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Volume 19 Issue 1, January 2016

DNA methylation regulates gene expression and orchestrates tissue differentiation and development as well as guides functional activity in adulthood. Jaffe et al. and Hannon et al. show that early developmental methylation QTLs are enriched in genomic regions associated with schizophrenia risk. The cover depicts mQTLs across the genome associated with developmental time periods of the human brain. Cover design is a mixed-media collage by Helen Spiers.14048

News & Views

  • Conclusive evidence for defective neurodevelopment in schizophrenia is lacking. Two DNA methylation studies now draw a link between fetal brain epigenomes, epigenetic alterations in the adult diseased brain and genetic risk for the disease.

    • Andrew J Sharp
    • Schahram Akbarian
    News & Views


  • Two studies invite us to reconsider the nature of striatal dopamine signals. Accumbens dopamine appears to signal the value of overt action and prediction errors arise from deviations in these signals.

    • Anne G E Collins
    • Michael J Frank
    News & Views
  • A working memory representation goes missing in monkey parietal cortex during categorization learning, but is still found in the prefrontal cortex.

    • Daniel Birman
    • Justin L Gardner
    News & Views
  • Predicting an individual's behavior is a formidable challenge for neuroimaging. A study now finds a strong link between an individual's ability to sustain attention and an extended, but specific, set of brain connections.

    • Stephen Smith
    News & Views
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Review Article

  • Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks and disruption of chromatin structure. In this Review, the authors describe the convergence of genetic, metabolic and microenvironmental factors on mechanisms of epigenetic deregulation in brain cancer.

    • Stephen C Mack
    • Christopher G Hubert
    • Jeremy N Rich
    Review Article
  • Tumor-associated macrophages (TAMs) establish a permissive microenvironment that positively influences glioma formation, progression and response to treatment. TAMs elaborate growth factors and cytokines that collectively facilitate tumor proliferation, survival and migration. Defining the distinct roles of these stromal cells in the glioma ecosystem may yield new opportunities for therapeutic targeting.

    • Dolores Hambardzumyan
    • David H Gutmann
    • Helmut Kettenmann
    Review Article
  • Reactive astrocytes have been proposed to become incompetent bystanders in epilepsy as a result of cellular changes rendering them incapable of performing housekeeping tasks. This review discusses new research that suggests that reactive astrocytes may drive the disease process by impairing the inhibitory action of neuronal GABA receptors.

    • Stefanie Robel
    • Harald Sontheimer
    Review Article
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Brief Communication

  • Mesolimbic dopamine has been implicated both in reward prediction and in promoting movement. This study demonstrates that the patterns of dopamine release in the nucleus accumbens core are shaped by the initiation of appropriate reward-guided actions and prospective response accuracy, and not just prediction errors.

    • Emilie C J Syed
    • Laura L Grima
    • Mark E Walton
    Brief Communication
  • The authors used a reversible inactivation technique that has not been used before in Old World monkeys, inhibitory chemogenetic receptors (DREADDs), to demonstrate that disconnecting a large region of monkey prefrontal cortex (orbitofrontal cortex) from a region in the temporal lobe (rhinal cortex) reduces sensitivity to differences in reward size.

    • Mark A G Eldridge
    • Walter Lerchner
    • Barry J Richmond
    Brief Communication
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  • DNA methylation in human brain shows dramatic variation across development. Genetic loci implicated in risk for schizophrenia are enriched for epigenetic states that show changes from the transition from prenatal to postnatal life. These findings suggest that early development is involved in both genetic and environmental risk factors for schizophrenia.

    • Andrew E Jaffe
    • Yuan Gao
    • Joel E Kleinman
  • There are widespread genetic effects on DNA methylation in the developing brain. Fetal brain mQTLs are enriched in regulatory domains, overlapping with variants influencing gene expression. Most are developmentally stable, but some are fetal specific. These mQTLs are enriched in genomic regions associated with schizophrenia, a neuropsychiatric disorder with neurodevelopmental origins.

    • Eilis Hannon
    • Helen Spiers
    • Jonathan Mill
  • Amyloid-β (Aβ) is generated by BACE-1-mediated cleavage of amyloid precursor protein (APP), and its deposition is a pathological hallmark of Alzheimer's disease. The authors find that APP and BACE-1 interact in biosynthetic and endocytic compartments in neurons. In axons, APP and BACE-1 interact during cotransport. The Alzheimer's disease–protective Icelandic mutation attenuates these interactions, suggesting a mechanism of protection.

