@article {2480, title = {Dopamine signaling regulates predator-driven changes in egg laying behavior.}, journal = {Elife}, volume = {12}, year = {2023}, month = {2023 Jul 11}, abstract = {

Prey respond to predators by altering their behavior to optimize their own fitness and survival. Specifically, prey are known to avoid predator-occupied territories to reduce their risk of harm or injury to themselves and their progeny. We probe the interactions between and its naturally cohabiting predator to reveal the pathways driving changes in prey behavior. While prefers to lay its eggs on a bacteria food lawn, the presence of a predator inside a lawn induces to lay more eggs away from that lawn. We confirm that this change in egg laying is in response to bites from predators, rather than to predatory secretions. Moreover, predator-exposed prey continue to lay their eggs away from the dense lawn even after the predator is removed, indicating a form of learning. Next, we find that mutants in dopamine synthesis significantly reduce egg laying behavior off the lawn in both predator-free and predator-inhabited lawns, which we can rescue by transgenic complementation or supplementation with exogenous dopamine. Moreover, we find that dopamine is likely released from multiple dopaminergic neurons and requires combinations of both D1- (DOP-1) and D2-like (DOP-2 and DOP-3) dopamine receptors to alter predator-induced egg laying behavior, whereas other combinations modify baseline levels of egg laying behavior. Together, we show that dopamine signaling can alter both predator-free and predator-induced foraging strategies, suggesting a role for this pathway in defensive behaviors.

}, keywords = {Animals, Caenorhabditis elegans, Dopamine, Eggs, Receptors, Dopamine, Signal Transduction}, issn = {2050-084X}, doi = {10.7554/eLife.83957}, author = {Pribadi, Amy and Rieger, Michael A and Rosales, Kaila and Reddy, Kirthi C and Chalasani, Sreekanth H} } @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 {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} } @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 {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 {1469, title = {Biosynthesis of Orthogonal Molecules Using Ferredoxin and Ferredoxin-NADP+ Reductase Systems Enables Genetically Encoded PhyB Optogenetics.}, journal = {ACS Synth Biol}, year = {2018}, month = {2018 Jan 24}, abstract = {

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

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

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

}, keywords = {Animal Structures, Animals, Brain, Cryopreservation, Drosophila, Imaging, Three-Dimensional, Mice, Microscopy, Electron, Scanning, Sense Organs}, issn = {2050-084X}, doi = {10.7554/eLife.35524}, author = {Tsang, Tin Ki and Bushong, Eric A and Boassa, Daniela and Hu, Junru and Romoli, Benedetto and Phan, Sebastien and Dulcis, Davide and Su, Chih-Ying and Ellisman, Mark H} } @article {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 {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 {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 {128, title = {Generation of functional human serotonergic neurons from fibroblasts.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Jan}, pages = {49-61}, abstract = {

The brain{\textquoteright}s serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.161}, author = {Vadodaria, K C and Mertens, J and Paquola, A and Bardy, C and Li, X and Jappelli, R and Fung, L and Marchetto, M C and Hamm, M and Gorris, M and Koch, P and Gage, F H} } @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 {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 {199, title = {From suffering to caring: a model of differences among older adults in levels of compassion.}, journal = {Int J Geriatr Psychiatry}, volume = {30}, year = {2015}, month = {2015 Feb}, pages = {185-91}, abstract = {

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

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

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

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

}, keywords = {Age Factors, Aged, Aged, 80 and over, Empathy, Female, Humans, Life Change Events, Male, Marital Status, Middle Aged, Regression Analysis, Resilience, Psychological, Sex Factors, Socioeconomic Factors}, issn = {1099-1166}, doi = {10.1002/gps.4123}, author = {Moore, Raeanne C and Martin, A{\textquoteright}verria Sirkin and Kaup, Allison R and Thompson, Wesley K and Peters, Matthew E and Jeste, Dilip V and Golshan, Shahrokh and Eyler, Lisa T} } @article {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 {1678, title = {Motion dependence of smooth pursuit eye movements in the marmoset.}, journal = {J Neurophysiol}, volume = {113}, year = {2015}, month = {2015 Jun 01}, pages = {3954-60}, abstract = {

Smooth pursuit eye movements stabilize slow-moving objects on the retina by matching eye velocity with target velocity. Two critical components are required to generate smooth pursuit: first, because it is a voluntary eye movement, the subject must select a target to pursue to engage the tracking system; and second, generating smooth pursuit requires a moving stimulus. We examined whether this behavior also exists in the common marmoset, a New World primate that is increasingly attracting attention as a genetic model for mental disease and systems neuroscience. We measured smooth pursuit in two marmosets, previously trained to perform fixation tasks, using the standard Rashbass step-ramp pursuit paradigm. We first measured the aspects of visual motion that drive pursuit eye movements. Smooth eye movements were in the same direction as target motion, indicating that pursuit was driven by target movement rather than by displacement. Both the open-loop acceleration and closed-loop eye velocity exhibited a linear relationship with target velocity for slow-moving targets, but this relationship declined for higher speeds. We next examined whether marmoset pursuit eye movements depend on an active engagement of the pursuit system by measuring smooth eye movements evoked by small perturbations of motion from fixation or during pursuit. Pursuit eye movements were much larger during pursuit than from fixation, indicating that pursuit is actively gated. Several practical advantages of the marmoset brain, including the accessibility of the middle temporal (MT) area and frontal eye fields at the cortical surface, merit its utilization for studying pursuit movements.

