Hot off the presses! Oct 20 Neuron

The Oct 20 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:

• FTD and ALS: Genetic Ties that Bind
  - Neuron 72(2):189-190 (2011)
  Curiously, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), seemingly disparate neurodegenerative disorders, can be inherited together. Two groups (DeJesus-Hernandez et al. and Renton et al.) show that the long sought after ALS/FTD mutation on chromosomal region 9p is a hexanucleotide expansion in C90RF72. These studies, plus a study on X-linked ALS/FTD, provide molecular starting points for identifying pathways that link ALS and FTD pathogenesis.
• Orienting Fate: Spatial Regulation of Neurogenic Divisions
  - Neuron 72(2):191-193 (2011)
  Cleavage plane orientation has been thought to govern the fate of neural stem cell progeny, but supporting evidence in the neocortex has been sparse. A new study by Postiglione et al. in this issue of Neuron shows that mouse Inscuteable-mediated control of cleavage plane orientation regulates the output of neural progenitor cells.
• Movement, Confusion, and Orienting in Frontal Cortices
  - Neuron 72(2):193-196 (2011)
  In this issue, two studies, by Ehrlich et al. and Hill et al., address the role of the frontal motor cortices in behavior of the rat and suggest a potential role for this structure in high-level control of diverse behaviors. Hill et al. show that motor cortical neurons predict whisker movements even without sensory feedback and that their activity reflects efferent control. Surprisingly, Ehrlich et al. report the participation of this same cortical region in the preparation and execution of orienting behaviors.
• Stimulation on Demand: Closing the Loop on Deep Brain Stimulation
  - Neuron 72(2):197-198 (2011)
  High-frequency open-loop deep brain stimulation (DBS) has been used to alleviate Parkinson's symptoms for almost 20 years. In this issue of Neuron, Rosin et al. present a closed-loop real-time approach that improves DBS and shines light on the etiology of motor symptoms in Parkinson's disease.
• Aligning Brains and Minds
  - Neuron 72(2):199-201 (2011)
  In this issue of Neuron, Haxby and colleagues describe a new method for aligning functional brain activity patterns across participants. Their study demonstrates that objects are similarly represented across different brains, allowing for reliable classification of one person's brain activity based on another's.
• Genetic Manipulation of Genes and Cells in the Nervous System of the Fruit Fly
  - Neuron 72(2):202-230 (2011)
  Research in the fruit fly Drosophila melanogaster has led to insights in neural development, axon guidance, ion channel function, synaptic transmission, learning and memory, diurnal rhythmicity, and neural disease that have had broad implications for neuroscience. Drosophila is currently the eukaryotic model organism that permits the most sophisticated in vivo manipulations to address the function of neurons and neuronally expressed genes. Here, we summarize many of the techniques that help assess the role of specific neurons by labeling, removing, or altering their activity. We also survey genetic manipulations to identify and characterize neural genes by mutation, overexpression, and protein labeling. Here, we attempt to acquaint the reader with available options and contexts to apply these methods.
• How Inhibition Shapes Cortical Activity
  - Neuron 72(2):231-243 (2011)
  Cortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions.
• Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
  - Neuron 72(2):245-256 (2011)
  Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
• A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
  - Neuron 72(2):257-268 (2011)
  The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to d! ate.
• Mouse Inscuteable Induces Apical-Basal Spindle Orientation to Facilitate Intermediate Progenitor Generation in the Developing Neocortex
  - Neuron 72(2):269-284 (2011)
  Neurons in the mammalian neocortex arise from asymmetric divisions of progenitors residing in the ventricular zone. While in most progenitor divisions, the mitotic spindle is parallel to the ventricular surface, some progenitors reorient the spindle and divide in oblique orientations. Here, we use conditional deletion and overexpression of mouse Inscuteable (mInsc) to analyze the relevance of spindle reorientation in cortical progenitors. Mutating mInsc almost abolishes oblique and vertical mitotic spindles, while mInsc overexpression has the opposite effect. Our data suggest that oblique divisions are essential for generating the correct numbers of neurons in all cortical layers. Using clonal analysis, we demonstrate that spindle orientation affects the rate of indirect neurogenesis, a process where progenitors give rise to basal progenitors, which in turn divide symmetrically into two differentiating neurons. Our results indicate that the orientation of progenitor ce! ll divisions is important for correct lineage specification in the developing mammalian brain.
