Adrenergic Signaling in Synaptic Plasticity and Learning

描述（由申请人提供）：我们建议研究 肾上腺素能信号在突触可塑性、学习和记忆中的作用 分子遗传学具体来说，我们已经创造了小鼠， 合成去甲肾上腺素（NE）和肾上腺素， 多巴胺B-羟化酶（Dbh）基因。纯合子（Dbh-/-）完全缺乏NE; 然而，NE可以在体内和体外快速恢复， NE的氨基酸前体（DOPS）。该模型与先前的模型相比具有几个优点。 药理学方法，包括效果的完整性，对NE的特异性， 和可逆性。先前使用各种技术的研究通常会产生 关于NE在突触可塑性中的作用的相互矛盾的结果， 学习和记忆。一些研究表明NE在形成中的作用 情感（厌恶）记忆。为了测试这种可能性，我们已经开始 表征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， 背景记忆而非线索记忆的巩固，表明海马 在没有NE的情况下，功能可能会改变。为此，我们开始 检查海马体的突触可塑性。初步结果显示， 研究表明，在CA 1区的长时程增强的晚期是 不足因为其他研究表明突触的关键作用 可塑性的区域CA 1的学习和记忆，我们建议检查是否 与学习和记忆有关的细胞内信号通路被改变 在CA 1区，在体外刺激引起LTP的晚期后， 在体内进行恐惧条件反射最后，我们将测试是否补偿 对于NE的缺乏发生在发育过程中，以及多巴胺是否释放， 从Dbh-/-小鼠的肾上腺素能终末中的至少部分替代 为NE。这些目标将通过使用第二种小鼠模型来实现 (Th-/-/Dat-Th+/-），其在肾上腺素能神经元中应缺乏DA和NE 具体来说这些小鼠中的一些将在存在NE的情况下饲养（通过供应NE）。 L-DOPA产前和产后）。L-DOPA将被撤回一半之前， 在上述研究中使用小鼠。

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.