Synapase Modification /Memory Retention /Life Span Model

该提案主要针对两个研究目标：衰老和功能性衰老的动物模型。该研究项目的长期目标是了解一种延长寿命的新型动物模型的神经特性，这些特性有助于其在衰老过程中保留学习记忆的能力。一般来说，研究表明，学习和记忆的能力平均在寿命的后期下降（例如，空间记忆力下降）。最近，我们研究小组的研究人员描述了一种延长寿命的动物模型，即生长激素受体敲除（GH-R-KO）小鼠，该小鼠在衰老期间（训练后28天）相对于对照组表现出记忆力的增强。此外，与年轻对照动物相比，这些小鼠在记忆保持方面没有表现出任何缺陷。记忆的获得和储存被认为与突触的潜在修饰有关。已经提出作为认知功能（学习和记忆）的假定生物学底物的两种形式的突触修饰是长时程增强（LTP）和长时程抑制（LTD）。虽然只有有限的证据将LTP或LTD与大脑在体内使用的机制直接联系起来，但一些研究已经注意到老年动物无法保持空间记忆与LTP更快衰减之间的相关性。此外，最近的数据表明，引发LTD和逆转LTP的能力也可能在衰老过程中增强。在这项研究中，行为特征化（即，抑制、回避任务、水迷宫）成年和老年GH-R-KO小鼠和对照将用于测试两种关于可能有助于在衰老期间保持记忆保持的机制的假设。将检查海马CA 1区。 假设1：显示学习记忆保留的老年GH-R-KO小鼠不显示LTP的加速衰减。如果LTP确实是学习和记忆的细胞相关物，那么人们可以预测它的加速衰减可以解释衰老过程中记忆保留的损伤。将对成年和老年GH-R-KO小鼠和对照进行行为表征。随后，将从这些动物制备海马切片，并在CA 1（放射层）中进行细胞外记录，以表征LTP衰减的时间过程。每5分钟使用4列100 Hz刺激（1 s持续时间）诱导LTP。 假设二：老年GH-R-KO小鼠表现出很少或没有损害的记忆保留没有表现出增强的能力，唤起LTD或逆转LTP在体外。由于改变这些性质也可能导致老化过程中保持性能的降低（即，遗忘的增加）在由行为学表征的动物制备的脑切片的海马区CA 1中进行细胞外记录，以评估：1）使用延长的低频刺激（LFS; 900个脉冲/1Hz）诱发LTD的能力和2）使用多个短持续时间LFS爆发（30个脉冲/1Hz;爆发之间10分钟）逆转LTP的能力。

This proposal focuses on two research objectives: animal models of aging and functional senescence. The long term goal of this research project is to understand the neurological properties of a novel animal model of extended life span that contribute to its capacity to retain learned memories during aging. In general, studies indicate that the ability to learn and remember declines, on average, in the latter part of the life span (e.g., decreased retention of spatial memory). Recently, an animal model of extended life span has been described by investigators in our research group, the growth hormone receptor knockout (GH-R-KO) mouse, that shows enhanced retention of memories during aging (28 days post training) relative to controls. Furthermore, these mice do not show any deficit in memory retention when compared with young control animals. The acquisition and storage of memory is believed to be associated with an underlying modification of synapses. Two forms of synaptic modification that have been proposed to be putative biological substrates for cognitive function (learning and memory) are long term potentiation (LTP) and long term depression (LTD). While only limited evidence directly links LTP or LTD with the mechanisms used by the brain in vivo, several studies have noted a correlation between the inability of aged animals to retain spatial memory and a quicker decay of LTP. Furthermore, recent data suggest that the ability to elicit LTD, and reverse LTP may also be enhanced during aging. In this study, behaviorally haracterized (Le., inhibitory ,avoidance task, water maze) adult and aged GH-R-KO mice and controls will be used to test two hypotheses concerning mechanisms that may contribute to a preservation of memory retention during aging. Hippocampal region CA1 will be examined. Hypothesis 1: Aged GH-R-KO mice showing retention of learned memory do not display an accelerated decay of LTP. If LTP is indeed a cellular correlate for learning and memory, then one would predict that its accelerate decay could account for an impairment in memory retention during aging. Adult and aged GH-R-KO mice and controls will be behaviorally characterized. Subsequently, hippocampal slices will be prepared from these animals and extracellular recordings will be made in CA1 (stratum radiatum) to characterize the time course of LTP decay. LTP will be induced using 4 trains of 100 Hz stimulation (1s duration) every 5 min. Hypothesis 2: Aged GH-R-KO mice showing little or no impairment in memory retention do not show an enhanced capacity to evoke LTD or reverse LTP in vitro. Since altering these properties could also contribute to a decrease in retention performance during aging (Le., increase in forgetting) extracellular recordings will be made in hippocampal region CA1 of brain slices prepared from behaviorally characterized animals to assess: 1) the capacity to evoke LTD using prolonged low frequency stimulation (LFS; 900 lpulses/l Hz) and 2) the capacity to reverse LTP using multiple short-duration LFS bursts (30pulses/lHz; 10 min between bursts).