@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} } @article {2288, title = {Electro-optical mechanically flexible coaxial microprobes for minimally invasive interfacing with intrinsic neural circuits.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Jun 07}, pages = {3286}, abstract = {

Central to advancing our understanding of neural circuits is developing minimally invasive, multi-modal interfaces capable of simultaneously recording and modulating neural activity. Recent devices have focused on matching the mechanical compliance of tissue to reduce inflammatory responses. However, reductions in the size of multi-modal interfaces are needed to further improve biocompatibility and long-term recording capabilities. Here a multi-modal coaxial microprobe design with a minimally invasive footprint (8-14 {\textmu}m diameter over millimeter lengths) that enables efficient electrical and optical interrogation of neural networks is presented. In the brain, the probes allowed robust electrical measurement and optogenetic stimulation. Scalable fabrication strategies can be used with various electrical and optical materials, making the probes highly customizable to experimental requirements, including length, diameter, and mechanical properties. Given their negligible inflammatory response, these probes promise to enable a new generation of readily tunable multi-modal devices for long-term, minimally invasive interfacing with neural circuits.

}, keywords = {Brain, Optogenetics}, issn = {2041-1723}, doi = {10.1038/s41467-022-30275-x}, author = {Ward, Spencer and Riley, Conor and Carey, Erin M and Nguyen, Jenny and Esener, Sadik and Nimmerjahn, Axel and Sirbuly, Donald J} } @article {2298, title = {Intestinal transgene delivery with native E.~coli chassis allows persistent physiological changes.}, journal = {Cell}, volume = {185}, year = {2022}, month = {2022 Aug 18}, pages = {3263-3277.e15}, abstract = {

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E.\ coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

}, keywords = {Animals, Bacteria, Escherichia coli, Gastrointestinal Microbiome, Mice, Microbiota, Transgenes}, issn = {1097-4172}, doi = {10.1016/j.cell.2022.06.050}, author = {Russell, Baylee J and Brown, Steven D and Siguenza, Nicole and Mai, Irene and Saran, Anand R and Lingaraju, Amulya and Maissy, Erica S and Dantas Machado, Ana C and Pinto, Antonio F M and Sanchez, Concepcion and Rossitto, Leigh-Ana and Miyamoto, Yukiko and Richter, R Alexander and Ho, Samuel B and Eckmann, Lars and Hasty, Jeff and Gonzalez, David J and Saghatelian, Alan and Knight, Rob and Zarrinpar, Amir} } @article {2291, title = {knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.}, journal = {Elife}, volume = {11}, year = {2022}, month = {2022 May 23}, abstract = {

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

}, keywords = {Animals, Brain, Disease Models, Animal, DNA Methyltransferase 3A, Histone Code, Histones, Mice, Mice, Knockout, Neurons, Polycomb Repressive Complex 2, Synapses}, issn = {2050-084X}, doi = {10.7554/eLife.66909}, author = {Li, Junhao and Pinto-Duarte, Ant{\'o}nio and Zander, Mark and Cuoco, Michael S and Lai, Chi-Yu and Osteen, Julia and Fang, Linjing and Luo, Chongyuan and Lucero, Jacinta D and Gomez-Castanon, Rosa and Nery, Joseph R and Silva-Garcia, Isai and Pang, Yan and Sejnowski, Terrence J and Powell, Susan B and Ecker, Joseph R and Mukamel, Eran A and Behrens, M Margarita} } @article {2289, title = {Lessons from the Stories of Women in Neuroscience.}, journal = {J Neurosci}, volume = {42}, year = {2022}, month = {2022 Jun 15}, pages = {4769-4773}, abstract = {

Women have been contributing to the field of neuroscience since its inception, but their accomplishments are often overlooked. Lack of recognition, among other issues, has led to progressively fewer women at each academic stage; although half of neuroscience graduate students are women, women comprise less than one-third of neuroscience faculty, and even fewer full professors. Those who reach this level continue to struggle to get their work recognized. Women from historically excluded backgrounds are even more starkly underrepresented and face added challenges related to racial, ethnic, and other biases. To increase the visibility of women in neuroscience, promote their voices, and learn about their career journeys, we created Stories of Women in Neuroscience (Stories of WiN). Stories of WiN shares the scientific and personal stories of women neuroscientists with diverse backgrounds, identities, research interests, and at various career stages. From \>70 women highlighted thus far, a major theme has emerged: there is not a single archetype of a woman neuroscientist, nor a single path to "success." Yet, through these diverse experiences run common threads, such as the importance of positive early research experiences, managing imposter syndrome, the necessity of work-life balance, and the challenges of fitting into-or resisting-the "scientist mold" within a patriarchal, racialized academic system. These commonalities reveal important considerations for supporting women neuroscientists. Through the lens of women highlighted by Stories of WiN, we explore the similarities among their journeys and detail specific actionable items to help encourage, support, and sustain women in neuroscience.

}, keywords = {Anxiety Disorders, Ethnicity, Female, Humans, Male, Neurosciences, Racial Groups, Self Concept}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0536-22.2022}, author = {Sibener, Leslie J and Kirchgessner, Megan A and Steiner, Sheila and Santiago, Chiaki and Cassataro, Daniela and Rossa, Marley and Profaci, Caterina P and Padilla-Coreano, Nancy} } @article {2179, title = {Valence opponency in peripheral olfactory processing.}, journal = {Proc Natl Acad Sci U S A}, volume = {119}, year = {2022}, month = {2022 Feb 01}, abstract = {

A hallmark of complex sensory systems is the organization of neurons into functionally meaningful maps, which allow for comparison and contrast of parallel inputs via lateral inhibition. However, it is unclear whether such a map exists in olfaction. Here, we address this question by determining the organizing principle underlying the stereotyped pairing of olfactory receptor neurons (ORNs) in sensory hairs, wherein compartmentalized neurons inhibit each other via ephaptic coupling. Systematic behavioral assays reveal that most paired ORNs antagonistically regulate the same type of behavior. Such valence opponency is relevant in critical behavioral contexts including place preference, egg laying, and courtship. Odor-mixture experiments show that ephaptic inhibition provides a peripheral means for evaluating and shaping countervailing cues relayed to higher brain centers. Furthermore, computational modeling suggests that this organization likely contributes to processing ratio information in odor mixtures. This olfactory valence map may have evolved to swiftly process ethologically meaningful odor blends without involving costly synaptic computation.

}, issn = {1091-6490}, doi = {10.1073/pnas.2120134119}, author = {Wu, Shiuan-Tze and Chen, Jen-Yung and Martin, Vanessa and Ng, Renny and Zhang, Ye and Grover, Dhruv and Greenspan, Ralph J and Aljadeff, Johnatan and Su, Chih-Ying} } @article {1789, title = {Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength.}, journal = {Elife}, volume = {10}, year = {2021}, month = {2021 Jan 21}, abstract = {

The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of , strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

}, issn = {2050-084X}, doi = {10.7554/eLife.63509}, author = {Li, Yunbo and Ritchie, Erin M and Steinke, Christopher L and Qi, Cai and Chen, Lizhen and Zheng, Binhai and Jin, Yishi} } @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 {1648, title = {Fast near-whole-brain imaging in adult Drosophila during responses to stimuli and behavior.}, journal = {PLoS Biol}, volume = {17}, year = {2019}, month = {2019 Feb}, pages = {e2006732}, abstract = {

Whole-brain recordings give us a global perspective of the brain in action. In this study, we describe a method using light field microscopy to record near-whole brain calcium and voltage activity at high speed in behaving adult flies. We first obtained global activity maps for various stimuli and behaviors. Notably, we found that brain activity increased on a global scale when the fly walked but not when it groomed. This global increase with walking was particularly strong in dopamine neurons. Second, we extracted maps of spatially distinct sources of activity as well as their time series using principal component analysis and independent component analysis. The characteristic shapes in the maps matched the anatomy of subneuropil regions and, in some cases, a specific neuron type. Brain structures that responded to light and odor were consistent with previous reports, confirming the new technique{\textquoteright}s validity. We also observed previously uncharacterized behavior-related activity as well as patterns of spontaneous voltage activity.

