Hot off the presses! May 26 Neuron

The May 26 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Global Challenges in Stem Cell Research and the Many Roads Ahead
  - Neuron 70(4):573-576 (2011)
  The field of stem cell research has grown to include a vibrant international community of scientists and clinicians who come from both academia and industry and who strive to shed light on the biology of these remarkable cells and find applications in drug discovery, disease modeling, and regenerative medicine.
• Responsibility Rewarded: Ethics, Engagement, and Scientific Autonomy in the Labyrinth of the Minotaur
  - Neuron 70(4):577-581 (2011)
  Dramatic changes in the stem cell ethical and research ecosystem in the last 10 years depended on active engagement among scientists, ethicists, government, and public. Tracing that story demonstrates the value of such engagement, and forecasts a successful method for meeting future challenges.
• Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb
  - Neuron 70(4):582-588 (2011)
  While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron.
• Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation
  - Neuron 70(4):589-596 (2011)
  Recently, investigation of new neurons in memory formation has focused on a specific function—pattern separation. However, it has been difficult to reconcile the form of separation tested in behavioral tasks with how it is conceptualized according to computational and electrophysiology perspectives. Here, we propose a memory resolution hypothesis that considers the unique information contributions of broadly tuned young neurons and highly specific mature neurons and describe how the fidelity of memories can relate to spatial and contextual discrimination. See the related Perspective from Sahay, Wilson, and Hen, "Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb," in this issue of Neuron.
• Translating Stem Cell Studies to the Clinic for CNS Repair: Current State of the Art and the Need for a Rosetta Stone
  - Neuron 70(4):597-613 (2011)
  Since their discovery twenty years ago and prospective isolation a decade later, neural stem cells (NSCs), their progenitors, and differentiated cell derivatives along with other stem-cell based strategies have advanced steadily toward clinical trials, spurred by the immense need to find reparative therapeutics for central nervous system (CNS) diseases and injury. Current phase I/II trials using stem cells in the CNS are the vanguard for the widely anticipated next generation of regenerative therapies and as such are pioneering the stem cell therapy process. While translation has typically been the purview of industry, academic researchers are increasingly driven to bring their findings toward treatments and face challenges in knowledge gap and resource access that are accentuated by the unique financial, manufacturing, scientific, and regulatory aspects of cell therapy. Solutions are envisioned that both address the significant unmet medical need and lead to increased! funding for basic and translational research.
• Neural Stem Cells: Historical Perspective and Future Prospects
  - Neuron 70(4):614-625 (2011)
  How a single fertilized cell generates diverse neuronal populations has been a fundamental biological problem since the 19th century. Classical histological methods revealed that postmitotic neurons are produced in a precise temporal and spatial order from germinal cells lining the cerebral ventricles. In the 20th century, DNA labeling and histo- and immunohistochemistry helped to distinguish the subtypes of dividing cells and delineate their locations in the ventricular and subventricular zones. Recently, genetic and cell biological methods have provided insights into sequential gene expression and molecular and cellular interactions that generate heterogeneous populations of NSCs leading to specific neuronal classes. This precisely regulated developmental process does not tolerate significant in vivo deviation, making replacement of adult neurons by NSCs during pathology a colossal challenge. In contrast, utilizing the trophic factors emanating from the NSC or their ! derivatives to slow down deterioration or prevent death of degenerating neurons may be a more feasible strategy.
• Constructing and Deconstructing Stem Cell Models of Neurological Disease
  - Neuron 70(4):626-644 (2011)
  Among the disciplines of medicine, the study of neurological disorders is particularly challenging. The fundamental inaccessibility of the human neural types affected by disease prevents their isolation for in vitro studies of degenerative mechanisms or for drug screening efforts. However, the ability to reprogram readily accessible tissue from patients into pluripotent stem (iPS) cells may now provide a general solution to this shortage of human neurons. Gradually improving methods for directing the differentiation of patient-specific stem cells has enabled the production of several neural cell types affected by disease. Furthermore, initial studies with stem cell lines derived from individuals with pediatric, monogenic disorders have validated the stem cell approach to disease modeling, allowing relevant neural phenotypes to be observed and studied. Whether iPS cell-derived neurons will always faithfully recapitulate the same degenerative processes observed in patien! ts and serve as platforms for drug discovery relevant to common late-onset diseases remains to be determined.
