@article {2481, title = {Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus).}, journal = {Front Aging Neurosci}, volume = {15}, year = {2023}, month = {2023}, pages = {1146245}, abstract = {

Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (\~{}10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.

}, issn = {1663-4365}, doi = {10.3389/fnagi.2023.1146245}, author = {Glavis-Bloom, Courtney and Vanderlip, Casey R and Weiser Novak, Sammy and Kuwajima, Masaaki and Kirk, Lyndsey and Harris, Kristen M and Manor, Uri and Reynolds, John H} } @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 {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 {2297, title = {Seasonal changes in day length induce multisynaptic neurotransmitter switching to regulate hypothalamic network activity and behavior.}, journal = {Sci Adv}, volume = {8}, year = {2022}, month = {2022 Sep 02}, pages = {eabn9867}, abstract = {

Seasonal changes in day length (photoperiod) affect numerous physiological functions. The suprachiasmatic nucleus (SCN)-paraventricular nucleus (PVN) axis plays a key role in processing photoperiod-related information. Seasonal variations in SCN and PVN neurotransmitter expression have been observed in humans and animal models. However, the molecular mechanisms by which the SCN-PVN network responds to altered photoperiod is unknown. Here, we show in mice that neuromedin S (NMS) and vasoactive intestinal polypeptide (VIP) neurons in the SCN display photoperiod-induced neurotransmitter plasticity. In vivo recording of calcium dynamics revealed that NMS neurons alter PVN network activity in response to winter-like photoperiod. Chronic manipulation of NMS neurons is sufficient to induce neurotransmitter switching in PVN neurons and affects locomotor activity. Our findings reveal previously unidentified molecular adaptations of the SCN-PVN network in response to seasonality and the role for NMS neurons in adjusting hypothalamic function to day length via a coordinated multisynaptic neurotransmitter switching affecting behavior.

}, issn = {2375-2548}, doi = {10.1126/sciadv.abn9867}, author = {Porcu, Alessandra and Nilsson, Anna and Booreddy, Sathwik and Barnes, Samuel A and Welsh, David K and Dulcis, Davide} } @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 {1469, title = {Biosynthesis of Orthogonal Molecules Using Ferredoxin and Ferredoxin-NADP+ Reductase Systems Enables Genetically Encoded PhyB Optogenetics.}, journal = {ACS Synth Biol}, year = {2018}, month = {2018 Jan 24}, abstract = {

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

}, issn = {2161-5063}, doi = {10.1021/acssynbio.7b00413}, author = {Kyriakakis, Phillip and Catanho, Marianne and Hoffner, Nicole and Thavarajah, Walter and Hu, Vincent J and Chao, Syh-Shiuan and Hsu, Athena and Pham, Vivian and Naghavian, Ladan and Dozier, Lara E and Patrick, Gentry N and Coleman, Todd P} } @article {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 {1696, title = {Multiplexed oscillations and phase rate coding in the basal forebrain.}, journal = {Sci Adv}, volume = {4}, year = {2018}, month = {2018 08}, pages = {eaar3230}, abstract = {

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

}, keywords = {Animals, Basal Forebrain, Male, Models, Neurological, Neurons, Rats, Rats, Long-Evans, Space Perception, Theta Rhythm}, issn = {2375-2548}, doi = {10.1126/sciadv.aar3230}, author = {Tingley, David and Alexander, Andrew S and Quinn, Laleh K and Chiba, Andrea A and Nitz, Douglas} } @article {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 {1676, title = {Single-Trial EEG Analysis Predicts Memory Retrieval and Reveals Source-Dependent Differences.}, journal = {Front Hum Neurosci}, volume = {12}, year = {2018}, month = {2018}, pages = {258}, abstract = {