    • Utpal Das
    • Lina Wang
    • Subhojit Roy
  • Oligodendrocyte death in the DTA mouse model leads to a fatal, secondary demyelinating disease associated with CNS T cell infiltration and myelin antigen-specific T cells in lymphoid organs, which can transfer a mild neurological disease to naive mice, indicating that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin. These results suggest that the disease-initiating event in the autoimmune disorder multiple sclerosis may occur within the CNS.

    • Maria Traka
    • Joseph R Podojil
    • Brian Popko
  • The c-fos gene is induced by a broad range of stimuli and is commonly used as a reliable marker for neural activity. The authors demonstrate that the combinatorial activation of multiple enhancers surrounding the c-fos gene is a critical mechanism of ensuring robust c-fos gene induction in response to various stimuli.

    • Jae-Yeol Joo
    • Katie Schaukowitch
    • Tae-Kyung Kim
  • Synaptic adhesion molecules are known to regulate synapse development, but growing evidence indicates that they also regulate synaptic function and plasticity. The authors report a novel synaptic adhesion molecule, IgSF11, that regulates excitatory synaptic transmission and plasticity through its dual interaction with the postsynaptic scaffold PSD-95 and AMPA receptors.

    • Seil Jang
    • Daeyoung Oh
    • Eunjoon Kim
  • The authors show that peripheral nerve injury induces de novo expression of colony-stimulating factor 1 (CSF1) in the injured sensory and motoneurons. CSF1, transported through axons, acts on its receptor on spinal cord microglia, inducing microglia proliferation and DAP12-dependent upregulation of pain-related microglial genes, eventually leading to neuropathic pain.

    • Zhonghui Guan
    • Julia A Kuhn
    • Allan I Basbaum
  • Seeking insight into dopamine's contribution to motivation and learning, the authors examined dopamine release in the rat nucleus accumbens during adaptive decision-making. Dopamine levels convey a running estimate of available future reward, which is used to decide whether it's worthwhile to engage in a behavioral task. Abrupt fluctuations serve as reward prediction errors, reinforcing behavioral choices.

    • Arif A Hamid
    • Jeffrey R Pettibone
    • Joshua D Berke
  • Sensory cortex spiking is well known to predict trial-to-trial variability in perceptual choice, but the origins of this choice-related activity are not fully understood. In the mouse somatosensory system, electrophysiology, imaging and optogenetic experiments reveal a progression of choice-related activity as touch signals flow from primary afferents to cortex.

    • Hongdian Yang
    • Sung E Kwon
    • Daniel H O'Connor
  • This study found that both the anterolateral (AL) and middle-lateral (ML) belt regions of the primate auditory cortex encoded acoustic stimulus features used to solve an auditory decision task. However, only AL activity was modulated by behavior and causally contributed sensory evidence to form the decision.

    • Joji Tsunada
    • Andrew S K Liu
    • Yale E Cohen
  • This study examines the effect of categorization-task training on parietal (PPC) and prefrontal (PFC) activity and finds a learning-dependent emergence of memory-related delay activity in PPC, whereas PFC shows delay-period selectivity both before and after categorization training. This reveals distinct roles of PFC and PPC in short-term working memory.

    • Arup Sarma
    • Nicolas Y Masse
    • David J Freedman
  • Using fMRI multi-voxel pattern decoding, human superior IPS, but not occipital cortex, was found to closely track behavioral measures of information storage in visual short-term memory (VSTM) across distractor presence and predictability. This suggests that superior IPS, and not occipital cortex, has a central role in VSTM storage in the human brain.

    • Katherine C Bettencourt
    • Yaoda Xu
  • Language consists of a hierarchy of linguistic units: words, phrases and sentences. The authors explore whether and how these abstract linguistic units are represented in the brain during speech comprehension. They find that cortical rhythms track the timescales of these linguistic units, revealing a hierarchy of neural processing timescales underlying internal construction of hierarchical linguistic structure.

    • Nai Ding
    • Lucia Melloni
    • David Poeppel
  • Although attentional abilities vary widely and have profound everyday effects, a standardized measure of these abilities is lacking. This study introduces a new fMRI measure based on patterns of whole-brain connectivity, which predicts adults' attention performance and children's ADHD symptoms from data acquired while individuals are resting in the scanner.

    • Monica D Rosenberg
    • Emily S Finn
    • Marvin M Chun


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