• Deriving Excitatory Neurons of the Neocortex from Pluripotent Stem Cells
  - Neuron 70(4):645-660 (2011)
  The human cerebral cortex is an immensely complex structure that subserves critical functions that can be disrupted in developmental and degenerative disorders. Recent innovations in cellular reprogramming and differentiation techniques have provided new ways to study the cellular components of the cerebral cortex. Here, we discuss approaches to generate specific subtypes of excitatory cortical neurons from pluripotent stem cells. We review spatial and temporal aspects of cortical neuron specification that can guide efforts to produce excitatory neuron subtypes with increased resolution. Finally, we discuss distinguishing features of human cortical development and their translational ramifications for cortical stem cell technologies.
• NG2-glia as Multipotent Neural Stem Cells: Fact or Fantasy?
  - Neuron 70(4):661-673 (2011)
  Cycling glial precursors—"NG2-glia"—are abundant in the developing and mature central nervous system (CNS). During development, they generate oligodendrocytes. In culture, they can revert to a multipotent state, suggesting that they might have latent stem cell potential that could be harnessed to treat neurodegenerative disease. This hope has been subdued recently by a series of fate-mapping studies that cast NG2-glia as dedicated oligodendrocyte precursors in the healthy adult CNS—though rare, neuron production in the piriform cortex remains a possibility. Following CNS damage, the repertoire of NG2-glia expands to include Schwann cells and possibly astrocytes—but so far not neurons. This reaffirms the central role of NG2-glia in myelin repair. The realization that oligodendrocyte generation continues throughout normal adulthood has seeded the idea that myelin genesis might also be involved in neural plasticity. We review these developments, highlighting a! reas of current interest, contention, and speculation.
• Lake-Front Property: A Unique Germinal Niche by the Lateral Ventricles of the Adult Brain
  - Neuron 70(4):674-686 (2011)
  New neurons and glial cells are generated in an extensive germinal niche adjacent to the walls of the lateral ventricles in the adult brain. The primary progenitors (B1 cells) have astroglial characteristics but retain important neuroepithelial properties. Recent work shows how B1 cells contact all major compartments of this niche. They share the "shoreline" on the ventricles with ependymal cells, forming a unique adult ventricular zone (VZ). In the subventricular zone (SVZ), B1 cells contact transit amplifying (type C) cells, chains of young neurons (A cells), and blood vessels. How signals from these compartments influence the behavior of B1 or C cells remains largely unknown, but recent work highlights growth factors, neurotransmitters, morphogens, and the extracellular matrix as key regulators of this niche. The integration of emerging molecular and anatomical clues forecasts an exciting new understanding of how the germ of youth is actively maintained in the a! dult brain.
• Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions
  - Neuron 70(4):687-702 (2011)
  Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms, and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field ! is poised to leap forward in the next decade.
• Integrating Physiological Regulation with Stem Cell and Tissue Homeostasis
  - Neuron 70(4):703-718 (2011)
  Stem cells are uniquely able to self-renew, to undergo multilineage differentiation, and to persist throughout life in a number of tissues. Stem cells are regulated by a combination of shared and tissue-specific mechanisms and are distinguished from restricted progenitors by differences in transcriptional and epigenetic regulation. Emerging evidence suggests that other aspects of cellular physiology, including mitosis, signal transduction, and metabolic regulation, also differ between stem cells and their progeny. These differences may allow stem cells to be regulated independently of differentiated cells in response to circadian rhythms, changes in metabolism, diet, exercise, mating, aging, infection, and disease. This allows stem cells to sustain homeostasis or to remodel relevant tissues in response to physiological change. Stem cells are therefore not only regulated by short-range signals that maintain homeostasis within their tissue of origin, but also by long-ran! ge signals that integrate stem cell function with systemic physiology.
• Neural Stem Cell Biology in Vertebrates and Invertebrates: More Alike than Different?
  - Neuron 70(4):719-729 (2011)
  Many of the regulatory mechanisms controlling neural stem cell behavior are proving to be conserved between organisms as diverse as worms and man. Common principles are emerging with respect to the regulation of neural stem cell division and the specification of distinct stem and progenitor cell types. Great progress has been made in recent years in identifying the cellular mechanisms underpinning these processes, thanks in large part to the cross-fertilization of research on different model systems. We review here recent findings that highlight hitherto unappreciated similarities in the cell and molecular biology of neural stem cell self-renewal and differentiation between invertebrates and vertebrates. As well as underscoring the possible conservation of stem cell mechanisms across phyla, these similarities are proving to be practically useful in studying neural stem cell biology in health and disease.
