@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 {1788, title = {Imaging brain activity during complex social behaviors in Drosophila with Flyception2.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 01 30}, pages = {623}, abstract = {

Optical in vivo recordings from freely walking Drosophila are currently possible only for limited behaviors. Here, we expand the range of accessible behaviors with a retroreflective marker-based tracking and ratiometric brain imaging system, permitting brain activity imaging even in copulating male flies. We discover that P1 neurons, active during courtship, are inactive during copulation, whereas GABAergic mAL neurons remain active during copulation, suggesting a countervailing role of mAL in opposing P1 activity during mating.

}, keywords = {Animals, Brain, Copulation, Courtship, Drosophila, Drosophila Proteins, Female, GABAergic Neurons, Male, Neuroimaging, Neurons, Olfactory Cortex, Sexual Behavior, Animal, Social Behavior}, issn = {2041-1723}, doi = {10.1038/s41467-020-14487-7}, author = {Grover, Dhruv and Katsuki, Takeo and Li, Jinfang and Dawkins, Thomas J and Greenspan, Ralph J} } @article {1693, title = {Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 04 05}, pages = {1560}, abstract = {

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

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

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

}, keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons}, issn = {2158-3188}, doi = {10.1038/s41398-018-0344-y}, author = {Moore, Spencer M and Seidman, Jason S and Ellegood, Jacob and Gao, Richard and Savchenko, Alex and Troutman, Ty D and Abe, Yohei and Stender, Josh and Lee, Daehoon and Wang, Sicong and Voytek, Bradley and Lerch, Jason P and Suh, Hoonkyo and Glass, Christopher K and Muotri, Alysson R} } @article {1695, title = {High-quality ultrastructural preservation using cryofixation for 3D electron microscopy of genetically labeled tissues.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 05 11}, abstract = {

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

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

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

}, keywords = {Animals, Basal Forebrain, Male, Models, Neurological, Neurons, Rats, Rats, Long-Evans, Space Perception, Theta Rhythm}, issn = {2375-2548}, doi = {10.1126/sciadv.aar3230}, author = {Tingley, David and Alexander, Andrew S and Quinn, Laleh K and Chiba, Andrea A and Nitz, Douglas} } @article {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 {1684, title = {Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 01 24}, pages = {E610-E618}, abstract = {

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

}, keywords = {Animals, Behavior, Animal, Cadherins, Cell Polarity, Cells, Cultured, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Locomotion, Male, Maze Learning, Mice, Knockout, Nerve Tissue Proteins, Pyramidal Cells, Receptors, Cell Surface, Synapses, Wnt-5a Protein}, issn = {1091-6490}, doi = {10.1073/pnas.1612062114}, author = {Thakar, Sonal and Wang, Liqing and Yu, Ting and Ye, Mao and Onishi, Keisuke and Scott, John and Qi, Jiaxuan and Fernandes, Catarina and Han, Xuemei and Yates, John R and Berg, Darwin K and Zou, Yimin} } @article {1468, title = {Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference.}, journal = {Neuron}, volume = {95}, year = {2017}, month = {2017 Sep 13}, pages = {1319-1333.e5}, abstract = {

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

}, keywords = {Animals, Choice Behavior, Dopamine, Dopamine Antagonists, GABA Antagonists, gamma-Aminobutyric Acid, Interneurons, MicroRNAs, Neurons, Neurotransmitter Agents, Olfactory Bulb, PAX6 Transcription Factor, Pheromones, Siblings, Social Behavior, Transcription Factors, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2017.08.023}, author = {Dulcis, Davide and Lippi, Giordano and Stark, Christiana J and Do, Long H and Berg, Darwin K and Spitzer, Nicholas C} } @article {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 {123, title = {Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {259-75}, abstract = {

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

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

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

}, keywords = {Animals, Animals, Genetically Modified, Brain, Callithrix, Cognition, Disease Models, Animal, Eye Movements, Haplorhini, Humans, Models, Animal, Rodentia, Social Behavior, Social Behavior Disorders, Vocalization, Animal}, issn = {1097-4199}, doi = {10.1016/j.neuron.2016.03.018}, author = {Miller, Cory T and Freiwald, Winrich A and Leopold, David A and Mitchell, Jude F and Silva, Afonso C and Wang, Xiaoqin} } @article {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 {1672, title = {Temporal and spatial tuning of dorsal lateral geniculate nucleus neurons in unanesthetized rats.}, journal = {J Neurophysiol}, volume = {115}, year = {2016}, month = {2016 06 01}, pages = {2658-71}, abstract = {

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

}, keywords = {Animals, Evoked Potentials, Visual, Geniculate Bodies, Male, Neurons, Rats, Rats, Long-Evans, Wakefulness}, issn = {1522-1598}, doi = {10.1152/jn.00812.2014}, author = {Sriram, Balaji and Meier, Philip M and Reinagel, Pamela} } @article {1679, title = {The marmoset monkey as a model for visual neuroscience.}, journal = {Neurosci Res}, volume = {93}, year = {2015}, month = {2015 Apr}, pages = {20-46}, abstract = {

