Endocannabinoid modulation of memory

描述（由申请人提供）：在大脑中发现由大麻素CB1受体和内源性大麻素（例如，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生理功能的极大兴趣。基于体内和体外的证据，该系统被认为在记忆随着时间的推移而退化（即遗忘）以及抑制不再强化的学习行为（即消失）的过程中发挥积极作用。在正常情况下，这些过程被进一步假设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传导来检查该系统的功能。虽然这些方法可以间接地暗示内源性大麻素的参与，但在小鼠中，负责内源性大麻素代谢的主要酶脂肪酸酰胺水解酶（FAAH）已经基因缺失（即FAAH（-/-）小鼠）以及选择性FAAH抑制剂的可用性将使我们能够确定这种内源性大麻素是否在记忆中起作用。此外，我们将研究内源性大麻素调节记忆的神经基质和受体作用机制。我们将确定anandamide和2-AG的水平是否被内源性大麻素作用下的行为程序所改变。最后还将进行实验以确定大麻素的记忆作用是否在海马中介导，海马是一个不仅包含CB1受体和内源性大麻素的大脑区域，而且已知在学习和记忆中发挥作用。总的来说，这些研究将进一步加深我们对该系统生理功能的理解，并弥合内源性大麻素系统在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.