@article {2268, title = {Adaptive integration of self-motion and goals in posterior parietal cortex.}, journal = {Cell Rep}, volume = {38}, year = {2022}, month = {2022 Mar 08}, pages = {110504}, abstract = {

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2022.110504}, author = {Alexander, Andrew S and Tung, Janet C and Chapman, G William and Conner, Allison M and Shelley, Laura E and Hasselmo, Michael E and Nitz, Douglas A} } @conference {1793, title = {Massively Parallel Causal Inference of Whole Brain Dynamics at Single Neuron Resolution}, booktitle = {2020 IEEE 26th International Conference on Parallel and Distributed Systems (ICPADS)}, year = {2020}, doi = {10.1109/ICPADS51040.2020.00035}, author = {Watanakeesuntorn, Wassapon and Takahashi, Keichi and Ichikawa, Kohei and Park, Joseph and Sugihara, George and Takano, Ryousei and Haga, Jason and Pao, Gerald M.} } @article {1806, title = {A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex}, journal = {Proceedings of the National Academy of Sciences}, volume = {117}, year = {2020}, pages = {29872{\textendash}29882}, abstract = {

The prefrontal cortex (PFC) enables humans{\textquoteright} ability to flexibly adapt to new environments and circumstances. Disruption of this ability is often a hallmark of prefrontal disease. Neural network models have provided tools to study how the PFC stores and uses information, yet the mechanisms underlying how the PFC is able to adapt and learn about new situations without disrupting preexisting knowledge remain unknown. We use a neural network architecture to show how hierarchical gating can naturally support adaptive learning while preserving memories from prior experience. Furthermore, we show how damage to our network model recapitulates disorders of the human PFC.The prefrontal cortex encodes and stores numerous, often disparate, schemas and flexibly switches between them. Recent research on artificial neural networks trained by reinforcement learning has made it possible to model fundamental processes underlying schema encoding and storage. Yet how the brain is able to create new schemas while preserving and utilizing old schemas remains unclear. Here we propose a simple neural network framework that incorporates hierarchical gating to model the prefrontal cortex{\textquoteright}s ability to flexibly encode and use multiple disparate schemas. We show how gating naturally leads to transfer learning and robust memory savings. We then show how neuropsychological impairments observed in patients with prefrontal damage are mimicked by lesions of our network. Our architecture, which we call DynaMoE, provides a fundamental framework for how the prefrontal cortex may handle the abundance of schemas necessary to navigate the real world.The code used to generate the data in this work is available at https://github.com/tsudacode/DynaMoE.

}, issn = {0027-8424}, doi = {10.1073/pnas.2009591117}, url = {https://www.pnas.org/content/117/47/29872}, author = {Tsuda, Ben and Tye, Kay M. and Siegelmann, Hava T. and Sejnowski, Terrence J.} } @article {1685, title = {Apical-Basal Polarity Signaling Components, Lgl1 and aPKCs, Control Glutamatergic Synapse Number and Function.}, journal = {iScience}, volume = {20}, year = {2019}, month = {2019 Oct 25}, pages = {25-41}, abstract = {

Normal synapse formation is fundamental to brain function. We show here that an apical-basal polarity (A-BP) protein, Lgl1, is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing the atypical protein kinase Cs (aPKCs). A planar cell polarity protein, Vangl2, which inhibits synapse formation, was decreased in synaptosome fractions of cultured cortical neurons from Lgl1 knockout embryos. Conditional knockout of Lgl1 in pyramidal neurons led to reduction of AMPA/NMDA ratio and impaired plasticity. Lgl1 is frequently deleted in Smith-Magenis syndrome (SMS). Lgl1 conditional knockout led to increased locomotion, impaired novel object recognition and social interaction. Lgl1+/- animals also showed increased synapse numbers, defects in open field and social interaction, as well as stereotyped repetitive behavior. Social interaction in Lgl1+/- could be rescued by NMDA antagonists. Our findings reveal a role of apical-basal polarity proteins in glutamatergic synapse development and function and also suggest a potential treatment for SMS patients with Lgl1 deletion.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2019.09.005}, author = {Scott, John and Thakar, Sonal and Mao, Ye and Qin, Huaping and Hejran, Helen and Lee, Su-Yee and Yu, Ting and Klezovitch, Olga and Cheng, Hongqiang and Mu, Yongxin and Ghosh, Sourav and Vasioukhin, Valeri and Zou, Yimin} } @article {1693, title = {Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 04 05}, pages = {1560}, abstract = {

In the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this underexplored form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to demonstrate that direct electrical ("ephaptic") interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.

