Ghrelin/GHS-R1a通路参与情绪记忆调控的分子细胞及环路机制研究

Ghrelin is an orexigenic peptide hormone which promots feeding and regulates energy balance in both human and rodents. Growing evidence have indicated that ghrelin and its receptor GHS-R1a plays certain roles in multiple brain functions including memory and emotion, however the underlying mechanism are uncertain yet. Surprisingly, our previous studies showed that activation of ghrelin/GHS-R1a signaling in vivo blocked different forms of learning and memory formation (including emotional memory) in both rats and mice, which is opposite to many previous reports showing that ghrelin enhances memory. The amygdala complex is strongly involved in the formation of emotional memories, and GHS-R1a was found to be highly expressed in the lateral amygdala versus the central nucleus. Therefore, we proposed here to use conditioned taste aversion and auditory fear conditioning, the two behavioral paradigams which depend on the function of amygdala, to study the effect and explore the underlying molecular cellular mechanisms mediating the effects of ghrelin/GHS-R1a signaling on emotional memories in both rats and mice. These studies will not only shed light on our understanding about multiple brain functions of ghrelin besides feeding and energy balance controls, it may also contribute to the development of new treatment for certain affective disorders, such as PTSD.

研究表明调节摄食和能量平衡的肽类激素ghrelin及其受体GHS-R1 a对记忆和情绪等脑高级功能有重要的调节作用，但其作用机制仍不明确。我们在前期动物实验中意外地发现，与以往的多数报道相反，在体激活ghrelin/GHS-R1a通路对多种形式的记忆（包括情绪记忆）的获取都有明显的抑制而不是促进作用。杏仁核是情绪记忆神经网络的核心，研究发现GHS-R1a在杏仁核（尤其是外侧核）有高表达。因此，本课题拟在已有研究积累上，结合条件性味觉厌恶和条件性听觉恐惧行为范式，以杏仁核及其神经环路为研究对象，运用多种先进的实验方法和技术手段，深入探讨ghrelin及其受体GHS-R1a参与情绪记忆调控的分子、细胞及环路机制。研究不仅可深化对ghrelin多重生理功能及作用机制的了解，同时对创伤后应激综合症（PTSD）等情绪障碍性精神疾病的治疗提供可能的理论指导。

研究表明调节摄食和能量平衡的肽类激素ghrelin及其受体GHS-R1 a对记忆和情绪等脑高级功能有重要的调节作用，但机制仍不明确，前期的基础和临床研究结果也多自相矛盾。我们在前期动物实验中意外地发现，与以往的多数报道相反，在体激活ghrelin/GHS-R1a通路对多种形式联合记忆（包括情绪记忆）的获取都有明显的抑制而不是促进作用。杏仁核和海马是情绪记忆形成的解剖基础，研究发现GHS-R1a在杏仁核（尤其是外侧核）和海马都有高表达。因此，本课题在已有研究积累上，结合味觉厌恶、恐惧记忆及其他多种行为学范式，以杏仁核、背侧海马及其神经环路为研究对象，运用电生理、生化、药理、分子生物及遗传学等多种先进的实验方法和技术手段，深入探讨ghrelin及其受体GHS-R1a参与情绪记忆调控的分子、细胞及环路机制。研究阐明了ghrelin/GHSR抑制味觉厌恶记忆形成和消退的分子、细胞及突触机制，并结合GHSR敲除、GHSR过表达和ghrelin局部脑区给药等研究手段，阐明了ghrelin/GHSR抑制海马依赖性多模式学习记忆的分子、细胞及突触机制。研究提示，GHSR对杏仁核和海马记忆环路的功能调控作用和机制可能是一致的。本研究不仅深化了对ghrelin多重生理功能及机制的了解，同时对创伤后应激综合症（PTSD）等情感障碍性精神疾病伴有的认知和情绪障碍的治疗提供可能的理论指导和治疗靶点。