Research Summary

The pathophysiology of neuropsychiatric disorders is poorly understood, severely limiting progress in identifying therapeutic tools. Confounding this issue is that there are no known neurobiological biomarkers for most affective disorders. Few genetic associations have been identified, since numerous genes, each with relatively small effects, contribute to the etiology of mental illness. Perturbations in neural development underlie the etiology of mental illness as well as pervasive developmental disorders such as autism.  Our lab is interested in the development and function of neural circuits. Specifically, we ask: what factors affect development (and therefore, function) of neural circuitry during CNS development, and, once the neurons and connections to their downstream targets are in place, what factors affect recruitment of individual neurons into a circuit?

(1) Correct development of neuronal circuitry is fundamental to supporting normal behavioral function. Although genes involved in neurotransmission and synapse formation and maintenance have been strongly implicated in the etiology of schizophrenia and autism spectrum disorders, the copious number of potential candidate genes, and their epistatic interactions with each other as well as with the environment, have confounded elucidation of individual genetic components. We exploit the genetic tractability of the Drosophila model system to identify genes affecting the sexually dimorphic development, and thus function, of a defined neural circuit. Neurogenesis, neuronal pathfinding, and synaptogenesis are highly conserved between humans and Drosophila, so the basic building blocks in creating, maintaining, and modifying neural circuits will also be conserved. We employ a simple model whereby we can assess both development and function of a specific behavioral circuit in the larval stage of the fruit fly (Drosophila melanogaster). The Drosophila foregut provides a simple model to assess changes in fiber architecture, since (1) the neurites are sufficiently limited to permit quantitation of varicosities and branching, (2) feeding behavior, the functional output of this circuit, is also easily measured, (3) non-invasive titration of brain transmitter levels during development is easily accomplished in Drosophila using standard transgenic techniques, and (4) the trophic and transmitter roles for transmitters and other trophic factors can be dissociated using both transgenic and pharmacological tools. A fundamental aspect of our approach is that changes in this specific neural circuit can be directly correlated with changes in feeding behavior, the circuit’s functional output. We are initiating genetic screens to identify additional factors critical for the development, and thus mature function, of this circuit.

(2) Dysregulation of the central stress response results in increased vulnerability to psychiatric disorders, and is a causative factor not only for first onset of a depressive episode, but also for relapse and recurrence. In addition, these contributions are modified by the environment as well as by early life experience. The response to early life stress is sexually dimorphic in that mature females demonstrate an increased sensitivity to life stress, and an increased risk of developing affective disorders, but males display an enhanced risk for schizophrenia. However, the relative contributions of gonadotropic hormones and sex-determining and other factors to the development of this sexual dimorphism is unclear. Thus, there is a need to develop models that facilitate the identification of genetic factors that predispose an individual to diminished resilience in response to stress, and to identify critical periods of developmental vulnerability. Unlike other animal models, the genetic and environmental background can be controlled in Drosophila, so that genetic variants with relatively small effects can be uncovered, and their interactions with other genes assessed, during vulnerable developmental windows and under stressful environmental conditions. We are identifying genes whose normal expression is critical for the development of a resilient stress response. We are also validating Drosophila as a model to demonstrate that early life events also affect plasticity and resilience of the adult Drosophila brain. This will permit elucidation of conserved genetic and environmental components modulating development of the stress circuitry during the vulnerable period of sexual maturation of the brain. These factors may prove useful as biomarkers for enhanced risk of impaired response to stress, and thus for depression, and may also provide useful therapeutic targets for the treatment of affective disorders.

