Adrenergic Signaling in Synaptic Plasticity and Learning

描述(由申请人提供)：我们建议研究 肾上腺素能信号在小鼠突触可塑性和学习记忆中的作用 分子遗传学。具体地说，我们创造了不能 靶向干扰去甲肾上腺素(NE)和肾上腺素 多巴胺B羟基酶(DBH)基因。纯合子(DBH-/-)完全缺乏去甲肾上腺素； 然而，在体内和体外使用合成的 去甲肾上腺素氨基酸前体(DOPS)。这种模式比以前的模式有几个优点 药理方法，包括作用的完整性，NE的特异性， 和可逆性。以前使用各种技术的研究通常会产生 关于去甲肾上腺素在突触可塑性中的作用的结果相互矛盾， 学习和记忆。一些研究表明去甲肾上腺素在形成过程中起了作用。 情感(厌恶)记忆。为了测试这种可能性，我们已经开始 描述DBH-/-小鼠学习和记忆厌恶事件的能力 使用恐惧条件反射。初步结果表明，在 背景记忆的巩固，但不是线索记忆，提示是海马区 在NE缺失的情况下，功能可能发生改变。出于这个原因，我们已经开始 检查海马区突触的可塑性。这些研究的初步结果 研究表明，CA1区长时程增强的晚期是 有缺陷。因为其他研究表明突触的关键作用 大脑中脑区的可塑性对于学习和记忆，我们建议检验 与学习和记忆有关的细胞内信号通路发生改变 在体外诱导LTP晚期的CA1区，以及 跟随体内的恐惧条件反射。最后，我们将测试补偿是否 因为在发育过程中发生去甲肾上腺素的缺失，以及多巴胺是否释放 来自DBH-/-小鼠的肾上腺素能终末至少可以部分替代 为东北。这些目标将通过使用第二个鼠标模型来实现 (Th-/-/Dat-Th/-)在肾上腺素能神经元中既缺乏去甲肾上腺素又缺乏多巴胺 具体地说。其中一些小鼠将在NE存在的情况下饲养(通过提供 L-DOPA产前和产后)。L-多巴将在2019年之前撤回一半 使用上述研究中的小鼠。

DESCRIPTION (provided by applicant): We propose to examine the role of adrenergic signaling in synaptic plasticity, learning and memory using mouse molecular genetics. Specifically, we have created mice that are unable to synthesize norepinephrine (NE) and epinephrine due to a targeted disruption of the dopamine B-hydroxylase (Dbh) gene. Homozygotes (Dbh-/-) completely lack NE; however NE can be restored rapidly in vivo and in vitro using the synthetic amino acid precursor of NE (DOPS). This model has several advantages over prior pharmacologic approaches, including completeness of effect, specificity for NE, and reversibility. Prior studies using various techniques have often generated conflicting results with regard to the roles of NE in synaptic plasticity, learning and memory. Some studies have suggested a role for NE in the formation of emotional (aversive) memories. To test this possibility, we have begun to characterize the ability of Dbh-/- mice to learn and remember an aversive event using fear conditioning. Preliminary results indicate a specific deficit in the consolidation of contextual but not cued memory, suggesting hippocampal function may be altered in the absence of NE. For this reason we have begun to examine synaptic plasticity in the hippocampus. Preliminary results from these studies suggest that the late phase of long-term potentiation in region CAl is deficient. Because other studies have suggested a critical role of synaptic plasticity in region CAl for learning and memory, we propose to examine whether intracellular signaling pathways implicated in learning and memory are altered in region CAl following stimuli that elicit the late phase of LTP in vitro, and following fear conditioning in vivo. Finally, we will test whether compensation for the absence of NE occurs during development, and whether dopamine released from the adrenergic terminals of Dbh-/- mice can substitute at least partially for NE. These goals will be achieved through the use of a second mouse model (Th-/-/Dat-Th+/-) that should lack DA as well as NE in the adrenergic neurons specifically. Some of these mice will be raised with NE present (by supplying L-DOPA pre- and postnatally). L-DOPA will then be withdrawn in half prior to using the mice in the above studies.