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Tim Tully

Publications and source records attributed to Tim Tully.

At least 19 recordsLinked to original sources
PubMed2005

GeneSeer: a sage for gene names and genomic resources.

BACKGROUND: Independent identification of genes in different organisms and assays has led to a multitude of names for each gene. This balkanization makes it difficult to use gene names to locate genomic resources, homologs in other species and relevant publications. METHODS: We solve the naming problem by collecting data from a variety of sources and building a name-translation database. We have also built a table of homologs across several model organisms: H. sapiens, M. musculus, R. norvegicus, D. melanogaster, C. elegans, S. cerevisiae, S. pombe and A. thaliana. This allows GeneSeer to draw phylogenetic trees and identify the closest homologs. This, in turn, allows the use of names from one species to identify homologous genes in another species. A website http://geneseer.cshl.org/ is connected to the database to allow user-friendly access to our tools and external genomic resources using familiar gene names. CONCLUSION: GeneSeer allows access to gene information through common names and can map sequences to names. GeneSeer also allows identification of homologs and paralogs for a given gene. A variety of genomic data such as sequences, SNPs, splice variants, expression patterns and others can be accessed through the GeneSeer interface. It is freely available over the web http://geneseer.cshl.org/ and can be incorporated in other tools through an http-based software interface described on the website. It is currently used as the search engine in the RNAi codex resource, which is a portal for short hairpin RNA (shRNA) gene-silencing constructs.

Alternative Splicing↗
PubMed2005

Deconstructing memory in Drosophila.

Unlike most organ systems, which have evolved to maintain homeostasis, the brain has been selected to sense and adapt to environmental stimuli by constantly altering interactions in a gene network that functions within a larger neural network. This unique feature of the central nervous system provides a remarkable plasticity of behavior, but also makes experimental investigations challenging. Each experimental intervention ramifies through both gene and neural networks, resulting in unpredicted and sometimes confusing phenotypic adaptations. Experimental dissection of mechanisms underlying behavioral plasticity ultimately must accomplish an integration across many levels of biological organization, including genetic pathways acting within individual neurons, neural network interactions which feed back to gene function, and phenotypic observations at the behavioral level. This dissection will be more easily accomplished for model systems such as Drosophila, which, compared with mammals, have relatively simple and manipulable nervous systems and genomes. The evolutionary conservation of behavioral phenotype and the underlying gene function ensures that much of what we learn in such model systems will be relevant to human cognition. In this essay, we have not attempted to review the entire Drosophila memory field. Instead, we have tried to discuss particular findings that provide some level of intellectual synthesis across three levels of biological organization: behavior, neural circuitry and biochemical pathways. We have attempted to use this integrative approach to evaluate distinct mechanistic hypotheses, and to propose critical experiments that will advance this field.

Adenylyl Cyclases↗
PubMed2005

NMDA receptors mediate olfactory learning and memory in Drosophila.

BACKGROUND: Molecular and electrophysiological properties of NMDARs suggest that they may be the Hebbian "coincidence detectors" hypothesized to underlie associative learning. Because of the nonspecificity of drugs that modulate NMDAR function or the relatively chronic genetic manipulations of various NMDAR subunits from mammalian studies, conclusive evidence for such an acute role for NMDARs in adult behavioral plasticity, however, is lacking. Moreover, a role for NMDARs in memory consolidation remains controversial. RESULTS: The Drosophila genome encodes two NMDAR homologs, dNR1 and dNR2. When coexpressed in Xenopus oocytes or Drosophila S2 cells, dNR1 and dNR2 form functional NMDARs with several of the distinguishing molecular properties observed for vertebrate NMDARs, including voltage/Mg(2+)-dependent activation by glutamate. Both proteins are weakly expressed throughout the entire brain but show preferential expression in several neurons surrounding the dendritic region of the mushroom bodies. Hypomorphic mutations of the essential dNR1 gene disrupt olfactory learning, and this learning defect is rescued with wild-type transgenes. Importantly, we show that Pavlovian learning is disrupted in adults within 15 hr after transient induction of a dNR1 antisense RNA transgene. Extended training is sufficient to overcome this initial learning defect, but long-term memory (LTM) specifically is abolished under these training conditions. CONCLUSIONS: Our study uses a combination of molecular-genetic tools to (1) generate genomic mutations of the dNR1 gene, (2) rescue the accompanying learning deficit with a dNR1+ transgene, and (3) rapidly and transiently knockdown dNR1+ expression in adults, thereby demonstrating an evolutionarily conserved role for the acute involvement of NMDARs in associative learning and memory.