}, issn = {1545-7885}, doi = {10.1371/journal.pbio.2006732}, author = {Aimon, Sophie and Katsuki, Takeo and Jia, Tongqiu and Grosenick, Logan and Broxton, Michael and Deisseroth, Karl and Sejnowski, Terrence J and Greenspan, Ralph J} } @article {1807, title = {Impairments in remote memory caused by the lack of Type 2 IP3 receptors}, journal = {Glia}, volume = {67}, year = {2019}, pages = {1976-1989}, abstract = {

Abstract The second messenger inositol 1,4,5-trisphosphate (IP3) is paramount for signal transduction in biological cells, mediating Ca2+ release from the endoplasmic reticulum. Of the three isoforms of IP3 receptors identified in the nervous system, Type 2 (IP3R2) is the main isoform expressed by astrocytes. The complete lack of IP3R2 in transgenic mice was shown to significantly disrupt Ca2+ signaling in astrocytes, while leaving neuronal intracellular pathways virtually unperturbed. Whether and how this predominantly nonneuronal receptor might affect long-term memory function has been a matter of intense debate. In this work, we found that the absence of IP3R2-mediated signaling did not disrupt normal learning or recent (24{\textendash}48 h) memory. Contrary to expectations, however, mice lacking IP3R2 exhibited remote (2{\textendash}4 weeks) memory deficits. Not only did the lack of IP3R2 impair remote recognition, fear, and spatial memories, but it also prevented naturally occurring post-encoding memory enhancements consequent to memory consolidation. Consistent with the key role played by the downscaling of synaptic transmission in memory consolidation, we found that NMDAR-dependent long-term depression was abnormal in ex vivo hippocampal slices acutely prepared from IP3R2-deficient mice, a deficit that could be prevented upon supplementation with D-serine - an NMDA-receptor co-agonist whose synthesis depends upon astrocytes{\textquoteright} activity. Our results reveal that IP3R2 activation, which in the brain is paramount for Ca2+ signaling in astrocytes, but not in neurons, can help shape brain plasticity by enhancing the consolidation of newly acquired information into long-term memories that can guide remote cognitive behaviors.

}, keywords = {astrocyte, Behavior, Ca2+ signaling, long-term memory, synaptic plasticity}, doi = {https://doi.org/10.1002/glia.23679}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.23679}, author = {Pinto-Duarte, Ant{\'o}nio and Roberts, Amanda J. and Ouyang, Kunfu and Sejnowski, Terrence J.} } @article {1670, title = {Neonatal Nicotine Exposure Primes Midbrain Neurons to a Dopaminergic Phenotype and Increases Adult Drug Consumption.}, journal = {Biol Psychiatry}, volume = {86}, year = {2019}, month = {2019 Sep 01}, pages = {344-355}, abstract = {

BACKGROUND: Nicotine intake induces addiction through neuroplasticity of the reward circuitry, altering the activity of dopaminergic neurons of the ventral tegmental area. Prior work demonstrated that altered circuit activity can change neurotransmitter expression in the developing and adult brain. Here we investigated the effects of neonatal nicotine exposure on the dopaminergic system and nicotine consumption in adulthood.

METHODS: Male and female mice were used for two-bottle-choice test, progressive ratio breakpoint test, immunohistochemistry, RNAscope, quantitative polymerase chain reaction, calcium imaging, and DREADD (designer receptor exclusively activated by designer drugs)-mediated chemogenic activation/inhibition experiments.

RESULTS: Neonatal nicotine exposure potentiates drug preference in adult mice, induces alterations in calcium spike activity of midbrain neurons, and increases the number of dopamine-expressing neurons in the ventral tegmental area. Specifically, glutamatergic neurons are first primed to express transcription factor Nurr1, then acquire the dopaminergic phenotype following nicotine re-exposure in adulthood. Enhanced neuronal activity combined with Nurr1 expression is both necessary and sufficient for the nicotine-mediated neurotransmitter plasticity to occur.

CONCLUSIONS: Our findings illuminate a new mechanism of neuroplasticity by which early nicotine exposure primes the reward system to display increased susceptibility to drug consumption in adulthood.

}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2019.04.019}, author = {Romoli, Benedetto and Lozada, Adrian F and Sandoval, Ivette M and Manfredsson, Fredric P and Hnasko, Thomas S and Berg, Darwin K and Dulcis, Davide} } @article {1683, title = {Scaling Principles of Distributed Circuits.}, journal = {Curr Biol}, volume = {29}, year = {2019}, month = {2019 Aug 05}, pages = {2533-2540.e7}, abstract = {

Identifying shared quantitative features of a neural circuit across species is important for 3 reasons. Often expressed in the form of power laws and called scaling relationships [1, 2], they reveal organizational principles of circuits, make insights gleaned from model systems widely applicable, and explain circuit performance and function, e.g., visual circuits [3, 4]. The visual circuit is topographic [5, 6], wherein retinal neurons target and activate predictable spatial loci in primary visual cortex. The brain, however, contains many circuits, where neuronal targets and activity are unpredictable and distributed throughout the circuit, e.g., olfactory circuits, in which glomeruli (or\ mitral cells) in the olfactory bulb synapse with neurons distributed throughout the piriform cortex [7-10]. It is unknown whether such circuits, which we term distributed circuits, are scalable. To determine whether distributed circuits scale, we obtained quantitative descriptions of the olfactory bulb and piriform cortex in six mammals using stereology techniques and light microscopy. Two conserved features provide evidence of scalability. First, the number of piriform neurons n and bulb glomeruli g scale as n\~{}g. Second, the average number of synapses between a bulb glomerulus and piriform neuron is invariant at one. Using theory and modeling, we show that these two features preserve the discriminatory ability and precision of odor information across the olfactory circuit. As both abilities depend on circuit size, manipulating size provides evolution with a way to adapt a species to its niche\ without designing developmental programs de novo. These principles might apply to other distributed circuits like the hippocampus.

}, issn = {1879-0445}, doi = {10.1016/j.cub.2019.06.046}, author = {Srinivasan, Shyam and Stevens, Charles F} } @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 {1581, title = {Deep(er) Learning.}, journal = {J Neurosci}, volume = {38}, year = {2018}, month = {2018 Aug 22}, pages = {7365-7374}, abstract = {

Animals successfully thrive in noisy environments with finite resources. The necessity to function with resource constraints has led evolution to design animal brains (and bodies) to be optimal in their use of computational power while being adaptable to their environmental niche. A key process undergirding this ability to adapt is the process of learning. Although a complete characterization of the neural basis of learning remains ongoing, scientists for nearly a century have used the brain as inspiration to design artificial neural networks capable of learning, a case in point being deep learning. In this viewpoint, we advocate that deep learning can be further enhanced by incorporating and tightly integrating five fundamental principles of neural circuit design and function: optimizing the system to environmental need and making it robust to environmental noise, customizing learning to context, modularizing the system, learning without supervision, and learning using reinforcement strategies. We illustrate how animals integrate these learning principles using the fruit fly olfactory learning circuit, one of nature{\textquoteright}s best-characterized and highly optimized schemes for learning. Incorporating these principles may not just improve deep learning but also expose common computational constraints. With judicious use, deep learning can become yet another effective tool to understand how and why brains are designed the way they are.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0153-18.2018}, author = {Srinivasan, Shyam and Greenspan, Ralph J and Stevens, Charles F and Grover, Dhruv} } @article {1582, title = {The distributed circuit within the piriform cortex makes odor discrimination robust.}, journal = {J Comp Neurol}, volume = {526}, year = {2018}, month = {2018 Dec 01}, pages = {2725-2743}, abstract = {

Distributed circuits wherein connections between subcircuit components seem randomly distributed are common to the olfactory circuit, hippocampus, and cerebellum. In such circuits, activation patterns seem random too, showing no detectable spatial preference, and contrast with regions that have topographic connections between subcircuits and topographic activation patterns. Quantitative studies of topographic circuits in the neocortex have yielded common principles of organization. Whether distributed circuits share similar principles of organization is unknown because similar quantitative information is missing and understanding the way they encode information remains a challenge. We addressed these needs by providing a quantitative description of the mouse piriform cortex, a paleocortical distributed circuit that subserves olfaction. The quantitative information provided two insights. First, with a nearly parameter-free model of the olfactory circuit, we show that the piriform cortex robustly maintains odor information and discrimination ability present in the olfactory bulb. Second, the paleocortex is quantitatively different from the neocortex: it has a lower surface area density, which decreases from the anterior to posterior paleocortex contrasting with the uniform neuronal density of the neocortex. These insights might also apply to other distributed circuits.

