LONGTERM DEPRESSION IN THE ADULT HIPPOCAMPUS IN VIVO

描述(调查人员摘要)：关于以下机制的知识 基础活动依赖的神经可塑性是理解不可或缺的 记忆功能正常和受损。该计划的总体目标 这项拨款申请中提出的实验是为了研究参数 对于作为基础的诱导和生化过程至关重要 突触长时抑制(LTD)的维持和表达 在体成人海马区谷氨酸能突触的强度。 对学习和记忆的正式模型的研究表明，突触 力量必须有能力既能减少，也能增加 以依赖使用的方式成功模拟这些认知过程。 诱导LTD的一个常见范例是交付延长的 对传入通路的低频刺激。然而，LTD在 已经发现这种方式只发生在体外制剂中，使用 幼年动物的组织。我们最近已经证明了重复的 双脉冲刺激连合通路可靠地诱导健壮 成年大鼠海马CA1区锥体细胞连合传入的LTD 在活体内。随后的实验表明，LTD的诱导由 双脉冲刺激依赖于N-甲基-D-天冬氨酸(NMDA) 受体的激活和时间上重叠的抑制性输入 γ-氨基丁酸激活介导的突触后细胞靶点 A(GABAA)受体。如果GABA能抑制很弱或不存在 兴奋性激活，LTD发展失败。的第一个目标是 目前的建议是测试GABAeric的程度 成对脉冲刺激期间的抑制控制 成对脉冲序列在体内诱导成年海马区LTD。这个 维系和表达LTD的机制 成对脉冲刺激目前尚不清楚。差异激活 蛋白激酶和磷酸酶通常被认为起着关键作用。 在调节双向活性依赖的突触可塑性方面。这个 因此，本提案的第二个和第三个目标是审查 成年海马体内蛋白质磷酸酶和蛋白质的变化 分别与LTD相关的蛋白激酶活性 成对脉冲刺激。拟议中的实验涉及一种罕见的 电生理学、药理学和生物化学的结合 洞察基础机制的技术 完整成人大脑中活动依赖的神经可塑性。

DESCRIPTION (Investigator's abstract): Knowledge of the mechanisms that underlie activity-dependent neural plasticity is integral to understanding both normal and impaired memory function. The overall goal of the experiments proposed in this grant application is to study parameters critical for the induction and biochemical processes that underlie the maintenance and expression of long-term depression (LTD) of synaptic strength of glutamatergic synapses in the adult hippocampus in vivo. Research with formal models of learning and memory has shown that synaptic strength must have the capacity to both decrease and increase in a use-dependent manner for successful simulation of these cognitive processes. A common paradigm for inducing LTD is the delivery of prolonged low-frequency stimulation to the afferent pathway. However, LTD induced in such a fashion has been found to occur only in in vitro preparations using tissue from young animals. We recently have demonstrated that repeated paired-pulse stimulation of the commissural pathway reliably induces robust LTD of the commissural input to CA1 pyramidal cells in the adult hippocampus in vivo. Subsequent experiments have revealed that the induction of LTD by paired-pulse stimulation is dependent on N-methyl-D-aspartate (NMDA) receptor activation and, temporally overlapping, inhibitory input to the postsynaptic cell target mediated by activation of gamma-amino-butyric acid A (GABAA) receptors. If GABAergic inhibition is weak or absent during excitatory activation, then LTD fails to develop. The first aim of the present proposal is to test whether or not the degree of GABAergic inhibition during paired-pulse stimulation controls the effectiveness of a train of paired pulses to induce LTD in the adult hippocampus in vivo. The mechanisms that underlie the maintenance and expression of LTD induced by paired-pulse stimulation currently are unknown. Differential activation of protein kinases and phosphatases commonly is thought to play a critical role in regulating bidirectional activity-dependent synaptic plasticity. The second and the third aim of the present proposal therefore is to examine in the adult hippocampus in vivo changes in protein phosphatase and protein kinase activity, respectively, in association with LTD induced by paired-pulse stimulation. The proposed experiments involve a rare combination of electrophysiological, pharmacological, and biochemical techniques to gain insight into the mechanisms that underlie activity-dependent neural plasticity in the intact adult brain.