A key subset of receptors involved in spinal-mediated biological rhythms

生物节律是几乎所有生物--从植物到哺乳动物--最重要的功能的基础。到目前为止，在脊椎动物物种中，昼夜节律可能是最具特色的节律功能之一。它涉及几种化学物质的释放，如伽马-氨基丁酸、褪黑素和5-羟色胺(5-羟色胺)，这些化学物质专门作用于大脑中某些受体亚型。在NSERC的资助下，我的团队发现了证据表明，存在一种部分可比的机制，参与控制另一种节奏功能，即运动。几年前，利用药理学、外科手术和遗传学方法，我们发现位于腰椎脊髓的一种特定亚型(1A)的5-羟色胺受体确实是运动活动的关键触发因素。我们最近扩大了这些观察范围，提供了更多的证据，证明其他脊髓介导的节律功能，如排尿、排便和射精，也严重依赖于5-HT1A受体的激活。然而，在完全了解5-羟色胺在生物节律中的复杂作用之前，仍有几个重要的问题需要阐明，特别是在脊髓中。例如，来自大脑的下行信号或来自周围神经的感觉信号在脊髓5-HT1a受体介导的节律中起什么作用？其他受体亚型或家族及其细胞内信号在这种脊髓功能中有什么贡献？在我的研究计划中提到的这类问题特别令人兴奋，因为它们有可能揭开5-羟色胺作为神经振荡活动的“触发器”这一新角色的细节，同时也揭示它作为神经功能的“调节器”的更广为人知的角色。因此，它将为脊椎动物物种中5-羟色胺活动的复杂性提供新的线索--通常在大脑中是抑制的，在脊髓中显然也是兴奋的。认为这项拟议研究的结果最终将帮助其他研究人员重新研究大脑调节的节奏功能的生理学，如睡眠、警觉或荷尔蒙释放，这并不是不合理的。我坚信，这一研究项目将为拉瓦尔大学的几名研究生和本科生提供丰富而富有成效的培训经验。

Biological rhythms underlie most vital functions in virtually all living organisms - from plants to mammals. In vertebrate species, the circadian rhythm is probably, as of now, one the best characterized rhythmic functions. It involves the release of several chemicals such as gamma-aminobutyric acid, melatonin and serotonin (5-HT) that act specifically upon some of their receptor subtypes in the brain. With NSERC funding, my group has found evidence suggesting the existence of a partially comparable mechanism involved in the control of another rhythmic function that is locomotion. A few years ago, using pharmacological, surgical, and genetic approaches, we found indeed a key role as a ‘trigger’ of locomotor activity for a specific subtype (1A) of 5-HT receptors located in the lumbar spinal cord. We recently expanded those observations by providing additional evidence that other spinal-mediated rhythmic functions such as micturition, defecation and ejaculation critically depend also upon activation of 5-HT1A receptors. However, several important questions remain to be elucidated prior to understand fully the complex role of 5-HT in biological rhythms, specifically in the spinal cord. For instance, what role descending signals from brain or sensory signals from peripheral nerves play in spinal 5-HT1A receptor-mediated rhythms? What contributions other subtypes or families of receptors and their intracellular signals have in such spinal functions? These kinds of questions, addressed in my research program, are particularly exciting given their potential to unravel the details of this new role of 5-HT as a ‘trigger’ of neural oscillatory activities, in parallel to its more widely known role as a ‘modulator’ of neural functions. As such it will shed a new light on the complexity of 5-HT actions in vertebrate species - generally inhibitory in the brain and apparently also excitatory in the spinal cord. It is not unreasonable to think that findings from the proposed research will eventually help other researchers revisiting the physiology of brain-mediated rhythmic functions such as sleeping, alertness, or hormonal release. I strongly believe that this research program will provide a rich and fruitful training experience for several graduate and undergraduate students here at Laval University.