1985 — 1987 |
Neckameyer, Wendi S |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Mutations Affecting Learning in Drosophila Melanogaster @ Massachusetts Institute of Technology |
0.901 |
1994 — 1996 |
Neckameyer, Wendi |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Rpg: Regulation of Neurotransmitter Transporters in Drosophila
9407849 Neckameyer ABSTRACT Synaptic transmission is critically dependent on the concentrations of neurotransmitter at the synaptic cleft. Upon release of the neurotransmitter at the cleft, neurotransmitter transporters contribute to the removal of transmitter into the presynaptic terminal. This limits the duration of the neurotransmitter action, and is thought to play a major role in maintaining neurotransmitter availability at a variety of synapses. The precise molecular mechanisms which regulate the activity of the neurotransmitter transporters are only beginning to be elucidated. Moreover, such work has not yet addressed the developmental and functional significance of perturbing these mechanisms in vivo. This application proposes to build upon our recent cloning of Drosphila neurotransmitter transporter cDNAs to examine the regulation of these important proteins. The choice of Drosophila enables us to bring to bear some of the unique advantages of this model system (such as the facility in generating both transgenic animals as well as mutations specific to genetic loci) on these important questions. These studies will take advantage of recombinant DNA methodology to (1) identify the specific neurotransmitter substrate for each of the transporters isolated thus far, and (2) to initiate a molecular genetic analysis of the transporter loci. These initial studies will lay the groundwork for future experiments that will assess the developmental and functional consequences in vivo of perturbing reuptake regulatory mechanisms by introducing altered transporter genes into the genome of Drosphila. These studies will increase our comprehension of the role that neurotransmitter transporters play in synaptic transmission.
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0.915 |
1995 — 1999 |
Neckameyer, Wendi |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Regulatory Mechanisms of Drosophila Tyrosine Hydroxylase
9423616 The Neurotransmitter dopamine has been strongly implicated in the physiological regulation of "simple" behaviors, such as motor control, as well as in higher order cognitive function. This work addresses the functional consequences of perturbing the normally exquisitely regulated levels of dopamine in the nervous system by manipulation of the regulatory mechanisms directing dopamine synthesis. The choice of Drosophila melanogaster as the model system facilitates the use of molecular genetic techniques to circumvent limitations encountered in other systems. These studies take advantage of recombinant DNA methodology to (1) modulate the expression of tyrosine hydroxylase, the rate-limiting biosynthetic enzyme in the synthesis of dopamine, and (2) determine the functional consequences of perturbing these mechanisms in the intact animal.
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0.915 |
1999 — 2001 |
Neckameyer, Wendi S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Analysis of the Drosophila Gaba Transporters
DESCRIPTION: (Applicant's Abstract) Transmitter reuptake mechanisms are essential not only for terminating neurotransmitter signaling at the synaptic cleft, but for maintaining transmitter stores within the presynaptic neuron. Reuptake of GABA, the major inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems, is the primary mechanism for termination of the signal propagated by GABA release. Perturbations in GABAergic neurotransmission are believed to underlie the etiologies of dementias, schizophrenia, and epilepsy. The goal of this work is to molecularly characterize the multiple GABA transporters in Drosophila melanogaster (DGATs), and to utilize the unique assets of this model system to study the functional consequences of perturbations in normal GABA reuptake mechanisms. The existence of experimentally accessible GABA transporter subtypes in Drosophila facilitates a molecular and genetic approach to the understanding of the actions of GABA and its effects on animal behavior. Diversity in the mammalian GABA transporter locus is believed to serve different aspects of GABAergic neurotransmission; preliminary work suggests the same is true in Drosophila. Targeting GABA reuptake is thus preferable to targeting GABA synthesis, since there are over 3000 GABAergic neurons in the Drosophila CNS. This application proposes to (1) identify and pharmacologically characterize distinct members of the DGAT family, (2) identify their temporal and spatial expression to provide insight into their functional roles, and (3) determine the behavioral consequences of perturbed GABAergic neurotransmission, using both pharmacological intervention and transgenic animals that overexpress a specific GABA transporter. The Drosophila GABA transporters are strikingly homologous to their mammalian counterparts, and thus the proposed experiments will extend our knowledge of basic regulatory mechanisms governing neuronal excitability, and will also provide information resulting in improved therapeutic targets for dementia and epilepsies.