• Nak Regulates Localization of Clathrin Sites in Higher-Order Dendrites to Promote Local Dendrite Growth
  - Neuron 72(2):285-299 (2011)
  During development, dendrites arborize in a field several hundred folds of their soma size, a process regulated by intrinsic transcription program and cell adhesion molecule (CAM)-mediated interaction. However, underlying cellular machineries that govern distal higher-order dendrite extension remain largely unknown. Here, we show that Nak, a clathrin adaptor-associated kinase, promotes higher-order dendrite growth through endocytosis. In nak mutants, both the number and length of higher-order dendrites are reduced, which are phenocopied by disruptions of clathrin-mediated endocytosis. Nak interacts genetically with components of the endocytic pathway, colocalizes with clathrin puncta, and is required for dendritic localization of clathrin puncta. More importantly, these Nak-containing clathrin structures preferentially localize to branching points and dendritic tips that are undergoing active growth. We present evidence that the Drosophila L1-CAM homolog Neuroglian is ! a relevant cargo of Nak-dependent internalization, suggesting that localized clathrin-mediated endocytosis of CAMs facilitates the extension of nearby higher-order dendrites. Video Abstract View Within Article
• Rapid Synthesis of the X-Linked Mental Retardation Protein OPHN1 Mediates mGluR-Dependent LTD through Interaction with the Endocytic Machinery
  - Neuron 72(2):300-315 (2011)
  Activation of group I metabotropic glutamate receptors leads to long-term depression (mGluR-LTD). Alterations in this form of plasticity have been linked to drug addiction and cognitive disorders. A key characteristic of mGluR-LTD is its dependence on rapid protein synthesis; however, the identities of the proteins mediating LTD remain elusive. Here, we identify the X-linked mental retardation protein OPHN1 as a molecule essential for mGluR-LTD in the hippocampus. mGluR-LTD induction elicits rapid dendritic OPHN1 synthesis, which is dependent on mGluR1 activation and independent of fragile X mental retardation protein (FMRP). This response is essential for mGluR-LTD, as acute blockade of OPHN1 synthesis impedes LTD. mGluR-induced OPHN1 mediates LTD and associated persistent decreases in surface AMPARs via interactions with endophilin A2/3. Importantly, this role of OPHN1 is separable from its effects on basal synaptic strength, which require OPHN1's Rho-GAP activity an! d interaction with Homer1b/c. Thus, our data establish a role for rapid OPHN1 synthesis in mGluR-LTD. Video Abstract View Within Article
• A Putative Vesicular Transporter Expressed in Drosophila Mushroom Bodies that Mediates Sexual Behavior May Define a Neurotransmitter System
  - Neuron 72(2):316-329 (2011)
  Vesicular transporters are required for the storage of all classical and amino acid neurotransmitters in synaptic vesicles. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila gene portabella (prt) that is structurally similar to known vesicular transporters. Both larval and adult brains express PRT in the KCs of the MBs. Additional PRT cells project to the central complex and optic ganglia. prt mutation causes an olfactory learning deficit and an unusual defect in the male's position during copulation that is rescued by expression in KCs. Because prt is expressed in neurons that lack other known vesicular transporters or neurot! ransmitters, it may define a previously unknown neurotransmitter system responsible for sexual behavior and a component of olfactory learning.
• A Cortical Substrate for Memory-Guided Orienting in the Rat
  - Neuron 72(2):330-343 (2011)
  Anatomical, stimulation, and lesion data have suggested a homology between the rat frontal orienting fields (FOF) (centered at +2 AP, ±1.3 ML mm from Bregma) and primate frontal cortices such as the frontal or supplementary eye fields. We investigated the functional role of the FOF using rats trained to perform a memory-guided orienting task, in which there was a delay period between the end of a sensory stimulus instructing orienting direction and the time of the allowed motor response. Unilateral inactivation of the FOF resulted in impaired contralateral responses. Extracellular recordings of single units revealed that 37% of FOF neurons had delay period firing rates that predicted the direction of the rats' later orienting motion. Our data provide the first electrophysiological and pharmacological evidence supporting the existence in the rat, as in the primate, of a frontal cortical area involved in the preparation and/or planning of orienting responses.