}, keywords = {Animals, Drosophila, Imaging, Three-Dimensional, Models, Biological, Olfactory Pathways, Olfactory Receptor Neurons, Sensilla, Smell}, issn = {2041-1723}, doi = {10.1038/s41467-019-09346-z}, author = {Zhang, Ye and Tsang, Tin Ki and Bushong, Eric A and Chu, Li-An and Chiang, Ann-Shyn and Ellisman, Mark H and Reingruber, J{\"u}rgen and Su, Chih-Ying} } @article {1669, title = {Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.}, journal = {Transl Psychiatry}, volume = {9}, year = {2019}, month = {2019 01 17}, pages = {24}, abstract = {

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5 cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5 cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5 animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5 adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

}, keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons}, issn = {2158-3188}, doi = {10.1038/s41398-018-0344-y}, author = {Moore, Spencer M and Seidman, Jason S and Ellegood, Jacob and Gao, Richard and Savchenko, Alex and Troutman, Ty D and Abe, Yohei and Stender, Josh and Lee, Daehoon and Wang, Sicong and Voytek, Bradley and Lerch, Jason P and Suh, Hoonkyo and Glass, Christopher K and Muotri, Alysson R} } @article {1469, title = {Biosynthesis of Orthogonal Molecules Using Ferredoxin and Ferredoxin-NADP+ Reductase Systems Enables Genetically Encoded PhyB Optogenetics.}, journal = {ACS Synth Biol}, year = {2018}, month = {2018 Jan 24}, abstract = {

Transplanting metabolic reactions from one species into another has many uses as a research tool with applications ranging from optogenetics to crop production. Ferredoxin (Fd), the enzyme that most often supplies electrons to these reactions, is often overlooked when transplanting enzymes from one species to another because most cells already contain endogenous Fd. However, we have shown that the production of chromophores used in Phytochrome B (PhyB) optogenetics is greatly enhanced in mammalian cells by expressing bacterial and plant Fds with ferredoxin-NADP+ reductases (FNR). We delineated the rate limiting factors and found that the main metabolic precursor, heme, was not the primary limiting factor for producing either the cyanobacterial or plant chromophores, phycocyanobilin or phytochromobilin, respectively. In fact, Fd is limiting, followed by Fd+FNR and finally heme. Using these findings, we optimized the PCB production system and combined it with a tissue penetrating red/far-red sensing PhyB optogenetic gene switch in animal cells. We further characterized this system in several mammalian cell lines using red and far-red light. Importantly, we found that the light-switchable gene system remains active for several hours upon illumination, even with a short light pulse, and requires very small amounts of light for maximal activation. Boosting chromophore production by matching metabolic pathways with specific ferredoxin systems will enable the unparalleled use of the many PhyB optogenetic tools and has broader implications for optimizing synthetic metabolic pathways.

}, issn = {2161-5063}, doi = {10.1021/acssynbio.7b00413}, author = {Kyriakakis, Phillip and Catanho, Marianne and Hoffner, Nicole and Thavarajah, Walter and Hu, Vincent J and Chao, Syh-Shiuan and Hsu, Athena and Pham, Vivian and Naghavian, Ladan and Dozier, Lara E and Patrick, Gentry N and Coleman, Todd P} } @article {1695, title = {High-quality ultrastructural preservation using cryofixation for 3D electron microscopy of genetically labeled tissues.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 05 11}, abstract = {

Electron microscopy (EM) offers unparalleled power to study cell substructures at the nanoscale. Cryofixation by high-pressure freezing offers optimal morphological preservation, as it captures cellular structures instantaneously in their near-native state. However, the applicability of cryofixation is limited by its incompatibility with diaminobenzidine labeling using genetic EM tags and the high-contrast staining required for serial block-face scanning electron microscopy (SBEM). In addition, it is challenging to perform correlated light and electron microscopy (CLEM) with cryofixed samples. Consequently, these powerful methods cannot be applied to address questions requiring optimal morphological preservation. Here, we developed an approach that overcomes these limitations; it enables genetically labeled, cryofixed samples to be characterized with SBEM and 3D CLEM. Our approach is broadly applicable, as demonstrated in cultured cells, olfactory organ and mouse brain. This optimization exploits the potential of cryofixation, allowing for quality ultrastructural preservation for diverse EM applications.