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1999 — 2003 |
Neckameyer, Wendi |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Regulatory Mechanisms of Drosphilia Tyrosine Hydroxylase
LAY ABSTRACT
Proposal #: IBN-9816566 PI Name: Wendi Neckameyer
Dopamine is required in several physiological contexts in the fruit fly Drosophila melanogaster, where it functions as a signaling molecule in developmental, reproductive and behavioral pathways. Given its multiple roles, the levels of dopamine must be precisely regulated in diverse tissues at different times throughout the life of the animal. Behavioral abnormalities may arise from disruption of normal dopaminergic neurotransmission, or from abnormally developed tissues. To distinguish between these two essential roles for dopamine, this application proposes to identify adult behaviors that are affected when dopamine levels are disrupted during development. A second goal is to identify the DNA sequence elements necessary for normal expression of the gene which encodes the rate-limiting step in dopamine synthesis. Specific perturbation of dopaminergic transmission within the central nervous system is critical for eventual elucidation of the role of dopamine in the modulation of behaviors. The multiple signaling roles for dopamine are both novel and vital, and appear to be evolutionarily conserved. The experiments outlined in this proposal demonstrate how the same signaling molecule may be recruited for use in several physiological contexts, and may have profound implications for the etiology of cognitive pathologies, including Parkinson's disease, schizophrenia, and depression.
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0.915 |
2006 — 2010 |
Neckameyer, Wendi |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Trophic Factors and the Development of Neural Circuitry
Neurotransmitters appear to play critical roles during development of the nervous system in addition to their functions as signaling molecules in the mature brain. However, the neurogenic roles for these molecules have not been fully elucidated. These experiments will test the hypothesis that the neurotransmitter serotonin (5-HT) is a trophic factor critical for the normal development of central nervous system (CNS) circuitry in the model system Drosophila melanogaster. Changes in 5-HT levels during CNS development should affect the development of the neural circuitry, and therefore affect functioning of the mature CNS. Genetic and transgenic tools will be used to constitutively alter 5-HT levels to establish that both the normal circuitry and the function of the CNS are affected. Similar tools will be used to temporally and spatially disrupt normal neuronal 5-HT levels to separate the neurogenic role of 5-HT from its function as a modulator of different behaviors. This award will focus on the serotonergic fibers innervating the gut as well as the antennal lobes and mushroom bodies, since these fibers are limited in number and thus provide a simple system in which to assess changes in varicosities, arborizations, and cell number. The function of these circuits will be analyzed by assessing feeding and olfactory behaviors, which have been shown to be affected by altered neuronal 5-HT levels. These experiments will elucidate the neurogenic role of 5-HT in the developing gut and olfactory circuitry and establish the functional consequences of defects in this process. This research program addresses a critical biological question (development of CNS circuitry), and will generate numerous reagents that will be made available to the scientific community.
Activities to be carried out under this award will have a direct impact on scientific education and training. Several undergraduates have directly participated in NSF research projects from this laboratory; seven have been coauthors on papers, and have presented their work at scientific meetings. In addition, Dr. Neckameyer has also hosted high school teachers and students in her laboratory in order to teach the concepts and techniques used in her work.
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0.915 |
2009 — 2010 |
Neckameyer, Wendi S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hormonal Factors and Recruitment of Neurons Into the Stress Response Circuitry
The mechanisms initiating developmental and behavioral changes in the brain during sexual maturity remain to be elucidated. We hypothesize that hormonal factors involved in determination of sex and sexual maturity also direct recruitment of neurons into behavioral circuits. The Drosophila dopamine (DA) neurons within the stress response circuitry can serve as a model in which to elucidate these factors. As for mammals, DA is integral to the stress response pathway, DA modulates analogous behaviors, and the DA biosynthetic pathways and reuptake mechanisms are highly conserved. If unique subsets of DA neurons are recruited into the stress response circuitry in the brains of sexually immature and mature male and female Drosophila, we predict differences in DA-modulated behaviors after exposure to stress. The DA neuronal population is stereospecific and limited in number, so one can map individual DA neurons unique to each circuit. The first aim tests whether the stress response circuitry is composed of unique subsets of DA neurons in sexually immature and mature male and female Drosophila. We have identified brain regions critical for the stress response using mutant strains with distinct anatomical brain defects and will identify the individual DA neurons affected by each mutation by immunohistochemical comparisons of their neuronal DA patterns with wild type. DA levels will be decreased in those neurons by targeted knockdown of DA synthesis using transgenic and genetic tools. Deviations from the normal response in sexually immature and mature male and females will identify the individual DA neurons unique to the stress response circuitry in the different populations. We will then test whether recruitment of DA neurons into the stress circuitry is influenced by factors that regulate sexual differentiation and sexual maturity. While the population of DA neurons is not sexually dimorphic, DA neurons recruited into the response circuits differ in males and females. Feminization of subsets of neurons in an otherwise male fly should alter the stress response if neurons critical for the response have been appropriately targeted. The actions of gonadotropic hormones affect the stress response as well as neuronal differentiation and reorganization. The impact of the hormonal environment surrounding the DA neurons can be assessed using pharmacological tools. The experiments proposed in this application will identify the specific DA neurons recruited into the stress response circuitry that occur during sexual differentiation and sexual maturity, and initiate identification of hormonal mediators affecting recruitment of individual neurons. This will provide a unique and innovative approach to modeling the development and organization of the stress circuitry in mammals.
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