}, keywords = {Acceleration, Animals, Callithrix, Motion, Motion Perception, Photic Stimulation, Pursuit, Smooth, Retina, Visual Fields}, issn = {1522-1598}, doi = {10.1152/jn.00197.2015}, author = {Mitchell, Jude F and Priebe, Nicholas J and Miller, Cory T} } @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 {122, title = {Transcriptional changes in sensory ganglia associated with primary afferent axon collateral sprouting in spared dermatome model.}, journal = {Genom Data}, volume = {6}, year = {2015}, month = {2015 Dec}, pages = {249-52}, abstract = {

Primary afferent collateral sprouting is a process whereby non-injured primary afferent neurons respond to some stimulus and extend new branches from existing axons. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity (e.g., [1], [2], [3], [4], [5], [6], [7], [8], [9]). In the model used here (the "spared dermatome" model), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Investigations of gene expression changes associated with collateral sprouting can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatments to promote functional recovery for spinal cord injury and other similar conditions. This report includes raw gene expression data files from microarray experiments in order to study the gene regulation in spared sensory ganglia in the initiation (7\ days) and maintenance (14\ days) phases of the spared dermatome model relative to intact ("na{\"\i}ve") sensory ganglia. Data has been deposited into GEO (GSE72551).

}, issn = {2213-5960}, doi = {10.1016/j.gdata.2015.10.005}, author = {Harrison, Benjamin J and Venkat, Gayathri and Hutson, Thomas and Rau, Kristofer K and Bunge, Mary Bartlett and Mendell, Lorne M and Gage, Fred H and Johnson, Richard D and Hill, Caitlin and Rouchka, Eric C and Moon, Lawrence and Petruska, Jeffrey C} } @article {203, title = {Gamma band activity and the P3 reflect post-perceptual processes, not visual awareness.}, journal = {Neuroimage}, volume = {101}, year = {2014}, month = {2014 Nov 1}, pages = {337-50}, abstract = {

A primary goal in cognitive neuroscience is to identify neural correlates of conscious perception (NCC). By contrasting conditions in which subjects are aware versus unaware of identical visual stimuli, a number of candidate NCCs have emerged; among them are induced gamma band activity in the EEG and the P3 event-related potential. In most previous studies, however, the critical stimuli were always directly relevant to the subjects{\textquoteright} task, such that aware versus unaware contrasts may well have included differences in post-perceptual processing in addition to differences in conscious perception per se. Here, in a series of EEG experiments, visual awareness and task relevance were manipulated independently. Induced gamma activity and the P3 were absent for task-irrelevant stimuli regardless of whether subjects were aware of such stimuli. For task-relevant stimuli, gamma and the P3 were robust and dissociable, indicating that each reflects distinct post-perceptual processes necessary for carrying-out the task but not for consciously perceiving the stimuli. Overall, this pattern of results challenges a number of previous proposals linking gamma band activity and the P3 to conscious perception.

}, keywords = {Adult, Attention, Awareness, Consciousness, Electroencephalography, Event-Related Potentials, P300, Female, Gamma Rhythm, Humans, Male, Psychomotor Performance, Visual Perception, Young Adult}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.07.024}, author = {Pitts, Michael A and Padwal, Jennifer and Fennelly, Daniel and Mart{\'\i}nez, Ant{\'\i}gona and Hillyard, Steven A} } @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 {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 {201, title = {Evidence that primary visual cortex is required for image, orientation, and motion discrimination by rats.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e56543}, abstract = {

The pigmented Long-Evans rat has proven to be an excellent subject for studying visually guided behavior including quantitative visual psychophysics. This observation, together with its experimental accessibility and its close homology to the mouse, has made it an attractive model system in which to dissect the thalamic and cortical circuits underlying visual perception. Given that visually guided behavior in the absence of primary visual cortex has been described in the literature, however, it is an empirical question whether specific visual behaviors will depend on primary visual cortex in the rat. Here we tested the effects of cortical lesions on performance of two-alternative forced-choice visual discriminations by Long-Evans rats. We present data from one highly informative subject that learned several visual tasks and then received a bilateral lesion ablating \>90\% of primary visual cortex. After the lesion, this subject had a profound and persistent deficit in complex image discrimination, orientation discrimination, and full-field optic flow motion discrimination, compared with both pre-lesion performance and sham-lesion controls. Performance was intact, however, on another visual two-alternative forced-choice task that required approaching a salient visual target. A second highly informative subject learned several visual tasks prior to receiving a lesion ablating \>90\% of medial extrastriate cortex. This subject showed no impairment on any of the four task categories. Taken together, our data provide evidence that these image, orientation, and motion discrimination tasks require primary visual cortex in the Long-Evans rat, whereas approaching a salient visual target does not.