The common marmoset (Callithrix jacchus) has been valuable as a primate model in biomedical research. Interest in this species has grown recently, in part due to the successful demonstration of transgenic marmosets. Here we examine the prospects of the marmoset model for visual neuroscience research, adopting a comparative framework to place the marmoset within a broader evolutionary context. The marmoset{\textquoteright}s small brain bears most of the organizational features of other primates, and its smooth surface offers practical advantages over the macaque for areal mapping, laminar electrode penetration, and two-photon and optical imaging. Behaviorally, marmosets are more limited at performing regimented psychophysical tasks, but do readily accept the head restraint that is necessary for accurate eye tracking and neurophysiology, and can perform simple discriminations. Their natural gaze behavior closely resembles that of other primates, with a tendency to focus on objects of social interest including faces. Their immaturity at birth and routine twinning also makes them ideal for the study of postnatal visual development. These experimental factors, together with the theoretical advantages inherent in comparing anatomy, physiology, and behavior across related species, make the marmoset an excellent model for visual neuroscience.

}, keywords = {Animals, Biological Evolution, Brain, Callithrix, Color Perception, Color Vision, Exploratory Behavior, Macaca, Models, Animal, Social Behavior, Vision, Binocular, Vision, Ocular, Visual Perception}, issn = {1872-8111}, doi = {10.1016/j.neures.2015.01.008}, author = {Mitchell, Jude F and Leopold, David A} } @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 {126, title = {REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II.}, journal = {J Neurosci}, volume = {35}, year = {2015}, month = {2015 Nov 4}, pages = {14872-84}, abstract = {

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

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

}, keywords = {Animals, Cell Differentiation, Cells, Cultured, Female, Hippocampus, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Neurons, Rats, Wistar, Repressor Proteins, Secretogranin II}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4286-14.2015}, author = {Kim, Hyung Joon and Denli, Ahmet M and Wright, Rebecca and Baul, Tithi D and Clemenson, Gregory D and Morcos, Ari S and Zhao, Chunmei and Schafer, Simon T and Gage, Fred H and Kagalwala, Mohamedi N} } @article {198, title = {Active vision in marmosets: a model system for visual neuroscience.}, journal = {J Neurosci}, volume = {34}, year = {2014}, month = {2014 Jan 22}, pages = {1183-94}, abstract = {

The common marmoset (Callithrix jacchus), a small-bodied New World primate, offers several advantages to complement vision research in larger primates. Studies in the anesthetized marmoset have detailed the anatomy and physiology of their visual system (Rosa et al., 2009) while studies of auditory and vocal processing have established their utility for awake and behaving neurophysiological investigations (Lu et al., 2001a,b; Eliades and Wang, 2008a,b; Osmanski and Wang, 2011; Remington et al., 2012). However, a critical unknown is whether marmosets can perform visual tasks under head restraint. This has been essential for studies in macaques, enabling both accurate eye tracking and head stabilization for neurophysiology. In one set of experiments we compared the free viewing behavior of head-fixed marmosets to that of macaques, and found that their saccadic behavior is comparable across a number of saccade metrics and that saccades target similar regions of interest including faces. In a second set of experiments we applied behavioral conditioning techniques to determine whether the marmoset could control fixation for liquid reward. Two marmosets could fixate a central point and ignore peripheral flashing stimuli, as needed for receptive field mapping. Both marmosets also performed an orientation discrimination task, exhibiting a saturating psychometric function with reliable performance and shorter reaction times for easier discriminations. These data suggest that the marmoset is a viable model for studies of active vision and its underlying neural mechanisms.

}, keywords = {Animals, Callithrix, Conditioning, Operant, Models, Animal, Neurophysiology, Neurosciences, Saccades, Vision, Ocular, Visual Perception}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.3899-13.2014}, author = {Mitchell, Jude F and Reynolds, John H and Miller, Cory T} } @article {140, title = {Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching.}, journal = {Neuron}, volume = {82}, year = {2014}, month = {2014 Jun 4}, pages = {1004-16}, abstract = {

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

}, keywords = {Animals, Brain-Derived Neurotrophic Factor, Calcium, Cells, Cultured, Female, gamma-Aminobutyric Acid, Glutamic Acid, JNK Mitogen-Activated Protein Kinases, Neurons, Phosphorylation, Proto-Oncogene Proteins c-jun, Signal Transduction, Spinal Cord, Xenopus laevis}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.04.029}, author = {Guemez-Gamboa, Alicia and Xu, Lin and Meng, Da and Spitzer, Nicholas C} } @article {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 {166, title = {A comprehensive wiring diagram of the protocerebral bridge for visual information processing in the Drosophila brain.}, journal = {Cell Rep}, volume = {3}, year = {2013}, month = {2013 May 30}, pages = {1739-53}, abstract = {