• Distributed Coding of Actual and Hypothetical Outcomes in the Orbital and Dorsolateral Prefrontal Cortex
  - Neuron 70(4):731-741 (2011)
  Knowledge about hypothetical outcomes from unchosen actions is beneficial only when such outcomes can be correctly attributed to specific actions. Here we show that during a simulated rock-paper-scissors game, rhesus monkeys can adjust their choice behaviors according to both actual and hypothetical outcomes from their chosen and unchosen actions, respectively. In addition, neurons in both dorsolateral prefrontal cortex and orbitofrontal cortex encoded the signals related to actual and hypothetical outcomes immediately after they were revealed to the animal. Moreover, compared to the neurons in the orbitofrontal cortex, those in the dorsolateral prefrontal cortex were more likely to change their activity according to the hypothetical outcomes from specific actions. Conjunctive and parallel coding of multiple actions and their outcomes in the prefrontal cortex might enhance the efficiency of reinforcement learning and also contribute to their context-dependent memory.
• CYY-1/Cyclin Y and CDK-5 Differentially Regulate Synapse Elimination and Formation for Rewiring Neural Circuits
  - Neuron 70(4):742-757 (2011)
  The assembly and maturation of neural circuits require a delicate balance between synapse formation and elimination. The cellular and molecular mechanisms that coordinate synaptogenesis and synapse elimination are poorly understood. In C. elegans, DD motoneurons respecify their synaptic connectivity during development by completely eliminating existing synapses and forming new synapses without changing cell morphology. Using loss- and gain-of-function genetic approaches, we demonstrate that CYY-1, a cyclin box-containing protein, drives synapse removal in this process. In addition, cyclin-dependent kinase-5 (CDK-5) facilitates new synapse formation by regulating the transport of synaptic vesicles to the sites of synaptogenesis. Furthermore, we show that coordinated activation of UNC-104/Kinesin3 and Dynein is required for patterning newly formed synapses. During the remodeling process, presynaptic components from eliminated synapses are recycled to new synapses, sugges! ting that signaling mechanisms and molecular motors link the deconstruction of existing synapses and the assembly of new synapses during structural synaptic plasticity.
• Nonapoptotic Function of BAD and BAX in Long-Term Depression of Synaptic Transmission
  - Neuron 70(4):758-772 (2011)
  It has recently been found that caspases not only function in apoptosis, but are also crucial for nonapoptotic processes such as NMDA receptor-dependent long-term depression (LTD) of synaptic transmission. It remains unknown, however, how caspases are activated and how neurons escape death in LTD. Here we show that caspase-3 is activated by the BAD-BAX cascade for LTD induction. This cascade is required specifically for NMDA receptor-dependent LTD but not for mGluR-LTD, and its activation is sufficient to induce synaptic depression. In contrast to apoptosis, however, BAD is activated only moderately and transiently and BAX is not translocated to mitochondria, resulting in only modest caspase-3 activation. We further demonstrate that the intensity and duration of caspase-3 activation determine whether it leads to cell death or LTD, thus fine-tuning of caspase-3 activation is critical in distinguishing between these two pathways.
• Microcircuits of Functionally Identified Neurons in the Rat Medial Entorhinal Cortex
  - Neuron 70(4):773-786 (2011)
  Extracellular recordings have elucidated spatial neural representations without identifying underlying microcircuits. We labeled neurons juxtacellularly in medial entorhinal cortex of freely moving rats with a friction-based, pipette-stabilization system. In a linear maze novel to the animals, spatial firing of superficial layer neurons was reminiscent of grid cell activity. Layer 2 stellate cells showed stronger theta modulation than layer 3 neurons, and both fired during the ascending phase of field potential theta. Deep-layer neurons showed little or no activity. Layer 2 stellate cells resided in hundreds of small patches. At the dorsomedial entorhinal border, we identified larger (putative parasubicular) patches, which contained polarized head-direction selective neurons firing during the descending theta phase. Three axon systems interconnected patches: centrifugal axons from superficial cells to single large patches, centripetal axons from large-patch cells to si! ngle small patches, and circumcurrent axons interconnecting large patches. Our microcircuit analysis during behavior reveals modularity of entorhinal processing. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (16704 K)
• Rethinking Motor Learning and Savings in Adaptation Paradigms: Model-Free Memory for Successful Actions Combines with Internal Models
  - Neuron 70(4):787-801 (2011)
  Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process: adaptation, which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning), and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually "hidden" behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task. (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases toward the repeated movement. (3) Operant ! reinforcement through association of the adapted movement with successful error reduction is responsible for savings.