Oxytocin (OT) functions as a hormone in labor and lactation and as a neuromodulator in the brain. OT receptors are present on OT neurons, which they autoregulate during somatodendritic OT release. During pregnancy and lactation, OT release is pulsatile, not continuous, and this pattern is critical to avoid OT receptor desensitization and insure proper hormone function at target smooth muscle in uterus and mammary gland. Neurons in the supraoptic (SON) and paraventricular nuclei (PVN) undergo remarkable plasticity during late pregnancy and lactation, including a glial-neuronal rearrangement and increases in synaptic activity. We have found enhanced spike afterhyperpolarizations (AHPs) during both periods. AHPs are critical in sculpting the short (~4 sec) high frequency (~50 Hz) bursts from OT neurons underlying this pulsatility, bursts that produce a bolus release of OT into the bloodstream to maximally contract uterine smooth muscle or mammary gland myoepithelium. Reproductive-associated plasticity in the SON and PVN depends on the pattern of ovarian steroid release during pregnancy and on the somatodendritic release of OT. We present the first in vivo evidence showing that central OT receptors are critical for the enhancement of the calcium-dependent AHPs normally manifest at late pregnancy. A specific OT antagonist administered chronically to the third ventricle during late pregnancy blocked this form of plasticity with no effect on VP neurons. In addition, we mimicked this plasticity by applying OT to hypothalamic slices from pregnant (E18-19) rats. The goal of this proposal is to understand the mechanisms of this adaptation made by OT neurons, and how it shapes OT neuronal firing to maximize hormone release and thereby insure normal parturition and lactation for infant development. Understanding the mechanisms of central OT receptor transduction at the OT neuron will have important applications for understanding the wider roles of OTRs in brain function. There are Three Specific Aims:
Specific Aim 1. To determine if the enhancement of AHPs in OT neurons by OT is specific to OT neurons and OT receptor activation, whether it is specific to pregnant animals, and whether it is due to a change in the Ca2+ sensitivity of the underlying currents.
Specific Aim 2. To test whether OT's effects on AHPs are mediated through a pERK 1/2-MAPK cascade, and whether it is associated with an increase expression of the AHP channels and/or the enzymes CK2 and PP2a, known to modulate AHP Ca2+ sensitivity.
Specific Aim 3. To determine how enhanced AHPs modulate OT neuronal bursts, and to determine whether the reinsertion of missing excitatory activity differentially alters OT firing pattern in lactating vs. virgin rats, in an OT-dependent manner.

Public Health Relevance

Oxytocin functions not only as a critical hormone in labor and lactation, but also as a neuromodulator in the brain, where it autoregulates OT neurons. This project explores the mechanisms and consequences of oxytocin-induced electrophysiological plasticity of oxytocin neurons during pregnancy and lactation.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Ilekis, John V
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University of Tennessee Health Science Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Wang, Lie; Chandaka, Giri Kumar; Foehring, Robert C et al. (2018) Changes in potassium channel modulation may underlie afterhyperpolarization plasticity in oxytocin neurons during late pregnancy. J Neurophysiol 119:1745-1752
Kirchner, Matthew K; Foehring, Robert C; Callaway, Joseph et al. (2018) Specificity in the interaction of high-voltage-activated Ca2+ channel types with Ca2+-dependent afterhyperpolarizations in magnocellular supraoptic neurons. J Neurophysiol 120:1728-1739
Armstrong, William E (2017) Kisspeptin: a new peptidergic system regulating oxytocin neurons and their reproductive plasticity in the hypothalamo-neurohypophysial system. J Physiol 595:611-612
Kirchner, Matthew K; Foehring, Robert C; Wang, Lie et al. (2017) Phosphatidylinositol 4,5-bisphosphate (PIP2 ) modulates afterhyperpolarizations in oxytocin neurons of the supraoptic nucleus. J Physiol 595:4927-4946
Chandaka, G K; Wang, L; Senogles, S et al. (2016) Late Pregnancy is a Critical Period for Changes in Phosphorylated Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 in Oxytocin Neurones. J Neuroendocrinol 28:
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Scroggs, Reese; Wang, Lie; Teruyama, Ryoichi et al. (2013) Variation in sodium current amplitude between vasopressin and oxytocin hypothalamic supraoptic neurons. J Neurophysiol 109:1017-24
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