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

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

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

}, keywords = {Animals, Contrast Sensitivity, Female, Male, Mice, Mice, Transgenic, Neurons, Parvalbumins, Photic Stimulation, Somatostatin, Space Perception, Visual Cortex}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5320-12.2013}, author = {Nienborg, Hendrikje and Hasenstaub, Andrea and Nauhaus, Ian and Taniguchi, Hiroki and Huang, Z Josh and Callaway, Edward M} } @article {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 {141, title = {Jellyfish nervous systems.}, journal = {Curr Biol}, volume = {23}, year = {2013}, month = {2013 Jul 22}, pages = {R592-4}, keywords = {Animals, Behavior, Animal, Cnidaria, Nerve Net, Nervous System, Nervous System Physiological Phenomena}, issn = {1879-0445}, doi = {10.1016/j.cub.2013.03.057}, author = {Katsuki, Takeo and Greenspan, Ralph J} } @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 {139, title = {Neurotransmitter switching in the adult brain regulates behavior.}, journal = {Science}, volume = {340}, year = {2013}, month = {2013 Apr 26}, pages = {449-53}, abstract = {

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

}, keywords = {Animals, Behavior, Animal, Brain, Cell Count, Dopamine, Dopaminergic Neurons, Hypothalamus, Male, Maze Learning, Photoperiod, Rats, Rats, Long-Evans, Receptors, Dopamine, Receptors, Somatostatin, Seasons, Somatostatin, Stress, Psychological, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.1234152}, author = {Dulcis, Davide and Jamshidi, Pouya and Leutgeb, Stefan and Spitzer, Nicholas C} } @article {1671, title = {Rats and humans differ in processing collinear visual features.}, journal = {Front Neural Circuits}, volume = {7}, year = {2013}, month = {2013}, pages = {197}, abstract = {

Behavioral studies in humans and rats demonstrate that visual detection of a target stimulus is sensitive to surrounding spatial patterns. In both species, the detection of an oriented visual target is affected when the surrounding region contains flanking stimuli that are collinear to the target. In many studies, collinear flankers have been shown to improve performance in humans, both absolutely (compared to performance with no flankers) and relative to non-collinear flankers. More recently, collinear flankers have been shown to impair performance in rats both absolutely and relative to non-collinear flankers. However, these observations spanned different experimental paradigms. Past studies in humans have shown that the magnitude and even sign of flanker effects can depend critically on the details of stimulus and task design. Therefore either task differences or species could explain the opposite findings. Here we provide a direct comparison of behavioral data between species and show that these differences persist--collinear flankers improve performance in humans, and impair performance in rats--in spite of controls that match stimuli, experimental paradigm, and learning procedure. There is evidence that the contrasts of the target and the flankers could affect whether surround processing is suppressive or facilitatory. In a second experiment, we explored a range of contrast conditions in the rat, to determine if contrast could explain the lack of collinear facilitation. Using different pairs of target and flanker contrast, the rat{\textquoteright}s collinear impairment was confirmed to be robust across a range of contrast conditions. We conclude that processing of collinear features is indeed different between rats and humans. We speculate that the observed difference between rat and human is caused by the combined impact of differences in the statistics in natural retinal images, the representational capacity of neurons in visual cortex, and attention.

}, keywords = {Animals, Attention, Contrast Sensitivity, Humans, Orientation, Pattern Recognition, Visual, Photic Stimulation, Rats, Visual Cortex, Visual Perception}, issn = {1662-5110}, doi = {10.3389/fncir.2013.00197}, author = {Meier, Philip M and Reinagel, Pamela} } @article {183, title = {Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice.}, journal = {Elife}, volume = {2}, year = {2013}, month = {2013}, pages = {e00312}, abstract = {

The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct representations of similar inputs. How pattern separation is achieved by the DG remains largely unclear. By examining neuronal activities at a population level, we revealed that, unlike CA1 neuron populations, dentate granule cell (DGC) ensembles activated by learning were not preferentially reactivated by memory recall. Moreover, when mice encountered an environment to which they had not been previously exposed, a novel DGC population-rather than the previously activated DGC ensembles that responded to past events-was selected to represent the new environmental inputs. This selection of a novel responsive DGC population could be triggered by small changes in environmental inputs. Therefore, selecting distinct DGC populations to represent similar but not identical inputs is a mechanism for pattern separation. DOI:http://dx.doi.org/10.7554/eLife.00312.001.