}, issn = {1096-9861}, doi = {10.1002/cne.24492}, author = {Srinivasan, Shyam and Stevens, Charles F} } @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 {1687, title = {How struggling adult readers use contextual information when comprehending speech: Evidence from event-related potentials.}, journal = {Int J Psychophysiol}, volume = {125}, year = {2018}, month = {2018 03}, pages = {1-9}, abstract = {

We investigated how struggling adult readers make use of sentence context to facilitate word processing when comprehending spoken language, conditions under which print decoding is not a barrier to comprehension. Stimuli were strongly and weakly constraining sentences (as measured by cloze probability), which ended with the most expected word based on those constraints or an unexpected but plausible word. Community-dwelling adults with varying literacy skills listened to continuous speech while their EEG was recorded. Participants, regardless of literacy level, showed N400 effects yoked to the cloze probability of the targets, with larger N400 amplitudes for less expected than more expected words. However, literacy-related differences emerged in an earlier time window of 170-300 ms: higher literacy adults produced a reduced negativity for strongly predictable targets over anterior channels, similar to previously reported effects on the Phonological Mapping Negativity (PMN), whereas low-literacy adults did not. Collectively, these findings suggest that in auditory sentence processing literacy may not notably affect the incremental activation of semantic features, but that comprehenders with underdeveloped literacy skills may be less likely to engage predictive processing. Thus, basic mechanisms of comprehension may be recruited differently as a function of literacy development-even in spoken language.

}, keywords = {Adult, Aged, Brain Mapping, Comprehension, Electroencephalography, Evoked Potentials, Female, Humans, Literacy, Male, Middle Aged, Neuropsychological Tests, Photic Stimulation, Reaction Time, Reading, Speech, Young Adult}, issn = {1872-7697}, doi = {10.1016/j.ijpsycho.2018.01.013}, author = {Ng, Shukhan and Payne, Brennan R and Stine-Morrow, Elizabeth A L and Federmeier, Kara D} } @article {1697, title = {A neural data structure for novelty detection.}, journal = {Proc Natl Acad Sci U S A}, volume = {115}, year = {2018}, month = {2018 12 18}, pages = {13093-13098}, abstract = {

Novelty detection is a fundamental biological problem that organisms must solve to determine whether a given stimulus departs from those previously experienced. In computer science, this problem is solved efficiently using a data structure called a Bloom filter. We found that the fruit fly olfactory circuit evolved a variant of a Bloom filter to assess the novelty of odors. Compared with a traditional Bloom filter, the fly adjusts novelty responses based on two additional features: the similarity of an odor to previously experienced odors and the time elapsed since the odor was last experienced. We elaborate and validate a framework to predict novelty responses of fruit flies to given pairs of odors. We also translate insights from the fly circuit to develop a class of distance- and time-sensitive Bloom filters that outperform prior filters when evaluated on several biological and computational datasets. Overall, our work illuminates the algorithmic basis of an important neurobiological problem and offers strategies for novelty detection in computational systems.

}, keywords = {Algorithms, Animals, Drosophila, Models, Biological, Nerve Net, Neural Networks (Computer), Odorants, Olfactory Pathways}, issn = {1091-6490}, doi = {10.1073/pnas.1814448115}, author = {Dasgupta, Sanjoy and Sheehan, Timothy C and Stevens, Charles F and Navlakha, Saket} } @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 {1468, title = {Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference.}, journal = {Neuron}, volume = {95}, year = {2017}, month = {2017 Sep 13}, pages = {1319-1333.e5}, abstract = {

Changes in social preference of amphibian larvae result from sustained exposure to kinship odorants. To understand the molecular and cellular mechanisms of this neuroplasticity, we investigated the effects of olfactory system activation on neurotransmitter (NT) expression in accessory olfactory bulb (AOB) interneurons during development. We show that protracted exposure to kin or non-kin odorants\ changes the number of dopamine (DA)- or gamma aminobutyric acid (GABA)-expressing neurons, with\ corresponding changes in attraction/aversion behavior. Changing the relative number of dopaminergic and GABAergic AOB interneurons or locally introducing DA or GABA receptor antagonists alters kinship preference. We then isolate AOB microRNAs (miRs) differentially regulated across these conditions. Inhibition of miR-375 and miR-200b reveals that they target Pax6 and Bcl11b to regulate the dopaminergic and GABAergic phenotypes. The results illuminate the role of NT switching governing experience-dependent social preference. VIDEO ABSTRACT.

}, keywords = {Animals, Choice Behavior, Dopamine, Dopamine Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Interneurons, MicroRNAs, Neurons, Neurotransmitter Agents, Olfactory Bulb, PAX6 Transcription Factor, Pheromones, Siblings, Social Behavior, Transcription Factors, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2017.08.023}, author = {Dulcis, Davide and Lippi, Giordano and Stark, Christiana J and Do, Long H and Berg, Darwin K and Spitzer, Nicholas C} } @article {1674, title = {Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.}, journal = {Int J Geriatr Psychiatry}, volume = {32}, year = {2017}, month = {2017 Mar}, pages = {341-349}, abstract = {

OBJECTIVE: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called {\textquoteright}inflammaging.{\textquoteright} Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults.

METHODS: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP).

RESULTS: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load.

CONCLUSIONS: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.

}, keywords = {Aged, Brain Mapping, C-Reactive Protein, Cognition, Cognitive Dysfunction, Female, Frontal Lobe, Humans, Inflammation, Interleukin-6, Magnetic Resonance Imaging, Male, Memory, Short-Term, Parietal Lobe, Rest}, issn = {1099-1166}, doi = {10.1002/gps.4482}, author = {Dev, Sheena I and Moore, Raeanne C and Soontornniyomkij, Benchawanna and Achim, Cristian L and Jeste, Dilip V and Eyler, Lisa T} } @article {123, title = {Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {259-75}, abstract = {

There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.

