De Novo Melatonin Synthesis in the Brain

所有脊椎动物都会在夜间的松果体中合成褪黑激素。这种夜间信号有助于同步生物钟的各个方面；向身体的各个器官发出信号，告诉他们一天中的什么时间，以及考虑到非赤道地区的一天的长度在一年的周期中发生变化，现在是什么季节。因此，脊椎动物的生理机能会根据一天或一年的时间进行适当的调整。在许多脊椎动物中，褪黑激素信号被用来计算生殖活动开始的时间。如果体内的各种组织没有同步，那么可能会发生严重的行为和生理紊乱。时差反应是人类独有的一个例子；在快速跨越不同时区后，不同器官的活动时间不同步。因此，在短期内，人们会有一种普遍的病态感觉，但持续的时差可能会对健康造成严重损害；包括认知等大脑功能的缺陷。这项建议建立在初步数据的基础上，支持大脑本身可以独立于松果体合成褪黑素的新想法，并探索了大脑中这种脑源性褪黑素可能发挥作用的新途径，特别是与季节性繁殖有关的途径。由此产生的数据将扩大我们对脊椎动物大脑一般如何工作的理解，以及这一新途径是如何调节昼夜生物学和生殖的。这些发现将对基础生物学、保护生物学、畜牧业和人类健康产生广泛的影响。所有被测试的脊椎动物的光周期涉及昼夜节律系统与生殖系统的整合。因此，哺乳动物使用褪黑激素信号来解码一天的长度及其变化方向，并调节它们的生殖反应也就不足为奇了。令人惊讶的是，鸟类拥有这种优雅的计时系统，但却被认为不会用它来调节它们生殖光周期反应的时间。因此，鸟类夜间释放褪黑素在生殖方面的作用尚不清楚。在鸟类身上，上述教条的问题在于，所有研究都集中在褪黑激素的传统来源上，松果体和视网膜。如果鸟类的下丘脑本身对光有反应，并能根据白天的时长合成褪黑素，那该怎么办？这一提议提供了强有力的初步数据，表明鸟类的大脑可以从头合成褪黑素，而且这种合成不依赖于眼睛或松果体等感觉器官。因此，神经来源的褪黑素，而不是来自其他来源的褪黑素，很可能是鸟类光周期机制的关键组成部分。具体地说，我们的目标是展示鸟类大脑中褪黑素的从头合成，探索其调节，确定神经源性褪黑素与之相互作用的神经通路，并最终确定其在生殖和其他生理方面的作用。大脑可以从头合成褪黑素的证明是全新的，对所有脊椎动物的神经内分泌过程都有影响，包括人类。这项工作由神经系统集群(NSC)资助，行为系统集群(BSC)在生物科学局的综合组织系统中提供支持。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

All vertebrates synthesize the hormone melatonin in their pineal gland at night. This nocturnal signal helps to synchronize aspects of circadian biology; signaling to the various organs of the body what time of day it is and, given that day length in non-equatorial zones changes over the annual cycle, what season it is. Thus, a vertebrate's physiology adjusts appropriately to the time of day or year. In many vertebrates, the melatonin signal is used to time the onset of reproductive activity. If there is no synchronization of the various tissues in the body, then serious behavioral and physiological disruption can occur. A uniquely human example of this is jet-lag; after flying across different time zones rapidly, there is asynchrony in the timing of activity in different internal organs. As a result, in the short-term there is a general feeling of morbidity, but constant jet-lag can have seriously detrimental health effects; including deficiencies in brain functions like cognition. This proposal builds on preliminary data supporting the novel idea that the brain itself can synthesize melatonin independently of the pineal gland, and explores novel pathways in the brain via which this brain-derived melatonin might be acting, especially as relates to seasonal reproduction. Resulting data will expand our understanding of how the vertebrate brain works in general, and how circadian biology and reproduction are regulated by this novel pathway. The findings will have broad implications for basic biology, conservation biology, animal husbandry and human health.Photoperiodism in all vertebrates tested involves integration of the circadian system with the reproductive system. As a result, it is not surprising that mammals use the melatonin signal to decode the length of the day, along with its direction of change, and regulate their reproductive responses. What is surprising is that birds possess this elegant time-keeping system and yet are thought not to use it to regulate the timing of their reproductive photoperiodic responses. Thus, the function of the nightly release of melatonin in birds is unknown with respect to reproduction. The problem with the above dogma in birds is that all studies have focused on traditional sources of melatonin, the pineal gland and the retina. What if the avian hypothalamus itself is responsive to light and can synthesize melatonin according to the prevailing day length? This proposal provides strong preliminary data indicating that the avian brain can synthesize melatonin de novo, and does so independently of sensory organs such as the eyes or pineal gland. Thus, neurally-derived melatonin, and not melatonin from other sources, may well be a key component of the photoperiodic machinery in birds. Specifically, we aim to demonstrate de novo melatonin synthesis by the avian brain, explore its regulation, identify neural pathways that neurally-derived melatonin interacts with, and eventually determine its role in reproduction and other aspects of physiology. Demonstration that the brain can synthesize melatonin de novo is entirely novel and has implications for all vertebrate neuroendocrine processes, including in humans. This work is funded by the Neural Systems Cluster (NSC) with support from the Behavioral Systems Cluster (BSC), in the Integrative Organismal Systems in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.