}, keywords = {Animals, Behavior, Animal, Brain Mapping, CA1 Region, Hippocampal, Conditioning (Psychology), Cues, Dentate Gyrus, Environment, Fear, Gene Expression Regulation, Genes, Reporter, Memory, Memory, Episodic, Mental Recall, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Neurons, Pattern Recognition, Physiological, Time Factors}, issn = {2050-084X}, doi = {10.7554/eLife.00312}, author = {Deng, Wei and Mayford, Mark and Gage, Fred H} } @article {164, title = {Vertebrate versus invertebrate neural circuits.}, journal = {Curr Biol}, volume = {23}, year = {2013}, month = {2013 Jun 17}, pages = {R504-6}, keywords = {Animals, Invertebrates, Nervous System, Nervous System Physiological Phenomena, Vertebrates}, issn = {1879-0445}, author = {Katz, Paul and Grillner, Sten and Wilson, Rachel and Borst, Alexander and Greenspan, Ralph and Buzs{\'a}ki, Gy{\"o}rgy and Martin, Kevan and Marder, Eve and Kristan, William and Friedrich, Rainer and Chklovskii, Dmitri Mitya} } @article {163, title = {Genes involved in sex pheromone discrimination in Drosophila melanogaster and their background-dependent effect.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e30799}, abstract = {

Mate choice is based on the comparison of the sensory quality of potential mating partners, and sex pheromones play an important role in this process. In Drosophila melanogaster, contact pheromones differ between male and female in their content and in their effects on male courtship, both inhibitory and stimulatory. To investigate the genetic basis of sex pheromone discrimination, we experimentally selected males showing either a higher or lower ability to discriminate sex pheromones over 20 generations. This experimental selection was carried out in parallel on two different genetic backgrounds: wild-type and desat1 mutant, in which parental males showed high and low sex pheromone discrimination ability respectively. Male perception of male and female pheromones was separately affected during the process of selection. A comparison of transcriptomic activity between high and low discrimination lines revealed genes not only that varied according to the starting genetic background, but varied reciprocally. Mutants in two of these genes, Shaker and quick-to-court, were capable of producing similar effects on discrimination on their own, in some instances mimicking the selected lines, in others not. This suggests that discrimination of sex pheromones depends on genes whose activity is sensitive to genetic context and provides a rare, genetically defined example of the phenomenon known as "allele flips," in which interactions have reciprocal effects on different genetic backgrounds.

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, Breeding, Courtship, Drosophila melanogaster, Female, Genes, Insect, Male, Mutation, Olfactory Perception, Reproduction, Sex Attractants, Sexual Behavior, Animal, Species Specificity}, issn = {1932-6203}, doi = {10.1371/journal.pone.0030799}, author = {Houot, Benjamin and Fraichard, St{\'e}phane and Greenspan, Ralph J and Ferveur, Jean-Fran{\c c}ois} } @article {196, title = {Collinear features impair visual detection by rats.}, journal = {J Vis}, volume = {11}, year = {2011}, month = {2011}, abstract = {

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

}, keywords = {Animals, Behavior, Animal, Conditioning (Psychology), Contrast Sensitivity, Lighting, Orientation, Photic Stimulation, Psychophysics, Rats, Retina, Space Perception}, issn = {1534-7362}, doi = {10.1167/11.3.22}, author = {Meier, Philip and Flister, Erik and Reinagel, Pamela} } @article {195, title = {Rat performance on visual detection task modeled with divisive normalization and adaptive decision thresholds.}, journal = {J Vis}, volume = {11}, year = {2011}, month = {2011}, abstract = {

Performance on any perceptual task depends on both the perceptual capacity and the decision strategy of the subject. We provide a model to fit both aspects and apply it to data from rats performing a detection task. When rats must detect a faint visual target, the presence of other nearby stimuli ("flankers") increases the difficulty of the task. In this study, we consider two specific factors. First, flankers could diminish the sensory response to the target via spatial contrast normalization in early visual processing. Second, rats may treat the sensory signal caused by the flankers as if it belonged to the target. We call this source confusion, which may be sensory, cognitive, or both. We account for contrast normalization and source confusion by fitting model parameters to the likelihood of the observed behavioral data. We test multiple combinations of target and flanker contrasts using a yes/no detection task. Contrast normalization was crucial to explain the rats{\textquoteright} flanker-induced detection impairment. By adding a decision variable to the contrast normalization framework, our model provides a new tool to assess differences in visual or cognitive brain function between normal and abnormal rodents.