Amino Acid Sequence↗
PubMed2004

Regulation of multimers via truncated isoforms: a novel mechanism to control nitric-oxide signaling.

Nitric oxide (NO) is an essential regulator of Drosophila development and physiology. We describe a novel mode of regulation of NO synthase (NOS) function that uses endogenously produced truncated protein isoforms of Drosophila NOS (DNOS). These isoforms inhibit NOS enzymatic activity in vitro and in vivo, reflecting their ability to form complexes with the full-length DNOS protein (DNOS1). Truncated isoforms suppress the antiproliferative action of DNOS1 in the eye imaginal disc by impacting the retinoblastoma-dependent pathway, yielding hyperproliferative phenotypes in pupae and adult flies. Our results indicate that endogenous products of the dNOS locus act as dominant negative regulators of NOS activity during Drosophila development.

Alternative Splicing↗
PubMed2004

Notch signaling in Drosophila long-term memory formation.

Notch (N) is a cell surface receptor that mediates an evolutionarily ancient signaling pathway to control an extraordinarily broad spectrum of cell fates and developmental processes. To gain insights into the functions of N signaling in the adult brain, we examined the involvement of N in Drosophila olfactory learning and memory. Long-term memory (LTM) was disrupted by blocking N signaling in conditional mutants or by acutely induced expression of a dominant-negative N transgene. In contrast, neither learning nor early memory were affected. Furthermore, induced overexpression of a wild-type (normal) N transgene specifically enhanced LTM formation. These experiments demonstrate that N signaling contributes to LTM formation in the Drosophila adult brain.

Animals↗
PubMed2004

radish encodes a phospholipase-A2 and defines a neural circuit involved in anesthesia-resistant memory.

BACKGROUND: In both vertebrate and invertebrate animals, anesthetic agents cause retrograde amnesia for recently experienced events. In contrast, older memories are resistant to the same treatments. In Drosophila, anesthesia-resistant memory (ARM) and long-term memory (LTM) are genetically distinct forms of long-lasting memory that exist in parallel for at least a day after training. ARM is disrupted in radish mutants but is normal in transgenic flies overexpressing a CREB repressor transgene. In contrast, LTM is normal in radish mutants but is disrupted in CREB repressor transgenic flies. To date, nothing is known about the molecular, genetic, or cell biological pathways underlying ARM. RESULTS: Here, we report the molecular identification of radish as a phospholipase-A2, providing the first clue about signaling pathways underlying ARM in any animal. An enhancer-trap allele of radish (C133) reveals expression in a novel anatomical pathway. Transgenic expression of PLA2 under control of C133 restores normal levels of ARM to radish mutants, whereas transient disruption of neural activity in C133 neurons inhibits memory retention. Notably, expression of C133 is not in mushroom bodies, the primary anatomical focus of olfactory memory research in Drosophila. CONCLUSIONS: Identification of radish as a phospholipase-A2 and the neural expression pattern of an enhancer-trap allele significantly broaden our understanding of the biochemistry and anatomy underlying olfactory memory in Drosophila.

Alleles↗
PubMed2003

Aging specifically impairs amnesiac-dependent memory in Drosophila.

Age-related memory impairment (AMI) is observed in many species. However, it is uncertain whether AMI results from a specific or a nonspecific decay in memory processing. In Drosophila, memory acquired after a single olfactory conditioning paradigm has three distinct phases: short-term memory (STM), middle-term memory (MTM), and longer-lasting anesthesia-resistant memory (ARM). Here, we demonstrate that age-related defects in olfactory memory are identical to those of the MTM mutant amnesiac (amn). Furthermore, amn flies do not exhibit an age-dependent decrease in memory, in contrast to other memory mutants. The absence of AMI in amn flies is restored by expression of an amn transgene predominantly in DPM cells. Thus, we propose that AMI in flies results from a specific decrease in amn-dependent MTM.

Aging↗
PubMed2003

Blockade of neurotransmission in Drosophila mushroom bodies impairs odor attraction, but not repulsion.