}, keywords = {Adenoviridae, Age Factors, Animals, Endothelin-1, Female, Genetic Vectors, Humans, Injections, Intramuscular, Locomotion, Magnetic Resonance Imaging, Microinjections, Muscle, Skeletal, Neuroimaging, Neurotrophin 3, Pyramidal Tracts, Rats, Recovery of Function, Spinal Cord, Stroke, Time Factors}, issn = {1460-2156}, doi = {10.1093/brain/awv341}, author = {Duricki, Denise A and Hutson, Thomas H and Kathe, Claudia and Soleman, Sara and Gonzalez-Carter, Daniel and Petruska, Jeffrey C and Shine, H David and Chen, Qin and Wood, Tobias C and Bernanos, Michel and Cash, Diana and Williams, Steven C R and Gage, Fred H and Moon, Lawrence D F} } @article {1681, title = {Marmosets: A Neuroscientific Model of Human Social Behavior.}, journal = {Neuron}, volume = {90}, year = {2016}, month = {2016 04 20}, pages = {219-33}, abstract = {

The common marmoset (Callithrix jacchus) has garnered interest recently as a powerful model for the future of neuroscience research. Much of this excitement has centered on the species{\textquoteright} reproductive biology and compatibility with gene editing techniques, which together have provided a path for transgenic marmosets to contribute to the study of disease as well as basic brain mechanisms. In step with technical advances is the need to establish experimental paradigms that optimally tap into the marmosets{\textquoteright} behavioral and cognitive capacities. While conditioned task performance of a marmoset can compare unfavorably with rhesus monkey performance on conventional testing paradigms, marmosets{\textquoteright} social behavior and cognition are more similar to that of humans. For example, marmosets are among only a handful of primates that, like humans, routinely pair bond and care cooperatively for their young. They are also notably pro-social and exhibit social cognitive abilities, such as imitation, that are rare outside of the Apes. In this Primer, we describe key facets of marmoset natural social behavior and demonstrate that emerging behavioral paradigms are well suited to isolate components of marmoset cognition that are highly relevant to humans. These approaches generally embrace natural behavior, which has been rare in conventional primate testing, and thus allow for a new consideration of neural mechanisms underlying primate social cognition and signaling. We anticipate that through parallel technical and paradigmatic advances, marmosets will\ become an essential model of human social behavior, including its dysfunction in neuropsychiatric disorders.

}, keywords = {Animals, Animals, Genetically Modified, Brain, Callithrix, Cognition, Disease Models, Animal, Eye Movements, Haplorhini, Humans, Models, Animal, Rodentia, Social Behavior, Social Behavior Disorders, Vocalization, Animal}, issn = {1097-4199}, doi = {10.1016/j.neuron.2016.03.018}, author = {Miller, Cory T and Freiwald, Winrich A and Leopold, David A and Mitchell, Jude F and Silva, Afonso C and Wang, Xiaoqin} } @article {125, title = {Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.}, journal = {Neurobiol Learn Mem}, volume = {129}, year = {2016}, month = {2016 Mar}, pages = {60-8}, abstract = {

Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness.

}, issn = {1095-9564}, doi = {10.1016/j.nlm.2015.10.013}, author = {Johnston, Stephen T and Shtrahman, Matthew and Parylak, Sarah and Gon{\c c}alves, J Tiago and Gage, Fred H} } @article {1672, title = {Temporal and spatial tuning of dorsal lateral geniculate nucleus neurons in unanesthetized rats.}, journal = {J Neurophysiol}, volume = {115}, year = {2016}, month = {2016 06 01}, pages = {2658-71}, abstract = {

Visual response properties of neurons in the dorsolateral geniculate nucleus (dLGN) have been well described in several species, but not in rats. Analysis of responses from the unanesthetized rat dLGN will be needed to develop quantitative models that account for visual behavior of rats. We recorded visual responses from 130 single units in the dLGN of 7 unanesthetized rats. We report the response amplitudes, temporal frequency, and spatial frequency sensitivities in this population of cells. In response to 2-Hz visual stimulation, dLGN cells fired 15.9 {\textpm} 11.4 spikes/s (mean {\textpm} SD) modulated by 10.7 {\textpm} 8.4 spikes/s about the mean. The optimal temporal frequency for full-field stimulation ranged from 5.8 to 19.6 Hz across cells. The temporal high-frequency cutoff ranged from 11.7 to 33.6 Hz. Some cells responded best to low temporal frequency stimulation (low pass), and others were strictly bandpass; most cells fell between these extremes. At 2- to 4-Hz temporal modulation, the spatial frequency of drifting grating that drove cells best ranged from 0.008 to 0.18 cycles per degree (cpd) across cells. The high-frequency cutoff ranged from 0.01 to 1.07 cpd across cells. The majority of cells were driven best by the lowest spatial frequency tested, but many were partially or strictly bandpass. We conclude that single units in the rat dLGN can respond vigorously to temporal modulation up to at least 30 Hz and spatial detail up to 1 cpd. Tuning properties were heterogeneous, but each fell along a continuum; we found no obvious clustering into discrete cell types along these dimensions.

}, keywords = {Animals, Evoked Potentials, Visual, Geniculate Bodies, Male, Neurons, Rats, Rats, Long-Evans, Wakefulness}, issn = {1522-1598}, doi = {10.1152/jn.00812.2014}, author = {Sriram, Balaji and Meier, Philip M and Reinagel, Pamela} } @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 {127, title = {Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.}, journal = {Nature}, volume = {527}, year = {2015}, month = {2015 Nov 5}, pages = {95-9}, abstract = {

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15\% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

}, keywords = {Action Potentials, Antipsychotic Agents, Bipolar Disorder, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques}, issn = {1476-4687}, doi = {10.1038/nature15526}, author = {Mertens, Jerome and Wang, Qiu-Wen and Kim, Yongsung and Yu, Diana X and Pham, Son and Yang, Bo and Zheng, Yi and Diffenderfer, Kenneth E and Zhang, Jian and Soltani, Sheila and Eames, Tameji and Schafer, Simon T and Boyer, Leah and Marchetto, Maria C and Nurnberger, John I and Calabrese, Joseph R and {\O}degaard, Ketil J and McCarthy, Michael J and Zandi, Peter P and Alda, Martin and Alba, Martin and Nievergelt, Caroline M and Mi, Shuangli and Brennand, Kristen J and Kelsoe, John R and Gage, Fred H and Yao, Jun} } @article {168, title = {High-throughput and quantitative approaches for measuring circadian rhythms in cyanobacteria using bioluminescence.}, journal = {Methods Enzymol}, volume = {551}, year = {2015}, month = {2015}, pages = {53-72}, abstract = {

The temporal measurement of a bioluminescent reporter has proven to be one of the most powerful tools for characterizing circadian rhythms in the cyanobacterium Synechococcus elongatus. Primarily, two approaches have been used to automate this process: (1) detection of cell culture bioluminescence in 96-well plates by a photomultiplier tube-based plate-cycling luminometer (TopCount Microplate Scintillation and Luminescence Counter, Perkin Elmer) and (2) detection of individual colony bioluminescence by iteratively rotating a Petri dish under a cooled CCD camera using a computer-controlled turntable. Each approach has distinct advantages. The TopCount provides a more quantitative measurement of bioluminescence, enabling the direct comparison of clock output levels among strains. The computer-controlled turntable approach has a shorter set-up time and greater throughput, making it a more powerful phenotypic screening tool. While the latter approach is extremely useful, only a few labs have been able to build such an apparatus because of technical hurdles involved in coordinating and controlling both the camera and the turntable, and in processing the resulting images. This protocol provides instructions on how to construct, use, and process data from a computer-controlled turntable to measure the temporal changes in bioluminescence of individual cyanobacterial colonies. Furthermore, we describe how to prepare samples for use with the TopCount to minimize experimental noise and generate meaningful quantitative measurements of clock output levels for advanced analysis.