}, keywords = {Animal Structures, Animals, Brain, Cryopreservation, Drosophila, Imaging, Three-Dimensional, Mice, Microscopy, Electron, Scanning, Sense Organs}, issn = {2050-084X}, doi = {10.7554/eLife.35524}, author = {Tsang, Tin Ki and Bushong, Eric A and Boassa, Daniela and Hu, Junru and Romoli, Benedetto and Phan, Sebastien and Dulcis, Davide and Su, Chih-Ying and Ellisman, Mark H} } @article {1696, title = {Multiplexed oscillations and phase rate coding in the basal forebrain.}, journal = {Sci Adv}, volume = {4}, year = {2018}, month = {2018 08}, pages = {eaar3230}, abstract = {

Complex behaviors demand temporal coordination among functionally distinct brain regions. The basal forebrain{\textquoteright}s afferent and efferent structure suggests a capacity for mediating this coordination at a large scale. During performance of a spatial orientation task, synaptic activity in this region was dominated by four amplitude-independent oscillations temporally organized by the phase of the slowest, a theta-frequency rhythm. Oscillation amplitudes were also organized by task epoch and positively correlated to the task-related modulation of individual neuron firing rates. For many neurons, spiking was temporally organized through phase precession against theta band field potential oscillations. Theta phase precession advanced in parallel to task progression, rather than absolute spatial location or time. Together, the findings reveal a process by which associative brain regions can integrate independent oscillatory inputs and transform them into sequence-specific, rate-coded outputs that are adaptive to the pace with which organisms interact with their environment.

}, keywords = {Animals, Basal Forebrain, Male, Models, Neurological, Neurons, Rats, Rats, Long-Evans, Space Perception, Theta Rhythm}, issn = {2375-2548}, doi = {10.1126/sciadv.aar3230}, author = {Tingley, David and Alexander, Andrew S and Quinn, Laleh K and Chiba, Andrea A and Nitz, Douglas} } @article {1686, title = {Spatial fine-mapping for gene-by-environment effects identifies risk hot spots for schizophrenia.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 13}, pages = {5296}, abstract = {

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122\%. Individuals living in a high gene-by-environmental risk locale have a 78\% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

}, keywords = {Chromosome Mapping, Denmark, Environment, Genetic Predisposition to Disease, Geography, Humans, Proof of Concept Study, Risk Factors, Schizophrenia}, issn = {2041-1723}, doi = {10.1038/s41467-018-07708-7}, author = {Fan, Chun Chieh and McGrath, John J and Appadurai, Vivek and Buil, Alfonso and Gandal, Michael J and Schork, Andrew J and Mortensen, Preben Bo and Agerbo, Esben and Geschwind, Sandy A and Geschwind, Daniel and Werge, Thomas and Thompson, Wesley K and Pedersen, Carsten B{\o}cker} } @article {1684, title = {Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 01 24}, pages = {E610-E618}, abstract = {

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of \~{}50\% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of \~{}50\% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

}, keywords = {Animals, Behavior, Animal, Cadherins, Cell Polarity, Cells, Cultured, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Locomotion, Male, Maze Learning, Mice, Knockout, Nerve Tissue Proteins, Pyramidal Cells, Receptors, Cell Surface, Synapses, Wnt-5a Protein}, issn = {1091-6490}, doi = {10.1073/pnas.1612062114}, author = {Thakar, Sonal and Wang, Liqing and Yu, Ting and Ye, Mao and Onishi, Keisuke and Scott, John and Qi, Jiaxuan and Fernandes, Catarina and Han, Xuemei and Yates, John R and Berg, Darwin K and Zou, Yimin} } @article {1688, title = {Subiculum neurons map the current axis of travel.}, journal = {Nat Neurosci}, volume = {20}, year = {2017}, month = {2017 02}, pages = {170-172}, abstract = {

Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180{\textdegree} apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context.

