A Novel Neural Pathway Controls Testosterone Release

描述（由申请人提供）：我们最近发现了下丘脑和睾丸之间的神经通路，其独立于垂体LH、睾丸LH受体或血流的变化以及各种循环因子而降低睾酮（T）。我们发现，灌胃（IG）注射酒精抑制睾丸间质细胞活性反应促性腺激素的部分通过激活这一途径，因此独立的外周机制。这种效应可通过侧脑室（icv）注射少量（5 μ l）酒精来模拟，酒精不会引起神经元损伤或渗漏到外周，但能迅速并显著地减弱T细胞对人绒毛膜促性腺激素（hCG）的反应。在特定目标1下，我们将通过将逆行跨神经节示踪剂伪狂犬病病毒的睾丸内注射与通过icv注射酒精在不同脑区引起的Fos反应相结合来进一步表征该途径。具体目标2将集中在睾丸信使通过酒精抑制Leydig细胞的活动，这一直是一个长期悬而未决的问题。具体来说，我们将确定一些分子的合成刺激睾丸IG或icv注射酒精，并调节随后的损失Leydig细胞的活动。然后，我们将转向与所提出的神经通路的生理重要性有关的假设。在具体目标3下，我们将研究该回路在介导酒精对性成熟的抑制作用中的作用，然后将该作用与外周介导的机制（如药物循环水平产生的直接睾丸效应）进行比较。最后，在具体目标4中，我们将探讨我们最近发现的酒精和其他压力源之间的一种新的相互作用。具体来说，我们发现，预先暴露于适度剂量的酒精，icv或IG注射，增加了轻度电击抑制Leydig细胞活性的能力。在这里，我们将测试的假设，即酒精发挥这种作用，通过增强压力相关的信号对下丘脑-睾丸通路的影响。总的来说，这些研究将促进我们对酒精对男性生殖功能的影响及其介导机制的理解。

DESCRIPTION (provided by applicant): We recently uncovered a neural pathway between the hypothalamus and the testes that decreases testosterone (T) independently of pituitary LH, changes in testicular LH receptors or blood flow, and various circulating factors. We showed that the intragastric (ig) injection of alcohol inhibits Leydig cell activity responsiveness to gonadotropins in part through activation of this pathway, and thus independently of peripheral mechanisms. This effect is mimicked by the intracerebroventricular (icv) injection of a small (5 mu l) volume of alcohol that does not cause neuronal damage or leak to the periphery, but quickly and significantly blunts the T response to human chorionic gonadotropin (hCG). Under Specific Aim 1, we will further characterize this pathway by combining the intratesticular injection of the retrograde transganglionic tracer pseudorabies virus with the Fos response that is elicited in various brain regions by the icv injection of alcohol. Specific Aim 2 will focus on the testicular messengers through which alcohol inhibits Leydig cell activity, which has been a long-standing and unresolved issue. Specifically, we will identify some of the molecules whose synthesis is stimulated in the testes by the ig or icv injection alcohol, and that modulate the ensuing loss of Leydig cell activity. We will then turn to hypotheses related to the physiological importance of the proposed neural pathway. Under Specific Aim 3, we will investigate the role of this circuit in mediating the inhibitory influence of alcohol on sexual maturation, then compare this role to that of peripherally-mediated mechanisms such as direct testicular effects exerted by circulating levels of the drug. Finally under Specific Aim 4, we will explore a novel interaction that we recently uncovered between alcohol and other stressors. Specifically, we showed that prior exposure to a modest dose of alcohol, injected icv or ig, increases the ability of mild electrofootshocks to inhibit Leydig cell activity. Here we will test the hypothesis that alcohol exerts this effect by augmenting the effect of stress-related signals on the hypothalamic-testicular pathway. Collectively, these studies will advance our understanding of the effects of alcohol on male reproductive functions and the mechanisms that mediate them.