The long-term objective of this research is to determine how ovarian steroids trigger luteinizing hormone-releasing hormone (LHRH) and LH surge release, thereby inducing ovulation. In these studies, we will investigate mechanisms through which potoperiod and estrogen signals interact to regulate novel dual-phenotype GABA/glutamate neurons in the anteroventral periventricular nucleus (AVPV) of females.
The specific aims of this proposal are: 1) To verify that GABA/glutamate neurons communicate directly with LHR neurons we will use anterograde and retrograde tracing and immunocytochemistry in rats and mice;2) We will use electrophysiological studies in which LHRH neurons are identified by GGP expression to verify that AVPV GABA/Glutamate neurons release predominantly GABA during the morning and predominantly glutamate in the afternoon;3) To determine whether vasopressin (VP) and/or noradrenaline (NA) trigger the midday rise in GABA release linked to the LH surge. We will examine the effects of specific VP and NA receptor antagonists on expression of a marker of GABA release, glutamic acid decarboxylase 67 (GAD67) mRNA. We will also determine whether changes in GAD67 mRNA levels are blocked when animals are placed in constant light and if such changes, as well as LH surge release, can be induced with VP and/or NA receptor agonists;4) To determine whether autofeedback inhibits GABA synthesis while stimulating glutamate release prior to the LH surge, we will administer GABAB receptor antagonists and measure changes in GAD67 mRNA levels in AVPV cell bodies, as well as vesicular GABA transporter and vesicular glutamate transporter in dual-phenotype terminals contacting LHRH neurons;5) We will determine whether VIP stimulates cAMP-dependent NT gene expression through ligand-independent activation of PR on the afternoon of the LH surge. The results of these studies may provide new targets for examination in humans and nonhuman primates and may lead to a better understanding of the neural aspects of puberty, infertility and hypothalamic aging. In addition, establishing that GABA neurons are able to switch from inhibitory neurotransmission to excitatory transmission will have important implications for understanding GABA and glutamatergic """"""""dual-signaling"""""""" in other brain regions. Finally, the results of these studies may provide key insights into how E2 regulates such diverse functions as sex-specific neurodevelopment, neuroprotection and neurodegeneration

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027305-14
Application #
7577588
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
1992-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
14
Fiscal Year
2009
Total Cost
$348,639
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Del Pino Sans, Javier; Clements, Kelsey J; Suvorov, Alexander et al. (2016) Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin may alter LH release patterns by abolishing sex differences in GABA/glutamate cell number and modifying the transcriptome of the male anteroventral periventricular nucleus. Neuroscience 329:239-53
Del Pino Sans, J; Krishnan, S; Aggison, L K et al. (2015) Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol. Neuroscience 303:312-22
Petersen, Sandra L; Krishnan, Sudha; Aggison, Leah K et al. (2012) Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical Nf?B signaling pathway. Front Neuroendocrinol 33:36-44
Porteous, Robert; Petersen, Sandra L; Yeo, Shel Hwa et al. (2011) Kisspeptin neurons co-express met-enkephalin and galanin in the rostral periventricular region of the female mouse hypothalamus. J Comp Neurol 519:3456-69
Intlekofer, K A; Petersen, S L (2011) 17?-estradiol and progesterone regulate multiple progestin signaling molecules in the anteroventral periventricular nucleus, ventromedial nucleus and sexually dimorphic nucleus of the preoptic area in female rats. Neuroscience 176:86-92
Liu, Xinhuai; Porteous, Robert; d'Anglemont de Tassigny, Xavier et al. (2011) Frequency-dependent recruitment of fast amino acid and slow neuropeptide neurotransmitter release controls gonadotropin-releasing hormone neuron excitability. J Neurosci 31:2421-30
Cao, Jinyan; Patisaul, Heather B; Petersen, Sandra L (2011) Aryl hydrocarbon receptor activation in lactotropes and gonadotropes interferes with estradiol-dependent and -independent preprolactin, glycoprotein alpha and luteinizing hormone beta gene expression. Mol Cell Endocrinol 333:151-9
Intlekofer, K A; Petersen, S L (2011) Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience 172:55-65
Moura, Paula J; Petersen, Sandra L (2010) Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy. Rev Neurosci 21:363-80
Hudgens, Edward D; Ji, Lan; Carpenter, Clifford D et al. (2009) The gad2 promoter is a transcriptional target of estrogen receptor (ER)alpha and ER beta: a unifying hypothesis to explain diverse effects of estradiol. J Neurosci 29:8790-7

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