}, keywords = {Action Potentials, Animals, Brain Mapping, Hippocampus, Male, Neurons, Orientation, Rats, Sprague-Dawley, Space Perception}, issn = {1546-1726}, doi = {10.1038/nn.4464}, author = {Olson, Jacob M and Tongprasearth, Kanyanat and Nitz, Douglas A} } @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 {199, title = {From suffering to caring: a model of differences among older adults in levels of compassion.}, journal = {Int J Geriatr Psychiatry}, volume = {30}, year = {2015}, month = {2015 Feb}, pages = {185-91}, abstract = {

OBJECTIVE: Compassion is an important contributor to pro-social behavior and maintenance of interpersonal relationships, yet little is known about what factors influence compassion in late life. The aim of this study was to test theories about how past and current stressors and emotional functioning, resilience, and demographic indicators of life experiences are related to compassion among older adults.

METHODS: One thousand and six older adults (50-99 years) completed a comprehensive survey including self-report measures of compassion, resilience, past and present stress, and emotional functioning (i.e., stressful life events, perceived stress, and current and prior depression and anxiety), and demographic information. The sample was randomly split, and exploratory and confirmatory regression analyses were conducted testing hypothesized relationships with compassion.

RESULTS: Exploratory stepwise regression analysis (n = 650) indicated that participants who reported higher levels of compassion were more likely to be female, not currently in a married/married-like relationship, reported higher resilience levels, and had experienced more significant life events. Age, income level, past and current mental distress, and interactions between resilience and other predictors were not significantly related to compassion. The associations between greater self-reported compassion and being female, having greater resilience, and having experienced more significant life events were supported by a confirmatory stepwise regression analysis (n = 356).

CONCLUSIONS: Older women report more compassion than older men. Resilience and significant life events, independently, also appear to facilitate a desire to help others, while current stress and past and present emotional functioning are less relevant. Specificity of findings to older adults is not yet known.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Empathy, Female, Humans, Life Change Events, Male, Marital Status, Middle Aged, Regression Analysis, Resilience, Psychological, Sex Factors, Socioeconomic Factors}, issn = {1099-1166}, doi = {10.1002/gps.4123}, author = {Moore, Raeanne C and Martin, A{\textquoteright}verria Sirkin and Kaup, Allison R and Thompson, Wesley K and Peters, Matthew E and Jeste, Dilip V and Golshan, Shahrokh and Eyler, Lisa T} } @article {205, title = {Age-related changes in tissue signal properties within cortical areas important for word understanding in 12- to 19-month-old infants.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Jul}, pages = {1948-55}, abstract = {

Recently, our laboratory has shown that the neural mechanisms for encoding lexico-semantic information in adults operate functionally by 12-18 months of age within left frontotemporal cortices (Travis et al., 2011. Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants. Cereb Cortex. 8:1832-1839). However, there is minimal knowledge of the structural changes that occur within these and other cortical regions important for language development. To identify regional structural changes taking place during this important period in infant development, we examined age-related changes in tissue signal properties of gray matter (GM) and white matter (WM) intensity and contrast. T1-weighted surface-based measures were acquired from 12- to 19-month-old infants and analyzed using a general linear model. Significant age effects were observed for GM and WM intensity and contrast within bilateral inferior lateral and anterovental temporal regions, dorsomedial frontal, and superior parietal cortices. Region of interest (ROI) analyses revealed that GM and WM intensity and contrast significantly increased with age within the same left lateral temporal regions shown to generate lexico-semantic activity in infants and adults. These findings suggest that neurophysiological processes supporting linguistic and cognitive behaviors may develop before cellular and structural maturation is complete within associative cortices. These results have important implications for understanding the neurobiological mechanisms relating structural to functional brain development.

}, keywords = {Aging, Brain Mapping, Cerebral Cortex, Comprehension, Female, Humans, Image Processing, Computer-Assisted, Infant, Language Development, Magnetic Resonance Imaging, Male, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bht052}, author = {Travis, Katherine E and Curran, Megan M and Torres, Christina and Leonard, Matthew K and Brown, Timothy T and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @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 {176, title = {Nerve growth factor is primarily produced by GABAergic neurons of the adult rat cortex.}, journal = {Front Cell Neurosci}, volume = {8}, year = {2014}, month = {2014}, pages = {220}, abstract = {