We used pattern classifiers to extract features related to recognition memory retrieval from the temporal information in single-trial electroencephalography (EEG) data during attempted memory retrieval. Two-class classification was conducted on correctly remembered trials with accurate context (or source) judgments vs. correctly rejected trials. The average accuracy for datasets recorded in a single session was 61\% while the average accuracy for datasets recorded in two separate sessions was 56\%. To further understand the basis of the classifier{\textquoteright}s performance, two other pattern classifiers were trained on different pairs of behavioral conditions. The first of these was designed to use information related to remembering the item and the second to use information related to remembering the contextual information (or source) about the item. Mollison and Curran (2012) had earlier shown that subjects{\textquoteright} familiarity judgments contributed to improved memory of spatial contextual information but not of extrinsic associated color information. These behavioral results were similarly reflected in the event-related potential (ERP) known as the FN400 (an early frontal effect relating to familiarity) which revealed differences between correct and incorrect context memories in the spatial but not color conditions. In our analyses we show that a classifier designed to distinguish between correct and incorrect context memories, more strongly involves early activity (400-500 ms) over the frontal channels for the location distinctions, than for the extrinsic color associations. In contrast, the classifier designed to classify memory for the item (without memory for the context), had more frontal channel involvement for the color associated experiments than for the spatial experiments. Taken together these results argue that location may be bound more tightly with the item than an extrinsic color association. The multivariate classification approach also showed that trial-by-trial variation in EEG corresponding to these ERP components were predictive of subjects{\textquoteright} behavioral responses. Additionally, the multivariate classification approach enabled analysis of error conditions that did not have sufficient trials for standard ERP analyses. These results suggested that false alarms were primarily attributable to item memory (as opposed to memory of associated context), as commonly predicted, but with little previous corroborating EEG evidence.

}, issn = {1662-5161}, doi = {10.3389/fnhum.2018.00258}, author = {Noh, Eunho and Liao, Kueida and Mollison, Matthew V and Curran, Tim and de Sa, Virginia R} } @article {1688, title = {Subiculum neurons map the current axis of travel.}, journal = {Nat Neurosci}, volume = {20}, year = {2017}, month = {2017 02}, pages = {170-172}, abstract = {

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

}, keywords = {Action Potentials, Animals, Brain Mapping, Hippocampus, Male, Neurons, Orientation, Rats, Sprague-Dawley, Space Perception}, issn = {1546-1726}, doi = {10.1038/nn.4464}, author = {Olson, Jacob M and Tongprasearth, Kanyanat and Nitz, Douglas A} } @article {1680, title = {Optogenetic manipulation of neural circuits in awake marmosets.}, journal = {J Neurophysiol}, volume = {116}, year = {2016}, month = {2016 09 01}, pages = {1286-94}, abstract = {

Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263-1268, 2005; Deisseroth K. Nat Methods 8: 26-29, 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains. Common marmosets (Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates. The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. In the present study we developed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by adeno-associated virus to express channelrhodopsin (ChR2) in awake marmosets. We found that large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species to elucidate the functional neural circuitry underlying perceptual and cognitive processes.

}, keywords = {Action Potentials, Animals, Bacterial Proteins, Brain, Callithrix, Dependovirus, Female, Genetic Vectors, Luminescent Proteins, Microelectrodes, Models, Animal, Neural Pathways, Neurons, Optogenetics, Photic Stimulation, Rhodopsin, Serogroup, Wakefulness}, issn = {1522-1598}, doi = {10.1152/jn.00197.2016}, author = {MacDougall, Matthew and Nummela, Samuel U and Coop, Shanna and Disney, Anita and Mitchell, Jude F and Miller, Cory T} } @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 {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 {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 {1675, title = {Using single-trial EEG to predict and analyze subsequent memory.}, journal = {Neuroimage}, volume = {84}, year = {2014}, month = {2014 Jan 01}, pages = {712-23}, abstract = {

