Vasopressin and the retina

所有的生物都与每天发生的有节奏的明暗变化同步。这些日常（昼夜节律）节律是由内部生物“时钟”产生的，这些时钟由大脑一个特殊区域的专门神经元协调——视交叉上核（SCN）。SCN的活动每天都与环境信号同步——主要是视网膜接收到的光信息，这些信息通过神经纤维传递给SCN。视网膜输入究竟是如何控制SCN的节律的还不清楚。包括基因激活和局部神经肽释放在内的几种机制都与这个“时钟”的调节有关。SCN中神经肽抗利尿激素的信号传导起着特别重要的作用——抗利尿激素对于在光暗周期变化后重新设置生物钟至关重要，例如在横贯大陆旅行或轮班工作期间。SCN含有大量的抗利尿激素神经元，但我们最近发现视网膜也含有许多抗利尿激素表达细胞，而且，令人惊讶的是，这些细胞只与SCN交流——它们只参与调节昼夜节律，而不参与正常的视力。因此，视网膜中这些新发现的抗利尿激素细胞是一个主要的、光激活的通路，在调节重要的昼夜节律中起着关键作用。拟议的研究将准确地定义这些细胞如何影响SCN，并将确定视网膜-SCN通路的调节如何有助于昼夜节律调节的变化。这些实验研究都将在实验鼠身上进行，包括使用非常复杂的遗传方法研究选择性破坏或激活这些细胞的效果。这些方法将包括在这些视网膜加压素细胞中插入一种基因，以便在深度麻醉的大鼠身上进行的实验中精确控制它们的活动。SCN是大脑下丘脑的一部分；从进化的角度来看，这是一种存在于所有脊椎动物身上的古老结构。在所有被研究过的哺乳动物物种中，SCN的组织方式非常相似，因此在老鼠身上的研究结果很可能被“翻译”为理解人类的节律是如何调节的。确定视网膜中对调节身体节律具有关键和选择性作用的特定细胞群，将为帮助恢复时差或轮班工作期间改变的昼夜节律开辟新的治疗可能性。流行病学表明，轮班工作伴随着重大健康风险，包括患癌症、抑郁症、睡眠障碍、胃肠道、代谢和心血管疾病的倾向增加，免疫反应下降，甚至寿命缩短。

All living beings are synchronized to the rhythmic light-dark changes that occur daily. These daily (circadian) rhythms are generated by internal biological 'clocks', and these clocks are co-ordinated by specialized neurons in one special region of the brain - the suprachiasmatic nucleus (SCN). The activity of the SCN is synchronized daily by environmental signals - mainly by information on light received by the retina, which is communicated by nerve fibers to the SCN.Exactly how the retinal input entrains the rhythm of the SCN is unclear. Several mechanisms, including gene activation and local neuropeptide release, have been linked to the regulation of this 'clock'. Signaling of the neuropeptide vasopressin in the SCN plays a particularly important role - vasopressin is critical for re-setting of the clock after a change in the light-dark cycle, for example during transcontinental travelling or shift work. The SCN contains a large population of vasopressin neurons, but we recently found that the retina also contains many vasopressin-expressing cells, and that, strikingly, these communicate exclusively with the SCN - they are involved only with regulating circadian rhythms, and not with normal vision. Thus, these newly discovered vasopressin cells in the retina are a major, light-activated pathway that has a key role in regulating important circadian rhythms. The proposed research will define exactly how these cells influence the SCN, and will establish how modulation of the retina-SCN pathway contributes to changes in circadian rhythm regulation. The experimental studies will all be on laboratory rats - and will include studying the effects of selectively destroying or activating these cells using very sophisticated genetic approaches. These approaches will involve inserting a gene into these retinal vasopressin cells to enable their activity to be controlled precisely in experiments that will be carried out in deeply anesthetized rats. The SCN is part of the hypothalamus of the brain; in evolutionary terms, this is an ancient structure that is present in all vertebrates. The SCN is organised in a very similar way in all mammalian species that have been studied, so findings from studies in the rat are likely to be "translatable" into understanding of how rhythms are regulated in people. Identifying a specific population of cells in the retina that has a key and selective role in regulating body rhythms will open up new therapeutic possibilities for helping to restore altered circadian rhythms during jet lag or rotating shift work. Epidemiology shows that rotational shift work is accompanied by major health risks, including increased propensity for cancer, depression, sleep disturbances, gastrointestinal, metabolic and cardiovascular disorders, decreased immune responses and even life span.