Endocannabinoid modulation of memory

描述(由申请人提供)：在大脑中发现了一个由大麻素CB1受体和内源性大麻素(如anandamide和2-AG)组成的内源性大麻素系统，这引起了人们对了解该系统的生理功能的极大兴趣。基于体内和体外的融合证据，这个系统被认为在记忆随时间退化(即遗忘)的过程中发挥积极作用，以及抑制不再强化的学习行为(即灭绝)。在正常情况下，这些过程是进一步假设的，以促进新信息的编码。本申请中提出的研究将通过永久(即，CB1(-/-)小鼠)或通过使用CB1受体拮抗剂SR 141716急性阻断内源性大麻素信号来检验该系统的功能。尽管这些方法可以间接地暗示内源性大麻素的参与，但在基因缺失的小鼠中(即FAAH(-/-)小鼠)以及选择性的FAAH抑制剂将使我们能够确定这种内源性大麻素是否在记忆中发挥作用。此外，我们将研究神经底物和受体的作用机制，这是内源性大麻素调节记忆的基础。我们将确定内源性大麻素紧张状态下的行为程序是否改变了ANANDAME和2-AG的水平。最后，还将进行实验，以确定大麻素的助记作用是否通过海马体介导，海马体是大脑的一个区域，不仅包含CB1受体和内源性大麻素，而且已知在学习和记忆中发挥作用。总之，这些研究将进一步加深我们对这一系统的生理功能的理解，并弥合内源性大麻素系统的体外和体内作用之间的差距。

DESCRIPTION (provided by applicant): The discovery of an endocannabinoid system in the brain consisting of cannabinoid CB1 receptors and endocannabinoids (e.g., anandamide and 2-AG) has generated a great deal of interest in understanding the physiological functions of this system. Based on converging in vivo and in vitro evidence this system has been proposed to play an active role in processes that underlie the degradation of memory over time (i.e., forgetting) as well as the suppression of learned behaviors that are no longer reinforced (i.e., extinction). Under normal circumstances, these processes are further hypothesized to facilitate the encoding of new information. The studies proposed in this application will examine the function of this system by blocking endocannabinoid signaling either permanently (i.e., CB1 (-/-) mice) or acutely through the use of the CB1 receptor antagonist SR 141716. Although these approaches can indirectly implicate the involvement of endocannabinoids, the availability of mice in which fatty acid amide hydrolase (FAAH), the primary enzyme responsible for anandamide metabolism, has been genetically deleted (i.e., FAAH (-/-) mice) along with a selective FAAH inhibitor will enable us to determine whether this endocannabinoid plays a role in memory. Additionally, we will investigate the neural substrates and receptor mechanisms of action that underlie endocannabinoid modulation of memory. We will ascertain whether the levels of anandamide and 2-AG are modified by behavioral procedures that are found to be under endocannabinoid tone. Finally experiments will also be conducted to determine whether the mnemonic effects of the cannabinoids are mediated in the hippocampus, a brain region that not only contains CB1 receptors and endocannabinoids, but also is known to play a role in learning and memory. Collectively, these studies will further our understanding of the physiological function of this system as well as bridge the gap between the in vitro and in vivo actions of the endocannabinoid system.