiliaan1 Departments of 1Anatomy, Donders Institute for Brain Cognition and Behaviour, 2Radiology, 3Geriatric Medicine, and 4Donders Centre for Cognitive Neuroimaging, Radboud university medical center, 6525 EZ Nijmegen, The Netherlands, and 5MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands It is well established that the cholesterol-transporter apolipoprotein (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of 4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock-out (KO) mice at 12 (adult) and 18 months of age. Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research. The Journal of Neuroscience, October 15, 2014 • 34(42):13963–13975 Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice Johanna Knoferle,1,2 Seo Yeon Yoon,1 X David Walker,1 Laura Leung,1,2 Anna K. Gillespie,1,3 Leslie M. Tong,1,3 Nga Bien-Ly,1,2 and Yadong Huang1,2,3,4,5 Gladstone Institute of Neurological Disease, San Francisco, California 94158, 2Department of Neurology and 3Biomedical Science Program, University of California, San Francisco, California 94143, 4Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, and 5Department of Pathology, University of California, San Francisco, California 94143 1 Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4. The Journal of Neuroscience, October 15, 2014 • 34(42):14069 –14078 SLC30A10 Is a Cell Surface-Localized Manganese Efflux Transporter, and ParkinsonismCausing Mutations Block Its Intracellular Trafficking and Efflux Activity Dinorah Leyva-Illades,1* Pan Chen,2* Charles E. Zogzas,1 Steven Hutchens,1 X Jonathan M. Mercado,1 X Caleb D. Swaim,1 Richard A. Morrisett,1 Aaron B. Bowman,3 Michael Aschner,2 and Somshuvra Mukhopadhyay1 Division of Pharmacology and Toxicology, College of Pharmacy, Institutes for Cellular and Molecular Biology and for Neuroscience, University of Texas at Austin, Austin, Texas 78701, 2Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and 3Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8552 1 Manganese (Mn) is an essential metal, but elevated cellular levels are toxic and may lead to the development of an irreversible parkinsonian-like syndrome that has no treatment. Mn-induced parkinsonism generally occurs as a result of exposure to elevated Mn levels in occupational or environmental settings. Additionally, patients with compromised liver function attributable to diseases, such as cirrhosis, fail to excrete Mn and may develop Mn-induced parkinsonism in the absence of exposure to elevated Mn. Recently, a new form of familial parkinsonism was reported to occur as a result of mutations in SLC30A10. The cellular function of SLC30A10 and the mechanisms by which mutations in this protein cause parkinsonism are unclear. Here, using a combination of mechanistic and functional studies in cell culture, Caenorhabditis elegans, and primary midbrain neurons, we show that SLC30A10 is a cell surface-localized Mn efflux transporter that reduces cellular Mn levels and protects against Mn-induced toxicity. Importantly, mutations in SLC30A10 that cause familial parkinsonism blocked the ability of the transporter to traffic to the cell surface and to mediate Mn efflux. Although expression of disease-causing SLC30A10 mutations were not deleterious by themselves, neurons and worms expressing these mutants exhibited enhanced sensitivity to Mn toxicity. Our results provide novel insights into the mechanisms involved in the onset of a familial form of parkinsonism and highlight the possibility of using enhanced Mn efflux as a therapeutic strategy for the potential management of Mn-induced parkinsonism, including that occurring as a result of mutations in SLC30A10. The Journal of Neuroscience, October 15, 2014 • 34(42):14079 –14095
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