}, keywords = {Adaptation, Physiological, Animals, Choice Behavior, Cognition, Conditioning (Psychology), Contrast Sensitivity, Male, Models, Neurological, Photic Stimulation, Psychomotor Performance, Rats, Rats, Long-Evans, Visual Perception}, issn = {1534-7362}, doi = {10.1167/11.9.1}, author = {Meier, Philip and Reinagel, Pamela} } @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 {136, title = {Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior.}, journal = {Neuron}, volume = {67}, year = {2010}, month = {2010 Jul 29}, pages = {321-34}, abstract = {

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

}, keywords = {Action Potentials, Animals, Behavior, Animal, Bromodeoxyuridine, Calcium, Electroporation, Embryo, Nonmammalian, gamma-Aminobutyric Acid, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Homeodomain Proteins, Membrane Potentials, Neurons, Otx Transcription Factors, Potassium Channels, Inwardly Rectifying, Raphe Nuclei, RNA, Messenger, Serotonin, Sodium Channels, Statistics, Nonparametric, Swimming, Transcription Factors, Tryptophan Hydroxylase, Xenopus laevis, Xenopus Proteins}, issn = {1097-4199}, doi = {10.1016/j.neuron.2010.06.006}, author = {Demarque, Micha{\"e}l and Spitzer, Nicholas C} } @article {174, title = {Adult neurogenesis: integrating theories and separating functions.}, journal = {Trends Cogn Sci}, volume = {14}, year = {2010}, month = {2010 Jul}, pages = {325-37}, abstract = {

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

}, keywords = {Adult, Adult Stem Cells, Animals, Cell Proliferation, Hippocampus, Humans, Models, Biological, Neurogenesis, Neurons}, issn = {1879-307X}, doi = {10.1016/j.tics.2010.04.003}, author = {Aimone, James B and Deng, Wei and Gage, Fred H} } @article {135, title = {cJun integrates calcium activity and tlx3 expression to regulate neurotransmitter specification.}, journal = {Nat Neurosci}, volume = {13}, year = {2010}, month = {2010 Aug}, pages = {944-50}, abstract = {

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

}, keywords = {Animals, Base Sequence, Calcium, Calcium Signaling, Electrophoretic Mobility Shift Assay, Gene Expression, Gene Expression Regulation, Developmental, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Molecular Sequence Data, Neurogenesis, Neurons, Neurotransmitter Agents, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Xenopus, Xenopus Proteins}, issn = {1546-1726}, doi = {10.1038/nn.2582}, author = {Marek, Kurt W and Kurtz, Lisa M and Spitzer, Nicholas C} } @article {182, title = {New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?}, journal = {Nat Rev Neurosci}, volume = {11}, year = {2010}, month = {2010 May}, pages = {339-50}, abstract = {

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

}, keywords = {Adult Stem Cells, Animals, Hippocampus, Humans, Learning, Memory, Models, Neurological, Neurogenesis, Neurons}, issn = {1471-0048}, doi = {10.1038/nrn2822}, author = {Deng, Wei and Aimone, James B and Gage, Fred H} } @article {177, title = {Sustained dorsal hippocampal activity is not obligatory for either the maintenance or retrieval of long-term spatial memory.}, journal = {Hippocampus}, volume = {20}, year = {2010}, month = {2010 Dec}, pages = {1366-75}, abstract = {

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

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

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

}, keywords = {Animals, Calcium Signaling, Cells, Cultured, Coculture Techniques, Myoblasts, Neurons, Neurotransmitter Agents, Xenopus laevis}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5659-09.2010}, author = {Xiao, Qian and Xu, Lin and Spitzer, Nicholas C} } @article {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 {175, title = {Computational influence of adult neurogenesis on memory encoding.}, journal = {Neuron}, volume = {61}, year = {2009}, month = {2009 Jan 29}, pages = {187-202}, abstract = {

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

}, keywords = {Age Factors, Algorithms, Animals, Cell Proliferation, Computer Simulation, Dentate Gyrus, Humans, Memory, Nerve Net, Neural Pathways, Neurogenesis, Neuronal Plasticity, Neurons, Stem Cells, Synapses, Time Perception}, issn = {1097-4199}, doi = {10.1016/j.neuron.2008.11.026}, author = {Aimone, James B and Wiles, Janet and Gage, Fred H} } @article {165, title = {The Drosophila foraging gene mediates adult plasticity and gene-environment interactions in behaviour, metabolites, and gene expression in response to food deprivation.}, journal = {PLoS Genet}, volume = {5}, year = {2009}, month = {2009 Aug}, pages = {e1000609}, abstract = {

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

}, keywords = {Animals, Carbohydrate Metabolism, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Drosophila Proteins, Ecosystem, Fats, Food Deprivation, Gene Expression, Signal Transduction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1000609}, author = {Kent, Clement F and Daskalchuk, Tim and Cook, Lisa and Sokolowski, Marla B and Greenspan, Ralph J} } @article {160, title = {A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.}, journal = {PLoS Comput Biol}, volume = {5}, year = {2009}, month = {2009 Mar}, pages = {e1000334}, abstract = {