Within the cortex, nerve growth factor (NGF) mediates the innervation of cholinergic neurons during development, maintains cholinergic corticopetal projections during adulthood and modulates cholinergic function through phenotypic control of the cholinergic gene locus. Recent studies suggest NGF may also play an important role in cortical plasticity in adulthood. Previously, NGF-producing cells have been shown to colocalize with GABAergic cell markers within the hippocampus, striatum, and basal forebrain. Classification of cells producing NGF in the cortex is lacking, however, and cholinergic corticopetal projections have been shown to innervate both pyramidal and GABAergic neurons in the cortex. In order to clarify potential trophic interactions between cortical neurons and cholinergic projections, we used double-fluorescent immunohistochemistry to classify NGF-expressing cells in several cortical regions, including the prefrontal cortex, primary motor cortex, parietal cortex and temporal cortex. Our results show that NGF colocalizes extensively with GABAergic cell markers in all cortical regions examined, with \>91\% of NGF-labeled cells coexpressing GAD65/67. Conversely, NGF-labeled cells exhibit very little co-localization with the excitatory cell marker CaMKIIα (\<5\% of cells expressing NGF). NGF expression was present in 56\% of GAD-labeled cells, suggesting that production is confined to a specific subset of GABAergic neurons. These findings demonstrate that GABAergic cells are the primary source of NGF production in the cortex, and likely support the maintenance and function of basal forebrain cholinergic projections in adulthood.

}, issn = {1662-5102}, doi = {10.3389/fncel.2014.00220}, author = {Biane, Jeremy and Conner, James M and Tuszynski, Mark H} } @article {185, title = {Neural language processing in adolescent first-language learners.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Oct}, pages = {2772-83}, abstract = {

The relation between the timing of language input and development of neural organization for language processing in adulthood has been difficult to tease apart because language is ubiquitous in the environment of nearly all infants. However, within the congenitally deaf population are individuals who do not experience language until after early childhood. Here, we investigated the neural underpinnings of American Sign Language (ASL) in 2 adolescents who had no sustained language input until they were approximately 14 years old. Using anatomically constrained magnetoencephalography, we found that recently learned signed words mainly activated right superior parietal, anterior occipital, and dorsolateral prefrontal areas in these 2 individuals. This spatiotemporal activity pattern was significantly different from the left fronto-temporal pattern observed in young deaf adults who acquired ASL from birth, and from that of hearing young adults learning ASL as a second language for a similar length of time as the cases. These results provide direct evidence that the timing of language experience over human development affects the organization of neural language processing.

}, keywords = {Adolescent, Adult, Age Factors, Cerebral Cortex, Critical Period (Psychology), Deafness, Female, Functional Laterality, Humans, Language Development, Learning, Magnetoencephalography, Male, Semantics, Sign Language, Young Adult}, issn = {1460-2199}, doi = {10.1093/cercor/bht137}, author = {Ferjan Ramirez, Naja and Leonard, Matthew K and Torres, Christina and Hatrak, Marla and Halgren, Eric and Mayberry, Rachel I} } @article {213, title = {Sparse and distributed coding of episodic memory in neurons of the human hippocampus.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Jul 1}, pages = {9621-6}, abstract = {

Neurocomputational models hold that sparse distributed coding is the most efficient way for hippocampal neurons to encode episodic memories rapidly. We investigated the representation of episodic memory in hippocampal neurons of nine epilepsy patients undergoing intracranial monitoring as they discriminated between recently studied words (targets) and new words (foils) on a recognition test. On average, single units and multiunits exhibited higher spike counts in response to targets relative to foils, and the size of this effect correlated with behavioral performance. Further analyses of the spike-count distributions revealed that (i) a small percentage of recorded neurons responded to any one target and (ii) a small percentage of targets elicited a strong response in any one neuron. These findings are consistent with the idea that in the human hippocampus episodic memory is supported by a sparse distributed neural code.

}, keywords = {Epilepsy, Hippocampus, Humans, Memory, Episodic, Models, Neurological, Neurophysiological Monitoring, Neuropsychological Tests}, issn = {1091-6490}, doi = {10.1073/pnas.1408365111}, author = {Wixted, John T and Squire, Larry R and Jang, Yoonhee and Papesh, Megan H and Goldinger, Stephen D and Kuhn, Joel R and Smith, Kris A and Treiman, David M and Steinmetz, Peter N} } @article {180, title = {Speech-specific tuning of neurons in human superior temporal gyrus.}, journal = {Cereb Cortex}, volume = {24}, year = {2014}, month = {2014 Oct}, pages = {2679-93}, abstract = {

How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45\% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words.

