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，该通路独立于垂体LH，睾丸LH受体或血流量的变化以及各种循环因子而降低睾酮(T)。我们发现，灌胃（ig）注射酒精抑制间质细胞对促性腺激素的活性反应，部分是通过激活这一途径，因此独立于外周机制。脑室内（icv）注射少量（5 μ l）酒精可以模拟这种效果，这种酒精不会造成神经元损伤或外周渗漏，但会迅速而显著地减弱T对人绒毛膜促性腺激素（hCG）的反应。在Specific Aim 1下，我们将通过结合睾丸内注射逆行跨神经节示踪剂伪狂犬病毒与icv注射酒精在不同脑区引发的Fos反应来进一步表征这一途径。特异性目标2将重点关注酒精抑制睾丸间质细胞活性的睾丸信使，这是一个长期存在且未解决的问题。具体来说，我们将确定一些分子，它们的合成在睾丸中被大剂量或微量注射酒精刺激，并调节随后的间质细胞活性丧失。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Specific Aim 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，然后将其与外周介导机制（如循环水平的药物施加的直接睾丸效应）的作用进行比较。最后，在具体目标4中，我们将探索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。具体地说，我们表明，事先暴露于适度剂量的酒精，注射icv或ig，增加轻度电脚刺激抑制间质细胞活性的能力。在这里，我们将测试酒精通过增强下丘脑-睾丸通路上的压力相关信号的作用来发挥这种作用的假设。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调解机制的理解。

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.