NSF PreDoctoral Fellowship Honorable Mention, 1981

National Research Service Award, NIH, 1982 - 1984

NIH Postdoctoral Fellowship (NINCDS), 1985 - 1988

Pharmaceutical Manufacturers' Association Starter Grant (PI), $25,000, 1993 - 1995

NARSAD Young Investigator Award (PI), $30,000, 1994 - 1996. "Regulation of Dopaminergic and Serotonergic Neurotransmission"

NSF Research Planning Grant (PI), $16,364, 1994 - 1996. "Regulation of Neurotransmitter Transporters in Drosophila"

NSF (PI), $164,622, 1995 - 1999. "Regulatory Mechanisms of Drosophila Tyrosine Hydroxylase"

NSF (PI), $117,810, 1999 - 2003. "Regulatory Mechanisms of Drosophila Tyrosine Hydroxylase"

NIMH RO1 (PI), $330,000, 1999 - 2003. "Molecular-Genetic Analysis of the Drosophila GABA Transporter Family"

NSF (PI) $240,000, 2006 – 2009. "Trophic Factors and the Development of Neural Circuitry”

President's Research Fund (PI) 1/1/11-12/31/11 "Identification of Trophic Factors for the Development of Neural Circuitry"

1R01MH083771-01A1 NIMH (PI) $561,746 2009-2012 "Hormonal Factors and Recruitment of Neurons into the Stress Response Circuitry"

NSF (PI) $240,000, 2006 – 2009 “Trophic Factors and the Development of Neural Circuitry”

Genetics Society of America

MS1 Small groups tutorials, Molecular Biology and Genetics
501 Genetics, Section Director
513 Dopamine Pharmacology, Parkinson's, and Schizophrenia

Publications

Neckameyer, W. S. and Quinn, W. 1989. Isolation and Characterization of the Gene for Drosophila Tyrosine Hydroxylase. Neuron 2: 1167-1175.

Neckameyer, W. S. and White, K. 1992. A Single Locus Encodes both Phenylalanine Hydroxylase and Tryptophan Hydroxylase Activities in Drosophila. J. Biol. Chem. 267: 4199-4206. 

Neckameyer, W. S. and White, K. 1993. Drosophila Tyrosine Hydroxylase is Encoded by the pale Locus. J. Neurogenet. 8: 189-199.

Neckameyer, W. S. 1996. Multiple Roles for Dopamine in Drosophila Development. Developmental Biology 176: 209 - 219, 1996. COVER ARTICLE, July issue

Neckameyer, W. S. 1998. Dopamine Modulates Female Sexual Receptivity in Drosophila melanogaster. J. Neurogenet. 12: 101-114.

Neckameyer, W. S. 1998. Dopamine and Mushroom Bodies in Drosophila: Experience-Dependent and –Independent Aspects of Sexual Behavior. Learning and Memory 5: 157-165.

Neckameyer, W. S. and R. Cooper. 1998. GABA Transporters in Drosophila: Molecular Cloning, Behavior and Physiology. Invertebrate Neuroscience 3: 279-294.

Cooper, R. and Neckameyer, W. 1999. Dopaminergic Modulodulation of Motor Neuron Activity and Neuromuscular Function in Drosophila melanogaster. Comp. Biochem. Physiol. B 122: 199-210.

Bainton, R. Tsai, L., Singh, C., Moore, M., Neckameyer, W. and Heberlein, U. 2000. Dopamine Mediates Acute Responses to Cocaine, Nicotine and Ethanol in Drosophila. Curr. Biol. 10: 187 - 194.

Neckameyer, W., Woodrome, S. Holt, B. and Mayer, A. 2000. Dopamine and senescence in Drosophila melanogaster. Neurobiol. Aging 21: 145-152.

Strawn, J., Neckameyer, W. and Cooper, R. 2000. The effects of 5HT on sensory, central and motor neurons driving the abdominal superficial flexor muscles in the crayfish. Comp. Biochem. Physiol. B.127: 533-550.

Neckameyer, W., O’Donnell, J., Huang, Z. and Stark, W. 2001. Dopamine and sensory tissue development in Drosophila. J Neurobiol. 15: 280-294. COVER ARTICLE

Leal, S. and Neckameyer, W. 2002. Pharmacological evidence for GABAergic regulation of specific behaviors in Drosophila melanogaster. J. Neurobiol. 50: 245-261.

Morin, D., Zini, R., Ligeret, H., Neckameyer, W., Labidalle, S., and Tillement, J.-P. 2003. Dual effect of ebselen on mitochondrial permeability transition. Biochem. Pharmacol. 65, 1643-1651.

Leal, S., Kumar, N. and Neckameyer, W. 2004. GABAergic modulation of motor-driven behaviors in juvenile Drosophila and evidence for a non-behavioral role for GABA transport. J. Neurobiol., 61, 189-208.