}, keywords = {Acoustic Stimulation, Adult, Humans, Male, Neurons, Phonetics, Speech Perception, Temporal Lobe}, issn = {1460-2199}, doi = {10.1093/cercor/bht127}, author = {Chan, Alexander M and Dykstra, Andrew R and Jayaram, Vinay and Leonard, Matthew K and Travis, Katherine E and Gygi, Brian and Baker, Janet M and Eskandar, Emad and Hochberg, Leigh R and Halgren, Eric and Cash, Sydney S} } @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 {204, title = {Independence of early speech processing from word meaning.}, journal = {Cereb Cortex}, volume = {23}, year = {2013}, month = {2013 Oct}, pages = {2370-9}, abstract = {

We combined magnetoencephalography (MEG) with magnetic resonance imaging and electrocorticography to separate in anatomy and latency 2 fundamental stages underlying speech comprehension. The first acoustic-phonetic stage is selective for words relative to control stimuli individually matched on acoustic properties. It begins \~{}60 ms after stimulus onset and is localized to middle superior temporal cortex. It was replicated in another experiment, but is strongly dissociated from the response to tones in the same subjects. Within the same task, semantic priming of the same words by a related picture modulates cortical processing in a broader network, but this does not begin until \~{}217 ms. The earlier onset of acoustic-phonetic processing compared with lexico-semantic modulation was significant in each individual subject. The MEG source estimates were confirmed with intracranial local field potential and high gamma power responses acquired in 2 additional subjects performing the same task. These recordings further identified sites within superior temporal cortex that responded only to the acoustic-phonetic contrast at short latencies, or the lexico-semantic at long. The independence of the early acoustic-phonetic response from semantic context suggests a limited role for lexical feedback in early speech perception.

}, keywords = {Adult, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Magnetoencephalography, Male, Speech Perception, Young Adult}, issn = {1460-2199}, doi = {10.1093/cercor/bhs228}, author = {Travis, Katherine E and Leonard, Matthew K and Chan, Alexander M and Torres, Christina and Sizemore, Marisa L and Qu, Zhe and Eskandar, Emad and Dale, Anders M and Elman, Jeffrey L and Cash, Sydney S and Halgren, Eric} } @article {189, title = {Neural stages of spoken, written, and signed word processing in beginning second language learners.}, journal = {Front Hum Neurosci}, volume = {7}, year = {2013}, month = {2013}, pages = {322}, abstract = {

WE COMBINED MAGNETOENCEPHALOGRAPHY (MEG) AND MAGNETIC RESONANCE IMAGING (MRI) TO EXAMINE HOW SENSORY MODALITY, LANGUAGE TYPE, AND LANGUAGE PROFICIENCY INTERACT DURING TWO FUNDAMENTAL STAGES OF WORD PROCESSING: (1) an early word encoding stage, and (2) a later supramodal lexico-semantic stage. Adult native English speakers who were learning American Sign Language (ASL) performed a semantic task for spoken and written English words, and ASL signs. During the early time window, written words evoked responses in left ventral occipitotemporal cortex, and spoken words in left superior temporal cortex. Signed words evoked activity in right intraparietal sulcus that was marginally greater than for written words. During the later time window, all three types of words showed significant activity in the classical left fronto-temporal language network, the first demonstration of such activity in individuals with so little second language (L2) instruction in sign. In addition, a dissociation between semantic congruity effects and overall MEG response magnitude for ASL responses suggested shallower and more effortful processing, presumably reflecting novice L2 learning. Consistent with previous research on non-dominant language processing in spoken languages, the L2 ASL learners also showed recruitment of right hemisphere and lateral occipital cortex. These results demonstrate that late lexico-semantic processing utilizes a common substrate, independent of modality, and that proficiency effects in sign language are comparable to those in spoken language.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2013.00322}, author = {Leonard, Matthew K and Ferjan Ramirez, Naja and Torres, Christina and Hatrak, Marla and Mayberry, Rachel I and Halgren, Eric} } @article {190, title = {Signed words in the congenitally deaf evoke typical late lexicosemantic responses with no early visual responses in left superior temporal cortex.}, journal = {J Neurosci}, volume = {32}, year = {2012}, month = {2012 Jul 11}, pages = {9700-5}, abstract = {