Olfaction can elicit a rich perceptual experience. It is not known, however, whether olfactory information is decomposed into various components and processed in distinct perceptual centers as in other sensory systems, such as vision, where neural representations of different visual sensations are segregated in different cortical regions, despite the fact that multiple structures of the primary olfactory cortex receive projections from the olfactory bulb. Here, we use Drosophila as a model to investigate whether different olfactory information may be processed in separate brain structures. Organizations of the peripheral olfactory system are remarkably similar from mammals to insects. As in vertebrates, the olfactory pathway in Drosophila follows similar convergence and divergence, and multiple high-order structures in the Drosophila brain, including the mushroom body (MB) and lateral horn (LH) of the protocerebrum, receive olfactory input. We specifically blocked neurotransmission in the MB while leaving the LH unaffected and examined its effect on olfactory avoidance and attraction behaviors. We show that blocking MB activity disrupted responses to attractive, but not repulsive, odors, and this finding suggests that attractive and repulsive olfactory information may be separately processed in higher olfactory centers of the Drosophila brain.

Animals↗
PubMed2003

A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4.

Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Interactions between epithelial nitric oxide signaling and phosphodiesterase activity in Drosophila.

Signaling by nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) modulates fluid transport in Drosophila melanogaster. Expression of an inducible transgene encoding Drosophila NO synthase (dNOS) increases both NOS activity in Malpighian (renal) tubules and DNOS protein in both type I (principal) and type II (stellate) cells. However, cGMP content is increased only in principal cells. DNOS overexpression results in elevated basal rates of fluid transport in the presence of the phosphodiesterase (PDE) inhibitor, Zaprinast. Direct assay of tubule cGMP-hydrolyzing phosphodiesterase (cG-PDE) activity in wild-type and dNOS transgenic lines shows that cG-PDE activity is Zaprinast sensitive and is elevated upon dNOS induction. Zaprinast treatment increases cGMP content in tubules, particularly at the apical regions of principal cells, suggesting localization of Zaprinast-sensitive cG-PDE to these areas. Potential cross talk between activated NO/cGMP and calcium signaling was assessed in vivo with a targeted aequorin transgene. Activated DNOS signaling alone does not modify either neuropeptide (CAP2b)- or cGMP-induced increases in cytosolic calcium levels. However, in the presence of Zaprinast, both CAP2b-and cGMP-stimulated calcium levels are potentiated upon DNOS overexpression. Use of the calcium channel blocker, verapamil, abolishes the Zaprinast-induced transport phenotype in dNOS-overexpressing tubules. Molecular genetic intervention in the NO/cGMP signaling pathway has uncovered a pivotal role for cell-specific cG-PDE in regulating the poise of the fluid transporting Malpighian tubule via direct effects on intracellular cGMP concentration and localization and via interactions with calcium signaling mechanisms.

Animals↗
PubMed2003

Characterization of Drosophila nitric oxide synthase: a biochemical study.

The heme and flavin-binding domains of Drosophila nitric oxide synthase (DNOS) were expressed in Escherichia coli using the expression vector pCW. The denatured molecular mass of the expressed protein was 152kDa along with a proteolytically cleaved product of 121kDa. The DNOS heme protein exhibited very low Ca(2+)/calmodulin-dependent NO synthase activity. The trypsin digestion patterns were different from nNOS. The full-length DNOS protein had high degree of stability against trypsin. The activity assay of trypsin-digested protein confirmed the same result. Urea dissociation profile of DNOS full-length protein showed that the reductase domain activity was much more susceptible towards urea than the oxygenase domain activity. Urea gradient gel of DNOS full-length protein established distinct transition of dissociation and unfolding in the range 3-4M urea. Reductase domain activity of full-length DNOS protein against external electron acceptors like cytochrome c indicated slow electron transfer from FMN. The bacterial expression of DNOS full-length protein represents an important development in structure-function studies of this enzyme and comparison with other mammalian NOS enzymes which is evolutionary significant.

Animals↗
PubMed2003

The staufen/pumilio pathway is involved in Drosophila long-term memory.

BACKGROUND: Memory formation after olfactory learning in Drosophila displays behavioral and molecular properties similar to those of other species. Particularly, long-term memory requires CREB-dependent transcription, suggesting the regulation of "downstream" genes. At the cellular level, long-lasting synaptic plasticity in many species also appears to depend on CREB-mediated gene transcription and subsequent structural and functional modification of relevant synapses. To date, little is known about the molecular-genetic mechanisms that contribute to this process during memory formation. RESULTS: We used two complementary strategies to identify these genes. From DNA microarrays, we identified 42 candidate memory genes that appear to be transcriptionally regulated in normal flies during memory formation. Via mutagenesis, we have independently identified 60 mutants with defective long-term memory and have defined molecular lesions for 58 of these. The pumilio translational repressor was found from both approaches, along with six additional genes with established roles in local control of mRNA translation. In vivo disruptions of four genes--staufen, pumilio, oskar, and eIF-5C--yield defective memory. CONCLUSIONS: Convergent findings from our behavioral screen for memory mutants and DNA microarray analysis of transcriptional responses during memory formation in normal animals suggest the involvement of the pumilio/staufen pathway in memory. Behavioral experiments confirm a role for this pathway and suggest a molecular mechanism for synapse-specific modification.