We show that it is possible to successfully predict subsequent memory performance based on single-trial EEG activity before and during item presentation in the study phase. Two-class classification was conducted to predict subsequently remembered vs. forgotten trials based on subjects{\textquoteright} responses in the recognition phase. The overall accuracy across 18 subjects was 59.6\% by combining pre- and during-stimulus information. The single-trial classification analysis provides a dimensionality reduction method to project the high-dimensional EEG data onto a discriminative space. These projections revealed novel findings in the pre- and during-stimulus periods related to levels of encoding. It was observed that the pre-stimulus information (specifically oscillatory activity between 25 and 35Hz) -300 to 0ms before stimulus presentation and during-stimulus alpha (7-12Hz) information between 1000 and 1400ms after stimulus onset distinguished between recollection and familiarity while the during-stimulus alpha information and temporal information between 400 and 800ms after stimulus onset mapped these two states to similar values.

}, keywords = {Adolescent, Adult, Brain, Electroencephalography, Humans, Male, Memory, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2013.09.028}, author = {Noh, Eunho and Herzmann, Grit and Curran, Tim and de Sa, Virginia R} } @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 {200, title = {Contrast dependence and differential contributions from somatostatin- and parvalbumin-expressing neurons to spatial integration in mouse V1.}, journal = {J Neurosci}, volume = {33}, year = {2013}, month = {2013 Jul 3}, pages = {11145-54}, abstract = {

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

}, keywords = {Animals, Contrast Sensitivity, Female, Male, Mice, Mice, Transgenic, Neurons, Parvalbumins, Photic Stimulation, Somatostatin, Space Perception, Visual Cortex}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5320-12.2013}, author = {Nienborg, Hendrikje and Hasenstaub, Andrea and Nauhaus, Ian and Taniguchi, Hiroki and Huang, Z Josh and Callaway, Edward M} } @article {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 {193, title = {Targeting single neuronal networks for gene expression and cell labeling in vivo.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Aug 26}, pages = {562-74}, abstract = {

To understand fine-scale structure and function of single mammalian neuronal networks, we developed and validated a strategy to genetically target and trace monosynaptic inputs to a single neuron in vitro and in vivo. The strategy independently targets a neuron and its presynaptic network for specific gene expression and fine-scale labeling, using single-cell electroporation of DNA to target infection and monosynaptic retrograde spread of a genetically modifiable rabies virus. The technique is highly reliable, with transsynaptic labeling occurring in every electroporated neuron infected by the virus. Targeting single neocortical neuronal networks in vivo, we found clusters of both spiny and aspiny neurons surrounding the electroporated neuron in each case, in addition to intricately labeled distal cortical and subcortical inputs. This technique, broadly applicable for probing and manipulating single neuronal networks with single-cell resolution in vivo, may help shed new light on fundamental mechanisms underlying circuit development and information processing by neuronal networks throughout the brain.

}, keywords = {Animals, Electroporation, Gene Expression, Genetic Vectors, Histological Techniques, In Vitro Techniques, Mice, Neocortex, Neural Pathways, Neuroanatomical Tract-Tracing Techniques, Neuronal Tract-Tracers, Neurons, Presynaptic Terminals, Pyramidal Cells, Rabies virus, Rats, Reproducibility of Results, Visual Cortex}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.08.001}, author = {Marshel, James H and Mori, Takuma and Nielsen, Kristina J and Callaway, Edward M} } @article {143, title = {Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila.}, journal = {Nat Neurosci}, volume = {10}, year = {2007}, month = {2007 Sep}, pages = {1160-7}, abstract = {

Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals.

}, keywords = {Analysis of Variance, Animals, Animals, Genetically Modified, Behavior, Animal, Drosophila, Drosophila Proteins, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Developmental, Membrane Proteins, Motor Activity, Receptor, Epidermal Growth Factor, Signal Transduction, Sleep}, issn = {1097-6256}, doi = {10.1038/nn1957}, author = {Foltenyi, Krisztina and Greenspan, Ralph J and Newport, John W} }