@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 {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 {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 {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 {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 {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 {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 {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 {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 {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 {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} }