Animals↗
PubMed2003

Neural substrates of memory: from synapse to system.

One of the fundamental challenges of modern neuroscience is to understand how memories are acquired, stored, and retrieved by the brain. In the broadest terms, attempts to dissect memory can be broken down into four experimental disciplines: (1) identification of molecular components, (2) ex vivo and in vivo cellular analysis of neuronal function, (3) theoretical modeling approaches of neural systems, and (4) organismal-level behavioral analyses. Our objective here is to offer a conceptually unifying perspective and to discuss this perspective in relation to an experiment analysis of memory in Drosophila.

Animals↗
PubMed2003

Targeting the CREB pathway for memory enhancers.

Today, the clinical notion of 'memory disorder' is largely synonymous with 'Alzheimer's disease.' Only 50% of all dementias are of the Alzheimer's type though, and dementias represent only the more severe of all learning/memory disorders that derive from heredity, disease, injury or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder. To date, therapeutic drugs of only one class have been approved for the treatment of Alzheimer's disease. Fortunately, basic research during the past 25 years has begun to define a 'chemistry of brain plasticity,' which is suggesting new gene targets for the discovery of memory enhancers.

Alzheimer Disease↗
PubMed2002

Effects of tyrosine hydroxylase mutants on locomotor activity in Drosophila: a study in functional genomics.

The brain of the adult fruit fly, Drosophila melanogaster, contains tyrosine hydroxylase, the rate-limiting enzyme required for catecholamine biosynthesis, as well as dopa decarboxylase. Catecholamines, principally dopamine, are also present. We have previously shown that pharmacological inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine results in a dose-related inhibition of locomotor activity in adult organisms. Similar results were found with reserpine, a well-known inhibitor of catecholamine uptake into storage granules. The drug-induced inhibition could be prevented in each case by the concomitant administration of L-dopa. The single-copy gene coding for tyrosine hydroxylase in Drosophila is pale (ple). Both null and temperature-sensitive loss of function mutant alleles of ple are recessive embryonic lethals. Heterozygous null mutant flies have normal locomotor activity demonstrating that only a single dose of the wild type form of ple is required to support normal function. Both hemizygous and homozygous temperature-sensitive ple mutants (ple(ts1)) also show normal locomotor activity at the permissive temperature for this mutant allele (18 degrees C), which progressively declines as the temperature is increased to its restrictive level (29 degrees C). These abnormal locomotor effects are reversible by L-dopa. Thus the effects on locomotor activity resulting from the pharmacological inhibition of catecholamine synthesis or storage are the same as those resulting from lack of tyrosine hydroxylase expression. These findings indicate that brain catecholamine loss decreases locomotor activity in the fly, as it does in mammals, and demonstrate the ability of functional genomic studies to mimic that of pharmacological inhibition of enzyme function or other similar processes.

Alleles↗
PubMed2002

Achieving and maintaining cognitive vitality with aging.

Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.

Aging↗
PubMedDate not supplied

CREB and the discovery of cognitive enhancers.

In the past few years, a series of molecular-genetic, biochemical, cellular and behavioral studies in fruit flies, sea slugs and mice have confirmed a long-standing notion that long-term memory formation depends on the synthesis of new proteins. Experiments focused on the cAMP-responsive transcription factor, CREB, have established that neural activity-induced regulation of gene transcription promotes a synaptic growth process that strengthens the connections among active neurons. This process constitutes a physical basis for the engram--and CREB is a "molecular switch" to produce the engram. Helicon Therapeutics has been formed to identify drug compounds that enhance memory formation via augmentation of CREB biochemistry. Candidate compounds have been identified from a high throughput cell-based screen and are being evaluated in animal models of memory formation. A gene discovery program also seeks to identify new genes, which function downstream of CREB during memory formation, as a source for new drug discoveries in the future. Together, these drug and gene discovery efforts promise new class of pharmaceutical therapies for the treatment of various forms of cognitive dysfunction.

Animals↗