@article {186, title = {Children{\textquoteright}s Task-Switching Efficiency: Missing Our Cue?}, journal = {Journal of Cognition and Development}, volume = {16}, year = {2015}, pages = {261{\textendash}285}, author = {Holt, Anna E and De{\'a}k, Gedeon} } @article {124, title = {Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders.}, journal = {Stem Cell Reports}, volume = {5}, year = {2015}, month = {2015 Dec 8}, pages = {933-45}, abstract = {

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

}, issn = {2213-6711}, doi = {10.1016/j.stemcr.2015.10.011}, author = {Brennand, Kristen J and Marchetto, M Carol and Benvenisty, Nissim and Br{\"u}stle, Oliver and Ebert, Allison and Izpisua Belmonte, Juan Carlos and Kaykas, Ajamete and Lancaster, Madeline A and Livesey, Frederick J and McConnell, Michael J and McKay, Ronald D and Morrow, Eric M and Muotri, Alysson R and Panchision, David M and Rubin, Lee L and Sawa, Akira and Soldner, Frank and Song, Hongjun and Studer, Lorenz and Temple, Sally and Vaccarino, Flora M and Wu, Jun and Vanderhaeghen, Pierre and Gage, Fred H and Jaenisch, Rudolf} } @article {173, title = {California can lead the way on brain research}, year = {2014}, url = {http://www.sacbee.com/opinion/op-ed/article2606601.html}, author = {Greenspan, RJ and Alivisatos, AP} } @article {179, title = {Changes in GABA and glutamate concentrations during memory tasks in patients with Parkinson{\textquoteright}s disease undergoing DBS surgery.}, journal = {Front Hum Neurosci}, volume = {8}, year = {2014}, month = {2014}, pages = {81}, abstract = {

Until now direct neurochemical measurements during memory tasks have not been accomplished in the human basal ganglia. It has been proposed, based on both functional imaging studies and psychometric testing in normal subjects and in patients with Parkinson{\textquoteright}s disease (PD), that the basal ganglia is responsible for the performance of feedback-contingent implicit memory tasks. To measure neurotransmitters, we used in vivo microdialysis during deep brain stimulation (DBS) surgery. We show in the right subthalamic nucleus (STN) of patients with PD a task-dependent change in the concentrations of glutamate and GABA during an implicit memory task relative to baseline, while no difference was found between declarative memory tasks. The five patients studied had a significant decrease in the percent concentration of GABA and glutamate during the performance of the weather prediction task (WPT). We hypothesize, based on current models of basal ganglia function, that this decrease in the concentration is consistent with expected dysfunction in basal ganglia networks in patients with PD.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2014.00081}, author = {Buchanan, Robert J and Darrow, David P and Meier, Kevin T and Robinson, Jennifer and Schiehser, Dawn M and Glahn, David C and Nadasdy, Zoltan} } @article {214, title = {Covariate-modulated local false discovery rate for genome-wide association studies.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Aug 1}, pages = {2098-104}, abstract = {

MOTIVATION: Genome-wide association studies (GWAS) have largely failed to identify most of the genetic basis of highly heritable diseases and complex traits. Recent work has suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS, given currently obtainable sample sizes. In this scenario, Bonferroni-derived thresholds are severely underpowered to detect the vast majority of associations. Local false discovery rate (fdr) methods provide more power to detect non-null associations, but implicit assumptions about the exchangeability of single nucleotide polymorphisms (SNPs) limit their ability to discover non-null loci.

METHODS: We propose a novel covariate-modulated local false discovery rate (cmfdr) that incorporates prior information about gene element-based functional annotations of SNPs, so that SNPs from categories enriched for non-null associations have a lower fdr for a given value of a test statistic than SNPs in unenriched categories. This readjustment of fdr based on functional annotations is achieved empirically by fitting a covariate-modulated parametric two-group mixture model. The proposed cmfdr methodology is applied to a large Crohn{\textquoteright}s disease GWAS.

