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 也可阻断海马长时程增强(LTP)的诱导。它 人们普遍认为，但没有直接支持的证据， NMDA拮抗剂阻断海马LTP诱导的能力 这些化合物对记忆的明显损害作用。然而，鉴于 申请人发现NMDA拮抗剂皮下注射 不会对海马神经元造成损害，导致急性 后扣带回神经元的病理形态变化 是否会出现学习/记忆能力受损与 这些化合物可能更多地与它们在大脑中的损伤作用有关 扣带回皮质对海马LTP的假设干扰作用较弱。这个 申请者已经证明，抗胆碱能药物可以防止扣带回 NMDA拮抗剂的神经毒性副作用，它们已经开发出 初步证据表明，抗胆碱能药物也可能抵消 NMDA拮抗剂引起的习得能力下降。在 目前的项目，将进一步探索这些初步发现，并， 与我们之前的工作一样，我们将系统地调查 感觉运动障碍等非关联性因素可能会起作用 影响我们的学习/记忆测量的表现。在另一个系列中 在实验中，我们将使用高剂量的NMDA受体 拮抗剂MK-801致大鼠双侧广泛坏死 在后扣带回/脾后皮质，大鼠将 测试行为，以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，我们还将进行 与我们的行为研究平行的电生理学研究 他们将把重点放在抗胆碱能药物是否能阻止NMDA 拮抗剂阻断海马LTP的诱导。此外，我们 将尝试在体内的扣带回皮质中诱导LTP，如果 如果成功，我们将确定MK-801块是否触发LTP和 抗胆碱能药是否阻止MK-801阻断扣带回LTP。 预计这些实验可能有助于阐明作用轨迹。 和NMDA拮抗剂可能损害学习/记忆的机制 表现，同时也澄清，如果有的话，是什么角色，无论是海马还是 扣带状LTP在明显的记忆干扰过程中起作用。

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.