}, keywords = {Animals, Discrimination (Psychology), Discrimination Learning, Male, Motion, Orientation, Photic Stimulation, Psychomotor Performance, Rats, Visual Cortex}, issn = {1932-6203}, doi = {10.1371/journal.pone.0056543}, author = {Petruno, Sarah K and Clark, Robert E and Reinagel, Pamela} } @article {161, title = {Neurogenetics.}, journal = {Curr Opin Neurobiol}, volume = {23}, year = {2013}, month = {2013 Feb}, pages = {1-2}, keywords = {Animals, Behavior, Genetics, Humans, Neurosciences}, issn = {1873-6882}, doi = {10.1016/j.conb.2012.12.001}, author = {Greenspan, Ralph and Petit, Christine} } @article {202, title = {Visual processing of contour patterns under conditions of inattentional blindness.}, journal = {J Cogn Neurosci}, volume = {24}, year = {2012}, month = {2012 Feb}, pages = {287-303}, abstract = {

An inattentional blindness paradigm was adapted to measure ERPs elicited by visual contour patterns that were or were not consciously perceived. In the first phase of the experiment, subjects performed an attentionally demanding task while task-irrelevant line segments formed square-shaped patterns or random configurations. After the square patterns had been presented 240 times, subjects{\textquoteright} awareness of these patterns was assessed. More than half of all subjects, when queried, failed to notice the square patterns and were thus considered inattentionally blind during this first phase. In the second phase of the experiment, the task and stimuli were the same, but following this phase, all of the subjects reported having seen the patterns. ERPs recorded over the occipital pole differed in amplitude from 220 to 260 msec for the pattern stimuli compared with the random arrays regardless of whether subjects were aware of the patterns. At subsequent latencies (300-340 msec) however, ERPs over bilateral occipital-parietal areas differed between patterns and random arrays only when subjects were aware of the patterns. Finally, in a third phase of the experiment, subjects viewed the same stimuli, but the task was altered so that the patterns became task relevant. Here, the same two difference components were evident but were followed by a series of additional components that were absent in the first two phases of the experiment. We hypothesize that the ERP difference at 220-260 msec reflects neural activity associated with automatic contour integration whereas the difference at 300-340 msec reflects visual awareness, both of which are dissociable from task-related postperceptual processing.

}, keywords = {Adult, Attention, Awareness, Brain, Brain Mapping, Electroencephalography, Evoked Potentials, Visual, Female, Humans, Male, Perceptual Masking, Photic Stimulation, Reaction Time, Visual Perception}, issn = {1530-8898}, doi = {10.1162/jocn_a_00111}, author = {Pitts, Michael A and Mart{\'\i}nez, Ant{\'\i}gona and Hillyard, Steven A} } @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 {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 {210, title = {Now or later? Striatum and insula activation to immediate versus delayed rewards.}, journal = {J Neurosci Psychol Econ}, volume = {3}, year = {2010}, month = {2010 May 1}, pages = {15-26}, abstract = {

Neuroimaging studies on delay discounting tasks that use reward delays ranging from minutes to days have implicated the insula and striatum in the processing of inter-temporal decisions. This study aimed at assessing whether these brain regions would also be involved in decision-making when subjects have to wait through the delays within the range of seconds. Employing functional magnetic resonance imaging (fMRI) in thirteen healthy volunteers, we repeatedly presented monetaryoptions with delays that differed within the range of multiple seconds. Using a region of interest approach, we found significant activation in the bilateral anterior insula and striatum when subjects chose either the immediate (smaller) or delayed (larger) option. In particular, insular activation was observed after the response and the delay, when the outcome of the immediate or the delayed choice was shown. Significantly greater activation was observed in the ventroanterior striatum while subjects chose the immediate, as opposed to the delayed, options, and also after receiving the outcome of waiting through the longer delay option. The evidence presented here indicates that both the ventral striatum and the insula are involved in the processing of choosing delay options as well as the consequences of choices with delays in the seconds{\textquoteright} range.

}, issn = {1937-321X}, doi = {10.1037/a0017252}, author = {Wittmann, Marc and Lovero, Kathryn L and Lane, Scott D and Paulus, Martin P} } @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 {209, title = {Temporal horizons in decision making.}, journal = {Journal of Neuroscience, Psychology, and Economics}, volume = {2}, year = {2009}, pages = {1}, author = {Wittmann, Marc and Paulus, Martin P} } @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} }