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

}, keywords = {Animals, Brain, Databases, Factual, Humans, Macaca, Mice, Models, Neurological, Nerve Net, Neuroanatomy, Research Design}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000334}, author = {Bohland, Jason W and Wu, Caizhi and Barbas, Helen and Bokil, Hemant and Bota, Mihail and Breiter, Hans C and Cline, Hollis T and Doyle, John C and Freed, Peter J and Greenspan, Ralph J and Haber, Suzanne N and Hawrylycz, Michael and Herrera, Daniel G and Hilgetag, Claus C and Huang, Z Josh and Jones, Allan and Jones, Edward G and Karten, Harvey J and Kleinfeld, David and K{\"o}tter, Rolf and Lester, Henry A and Lin, John M and Mensh, Brett D and Mikula, Shawn and Panksepp, Jaak and Price, Joseph L and Safdieh, Joseph and Saper, Clifford B and Schiff, Nicholas D and Schmahmann, Jeremy D and Stillman, Bruce W and Svoboda, Karel and Swanson, Larry W and Toga, Arthur W and Van Essen, David C and Watson, James D and Mitra, Partha P} } @article {142, title = {Selection, gene interaction, and flexible gene networks.}, journal = {Cold Spring Harb Symp Quant Biol}, volume = {74}, year = {2009}, month = {2009}, pages = {131-8}, abstract = {

Recent results from a variety of different kinds of experiments, mainly using behavior as an assay, and ranging from laboratory selection experiments to gene interaction studies, show that a much wider range of genes can affect phenotype than those identified as "core genes" in classical mutant screens. Moreover, very pleiotropic genes can produce specific phenotypes when mild variants are combined. These studies also show that gene networks readily change configuration and the relationships between interacting genes in response to the introduction of additional genetic variants, suggesting that the networks range widely and have a high degree of flexibility and malleability. Such flexibility, in turn, offers a plausible mechanism for the molding of phenotypes through microevolution, as a prerequisite to making a suitable environment for the acceptance of newly arising large-effect mutations in the transition from microevolution to macroevolution.

}, keywords = {Animals, Biological Evolution, Drosophila melanogaster, Epistasis, Genetic, Escherichia coli, Female, Gene Regulatory Networks, Genes, Insect, Genetic Association Studies, Male, Models, Genetic, Mutation, Selection, Genetic}, issn = {1943-4456}, doi = {10.1101/sqb.2009.74.029}, author = {Greenspan, R J} } @article {132, title = {Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification.}, journal = {J Neurosci}, volume = {28}, year = {2008}, month = {2008 Apr 30}, pages = {4777-84}, abstract = {

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

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

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

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

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

}, keywords = {Animals, Calcium, Gene Expression Regulation, Developmental, Muscle, Skeletal, Neuromuscular Junction, Neurotransmitter Agents, Receptors, Neurotransmitter, Spinal Cord, Synapses, Xenopus}, issn = {0027-8424}, doi = {10.1073/pnas.0607450104}, author = {Borodinsky, Laura N and Spitzer, Nicholas C} } @article {144, title = {Serotonin and neuropeptide F have opposite modulatory effects on fly aggression.}, journal = {Nat Genet}, volume = {39}, year = {2007}, month = {2007 May}, pages = {678-82}, abstract = {

Both serotonin (5-HT) and neuropeptide Y have been shown to affect a variety of mammalian behaviors, including aggression. Here we show in Drosophila melanogaster that both 5-HT and neuropeptide F, the invertebrate homolog of neuropeptide Y, modulate aggression. We show that drug-induced increases of 5-HT in the fly brain increase aggression. Elevating 5-HT genetically in the serotonergic circuits recapitulates these pharmacological effects, whereas genetic silencing of these circuits makes the flies behaviorally unresponsive to the drug-induced increase of 5-HT but leaves them capable of aggression. Genetic silencing of the neuropeptide F (npf) circuit also increases fly aggression, demonstrating an opposite modulation to 5-HT. Moreover, this neuropeptide F effect seems to be independent of 5-HT. The implication of these two modulatory systems in fly and mouse aggression suggest a marked degree of conservation and a deep molecular root for this behavior.

}, keywords = {Aggression, Analysis of Variance, Animals, Behavior, Animal, Biological Evolution, Brain, Drosophila melanogaster, Drosophila Proteins, Gene Silencing, Neuropeptides, Reverse Transcriptase Polymerase Chain Reaction, Serotonin}, issn = {1061-4036}, doi = {10.1038/ng2029}, author = {Dierick, Herman A and Greenspan, Ralph J} } @article {145, title = {Molecular analysis of flies selected for aggressive behavior.}, journal = {Nat Genet}, volume = {38}, year = {2006}, month = {2006 Sep}, pages = {1023-31}, abstract = {

Aggressive behavior is pervasive throughout the animal kingdom, and yet very little is known about its molecular underpinnings. To address this problem, we have developed a population-based selection procedure to increase aggression in Drosophila melanogaster. We measured changes in aggressive behavior in the selected subpopulations with a new two-male arena assay. In only ten generations of selection, the aggressive lines became markedly more aggressive than the neutral lines. After 21 generations, the fighting index increased more than 30-fold. Using microarray analysis, we identified genes with differing expression levels in the aggressive and neutral lines as candidates for this strong behavioral selection response. We tested a small set of these genes through mutant analysis and found that one significantly increased fighting frequency. These results suggest that selection for increases in aggression can be used to molecularly dissect this behavior.

