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.

Public Health Relevance

The long-term goal of this research is to establish the stress response in Drosophila as a model that can be utilized to elucidate how gender and sexual maturity affect recruitment of individual neurons into functioning neuronal circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083771-02
Application #
7894693
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2009-08-01
Project End
2012-09-30
Budget Start
2010-08-01
Budget End
2012-09-30
Support Year
2
Fiscal Year
2010
Total Cost
$262,297
Indirect Cost
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Neckameyer, Wendi S; R Nieto-Romero, Andres (2015) Response to stress in Drosophila is mediated by gender, age and stress paradigm. Stress 18:254-66
Argue, Kathryn J; Neckameyer, Wendi S (2014) Altering the sex determination pathway in Drosophila fat body modifies sex-specific stress responses. Am J Physiol Regul Integr Comp Physiol 307:R82-92
Neckameyer, Wendi S; Argue, Kathryn J (2013) Comparative approaches to the study of physiology: Drosophila as a physiological tool. Am J Physiol Regul Integr Comp Physiol 304:R177-88
Argue, Kathryn J; Neckameyer, Wendi S (2013) Temporally dimorphic recruitment of dopamine neurons into stress response circuitry in Drosophila. Behav Neurosci 127:725-33
Argue, Kathryn J; Neckameyer, Wendi S (2013) Sexually dimorphic recruitment of dopamine neurons into the stress response circuitry. Behav Neurosci 127:734-43
Argue, Kathryn J; Yun, Amber J; Neckameyer, Wendi S (2013) Early manipulation of juvenile hormone has sexually dimorphic effects on mature adult behavior in Drosophila melanogaster. Horm Behav 64:589-97