}, keywords = {Circadian Clocks, Culture Techniques, Cyanobacteria, Image Processing, Computer-Assisted, Luminescent Measurements}, issn = {1557-7988}, doi = {10.1016/bs.mie.2014.10.010}, author = {Shultzaberger, Ryan K and Paddock, Mark L and Katsuki, Takeo and Greenspan, Ralph J and Golden, Susan S} } @article {129, title = {Primate-specific ORF0 contributes to retrotransposon-mediated diversity.}, journal = {Cell}, volume = {163}, year = {2015}, month = {2015 Oct 22}, pages = {583-93}, abstract = {

LINE-1 retrotransposons are fast-evolving mobile genetic entities that play roles in gene regulation, pathological conditions, and evolution. Here, we show that the primate LINE-1 5{\textquoteright}UTR contains a primate-specific open reading frame (ORF) in the antisense orientation that we named ORF0. The gene product of this ORF localizes to promyelocytic leukemia-adjacent nuclear bodies. ORF0 is present in more than 3,000 loci across human and chimpanzee genomes and has a promoter and a conserved strong Kozak sequence that supports translation. By virtue of containing two splice donor sites, ORF0 can also form fusion proteins with proximal exons. ORF0 transcripts are readily detected in induced pluripotent stem (iPS) cells from both primate species. Capped and polyadenylated ORF0 mRNAs are present in the cytoplasm, and endogenous ORF0 peptides are identified upon proteomic analysis. Finally, ORF0 enhances LINE-1 mobility. Taken together, these results suggest a role for ORF0 in retrotransposon-mediated diversity.

}, keywords = {5{\textquoteright} Untranslated Regions, Amino Acid Sequence, Animals, Base Sequence, Cytoplasm, Humans, Long Interspersed Nucleotide Elements, Molecular Sequence Data, Nuclear Proteins, Open Reading Frames, Pan troglodytes, Retroelements, Ribosomes, RNA Processing, Post-Transcriptional, RNA, Antisense, RNA, Messenger, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2015.09.025}, author = {Denli, Ahmet M and Narvaiza, I{\~n}igo and Kerman, Bilal E and Pena, Monique and Benner, Christopher and Marchetto, Maria C N and Diedrich, Jolene K and Aslanian, Aaron and Ma, Jiao and Moresco, James J and Moore, Lynne and Hunter, Tony and Saghatelian, Alan and Gage, Fred H} } @article {126, title = {REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II.}, journal = {J Neurosci}, volume = {35}, year = {2015}, month = {2015 Nov 4}, pages = {14872-84}, abstract = {

UNLABELLED: RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non-cell-autonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non-cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non-cell-autonomously via SCG2.

SIGNIFICANCE STATEMENT: Our results reveal that REST regulates differentiation and maturation of neural progenitor cells in vitro by orchestrating both cell-intrinsic and non-cell-autonomous factors and that Scg2 is a major secretory target of REST with a differentiation-enhancing activity in a paracrine manner. In vivo, REST depletion causes accelerated differentiation of newborn neurons at the expense of spine defects, suggesting a potential role for REST in the timing of the maturation of granule neurons.

}, keywords = {Animals, Cell Differentiation, Cells, Cultured, Female, Hippocampus, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Neurons, Rats, Wistar, Repressor Proteins, Secretogranin II}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4286-14.2015}, author = {Kim, Hyung Joon and Denli, Ahmet M and Wright, Rebecca and Baul, Tithi D and Clemenson, Gregory D and Morcos, Ari S and Zhao, Chunmei and Schafer, Simon T and Gage, Fred H and Kagalwala, Mohamedi N} } @article {121, title = {Synaptic activity: An emerging player in schizophrenia.}, journal = {Brain Res}, year = {2015}, month = {2015 Dec 23}, abstract = {

Schizophrenia is a polygenic disorder with a complex etiology. While the genetic and molecular underpinnings of the disease are poorly understood, variations in genes encoding synaptic pathways are consistently implicated. Although its impact is still an open question, a deficit in synaptic activity provides an attractive model to explain the cognitive etiology of schizophrenia. Recent advances in high-throughput imaging and functional studies bring new hope for the application of in vitro disease modeling with patient-derived neurons to empirically ascertain the extent to which these synaptic pathways are involved in the disease. In addition, the emergent avenue of research targeted to probe neuronal connections is revealing critical insight into circuitry and may influence how we think about psychiatric disorders in the near future. This article is part of a Special Issue entitled SI: Exploiting human neurons.

}, issn = {1872-6240}, doi = {10.1016/j.brainres.2015.12.028}, author = {Sarkar, Anindita and Marchetto, Maria C and Gage, Fred H} } @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 {140, title = {Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching.}, journal = {Neuron}, volume = {82}, year = {2014}, month = {2014 Jun 4}, pages = {1004-16}, abstract = {

Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis, but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-gamma-aminobutyric acid (GABA) switching is cell autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that brain-derived neurotrophic factor (BDNF) is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons.

}, keywords = {Animals, Brain-Derived Neurotrophic Factor, Calcium, Cells, Cultured, Female, gamma-Aminobutyric Acid, Glutamic Acid, JNK Mitogen-Activated Protein Kinases, Neurons, Phosphorylation, Proto-Oncogene Proteins c-jun, Signal Transduction, Spinal Cord, Xenopus laevis}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.04.029}, author = {Guemez-Gamboa, Alicia and Xu, Lin and Meng, Da and Spitzer, Nicholas C} } @article {167, title = {Prospective Optimization.}, journal = {Proc IEEE Inst Electr Electron Eng}, volume = {102}, year = {2014}, month = {2014 May}, abstract = {

Human performance approaches that of an ideal observer and optimal actor in some perceptual and motor tasks. These optimal abilities depend on the capacity of the cerebral cortex to store an immense amount of information and to flexibly make rapid decisions. However, behavior only approaches these limits after a long period of learning while the cerebral cortex interacts with the basal ganglia, an ancient part of the vertebrate brain that is responsible for learning sequences of actions directed toward achieving goals. Progress has been made in understanding the algorithms used by the brain during reinforcement learning, which is an online approximation of dynamic programming. Humans also make plans that depend on past experience by simulating different scenarios, which is called prospective optimization. The same brain structures in the cortex and basal ganglia that are active online during optimal behavior are also active offline during prospective optimization. The emergence of general principles and algorithms for goal-directed behavior has consequences for the development of autonomous devices in engineering applications.

}, issn = {0018-9219}, doi = {10.1109/JPROC.2014.2314297}, author = {Sejnowski, Terrence J and Poizner, Howard and Lynch, Gary and Gepshtein, Sergei and Greenspan, Ralph J} } @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 {197, title = {Tool morphology constrains the effects of tool use on body representations.}, journal = {J Exp Psychol Hum Percept Perform}, volume = {40}, year = {2014}, month = {2014 Dec}, pages = {2143-53}, abstract = {

What factors constrain whether tool use modulates the user{\textquoteright}s body representations? To date, studies on representational plasticity following tool use have primarily focused on the act of using the tool. Here, we investigated whether the tool{\textquoteright}s morphology also serves to constrain plasticity. In 2 experiments, we varied whether the tool was morphologically similar to a target body part (Experiment 1, hand; Experiment 2, arm). Participants judged the tactile distance between pairs of points applied to their tool-using target body surface and forehead (control surface) before and after tool use. We applied touch in 2 orientations, allowing us to quantify how tool use modulates the representation{\textquoteright}s shape. Significant representational plasticity in hand shape (increase in width, decrease in length) was found when the tool was morphologically similar to a hand (Experiment 1A), but not when the tool was arm-shaped (Experiment 1B). Conversely, significant representational plasticity was found on the arm when the tool was arm-shaped (Experiment 2B), but not when hand-shaped (Experiment 2A). Taken together, our results indicate that morphological similarity between the tool and the effector constrains tool-induced representational plasticity. The embodiment of tools may thus depend on a match-to-template process between tool morphology and representation of the body.