Coleman, C. and Neckameyer, W. 2004. Substrate determines the biochemical regulation of the dual-function enzyme, Drosophila tryptophan-phenylalanine hydroxylase. Invertebrate Neuroscience 5, 85-96.

Coleman, C. and Neckameyer, W. 2005. Serotonin synthesis by two distinct enzymes in Drosophila melanogaster. Arch. Insect Biochem. Physiol. 59, 12-31.

Neckameyer, W. and Weinstein, J. 2005. Stress affects dopaminergic signaling pathways in Drosophila melanogaster. Stress 8, 117-132.

Neckameyer, W., Holt, B. and Paradowski, T. 2005. Biochemical conservation of recombinant Drosophila tyrosine hydroxylase with its mammalian cognates. Biochemical Genetics 43, 425-443.

Wang, D., Qian, L., Xiong, H., Liu, J., Neckameyer, W., Oldham, S., Xia, K., Wang, J., Bodmer, R. and Zhang, Z. 2006. Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc. Natl. Acad. Sci. USA 103: 13520-13525.

Neckameyer, W., Coleman, C., Goodwin, S. and Eadie, S. 2007. Compartmentalization of neuronal and peripheral serotonin synthesis in Drosophila melanogaster. Genes, Brains and Behavior 6: 256 – 269.

Smith. E., Hoi, J., Eissenberg. J., Shoemaker, J., Neckameyer. W. Ilvarsonn, A., Harshman, L., Schlegel. V., and Zempleni, J. 2007. Selection Of Drosophila On A Biotin-Deficient Diet For Multiple Generations Increases Stress Resistance And Lifespan Through Alterations In Gene Expression And Histone Biotinylation Patterns. Journal of Nutrition 137: 2006-2012.

Neckameyer, W. and Matsuo, H. (2008)Distinct neural circuits reflect sex, sexual maturity, and reproductive status in response to stress in Drosophila melanogaster. Neuroscience 156: 841-856

Drobysheva, D., Ameel, K., Welch, B., Ellison, E., Chaichana, K., Hoang, B., Sharma, S., Neckameyer, W., Sinakevitch, I., Murphy, K., and Schmid, S. (2008) An optimized method for histological detection of dopaminergic neurons in Drosophila melanogaster. Journal of Histochemistry & Cytochemistry 56: 1049-1063.

Bowling, K., Huang, Z., Xu, D., Funderburk, C., Karnik, N., Ferdousy, F., Neckameyer, W. and O’Donnell, J. (2008) Direct binding of GTP cyclohydrolase and tyrosine hydroxylase: regulatory interactions between key enzymes in dopamine biosynthesis. J. Biol. Chem. J. Biol. Chem. 283: 31449-31459

Neckameyer, W. Trophic and transmitters roles for serotonin at the same neural circuit. Development, submitted.

Neckameyer, W., A tropic role for serotonin in the development of a simple feeding circuit. Dev. Neurosci. 2010, 32:217-237.

Neckameyer WS, Argue KJ. 2103. Comparative approaches to the study of physiology: Drosophila as a physiological tool. Am J Physiol Regul Integr Comp Physiol. 304(3):R177-88.

Book Chapters (2):

Neckameyer, W. S. Dopamine in Drosophila: Neuronal and Developmental Roles. In: “The Development of Dopaminergic Neurons,” Umberto di Porzzio, ed. Landes Bioscience, pp. 157-174, 1999.

Neckameyer, W. S. and Leal, S. 2002. Biogenic Amines as Circulating Hormones in Insects. In, "Hormones, Brain and Behavior," Academic Press, D. Pfaff, A. Arnold, A. Etgen, S. Farbach, R. Moss and R. Rubin, Eds. Chap. 38, Vol 3., pp. 141-166. Revision: Sprin, 2009.

Reviews (2):

Neckameyer, W. 2002. Molded by our genes. Nature Genetics 30:137.

Leal, S. and  Neckameyer, W. 2002. Talking the talk: the role of VEGF proteins in cell signaling. Trends. Endocrin. Metab. 13, 319-320.