Alonso Mariana, Vianna Monica R M, Depino Amaicha M, Mello e Souza Tadeu, Pereira Patricia, Szapiro German, Viola Haydee, Pitossi Fernando, Izquierdo Ivan, Medina Jorge H
Instituto de Biologia Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
Hippocampus. 2002;12(4):551-60. doi: 10.1002/hipo.10035.
Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. Because brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, we examined the role of BDNF in STM and LTM formation of a hippocampal-dependent one-trial fear-motivated learning task in rats. Using a competitive RT-PCR quantitation method, we found that inhibitory avoidance training is associated with a rapid and transient increase in BDNF mRNA expression in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody into the CA, region of the dorsal hippocampus decreased extracellular signal-regulated kinase 2 (ERK2) activation and impaired STM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 activation and facilitated STM. The infusion of anti-BDNF antibody impaired LTM when given 15 min before or 1 and 4 hr after training, but not at 0 or 6 hr posttraining, indicating that two hippocampal BDNF-sensitive time windows are critical for LTM formation. At the same time points, PD098059 produced no LTM deficits. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of an inhibitory avoidance learning. Additionally, they suggest that this requirement involves ERK1/2-dependent and -independent mechanisms.
大脑中的信息存储是一个具有时间梯度的过程，涉及不同的记忆类型或阶段。一个多世纪以来，人们一直认为，在形成长期记忆（LTM）的过程中，一个或多个短期记忆（STM）过程参与了新信息的处理。由于脑源性神经营养因子（BDNF）可调节成年海马体中的短期突触功能和活动依赖性突触可塑性，我们研究了BDNF在大鼠海马体依赖性单次恐惧动机学习任务的STM和LTM形成中的作用。使用竞争性RT-PCR定量方法，我们发现抑制性回避训练与海马体中BDNF mRNA表达的快速短暂增加有关。向背侧海马体的CA区域双侧注入功能阻断性抗BDNF抗体可降低细胞外信号调节激酶2（ERK2）的激活，并损害STM保持分数。PD098059抑制ERK1/2激活也产生了类似的效果。相反，海马体内注射重组人BDNF可增加ERK1/2的激活并促进STM。在训练前15分钟或训练后1小时和4小时给予抗BDNF抗体可损害LTM，但在训练后0小时或6小时给予则不会，这表明两个海马体BDNF敏感时间窗口对LTM形成至关重要。在相同时间点，PD098059未产生LTM缺陷。因此，我们的结果表明，内源性BDNF是抑制性回避学习的STM和LTM形成所必需的。此外，它们表明这种需求涉及ERK1/2依赖性和非依赖性机制。