}, keywords = {Adolescent, Adult, Body Image, Discrimination (Psychology), Distance Perception, Female, Form Perception, Humans, Judgment, Male, Size Perception, Tool Use Behavior, Touch Perception, Young Adult}, issn = {1939-1277}, doi = {10.1037/a0037777}, author = {Miller, Luke E and Longo, Matthew R and Saygin, Ayse P} } @article {138, title = {Activity-dependent competition regulates motor neuron axon pathfinding via PlexinA3.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Jan 22}, pages = {1524-9}, abstract = {

The role of electrical activity in axon guidance has been extensively studied in vitro. To better understand its role in the intact nervous system, we imaged intracellular Ca(2+) in zebrafish primary motor neurons (PMN) during axon pathfinding in vivo. We found that PMN generate specific patterns of Ca(2+) spikes at different developmental stages. Spikes arose in the distal axon of PMN and were propagated to the cell body. Suppression of Ca(2+) spiking activity in single PMN led to stereotyped errors, but silencing all electrical activity had no effect on axon guidance, indicating that an activity-based competition rule regulates this process. This competition was not mediated by synaptic transmission. Combination of PlexinA3 knockdown with suppression of Ca(2+) activity in single PMN produced a synergistic increase in the incidence of pathfinding errors. However, expression of PlexinA3 transcripts was not regulated by activity. Our results provide an in vivo demonstration of the intersection of spontaneous electrical activity with the PlexinA3 guidance molecule receptor in regulation of axon pathfinding.

}, keywords = {Animals, Animals, Genetically Modified, Axons, Calcium Signaling, Gene Knockdown Techniques, Humans, Motor Neurons, Neural Pathways, Potassium Channels, Inwardly Rectifying, Receptors, Cell Surface, Recombinant Proteins, Synaptic Transmission, Zebrafish, Zebrafish Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.1213048110}, author = {Plazas, Paola V and Nicol, Xavier and Spitzer, Nicholas C} } @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 {158, title = {Neuroscience. The brain activity map.}, journal = {Science}, volume = {339}, year = {2013}, month = {2013 Mar 15}, pages = {1284-5}, keywords = {Brain Diseases, Brain Mapping, Hippocampus, Humans, Neural Pathways, Neurons}, issn = {1095-9203}, doi = {10.1126/science.1236939}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Deisseroth, Karl and Donoghue, John P and Greenspan, Ralph J and McEuen, Paul L and Roukes, Michael L and Sejnowski, Terrence J and Weiss, Paul S and Yuste, Rafael} } @article {139, title = {Neurotransmitter switching in the adult brain regulates behavior.}, journal = {Science}, volume = {340}, year = {2013}, month = {2013 Apr 26}, pages = {449-53}, abstract = {

Neurotransmitters have been thought to be fixed throughout life, but whether sensory stimuli alter behaviorally relevant transmitter expression in the mature brain is unknown. We found that populations of interneurons in the adult rat hypothalamus switched between dopamine and somatostatin expression in response to exposure to short- and long-day photoperiods. Changes in postsynaptic dopamine receptor expression matched changes in presynaptic dopamine, whereas somatostatin receptor expression remained constant. Pharmacological blockade or ablation of these dopaminergic neurons led to anxious and depressed behavior, phenocopying performance after exposure to the long-day photoperiod. Induction of newly dopaminergic neurons through exposure to the short-day photoperiod rescued the behavioral consequences of lesions. Natural stimulation of other sensory modalities may cause changes in transmitter expression that regulate different behaviors.

}, keywords = {Animals, Behavior, Animal, Brain, Cell Count, Dopamine, Dopaminergic Neurons, Hypothalamus, Male, Maze Learning, Photoperiod, Rats, Rats, Long-Evans, Receptors, Dopamine, Receptors, Somatostatin, Seasons, Somatostatin, Stress, Psychological, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.1234152}, author = {Dulcis, Davide and Jamshidi, Pouya and Leutgeb, Stefan and Spitzer, Nicholas C} } @article {188, title = {Static sound timing alters sensitivity to low-level visual motion.}, journal = {J Vis}, volume = {12}, year = {2012}, month = {2012}, abstract = {

Visual motion processing is essential to survival in a dynamic world and is probably the best-studied facet of visual perception. It has been recently discovered that the timing of brief static sounds can bias visual motion perception, an effect attributed to "temporal ventriloquism" whereby the timing of the sounds "captures" the timing of the visual events. To determine whether this cross-modal interaction is dependent on the involvement of higher-order attentive tracking mechanisms, we used near-threshold motion stimuli that isolated low-level pre-attentive visual motion processing. We found that the timing of brief sounds altered sensitivity to these visual motion stimuli in a manner that paralleled changes in the timing of the visual stimuli. Our findings indicate that auditory timing impacts visual motion processing very early in the processing hierarchy and without the involvement of higher-order attentional and/or position tracking mechanisms.

}, keywords = {Acoustic Stimulation, Attention, Auditory Perception, Humans, Motion Perception, Photic Stimulation, Sound, Time Perception}, issn = {1534-7362}, doi = {10.1167/12.11.2}, author = {Kafaligonul, Hulusi and Stoner, Gene R} } @article {212, title = {Neural substrates of time perception and impulsivity.}, journal = {Brain Res}, volume = {1406}, year = {2011}, month = {2011 Aug 11}, pages = {43-58}, abstract = {

Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18s using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s intervals within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the {\textquoteright}core control network{\textquoteright} - encompassing the inferior frontal and medial frontal cortices, the anterior insula as well as the inferior parietal cortex - were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.

}, keywords = {Adolescent, Brain, Brain Mapping, Female, Humans, Image Processing, Computer-Assisted, Impulsive Behavior, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Oxygen, Personality Inventory, Reaction Time, Self Report, Surveys and Questionnaires, Time Factors, Time Perception, Young Adult}, issn = {1872-6240}, doi = {10.1016/j.brainres.2011.06.048}, author = {Wittmann, Marc and Simmons, Alan N and Flagan, Taru and Lane, Scott D and Wackermann, Ji{\v r}{\'\i} and Paulus, Martin P} } @article {137, title = {Spatial and temporal second messenger codes for growth cone turning.}, journal = {Proc Natl Acad Sci U S A}, volume = {108}, year = {2011}, month = {2011 Aug 16}, pages = {13776-81}, abstract = {

Cyclic AMP (cAMP) and calcium are ubiquitous, interdependent second messengers that regulate a wide range of cellular processes. During development of neuronal networks they are critical for the first step of circuit formation, transducing signals required for axon pathfinding. Surprisingly, the spatial and temporal cAMP and calcium codes used by axon guidance molecules are unknown. Here, we identify characteristics of cAMP and calcium transients generated in growth cones during Netrin-1-dependent axon guidance. In filopodia, Netrin-1-dependent Deleted in Colorectal Cancer (DCC) receptor activation induces a transient increase in cAMP that causes a brief increase in calcium transient frequency. In contrast, activation of DCC in growth cone centers leads to a transient calcium-dependent cAMP increase and a sustained increase in frequency of calcium transients. We show that filopodial cAMP transients regulate spinal axon guidance in vitro and commissural axon pathfinding in vivo. These growth cone codes provide a basis for selective activation of specific downstream effectors.

}, keywords = {Animals, Axons, Calcium, Cells, Cultured, Cyclic AMP, Growth Cones, Nerve Growth Factors, Neurons, Pseudopodia, Receptors, Cell Surface, Second Messenger Systems, Tumor Suppressor Proteins, Xenopus}, issn = {1091-6490}, doi = {10.1073/pnas.1100247108}, author = {Nicol, Xavier and Hong, Kwan Pyo and Spitzer, Nicholas C} } @article {211, title = {Accumulation of neural activity in the posterior insula encodes the passage of time.}, journal = {Neuropsychologia}, volume = {48}, year = {2010}, month = {2010 Aug}, pages = {3110-20}, abstract = {

A number of studies have examined the perception of time with durations ranging from milliseconds to a few seconds, however the neural basis of these processes are still poorly understood and the neural substrates underlying the perception of multiple-second intervals are unknown. Here we present evidence of neural systems activity in circumscribed areas of the human brain involved in the encoding of intervals with durations of 9 and 18s in a temporal reproduction task using event-related functional magnetic resonance imaging (fMRI). During the encoding there was greater activation in more posterior parts of the medial frontal and insular cortex whereas the reproduction phase involved more anterior parts of these brain structures. Intriguingly, activation curves over time show an accumulating pattern of neural activity, which peaks at the end of the interval within bilateral posterior insula and superior temporal cortex when individuals are presented with 9- and 18-s tone intervals. This is consistent with an accumulator-type activity, which encodes duration in the multiple seconds range. Given the close connection between the dorsal posterior insula and ascending internal body signals, we suggest that the accumulation of physiological changes in body states constitutes our experience of time. This is the first time that an accumulation function in the posterior insula is detected that might be correlated with the encoding of time intervals.

