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Volume 19 Issue 3, March 2016

Theory and experiment have long traveled in lockstep in the physical sciences. This balance has been firmly tilted towards experiment in biology, including neuroscience. More complete biological understanding, and better experimental design, must rest on a foundation of neural theory. Without this, it might truly be turtles all the way down. Artwork by Lewis Long.347–413


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  • Theoretical approaches have long shaped neuroscience, but current needs for theory are elevated and prospects for advancement are bright. Advances in measuring and manipulating neurons demand new models and analyses to guide interpretation. Advances in theoretical neuroscience offer new insights into how signals evolve across areas and new approaches for connecting population activity with behavior. These advances point to a global understanding of brain function based on a hybrid of diverse approaches.

    • Anne K Churchland
    • L F Abbott
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Review Article

  • Despite representing a minority of cortical cells, inhibitory neurons deeply shape cortical responses. Inhibitory currents closely track excitatory currents, opening only brief windows of opportunity for a neuron to fire. This explains the variability of cortical spike trains, but may also, paradoxically, render a spiking network maximally efficient and precise.

    • Sophie Denève
    • Christian K Machens
    Review Article
  • The state of the nervous system shifts constantly. Most studies focus on how state determines the average neural response, with little attention to the trial-to-trial fluctuations of brain activity. We review recent theoretical advances in modeling the physiological mechanisms responsible for state-dependent modulations in the correlated fluctuations of neuronal populations.

    • Brent Doiron
    • Ashok Litwin-Kumar
    • Krešimir Josić
    Review Article
  • What are the challenges associated with storing information over time in the brain? Here the authors explore the computational principles by which biological memory might be built. They develop a high-level view of shared problems and themes in short- and long-term memory and highlight questions for future research.

    • Rishidev Chaudhuri
    • Ila Fiete
    Review Article
  • The complexity of problems and data in psychiatry requires powerful computational approaches. Computational psychiatry is an emerging field encompassing mechanistic theory-driven models and theoretically agnostic data-driven analyses that use machine-learning techniques. Clinical applications will benefit from relating theoretically meaningful process variables to complex psychiatric outcomes through data-driven techniques.

    • Quentin J M Huys
    • Tiago V Maia
    • Michael J Frank
    Review Article
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News & Views

  • A clinical trial inspired and guided by optogenetics experiments in rodents reports the outcome of targeted transcranial magnetic stimulation in patients suffering from cocaine addiction.

    • Emily Ferenczi
    • Karl Deisseroth
    News & Views
  • Depression of AMPA receptor–mediated synaptic currents and impairment of long-term potentiation, triggered by amyloid-β, are the hallmarks of Alzheimer's pathophysiology. These dysfunctions are now linked to upregulated PDZ domain–dependent PTEN translocation to spines, contributing to cognitive deficits in model mice.

    • Samuel Frere
    • Inna Slutsky
    News & Views
  • In this issue of Nature Neuroscience, Eshel et al. characterize the homogeneity with which individual dopamine neurons encode reward prediction error, a teaching signal that is thought to be crucial for associative learning.

    • Nathan F Parker
    • Ilana B Witten
    News & Views
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  • The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

    • Barbara Franke
    • Jason L Stein
    • Patrick F Sullivan
  • The loss of nerve cells in the brain is the main event causing life-long deficits and neurological problems after stroke. Weilinger et al. show that NMDA receptors cause nerve cell death during stroke in an unexpected way. Although they require ligand binding and recruitment of downstream pannexin channels, NMDA receptors do not use the receptor's ion channel.

    • Nicholas L Weilinger
    • Alexander W Lohman
    • Roger J Thompson
  • In this study, the authors show that PTEN alters synaptic function after PDZ-dependent recruitment into spines induced by amyloid-β. This mechanism is crucial for pathogenesis, as preventing PTEN-PDZ interactions renders neurons resistant to amyloid-β and rescues cognitive function in Alzheimer's disease models. This suggests that PTEN is a critical effector of the synaptic pathology associated with Alzheimer's disease.

    • Shira Knafo
    • Cristina Sánchez-Puelles
    • José A Esteban
  • This study shows that learning-induced plasticity of local parvalbumin (PV) basket cells is specifically required for long-term, but not short to intermediate-term, memory consolidation in mice. PV plasticity depends on local D1/5 dopamine receptor signaling 12–14 h after acquisition for its continuance, ensuring enhanced sharp-wave ripple densities and memory consolidation.

    • Smitha Karunakaran
    • Ananya Chowdhury
    • Pico Caroni
  • Unlike artificial sweeteners, sugar promotes ingestive behavior via both gustatory and post-ingestive pathways. Tellez et al. find that separate basal ganglia circuits mediate the hedonic and nutritional actions of sugar. They demonstrate that sugar recruits a dedicated striatofugal pathway that acts to prioritize calorie-seeking over taste quality.

    • Luis A Tellez
    • Wenfei Han
    • Ivan E de Araujo
  • The role of subcortical acetylcholine in decision-making under uncertainty is ill-defined. By combining genetic tools, computational modeling and a new multi-armed bandit task for mice, the authors show that nicotinic acetylcholine receptors expressed in the ventral tegmental area drive the motivation to seek reward uncertainty.

    • Jérémie Naudé
    • Stefania Tolu
    • Philippe Faure
  • Dopamine neurons in the ventral tegmental area are thought to signal reward prediction error. The authors show that these neurons respond with striking homogeneity during classical conditioning. All dopamine neurons appear to calculate reward prediction error similarly, enabling robust and consistent broadcasting of this signal throughout the brain.

    • Neir Eshel
    • Ju Tian
    • Naoshige Uchida
  • Wallach et al. use closed-loop artificial whisking in anesthetized rats to show that vibrissal mechanoreceptors extract phase information from on-going whisker kinematics in a frequency- and amplitude-invariant manner. Brainstem paralemniscal neurons preserve this phase information while filtering out information about whisker offset; lemniscal neurons preserve both types of information.

    • Avner Wallach
    • Knarik Bagdasarian
    • Ehud Ahissar
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  • Gene-regulatory elements are drivers of evolutionary divergence, yet where these are located and which are evolutionarily relevant is unclear. In this work, large-scale epigenomic analysis of human, rhesus and chimpanzee brain tissue allowed the identification of human-specific gene-regulatory changes that contributed to the emergence of the human brain.

    • Marit W Vermunt
    • Sander C Tan
    • Menno P Creyghton
  • Heterogeneity within distinct cell populations resident in the central nervous system is increasingly recognized as important for functional diversity, plasticity and sensitivity to neurological disease. The authors demonstrate genome-wide diversity of microglia dependent on brain localization in the young adult and show that aging of microglia occurs in a regionally variable manner.

    • Kathleen Grabert
    • Tom Michoel
    • Barry W McColl
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Technical Report

  • Recurrent, reciprocal genomic disorders due to non-allelic homologous recombination (NAHR) are a major cause of human disease. The authors developed a CRISPR/Cas9 genome engineering method that directly targets segmental duplications and efficiently mimics the NAHR-mediated mechanism of microdeletion and microduplication that occurs in vivo using 16p11.2 and 15q13.3 as proof-of-principle models.

    • Derek J C Tai
    • Ashok Ragavendran
    • Michael E Talkowski
    Technical Report
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