• Primary Motor Cortex Reports Efferent Control of Vibrissa Motion on Multiple Timescales
  - Neuron 72(2):344-356 (2011)
  Exploratory whisking in rat is an example of self-generated movement on multiple timescales, from slow variations in the envelope of whisking to the rapid sequence of muscle contractions during a single whisk cycle. We find that, as a population, spike trains of single units in primary vibrissa motor cortex report the absolute angle of vibrissa position. This representation persists after sensory nerve transection, indicating an efferent source. About two-thirds of the units are modulated by slow variations in the envelope of whisking, while relatively few units report rapid changes in position within the whisk cycle. The combined results from this study and past measurements, which show that primary sensory cortex codes the whisking envelope as a motor copy signal, imply that signals present in both sensory and motor cortices are necessary to compute angular coordinates based on vibrissa touch.
• Multisensory Integration of Natural Odors and Sounds in the Auditory Cortex
  - Neuron 72(2):357-369 (2011)
  Motherhood is associated with different forms of physiological alterations including transient hormonal changes and brain plasticity. The underlying impact of these changes on the emergence of maternal behaviors and sensory processing within the mother's brain are largely unknown. By using in vivo cell-attached recordings in the primary auditory cortex of female mice, we discovered that exposure to pups' body odor reshapes neuronal responses to pure tones and natural auditory stimuli. This olfactory-auditory interaction appeared naturally in lactating mothers shortly after parturition and was long lasting. Naive virgins that had experience with the pups also showed an appearance of olfactory-auditory integration in A1, suggesting that multisensory integration may be experience dependent. Neurons from lactating mothers were more sensitive to sounds as compared to those from experienced mice, independent of the odor effects. These uni- and multisensory cortical changes m! ay facilitate the detection and discrimination of pup distress calls and strengthen the bond between mothers and their neonates. Video Abstract View Within Article
• Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism
  - Neuron 72(2):370-384 (2011)
  Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson's disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Suc! h strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.
• Lichtheim 2: Synthesizing Aphasia and the Neural Basis of Language in a Neurocomputational Model of the Dual Dorsal-Ventral Language Pathways
  - Neuron 72(2):385-396 (2011)
  Traditional neurological models of language were based on a single neural pathway (the dorsal pathway underpinned by the arcuate fasciculus). Contemporary neuroscience indicates that anterior temporal regions and the "ventral" language pathway also make a significant contribution, yet there is no computationally-implemented model of the dual pathway, nor any synthesis of normal and aphasic behavior. The "Lichtheim 2" model was implemented by developing a new variety of computational model which reproduces and explains normal and patient data but also incorporates neuroanatomical information into its architecture. By bridging the "mind-brain" gap in this way, the resultant "neurocomputational" model provides a unique opportunity to explore the relationship between lesion location and behavioral deficits, and to provide a platform for simulating functional neuroimaging data.
• Syntactic Processing Depends on Dorsal Language Tracts
  - Neuron 72(2):397-403 (2011)
  Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts—the superior longitudinal fasciculus including its arcuate component—was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts—the extreme capsule fiber system or ! the uncinate fasciculus—was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.
• A Common, High-Dimensional Model of the Representational Space in Human Ventral Temporal Cortex
  - Neuron 72(2):404-416 (2011)
  We present a high-dimensional model of the representational space in human ventral temporal (VT) cortex in which dimensions are response-tuning functions that are common across individuals and patterns of response are modeled as weighted sums of basis patterns associated with these response tunings. We map response-pattern vectors, measured with fMRI, from individual subjects' voxel spaces into this common model space using a new method, "hyperalignment." Hyperalignment parameters based on responses during one experiment—movie viewing—identified 35 common response-tuning functions that captured fine-grained distinctions among a wide range of stimuli in the movie and in two category perception experiments. Between-subject classification (BSC, multivariate pattern classification based on other subjects' data) of response-pattern vectors in common model space greatly exceeded BSC of anatomically aligned responses and matched within-subject classification. Results ! indicate that population codes for complex visual stimuli in VT cortex are based on response-tuning functions that are common across individuals.
• SnapShot: Genetics of Autism
  - Neuron 72(2):418-418.e1 (2011)