Reproductive Plasticity in Oxytocin Neurons

描述（由申请人提供）：催产素（OT）在分娩和哺乳中作为一种激素，在大脑中作为一种神经调节剂。OT受体存在于OT神经元上，它们在体树突OT释放过程中进行自动调节。在怀孕和哺乳期间，OT的释放是脉动的，不是连续的，这种模式对于避免OT受体脱敏和确保子宫和乳腺目标平滑肌正常的激素功能至关重要。视上核（SON）和室旁核（PVN）中的神经元在妊娠晚期和哺乳期经历了显著的可塑性，包括胶质-神经元重排和突触活动的增加。我们发现在这两个时期都有增强的超极化后尖峰（ahp）。ahp在塑造短（~4秒）高频率（~50赫兹）的脉冲中起着至关重要的作用，在这种搏动的基础上，脉冲产生大量的OT释放到血液中，最大限度地收缩子宫平滑肌或乳腺肌上皮。SON和PVN的生殖相关可塑性取决于妊娠期间卵巢类固醇释放的模式和OT的体树突释放。我们提出了第一个体内证据，表明中枢OT受体对钙依赖性ahp的增强至关重要，通常在妊娠后期表现出来。妊娠后期长期给予第三脑室的特异性OT拮抗剂阻断了这种形式的可塑性，对副脑室神经元没有影响。此外，我们通过将OT应用于怀孕大鼠（E18-19）的下丘脑切片来模拟这种可塑性。本研究的目标是了解OT神经元的适应机制，以及它如何塑造OT神经元的放电，以最大限度地释放激素，从而确保婴儿发育的正常分娩和哺乳。了解中枢OT受体在OT神经元的转导机制将对理解OT受体在脑功能中的更广泛作用具有重要的应用。有三个明确的目标：确定OT对OT神经元ahp的增强是否特异性于OT神经元和OT受体激活，是否特异性于怀孕动物，以及是否由于潜在电流Ca2+敏感性的变化。具体目标2。测试OT是否对

DESCRIPTION (provided by applicant): 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.