}, keywords = {Aggression, Agonistic Behavior, Animals, Behavior, Animal, DNA Mutational Analysis, Drosophila melanogaster, Male, Oligonucleotide Array Sequence Analysis, RNA, Selection, Genetic}, issn = {1061-4036}, doi = {10.1038/ng1864}, author = {Dierick, Herman A and Greenspan, Ralph J} } @article {146, title = {The nature of genetic influences on behavior: lessons from "simpler" organisms.}, journal = {Am J Psychiatry}, volume = {163}, year = {2006}, month = {2006 Oct}, pages = {1683-94}, abstract = {

Substantial advances have been made in recent years in the understanding of the genetic basis of behavior in "simpler" organisms, especially the mouse and the fruit fly Drosophila. The authors examine the degree of similarity between the genetic underpinnings of psychiatric illness and genetic influences on behavior in such simpler organisms. Six topics are reviewed: 1) the extent of natural genetic variation, 2) the multigenic nature of natural variation, 3) the impact of individual genes on multiple traits, 4) gene-environment interactions, 5) genetic effects on the environment, and 6) gene-by-sex interactions. The results suggest that the pattern of results emerging in psychiatric genetics is generally consistent with the findings of behavioral genetics in simpler organisms. Across the animal kingdom, individual differences in behavior are nearly always influenced by genetic factors which, in turn, result from a substantial number of individual genes, each with a small effect. Nearly all genes that affect behavior influence multiple phenotypes. The impact of individual genes can be substantially modified by other genes and/or by environmental experiences. Many animals alter their environment, and the nature of that alteration is influenced by genes. For some behaviors, the pathway from genes to behavior differs meaningfully in males and females. With respect to the broad patterns of genetic influences on behavior, Homo sapiens appears to be typical of other animal species.

}, keywords = {Animals, Drosophila, Genetics, Behavioral, Humans, Mental Disorders, Mice, Physiology, Comparative}, issn = {0002-953X}, doi = {10.1176/ajp.2006.163.10.1683}, author = {Kendler, Kenneth S and Greenspan, Ralph J} } @article {147, title = {Dopaminergic modulation of arousal in Drosophila.}, journal = {Curr Biol}, volume = {15}, year = {2005}, month = {2005 Jul 12}, pages = {1165-75}, abstract = {

BACKGROUND: Arousal levels in the brain set thresholds for behavior, from simple to complex. The mechanistic underpinnings of the various phenomena comprising arousal, however, are still poorly understood. Drosophila behaviors have been studied that span different levels of arousal, from sleep to visual perception to psychostimulant responses.

RESULTS: We have investigated neurobiological mechanisms of arousal in the Drosophila brain by a combined behavioral, genetic, pharmacological, and electrophysiological approach. Administration of methamphetamine (METH) suppresses sleep and promotes active wakefulness, whereas an inhibitor of dopamine synthesis promotes sleep. METH affects courtship behavior by increasing sexual arousal while decreasing successful sexual performance. Electrophysiological recordings from the medial protocerebrum of wild-type flies showed that METH ingestion has rapid and detrimental effects on a brain response associated with perception of visual stimuli. Recordings in genetically manipulated animals show that dopaminergic transmission is required for these responses and that visual-processing deficits caused by attenuated dopaminergic transmission can be rescued by METH.

CONCLUSIONS: We show that changes in dopamine levels differentially affect arousal for behaviors of varying complexity. Complex behaviors, such as visual perception, degenerate when dopamine levels are either too high or too low, in accordance with the inverted-U hypothesis of dopamine action in the mammalian brain. Simpler behaviors, such as sleep and locomotion, show graded responses that follow changes in dopamine level.

}, keywords = {Animals, Animals, Genetically Modified, Arousal, Brain, Dopa Decarboxylase, Dopamine, Dose-Response Relationship, Drug, Drosophila, Drosophila Proteins, Dynamins, Electrophysiology, Methamphetamine, Mutation, Sexual Behavior, Animal, Sleep, Visual Perception}, issn = {0960-9822}, doi = {10.1016/j.cub.2005.05.025}, author = {Andretic, Rozi and van Swinderen, Bruno and Greenspan, Ralph J} } @article {130, title = {Activity-dependent homeostatic specification of transmitter expression in embryonic neurons.}, journal = {Nature}, volume = {429}, year = {2004}, month = {2004 Jun 3}, pages = {523-30}, abstract = {

