食物诱导节律的产生及雌激素在其产生中的作用

By entrainment of environmental light signaling from RHT tract to the Suprachiasmatic Nuclei (SCN), mammals display and maintain sustainable circadian rhythms in gene expression, physiological and behavioral parameters. Therefore, the SCN clock has been considered as the master or central clock to control the circadian rhythms. It is generally believed that peripheral clocks and other environmental cues functioned as passive clocks or secondary environmental factors which are under the control of the SCN clock. Our previous results showed that under food restriction protocol and constant darkness, the phase of locomotor activity from food anticipatory activity and SCN-controlled rhythm merged together to form a stable circadian rhythms in locomotor activity in most of the female mice, but not in male mice. We named this type rhythm as food entrainable rhythm (FEO). As previous study revealed that (1) Intergeniculate leaflet (IGL) is responsible for the receipt of non-photic signal, and then projection to the SCN,(2) only estrogen receptor but not androgen receptor presented in the IGL, we hypothesized that under stimulation of estrogen, the IGL is the tissue which accept the food signaling and project to the SCN, in turn, coupling the SCN clock with FAA to form FEO. In this project, by employing the techniques from molecular biology, biochemistry, pharmacological , anatomic analysis and behavioral manipulation, we are going to (1) investigate if the IGL is organ that generate FEO, and (2) explore whether the interaction of estrogen and their receptor in thalamic IGL controls the FEO. It is our expectation the current research will prompt our understanding the mechanism of FEO and provide frame work regarding the role of estrogen in generating the FEO.

环境光信号通过对视交叉上核（SCN）的调控，维持了哺乳动物基因表达、生理和行为的24小时节律，因此，SCN被认为是控制生物节律的主控组织。外周组织生物钟系统或其它形式的环境信号被认为是从属于SCN主控生物钟的二级生物钟系统，或非主效环境调控因子。我们前期研究表明，在全黑环境下，限制性饮食可使雌鼠SCN固有的节律与食物期待节律迭合，形成单一的活动节律，我们称之为食物诱导节律。鉴于他人数据：（1）外界的非光信号能被膝间小叶（IGL）组织接收并整合后投射至SCN；（2）IGL组织只含雌激素受体，我们提出假设：IGL在雌激素的介导下，可作为食物诱导节律的中枢器官。本项目拟运用动物行为学、分子生物学、药理学等技术，利用食物诱导节律模型小鼠、组织损毁小鼠、基因敲除小鼠从内分泌、解剖、药理三个水平确定食物诱导节律的中枢器官，阐明雌激素在食物诱导节律中的作用及途径，从而为揭示食物诱导节律的机制奠定基础。

食物期待行为是通过限制性饮食在实验小鼠中诱导的不依赖于光诱导节律的节律性期待行为，其产生的内在机制尚不清楚。在本项目中，我们系统地研究和比较了雌性和雄性小鼠在正常光照和全黑条件下的食物期待行为。我们发现，在正常光照条件下，雄性小鼠表现出比雌性小鼠更强的食物期待行为；与此相一致，雄性小鼠能量消耗和体重改变也较雌性小鼠显著不同。性器官摘除试验可以消除雌雄小鼠在食物期待行为上的差异，提示性激素参与调控食物期待行为。限制性饮食可使血浆中胃饥饿素表达相位前移，并且在雌鼠中的水平高于雄鼠。雌雄Per1敲除小鼠均表现出正常的食物期待行为，提示该节律基因并不参与雌雄小鼠食物期待行为的调控；而雌雄Per2敲除小鼠并没有表现出食物期待行为。同时，在全黑条件下进行限制性饮食后，正常雌雄小鼠也表现出不同的节律行为，并且这种差异在性器官摘除后消失了。此外，我们还设计了不同的限制性饮食模式，并比较了食物期待行为建立的快慢和强弱。我们的研究为理解食物期待行为的内在机制提供了重要的生物学证据。