}, keywords = {Adult, Analysis of Variance, Brain Mapping, Cerebral Cortex, Factor Analysis, Statistical, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Oxygen, Reaction Time, Time Factors, Time Perception, Young Adult}, issn = {1873-3514}, doi = {10.1016/j.neuropsychologia.2010.06.023}, author = {Wittmann, Marc and Simmons, Alan N and Aron, Jennifer L and Paulus, Martin P} } @article {136, title = {Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Jul 29}, pages = {321-34}, abstract = {

Genetic programs, environmental factors, and electrical activity interact to drive the maturation of the brain. Although the cascade of transcription factors that leads to specification of the serotonergic phenotype has been well characterized, its interactions with electrical activity are not known. Here we show that spontaneous calcium spike activity in the hindbrain of developing Xenopus laevis larvae modulates the specification of serotonergic neurons via regulation of expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2 but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Using global manipulation of activity and targeted alteration of Lmx1b expression, we also demonstrate that changes in the number of serotonergic neurons change larval swimming behavior. The results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior.

}, keywords = {Action Potentials, Animals, Behavior, Animal, Bromodeoxyuridine, Calcium, Electroporation, Embryo, Nonmammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Homeodomain Proteins, Membrane Potentials, Neurons, Otx Transcription Factors, Potassium Channels, Inwardly Rectifying, Raphe Nuclei, RNA, Messenger, Serotonin, Sodium Channels, Statistics, Nonparametric, Swimming, Transcription Factors, Tryptophan Hydroxylase, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.06.006}, author = {Demarque, Micha{\"e}l and Spitzer, Nicholas C} } @article {187, title = {Auditory modulation of visual apparent motion with short spatial and temporal intervals.}, journal = {J Vis}, volume = {10}, year = {2010}, month = {2010}, pages = {31}, abstract = {

Recently, E. Freeman and J. Driver (2008) reported a cross-modal temporal interaction in which brief sounds drive the perceived direction of visual apparent-motion, an effect they attributed to "temporal capture" of the visual stimuli by the sounds (S. Morein-Zamir, S. Soto-Faraco, \& A. Kingstone, 2003). Freeman and Driver used "long-range" visual motion stimuli, which travel over long spatial and temporal intervals and engage high-order cortical areas (K. G. Claeys, D. T. Lindsey, E. De Schutter, \& G. A. Orban, 2003; Y. Zhuo et al., 2003). We asked whether Freeman and Driver{\textquoteright}s temporal effects extended to the short-range apparent-motion stimuli that engage cortical area MT, a lower-order area with well-established spatiotemporal selectivity for visual motion (e.g. A. Mikami, 1991, 1992; A. Mikami, W. T. Newsome, \& R. H. Wurtz, 1986a, 1986b; W. T. Newsome, A. Mikami, \& R. H. Wurtz, 1986). Consistent with a temporal-capture account, we found that static sounds bias the perception of both the direction (Experiment 1) and the speed (Experiment 2) of short-range motion. Our results suggest that auditory timing may interact with visual spatiotemporal processing as early as cortical area MT. Examination of the neuronal responses of this well-studied area to the stimuli used in this study would provide a test and might provide insight into the neuronal representation of time.

}, keywords = {Acoustic Stimulation, Auditory Perception, Humans, Motion Perception, Photic Stimulation, Temporal Lobe, Time Perception, Visual Cortex}, issn = {1534-7362}, doi = {10.1167/10.12.31}, author = {Kafaligonul, Hulusi and Stoner, Gene R} } @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 {177, title = {Sustained dorsal hippocampal activity is not obligatory for either the maintenance or retrieval of long-term spatial memory.}, journal = {Hippocampus}, volume = {20}, year = {2010}, month = {2010 Dec}, pages = {1366-75}, abstract = {

Memories are initially stored in a labile state and are subject to modification by a variety of treatments, including disruption of hippocampal function. We infused a sodium channel blocker (or CNQX) to inactivate the rat dorsal hippocampus reversibly for 1 week following training on a task of spatial memory (the water maze). Previous work with conventional lesions has established that the dorsal hippocampus is essential for both the acquisition and expression of memory in this task. The question in the present study was whether chronic disruption of neuronal activity in the dorsal hippocampus after training would abolish memory or whether memory would survive extended disruption of hippocampal activity. As expected from earlier work, we found that performance was impaired during the infusion period. The critical test occurred 1 week after the lesion was reversed. We found that retention of the water maze recovered to control levels. Accordingly, sustained hippocampal activity following training is not obligatory for either the maintenance of long-term spatial memory or its subsequent retrieval.

}, keywords = {6-Cyano-7-nitroquinoxaline-2,3-dione, Animals, Excitatory Amino Acid Antagonists, Hippocampus, Male, Maze Learning, Memory, Rats, Rats, Long-Evans, Space Perception, Spatial Behavior}, issn = {1098-1063}, doi = {10.1002/hipo.20722}, author = {Broadbent, Nicola J and Squire, Larry R and Clark, Robert E} } @article {134, title = {Target-dependent regulation of neurotransmitter specification and embryonic neuronal calcium spike activity.}, journal = {J Neurosci}, volume = {30}, year = {2010}, month = {2010 Apr 21}, pages = {5792-801}, abstract = {

Neurotransmitter specification has been shown to depend on genetic programs and electrical activity; however, target-dependent regulation also plays important roles in neuronal development. We have investigated the impact of muscle targets on transmitter specification in Xenopus spinal neurons using a neuron-muscle coculture system. We find that neuron-muscle contact reduces the number of neurons expressing the noncholinergic transmitters GABA, glycine, and glutamate, while having no effect on the incidence of ChAT expression. We show that muscle activity is necessary for target-dependent reduction of noncholinergic transmitter expression. In addition, we demonstrate that coculture with muscle cells suppresses early spontaneous calcium spike activity in neurons and the presence of muscle cells abolishes activity-dependent transmitter specification. The results indicate that target-dependent regulation can be crucial in establishing neurotransmitter phenotypes and altering early neuronal excitability.

}, keywords = {Animals, Calcium Signaling, Cells, Cultured, Coculture Techniques, Myoblasts, Neurons, Neurotransmitter Agents, Xenopus laevis}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5659-09.2010}, author = {Xiao, Qian and Xu, Lin and Spitzer, Nicholas C} } @article {165, title = {The Drosophila foraging gene mediates adult plasticity and gene-environment interactions in behaviour, metabolites, and gene expression in response to food deprivation.}, journal = {PLoS Genet}, volume = {5}, year = {2009}, month = {2009 Aug}, pages = {e1000609}, abstract = {

Nutrition is known to interact with genotype in human metabolic syndromes, obesity, and diabetes, and also in Drosophila metabolism. Plasticity in metabolic responses, such as changes in body fat or blood sugar in response to changes in dietary alterations, may also be affected by genotype. Here we show that variants of the foraging (for) gene in Drosophila melanogaster affect the response to food deprivation in a large suite of adult phenotypes by measuring gene by environment interactions (GEI) in a suite of food-related traits. for affects body fat, carbohydrates, food-leaving behavior, metabolite, and gene expression levels in response to food deprivation. This results in broad patterns of metabolic, genomic, and behavioral gene by environment interactions (GEI), in part by interaction with the insulin signaling pathway. Our results show that a single gene that varies in nature can have far reaching effects on behavior and metabolism by acting through multiple other genes and pathways.

