De Novo Melatonin Synthesis in the Brain

所有脊椎动物的松果体都在夜间合成褪黑激素。这种夜间信号有助于同步昼夜节律生物学的各个方面；它向身体的各个器官发出信号，告诉它们现在是一天中的什么时间，鉴于非赤道地区的白昼长度随年周期而变化，它是什么季节。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确定生殖活动开始的时间。如果身体的各种组织没有同步，那么就会发生严重的行为和生理破坏。人类独有的一个例子就是时差反应；在快速飞越不同时区后，不同内脏器官的活动时间是不同步的。因此，在短期内会有一种普遍的病态感，但持续的时差会对健康产生严重的有害影响；包括认知等大脑功能的缺陷。这一建议建立在支持大脑本身可以独立于松果体合成褪黑激素这一新观点的初步数据之上，并探索了大脑中这种脑源性褪黑激素可能起作用的新途径，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如何工作的理解，以及这种新途径如何调节昼夜生物学和生殖。这一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。所有脊椎动物的光周期现象都涉及到昼夜节律系统与生殖系统的整合。因此，哺乳动物使用褪黑素信号来解码一天的长度，以及它的变化方向，并调节它们的生殖反应，这并不奇怪。令人惊讶的是，鸟类拥有这种优雅的计时系统，但人们认为它们不会用它来调节生殖光周期反应的时间。因此，鸟类夜间释放褪黑激素的功能在繁殖方面是未知的。上述教条在鸟类中的问题在于，所有的研究都集中在褪黑素的传统来源，松果体和视网膜上。如果鸟类下丘脑本身对光有反应，可以根据白天的长度合成褪黑激素呢？这一提议提供了强有力的初步数据，表明鸟类大脑可以独立于眼睛或松果体等感觉器官合成褪黑素。因此，神经来源的褪黑素，而不是其他来源的褪黑素，很可能是鸟类光周期机制的关键组成部分。具体来说，我们的目标是证明褪黑素在鸟类大脑中的新生合成，探索其调控，识别神经源性褪黑素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激素的证明是全新的，对包括人类在内的所有脊椎动物的神经内分泌过程都有影响。这项工作由神经系统集群（NSC）资助，并得到了行为系统集群（BSC）的支持，该集群隶属于生物科学理事会的综合有机体系统。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.