Congenitally deaf individuals receive little or no auditory input, and when raised by deaf parents, they acquire sign as their native and primary language. We asked two questions regarding how the deaf brain in humans adapts to sensory deprivation: (1) is meaning extracted and integrated from signs using the same classical left hemisphere frontotemporal network used for speech in hearing individuals, and (2) in deafness, is superior temporal cortex encompassing primary and secondary auditory regions reorganized to receive and process visual sensory information at short latencies? Using MEG constrained by individual cortical anatomy obtained with MRI, we examined an early time window associated with sensory processing and a late time window associated with lexicosemantic integration. We found that sign in deaf individuals and speech in hearing individuals activate a highly similar left frontotemporal network (including superior temporal regions surrounding auditory cortex) during lexicosemantic processing, but only speech in hearing individuals activates auditory regions during sensory processing. Thus, neural systems dedicated to processing high-level linguistic information are used for processing language regardless of modality or hearing status, and we do not find evidence for rewiring of afferent connections from visual systems to auditory cortex.

}, keywords = {Adolescent, Adult, Brain Mapping, Deafness, Evoked Potentials, Female, Functional Laterality, Humans, Magnetic Fields, Magnetic Resonance Imaging, Magnetoencephalography, Male, Photic Stimulation, Semantics, Sign Language, Temporal Lobe, Time Factors, Young Adult}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.1002-12.2012}, author = {Leonard, Matthew K and Ferjan Ramirez, Naja and Torres, Christina and Travis, Katherine E and Hatrak, Marla and Mayberry, Rachel I and Halgren, Eric} } @article {192, title = {Language proficiency modulates the recruitment of non-classical language areas in bilinguals.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e18240}, abstract = {

Bilingualism provides a unique opportunity for understanding the relative roles of proficiency and order of acquisition in determining how the brain represents language. In a previous study, we combined magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to examine the spatiotemporal dynamics of word processing in a group of Spanish-English bilinguals who were more proficient in their native language. We found that from the earliest stages of lexical processing, words in the second language evoke greater activity in bilateral posterior visual regions, while activity to the native language is largely confined to classical left hemisphere fronto-temporal areas. In the present study, we sought to examine whether these effects relate to language proficiency or order of language acquisition by testing Spanish-English bilingual subjects who had become dominant in their second language. Additionally, we wanted to determine whether activity in bilateral visual regions was related to the presentation of written words in our previous study, so we presented subjects with both written and auditory words. We found greater activity for the less proficient native language in bilateral posterior visual regions for both the visual and auditory modalities, which started during the earliest word encoding stages and continued through lexico-semantic processing. In classical left fronto-temporal regions, the two languages evoked similar activity. Therefore, it is the lack of proficiency rather than secondary acquisition order that determines the recruitment of non-classical areas for word processing.

}, keywords = {Adult, Brain Mapping, Female, Humans, Language, Language Development, Magnetic Resonance Imaging, Magnetoencephalography, Male, Multilingualism, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0018240}, author = {Leonard, Matthew K and Torres, Christina and Travis, Katherine E and Brown, Timothy T and Hagler, Donald J and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {206, title = {Spatiotemporal neural dynamics of word understanding in 12- to 18-month-old-infants.}, journal = {Cereb Cortex}, volume = {21}, year = {2011}, month = {2011 Aug}, pages = {1832-9}, abstract = {

Learning words is central in human development. However, lacking clear evidence for how or where language is processed in the developing brain, it is unknown whether these processes are similar in infants and adults. Here, we use magnetoencephalography in combination with high-resolution structural magnetic resonance imaging to noninvasively estimate the spatiotemporal distribution of word-selective brain activity in 12- to 18-month-old infants. Infants watched pictures of common objects and listened to words that they understood. A subset of these infants also listened to familiar words compared with sensory control sounds. In both experiments, words evoked a characteristic event-related brain response peaking \~{}400 ms after word onset, which localized to left frontotemporal cortices. In adults, this activity, termed the N400m, is associated with lexico-semantic encoding. Like adults, we find that the amplitude of the infant N400m is also modulated by semantic priming, being reduced to words preceded by a semantically related picture. These findings suggest that similar left frontotemporal areas are used for encoding lexico-semantic information throughout the life span, from the earliest stages of word learning. Furthermore, this ontogenetic consistency implies that the neurophysiological processes underlying the N400m may be important both for understanding already known words and for learning new words.