}, keywords = {Animals, Carbohydrate Metabolism, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Drosophila Proteins, Ecosystem, Fats, Food Deprivation, Gene Expression, Signal Transduction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1000609}, author = {Kent, Clement F and Daskalchuk, Tim and Cook, Lisa and Sokolowski, Marla B and Greenspan, Ralph J} } @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 {132, title = {Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification.}, journal = {J Neurosci}, volume = {28}, year = {2008}, month = {2008 Apr 30}, pages = {4777-84}, abstract = {

Neurotransmitter signaling in the mature nervous system is well understood, but the functions of transmitters in the immature nervous system are less clear. Although transmitters released during embryogenesis regulate neuronal proliferation and migration, little is known about their role in regulating early neuronal differentiation. Here, we show that GABA and glutamate drive calcium-dependent embryonic electrical activity that regulates transmitter specification. The number of neurons expressing different transmitters changes when GABA or glutamate signaling is blocked chronically, either using morpholinos to knock down transmitter-synthetic enzymes or applying pharmacological receptor antagonists during a sensitive period of development. We find that calcium spikes are triggered by metabotropic GABA and glutamate receptors, which engage protein kinases A and C. The results reveal a novel role for embryonically expressed neurotransmitters.

}, keywords = {Animals, Antigens, CD57, Calcium, Choline O-Acetyltransferase, Embryo, Nonmammalian, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Glutamate Decarboxylase, Glutamic Acid, Health Services Research, Larva, Morpholines, Neurons, Phosphoserine, Receptors, GABA, Receptors, Glutamate, Synapses, Vesicular Glutamate Transport Proteins, Xenopus}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4873-07.2008}, author = {Root, Cory M and Vel{\'a}zquez-Ulloa, Norma A and Monsalve, Gabriela C and Minakova, Elena and Spitzer, Nicholas C} } @article {133, title = {Illumination controls differentiation of dopamine neurons regulating behaviour.}, journal = {Nature}, volume = {456}, year = {2008}, month = {2008 Nov 13}, pages = {195-201}, abstract = {

Specification of the appropriate neurotransmitter is a crucial step in neuronal differentiation because it enables signalling among populations of neurons. Experimental manipulations demonstrate that both autonomous and activity-dependent genetic programs contribute to this process during development, but whether natural environmental stimuli specify transmitter expression in a neuronal population is unknown. We investigated neurons of the ventral suprachiasmatic nucleus that regulate neuroendocrine pituitary function in response to light in teleosts, amphibia and primates. Here we show that altering light exposure, which changes the sensory input to the circuit controlling adaptation of skin pigmentation to background, changes the number of neurons expressing dopamine in larvae of the amphibian Xenopus laevis in a circuit-specific and activity-dependent manner. Neurons newly expressing dopamine then regulate changes in camouflage colouration in response to illumination. Thus, physiological activity alters the numbers of behaviourally relevant amine-transmitter-expressing neurons in the brain at postembryonic stages of development. The results may be pertinent to changes in cognitive states that are regulated by biogenic amines.

}, keywords = {Animals, Behavior, Animal, Cell Count, Cell Differentiation, Chelating Agents, Dopamine, Egtazic Acid, Gene Expression Regulation, Developmental, Larva, Light, Lighting, Melanotrophs, Neurons, Neuropeptide Y, Photic Stimulation, Skin Pigmentation, Sodium Channel Blockers, Suprachiasmatic Nucleus, Tetrodotoxin, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature07569}, author = {Dulcis, Davide and Spitzer, Nicholas C} } @article {131, title = {Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 Jan 2}, pages = {335-40}, abstract = {

Signaling in the nervous system requires matching of neurotransmitter receptors with cognate neurotransmitters at synapses. The vertebrate neuromuscular junction is the best studied cholinergic synapse, but the mechanisms by which acetylcholine is matched with acetylcholine receptors are not fully understood. Because alterations in neuronal calcium spike activity alter transmitter specification in embryonic spinal neurons, we hypothesized that receptor expression in postsynaptic cells follows changes in transmitter expression to achieve this specific match. We find that embryonic vertebrate striated muscle cells normally express receptors for glutamate, GABA, and glycine as well as for acetylcholine. As maturation progresses, acetylcholine receptor expression prevails. Receptor selection is altered when early neuronal calcium-dependent activity is perturbed, and remaining receptor populations parallel changes in transmitter phenotype. In these cases, glutamatergic, GABAergic, and glycinergic synaptic currents are recorded from muscle cells, demonstrating that activity regulates matching of transmitters and their receptors in the assembly of functional synapses.

}, keywords = {Animals, Calcium, Gene Expression Regulation, Developmental, Muscle, Skeletal, Neuromuscular Junction, Neurotransmitter Agents, Receptors, Neurotransmitter, Spinal Cord, Synapses, Xenopus}, issn = {0027-8424}, doi = {10.1073/pnas.0607450104}, author = {Borodinsky, Laura N and Spitzer, Nicholas C} } @article {130, title = {Activity-dependent homeostatic specification of transmitter expression in embryonic neurons.}, journal = {Nature}, volume = {429}, year = {2004}, month = {2004 Jun 3}, pages = {523-30}, abstract = {

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.

}, keywords = {Action Potentials, Animals, Calcium, Calcium Signaling, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Homeostasis, Humans, Neurons, Neurotransmitter Agents, Organ Specificity, Phenotype, Potassium Channels, Inwardly Rectifying, Rats, Sodium Channels, Spinal Cord, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature02518}, author = {Borodinsky, Laura N and Root, Cory M and Cronin, Julia A and Sann, Sharon B and Gu, Xiaonan and Spitzer, Nicholas C} } @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} } @article {153, title = {Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.}, journal = {Science}, volume = {277}, year = {1997}, month = {1997 Aug 8}, pages = {834-6}, abstract = {

Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the foraging gene (for), a gene that has two naturally occurring variants in Drosophila melanogaster food-search behavior: rover and sitter. Molecular mapping placed for mutations in the dg2 gene, which encodes a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Rovers had higher PKG activity than sitters, and transgenic sitters expressing a dg2 complementary DNA from rover showed transformation of behavior to rover. Thus, PKG levels affected food-search behavior, and natural variation in PKG activity accounted for a behavioral polymorphism.

}, keywords = {Animals, Animals, Genetically Modified, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Feeding Behavior, Genes, Insect, Larva, Phenotype, Polymorphism, Genetic, Signal Transduction}, issn = {0036-8075}, author = {Osborne, K A and Robichon, A and Burgess, E and Butland, S and Shaw, R A and Coulthard, A and Pereira, H S and Greenspan, R J and Sokolowski, M B} } @article {154, title = {Genetic feminization of brain structures and changed sexual orientation in male Drosophila.}, journal = {Science}, volume = {267}, year = {1995}, month = {1995 Feb 10}, pages = {902-5}, abstract = {

The neural basis of sexual orientation in Drosophila was studied by the production of males with regionally feminized brains. Such flies express the female form of the sex determination gene transformer in a limited number of neurons under the control of GAL4 enhancer trap inserts. This method facilitated the creation of lines with a stable pattern of feminization. In tests of sexual preferences, flies that were feminized in a portion of the antennal lobes or in a subset of the corpora pedunculata (mushroom bodies) courted both males and females. These two brain structures, both of which are involved in olfactory processing, may function in the recognition of sex-specific pheromones, in the control of sex-specific behaviors, or both.

}, keywords = {Animals, Bisexuality, Brain, Drosophila melanogaster, Female, Genes, Insect, Male, Sex Attractants, Sexual Behavior, Animal, Smell}, issn = {0036-8075}, author = {Ferveur, J F and St{\"o}rtkuhl, K F and Stocker, R F and Greenspan, R J} }