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

}, keywords = {Action Potentials, Animals, Calcium, Calcium Signaling, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Homeostasis, Humans, Neurons, Neurotransmitter Agents, Organ Specificity, Phenotype, Potassium Channels, Inwardly Rectifying, Rats, Sodium Channels, Spinal Cord, Xenopus laevis}, issn = {1476-4687}, doi = {10.1038/nature02518}, author = {Borodinsky, Laura N and Root, Cory M and Cronin, Julia A and Sann, Sharon B and Gu, Xiaonan and Spitzer, Nicholas C} } @article {148, title = {Cognitive consonance: complex brain functions in the fruit fly and its relatives.}, journal = {Trends Neurosci}, volume = {27}, year = {2004}, month = {2004 Dec}, pages = {707-11}, abstract = {

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

}, keywords = {Animals, Bees, Behavior, Animal, Brain, Cognition, Drosophila melanogaster, Humans, Perception, Spiders}, issn = {0166-2236}, doi = {10.1016/j.tins.2004.10.002}, author = {Greenspan, Ralph J and van Swinderen, Bruno} } @article {149, title = {Salience modulates 20-30 Hz brain activity in Drosophila.}, journal = {Nat Neurosci}, volume = {6}, year = {2003}, month = {2003 Jun}, pages = {579-86}, abstract = {

Fruit flies selectively orient toward the visual stimuli that are most salient in their environment. We recorded local field potentials (LFPs) from the brains of Drosophila melanogaster as they responded to the presentation of visual stimuli. Coupling of salience effects (odor, heat or novelty) to these stimuli modulated LFPs in the 20-30 Hz range by evoking a transient, selective increase. We demonstrated the association of these responses with behavioral tracking and initiated a genetic approach to investigating neural correlates of perception.

}, keywords = {Action Potentials, Animals, Attention, Behavior, Animal, Brain, Cues, Drosophila, Drosophila Proteins, Exploratory Behavior, Mutation, Neurons, Orientation, Retina, Smell, Synaptic Transmission, Thermosensing, Visual Pathways, Visual Perception}, issn = {1097-6256}, doi = {10.1038/nn1054}, author = {van Swinderen, Bruno and Greenspan, Ralph J} } @article {150, title = {Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait.}, journal = {Nat Genet}, volume = {31}, year = {2002}, month = {2002 Aug}, pages = {349-53}, abstract = {

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

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, DNA, Complementary, Drosophila melanogaster, Female, Genetics, Behavioral, Mutation, Oligonucleotide Array Sequence Analysis}, issn = {1061-4036}, doi = {10.1038/ng893}, author = {Toma, Daniel P and White, Kevin P and Hirsch, Jerry and Greenspan, Ralph J} } @article {151, title = {The flexible genome.}, journal = {Nat Rev Genet}, volume = {2}, year = {2001}, month = {2001 May}, pages = {383-7}, abstract = {

A principal assumption underlying contemporary genetic analysis is that the normal function of a gene can be inferred directly from its mutant phenotype. The interactivity among genes that is now being revealed calls this assumption into question and indicates that there might be considerable flexibility in the capacity of the genome to respond to diverse conditions. The reservoir for much of this flexibility resides in the nonspecificity and malleability of gene action.

}, keywords = {Animals, Chromosome Mapping, Genes, Genome, Humans, Phenotype}, issn = {1471-0056}, doi = {10.1038/35072018}, author = {Greenspan, R J} } @article {152, title = {Correlates of sleep and waking in Drosophila melanogaster.}, journal = {Science}, volume = {287}, year = {2000}, month = {2000 Mar 10}, pages = {1834-7}, abstract = {

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

}, keywords = {Animals, Arylamine N-Acetyltransferase, Behavior, Animal, Biogenic Monoamines, Caffeine, Carrier Proteins, Circadian Rhythm, Cytochrome P-450 Enzyme System, Drosophila melanogaster, Drosophila Proteins, Fatty Acid Synthases, Female, Gene Dosage, Gene Expression Profiling, Genes, Insect, Homeostasis, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Hydroxyzine, Mutation, Rest, Sleep, Transcription, Genetic, Wakefulness}, issn = {0036-8075}, author = {Shaw, P J and Cirelli, C and Greenspan, R J and Tononi, G} } @article {153, title = {Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.}, journal = {Science}, volume = {277}, year = {1997}, month = {1997 Aug 8}, pages = {834-6}, abstract = {

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

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

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

}, keywords = {Animals, Bisexuality, Brain, Drosophila melanogaster, Female, Genes, Insect, Male, Sex Attractants, Sexual Behavior, Animal, Smell}, issn = {0036-8075}, author = {Ferveur, J F and St{\"o}rtkuhl, K F and Stocker, R F and Greenspan, R J} } @article {155, title = {Understanding the genetic construction of behavior.}, journal = {Sci Am}, volume = {272}, year = {1995}, month = {1995 Apr}, pages = {72-8}, keywords = {Animals, Drosophila melanogaster, Female, Genetics, Behavioral, Humans, Male, Sexual Behavior, Animal}, issn = {0036-8733}, author = {Greenspan, R J} }