RESULTS: Use of cmfdr dramatically improves power, e.g. increasing the number of loci declared significant at the 0.05 fdr level by a factor of 5.4. We also demonstrate that SNPs were declared significant using cmfdr compared with usual fdr replicate in much higher numbers, while maintaining similar replication rates for a given fdr cutoff in de novo samples, using the eight Crohn{\textquoteright}s disease substudies as independent training and test datasets. Availability an implementation: https://sites.google.com/site/covmodfdr/

CONTACT: : wes.stat@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Analysis of Variance, Bayes Theorem, Computational Biology, False Positive Reactions, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu145}, author = {Zablocki, Rong W and Schork, Andrew J and Levine, Richard A and Andreassen, Ole A and Dale, Anders M and Thompson, Wesley K} } @article {166, title = {A comprehensive wiring diagram of the protocerebral bridge for visual information processing in the Drosophila brain.}, journal = {Cell Rep}, volume = {3}, year = {2013}, month = {2013 May 30}, pages = {1739-53}, abstract = {

How the brain perceives sensory information and generates meaningful behavior depends critically on its underlying circuitry. The protocerebral bridge (PB) is a major part of the insect central complex (CX), a premotor center that may be analogous to the human basal ganglia. Here, by deconstructing hundreds of PB single neurons and reconstructing them into a common three-dimensional framework, we have constructed a comprehensive map of PB circuits with labeled polarity and predicted directions of information flow. Our analysis reveals a highly ordered information processing system that involves directed information flow among CX subunits through 194 distinct PB neuron types. Circuitry properties such as mirroring, convergence, divergence, tiling, reverberation, and parallel signal propagation were observed; their functional and evolutional significance is discussed. This layout of PB neuronal circuitry may provide guidelines for further investigations on transformation of sensory (e.g., visual) input into locomotor commands in fly brains.

}, keywords = {Animals, Brain, Drosophila, Models, Biological, Neurons}, issn = {2211-1247}, doi = {10.1016/j.celrep.2013.04.022}, author = {Lin, Chih-Yung and Chuang, Chao-Chun and Hua, Tzu-En and Chen, Chun-Chao and Dickson, Barry J and Greenspan, Ralph J and Chiang, Ann-Shyn} } @article {200, title = {Contrast dependence and differential contributions from somatostatin- and parvalbumin-expressing neurons to spatial integration in mouse V1.}, journal = {J Neurosci}, volume = {33}, year = {2013}, month = {2013 Jul 3}, pages = {11145-54}, abstract = {

A characteristic feature in the primary visual cortex is that visual responses are suppressed as a stimulus extends beyond the classical receptive field. Here, we examined the role of inhibitory neurons expressing somatostatin (SOM$^{+}$) or parvalbumin (PV$^{+}$) on surround suppression and preferred receptive field size. We recorded multichannel extracellular activity in V1 of transgenic mice expressing channelrhodopsin in SOM$^{+}$ neurons or PV$^{+}$ neurons. Preferred size and surround suppression were measured using drifting square-wave gratings of varying radii and at two contrasts. Consistent with findings in primates, we found that the preferred size was larger for lower contrasts across all cortical depths, whereas the suppression index (SI) showed a trend to decrease with contrast. We then examined the effect of these metrics on units that were suppressed by photoactivation of either SOM$^{+}$ or PV$^{+}$ neurons. When activating SOM$^{+}$ neurons, we found a significant increase in SI at cortical depths \>400 μm, whereas activating PV$^{+}$ neurons caused a trend toward lower SIs regardless of cortical depth. Conversely, activating PV$^{+}$ neurons significantly increased preferred size across all cortical depths, similar to lowering contrast, whereas activating SOM$^{+}$ neurons had no systematic effect on preferred size across all depths. These data suggest that SOM$^{+}$ and PV$^{+}$ neurons contribute differently to spatial integration. Our findings are compatible with the notion that SOM$^{+}$ neurons mediate surround suppression, particularly in deeper cortex, whereas PV$^{+}$ activation decreases the drive of the input to cortex and therefore resembles the effects on spatial integration of lowering contrast.

}, keywords = {Animals, Contrast Sensitivity, Female, Male, Mice, Mice, Transgenic, Neurons, Parvalbumins, Photic Stimulation, Somatostatin, Space Perception, Visual Cortex}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5320-12.2013}, author = {Nienborg, Hendrikje and Hasenstaub, Andrea and Nauhaus, Ian and Taniguchi, Hiroki and Huang, Z Josh and Callaway, Edward M} } @article {196, title = {Collinear features impair visual detection by rats.}, journal = {J Vis}, volume = {11}, year = {2011}, month = {2011}, abstract = {

We measure rats{\textquoteright} ability to detect an oriented visual target grating located between two flanking stimuli ("flankers"). Flankers varied in contrast, orientation, angular position, and sign. Rats are impaired at detecting visual targets with collinear flankers, compared to configurations where flankers differ from the target in orientation or angular position. In particular, rats are more likely to miss the target when flankers are collinear. The same impairment is found even when the flanker luminance was sign-reversed relative to the target. These findings suggest that contour alignment alters visual processing in rats, despite their lack of orientation columns in the visual cortex. This is the first report that the arrangement of visual features relative to each other affects visual behavior in rats. To provide a conceptual framework for our findings, we relate our stimuli to a contrast normalization model of early visual processing. We suggest a pattern-sensitive generalization of the model that could account for a collinear deficit. These experiments were performed using a novel method for automated high-throughput training and testing of visual behavior in rodents.

