Lactation, a state common to all female mammals, is characterized by an inhibition of gonadotropin secretion. The primary hypothesis underlying the proposed experiments is that the neural systems activated by the suckling stimulus suppress GnRH activity, the neuronal system in the hypothalamus that governs female reproductive cyclicity. The goal of these studies is to identify neuronal systems that mediate the inhibitory effects of the suckling stimulus on GnRH neuronal activity. We have designed an acute resuckling model that emphasizes the neural effects of the suckling stimulus and reduces some of the complexity associated with lactation, such as chronic hyperprolactinemia and elevated levels of progesterone. In this model, the 8-pup litters are removed for 48 hrs. to allow for recovery from the effects of suckling. Reinitiation of suckling stimulus for 8-12 hrs. is effective in reimposing the inhibition on GnRH, indicating that neuronal systems inhibitory to GnRH are activated during this time. Because the suckling stimulus is applied acutely, immediate early gene expression, such as cFos, is induced in activated neurons, and therefore, can serve as a marker to identify activated populations of neurons. Using this technique, we have identified the following areas in the hypothalamus that are specifically activated by acute resuckling: the periventricular preoptic area, medial preoptic area, anterior hypothalamus and paraventricular nucleus. We propose that putative inhibitory neuronal subtypes in these areas are the most likely candidates for mediating the inhibition of GnRH activity: Similarly, we propose that the catecholaminergic systems in the brainstem, which are also activated by acute resuckling, are the most likely candidates for relaying the effects of suckling to the hypothalamus.
SPECIFIC AIM 1 will identify specific neuronal pathways activated in response to the suckling stimulus that mediate the suppression of GnRH neuronal activity. Experiments include determining the projections of the activated neurons in the periventricular preoptic area, medial preoptic area, anterior hypothalamus and paraventricular nucleus to areas of GnRH cell bodies and identifying the phenotype of activated neurons of interest. Putative inhibitory neuronal subtypes, such as GABA or CRF, will be identified by determining the effectiveness of specific antagonists in reversing the inhibitory effects of the suckling stimulus on GnRH. These studies will provide for the first time detailed information about the specific afferent neuronal pathways mediating GnRH neuronal activity and will identify the neuronal systems in the brainstem that relay the signals from suckling to the hypothalamus.
SPECIFIC AIM 2 will assess whether the increase in NPY neuronal function within the arcuate nucleus during lactation contributes to the inhibition of GnRH neuronal function. The proposed inhibitory effects of NPY will be assessed by using pharmacological probes to inhibit its activity. Tract-tracing techniques will be used to determine the projections of the activated NPY neurons, which will provide information as to their site of action. An understanding of the mechanisms by which the suckling stimulus imposes an inhibition on GnRH neuronal function will provide information that is relevant to other hypothalamic causes of infertility and may suggest new approaches for contraception.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD014643-16
Application #
2332233
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1979-12-01
Project End
2000-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
16
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Oregon Regional Primate Research Center
Department
Type
DUNS #
City
Beaverton
State
OR
Country
United States
Zip Code
97006
True, C; Takahashi, D; Kirigiti, M et al. (2017) Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin-releasing hormone neurones in the female rhesus macaque. J Neuroendocrinol 29:
Baquero, Arian F; Kirigiti, Melissa A; Baquero, Karalee C et al. (2015) Developmental changes in synaptic distribution in arcuate nucleus neurons. J Neurosci 35:8558-69
Baquero, Arian F; de Solis, Alain J; Lindsley, Sarah R et al. (2014) Developmental switch of leptin signaling in arcuate nucleus neurons. J Neurosci 34:9982-94
Verma, Saurabh; Kirigiti, Melissa A; Millar, Robert P et al. (2014) Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART. Neuroendocrinology 99:190-203
True, Cadence; Verma, Saurabh; Grove, Kevin L et al. (2013) Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. Endocrinology 154:2821-32
Nicol, L E; Grant, W F; Grant, W R et al. (2013) Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates. J Endocrinol 217:207-13
Lee, Shin J; Verma, Saurabh; Simonds, Stephanie E et al. (2013) Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J Neurosci 33:15306-17
Lee, Shin J; Kirigiti, Melissa; Lindsley, Sarah R et al. (2013) Efferent projections of neuropeptide Y-expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models. J Comp Neurol 521:1891-914
True, C; Kirigiti, M A; Kievit, P et al. (2011) Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance. J Neuroendocrinol 23:1099-112
Sullivan, Elinor L; Smith, M Susan; Grove, Kevin L (2011) Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood. Neuroendocrinology 93:1-8

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