}, keywords = {Adult, Brain Mapping, Cerebral Cortex, Evoked Potentials, Auditory, Female, Humans, Infant, Language Tests, Learning, Magnetic Resonance Imaging, Magnetoencephalography, Male, Neurons, Speech Perception, Vocabulary}, issn = {1460-2199}, doi = {10.1093/cercor/bhq259}, author = {Travis, Katherine E and Leonard, Matthew K and Brown, Timothy T and Hagler, Donald J and Curran, Megan and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {191, title = {Spatiotemporal dynamics of bilingual word processing.}, journal = {Neuroimage}, volume = {49}, year = {2010}, month = {2010 Feb 15}, pages = {3286-94}, abstract = {

Studies with monolingual adults have identified successive stages occurring in different brain regions for processing single written words. We combined magnetoencephalography and magnetic resonance imaging to compare these stages between the first (L1) and second (L2) languages in bilingual adults. L1 words in a size judgment task evoked a typical left-lateralized sequence of activity first in ventral occipitotemporal cortex (VOT: previously associated with visual word-form encoding) and then ventral frontotemporal regions (associated with lexico-semantic processing). Compared to L1, words in L2 activated right VOT more strongly from approximately 135 ms; this activation was attenuated when words became highly familiar with repetition. At approximately 400 ms, L2 responses were generally later than L1, more bilateral, and included the same lateral occipitotemporal areas as were activated by pictures. We propose that acquiring a language involves the recruitment of right hemisphere and posterior visual areas that are not necessary once fluency is achieved.

}, keywords = {Adolescent, Adult, Brain, Brain Mapping, Female, Functional Laterality, Humans, Magnetoencephalography, Male, Multilingualism, Nerve Net, Pattern Recognition, Visual, Reading, Semantics, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2009.12.009}, author = {Leonard, Matthew K and Brown, Timothy T and Travis, Katherine E and Gharapetian, Lusineh and Hagler, Donald J and Dale, Anders M and Elman, Jeffrey L and Halgren, Eric} } @article {160, title = {A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.}, journal = {PLoS Comput Biol}, volume = {5}, year = {2009}, month = {2009 Mar}, pages = {e1000334}, abstract = {

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

}, keywords = {Animals, Brain, Databases, Factual, Humans, Macaca, Mice, Models, Neurological, Nerve Net, Neuroanatomy, Research Design}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000334}, author = {Bohland, Jason W and Wu, Caizhi and Barbas, Helen and Bokil, Hemant and Bota, Mihail and Breiter, Hans C and Cline, Hollis T and Doyle, John C and Freed, Peter J and Greenspan, Ralph J and Haber, Suzanne N and Hawrylycz, Michael and Herrera, Daniel G and Hilgetag, Claus C and Huang, Z Josh and Jones, Allan and Jones, Edward G and Karten, Harvey J and Kleinfeld, David and K{\"o}tter, Rolf and Lester, Henry A and Lin, John M and Mensh, Brett D and Mikula, Shawn and Panksepp, Jaak and Price, Joseph L and Safdieh, Joseph and Saper, Clifford B and Schiff, Nicholas D and Schmahmann, Jeremy D and Stillman, Bruce W and Svoboda, Karel and Swanson, Larry W and Toga, Arthur W and Van Essen, David C and Watson, James D and Mitra, Partha P} } @article {150, title = {Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait.}, journal = {Nat Genet}, volume = {31}, year = {2002}, month = {2002 Aug}, pages = {349-53}, abstract = {

Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never been identified using this classical model. To identify the individual genes involved in geotaxic response, we used cDNA microarrays to identify candidate genes and assessed fly lines mutant in these genes for behavioral confirmation. We have thus determined the identities of several genes that contribute to the complex, polygenic behavior of geotaxis.

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, DNA, Complementary, Drosophila melanogaster, Female, Genetics, Behavioral, Mutation, Oligonucleotide Array Sequence Analysis}, issn = {1061-4036}, doi = {10.1038/ng893}, author = {Toma, Daniel P and White, Kevin P and Hirsch, Jerry and Greenspan, Ralph J} } @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} }