}, keywords = {Animals, Behavior, Animal, Conditioning (Psychology), Contrast Sensitivity, Lighting, Orientation, Photic Stimulation, Psychophysics, Rats, Retina, Space Perception}, issn = {1534-7362}, doi = {10.1167/11.3.22}, author = {Meier, Philip and Flister, Erik and Reinagel, Pamela} } @article {135, title = {cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.}, journal = {Nat Neurosci}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {944-50}, abstract = {

Neuronal differentiation is accomplished through cascades of intrinsic genetic factors initiated in neuronal progenitors by external gradients of morphogens. Activity has been thought to be important only late in development, but recent evidence suggests that activity also regulates early neuronal differentiation. Activity in post-mitotic neurons before synapse formation can regulate phenotypic specification, including neurotransmitter choice, but the mechanisms are not clear. We identified a mechanism that links endogenous calcium spike activity with an intrinsic genetic pathway to specify neurotransmitter choice in neurons in the dorsal embryonic spinal cord of Xenopus tropicalis. Early activity modulated transcription of the GABAergic/glutamatergic selection gene tlx3 through a variant cAMP response element (CRE) in its promoter. The cJun transcription factor bound to this CRE site, modulated transcription and regulated neurotransmitter phenotype via its transactivation domain. Calcium signaled through cJun N-terminal phosphorylation, which integrated activity-dependent and intrinsic neurotransmitter specification. This mechanism provides a basis for early activity to regulate genetic pathways at critical decision points, switching the phenotype of developing neurons.

}, keywords = {Animals, Base Sequence, Calcium, Calcium Signaling, Electrophoretic Mobility Shift Assay, Gene Expression, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Molecular Sequence Data, Neurogenesis, Neurons, Neurotransmitter Agents, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Xenopus, Xenopus Proteins}, issn = {1546-1726}, doi = {10.1038/nn.2582}, author = {Marek, Kurt W and Kurtz, Lisa M and Spitzer, Nicholas C} } @article {175, title = {Computational influence of adult neurogenesis on memory encoding.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {187-202}, abstract = {

Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.

}, keywords = {Age Factors, Algorithms, Animals, Cell Proliferation, Computer Simulation, Dentate Gyrus, Humans, Memory, Nerve Net, Neural Pathways, Neurogenesis, Neuronal Plasticity, Neurons, Stem Cells, Synapses, Time Perception}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.11.026}, author = {Aimone, James B and Wiles, Janet and Gage, Fred H} } @article {148, title = {Cognitive consonance: complex brain functions in the fruit fly and its relatives.}, journal = {Trends Neurosci}, volume = {27}, year = {2004}, month = {2004 Dec}, pages = {707-11}, abstract = {

The fruit fly, Drosophila melanogaster, has become a model for the study of a growing number of human characteristics because of the power of its genetics. Higher cognitive functions, however, might be assumed to be out of reach for the little fly. But the cumulative history of cognitive studies in insects and some of their arachnid relatives, as well as specific probing of the capabilities of fruit flies, suggests that even in this ethereal realm these creatures have much to contribute. What are the degrees of sophistication in cognitive behavior displayed by these organisms, how have they been demonstrated, and what is their potential for understanding how our own brains work?

}, keywords = {Animals, Bees, Behavior, Animal, Brain, Cognition, Drosophila melanogaster, Humans, Perception, Spiders}, issn = {0166-2236}, doi = {10.1016/j.tins.2004.10.002}, author = {Greenspan, Ralph J and van Swinderen, Bruno} } @article {152, title = {Correlates of sleep and waking in Drosophila melanogaster.}, journal = {Science}, volume = {287}, year = {2000}, month = {2000 Mar 10}, pages = {1834-7}, abstract = {

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

}, keywords = {Animals, Arylamine N-Acetyltransferase, Behavior, Animal, Biogenic Monoamines, Caffeine, Carrier Proteins, Circadian Rhythm, Cytochrome P-450 Enzyme System, Drosophila melanogaster, Drosophila Proteins, Fatty Acid Synthases, Female, Gene Dosage, Gene Expression Profiling, Genes, Insect, Homeostasis, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Hydroxyzine, Mutation, Rest, Sleep, Transcription, Genetic, Wakefulness}, issn = {0036-8075}, author = {Shaw, P J and Cirelli, C and Greenspan, R J and Tononi, G} }