GLUTAMATE RECEPTORS, MEMORY AND LONG TERM POTENTIATION

已经反复证明，NMDA亚型的拮抗剂， 谷氨酸受体干扰学习/记忆任务的表现， 还阻断海马长时程增强（LTP）的诱导。它 一般认为，但没有直接支持的证据， NMDA拮抗剂阻断海马LTP诱导的能力是 这些化合物明显的记忆损害作用。但鉴于 申请人的发现是皮下剂量的NMDA拮抗剂 对海马神经元没有损伤作用， 后扣带回神经元的病理形态学变化， 是否会出现与以下因素相关的学习/记忆能力受损 这些化合物可能更多地与它们的大脑损伤作用有关， 扣带皮层比假设的干扰海马LTP。的 申请人已经证明抗胆碱能药物可以防止扣带细胞 NMDA拮抗剂的神经毒性副作用，他们已经开发 初步证据表明，抗胆碱能药物也可以抵消 NMDA拮抗剂诱导的获得能力受损。在 在本项目中，将进一步探讨这些初步结果， 与我们以前的工作一样，我们将系统地研究 非关联因素，如感觉运动障碍，可能会在 影响我们的学习记忆能力在另一系列 在实验中，我们将给予高剂量的NMDA受体 拮抗剂MK-801，以造成广泛的双侧坏死 在后扣带/压后皮质，大鼠将 通过行为测试来确定这种治疗是否会损害学习/记忆 或其他行为功能。在这个项目中，我们还将 电生理学研究与我们的行为研究平行， 他们将关注抗胆碱能药物是否能阻止NMDA 拮抗剂阻断海马LTP的诱导。另外我们 将尝试在体内扣带皮层中诱导LTP，如果 如果成功，我们将确定MK-801是否阻断扣带回LTP， 抗胆碱能药物是否阻止MK-801阻断扣带回LTP。 预计这些实验可能有助于澄清作用的轨迹 以及NMDA拮抗剂可能损害学习/记忆的机制 表现，同时也澄清了什么样的作用，如果有的话，无论是海马或 扣带LTP在表观记忆干扰过程中起重要作用。

It has been shown repeatedly that antagonists of the NMDA subtype of glutamate receptor interfere with performance on learning/memory tasks and also block the induction of hippocampal long term potentiation (LTP). It is generally believed, but without directly supporting evidence, that the ability of NMDA antagonists to block hippocampal LTP induction underlies the apparent memory impairing actions of these compounds. However, in view of the applicants' finding that NMDA antagonists, at subcutaneous doses which do not have damaging effects on hippocampal neurons, cause acute pathomorphological changes in posterior cingulate neurons, the question arises whether the impaired learning/memory performance associated with these compounds might relate more to their brain damaging action in the cingulate cortex than to postulated interference in hippocampal LTP. The applicants have shown that anticholinergic drugs prevent the cingulate neurotoxic side effects of NMDA antagonists, and they have developed preliminary evidence that anticholinergic drugs may also counteract the impaired acquisition performance induced by NMDA antagonists. In the present Project, these preliminary findings will be further explored and, as in our previous work, we will systematically investigate the role that nonassociative factors such as sensorimotor disturbances may play in affecting performance on our learning/memory measures. In another series of experiments, we will administer high doses of the NMDA receptor antagonist MK-801 to rats in order to create extensive bilateral necrosis in the posterior cingulate/retrosplenial cortices, and the rats will be tested behavioraIly to determine if this treatment impairs learning/memory or other behavioral functions. In this Project we will also conduct electrophysiologic studies that are parallel to our behavioral work in that they will focus on whether anticholinergic drugs prevent NMDA antagonists from blocking the induction of hippocmpal LTP. In addition, we will attempt to induce LTP in the in vivo cingulate cortex and, if successful, we will determine whether MK-801 blocks cingulate LTP and whether anticholinergic agents prevent MK-801 from blocking cingulate LTP. It is expected that these experiments may help clarify the locus of action and mechanism by which NMDA antagonists may impair learning/memory performance while also clarifying what role, if any, either hippocampal or cingulate LTP plays in the apparent memory disrupting process.