NOVELTY INDUCED FACILITATION OF HIPPOCAMPAL LTP

本项目的目的是研究新颖性诱导的长时程增强(LTP)易化现象。LTP是突触可塑性的一种机制，可能是某些形式学习的基础。LTP在内侧穿支路向齿状回的投射诱导DIN觉醒，自由活动的动物在一次刺激后3-5天持续6/24/51。然而，如果在探索新环境的前5-20分钟内诱导LTP，那么LTP的诱导概率和LTP的大小都会进一步增加，在新环境中诱导的LTP在一次刺激后平均持续10天。这些效应与大脑温度、运动以及探索过程中出现的theta节律无关。重要的是，反复暴露在相同的新环境中会产生越来越少的LTP促进作用。相比之下，在家中诱导的LTP在大小和时间上与重复诱导一致。因此，对环境的熟悉似乎会降低新颖性促进效应。这些数据表明，与发现新颖性和/或与探索性行为相关的觉醒相关的过程(S)有助于LTP的诱导和寿命。在这些研究中，我们将解决新奇诱导的易化的行为、药理学和解剖学方面的问题。具体目标1的研究将确定促进的时间进程，并评估在新环境中放置后促进的寿命。我们还将评估熟悉程度是否支持反复暴露于相同的新环境中观察到的减少，方法是确定将动物返回熟悉的环境是否会迅速逆转新奇诱导的促进作用，以及不同的新环境是否会导致LTP促进的重新出现。在具体目标2中，将使用药理学方法来确定在探索和觉醒过程中活跃的神经调节系统是否有助于新奇诱导的LTP诱导和维持。我们将研究胆碱能、肾上腺素能和阿片能神经调节系统对这种易化效应的贡献，每个系统在探索过程中都是活跃的。在具体目标3的研究中，我们将确定新的环境是否类似地改变了Schaffer-CA1投射、连合-CA3投射和直接向海马区CA3的穿支路径投射中的LTP诱导和LTP维持。这些研究将使我们能够确定新颖性和神经调制系统对海马区初级突触系统LTP诱导的影响，并解决神经调节剂和新颖性检测在记忆存储过程中的作用，这可能与记忆障碍和当前的海马信息处理模式有关。

The goal of this project is to investigate the phenomenon of novelty- induced facilitation of long-term potentiation (LTP). LTP is a mechanism of synaptic plasticity that may underlie certain forms of learning. LTP induced in medial perforant path projections to the dentate gyrus induce din awake, freely-moving animals persists from 3-5 days following a single stimulation session 6/24/51. However, if LTP is induced during the first 5-20 minute period of exploration of a novel environment, then both the probability of LTP induction and the magnitude of LTP are increased Further, LTP induced in a novel environment persists for an average of 10 days following a single stimulation session. These effects are independent from both brain temperature and movement, as well as theta rhythm occurring during exploration. Importantly, repeated exposure to the same novel environment produces progressively less facilitation of LTP. By contrast, LTP induced in the home cage is consistent in magnitude and time course with repeated induction. Thus, it appears familiarity with the environment reduces the novelty facilitation effect. These data indicate that processes(s) associated with the detection of novelty and/or arousal associated with exploratory behaviors facilitate LTP induction and longevity. In these studies, we will address behavioral, pharmacological and anatomical aspects of novelty-induced facilitation. The studies in Specific Aim 1 will determine the time course of facilitation, and assess the longevity of facilitation following placement in a novel environment. We will also assess whether familiarity underlies the decrement observed with repeated exposures to the same novel environment by determining if returning the animal to a familiar environment rapidly reverses the effect of novelty-induced facilitation, and if distinct novel environments lead to re-emergence of LTP facilitation. In Specific Aim 2, pharmacological methods will be used to determine if neuromodulatory systems that are active during exploration and arousal contribute novelty-induced facilitation of LTP induction and maintenance. We will investigate the contribution of cholinergic, adrenergic and opiodergic neuromodulatory systems to this facilitation effect, each of which are active during exploration. The studies of Specific Aim 3, we will determine if novel environments similarly alter LTP induction and LTP maintenance in Schaffer-CA1 projections, commissural-CA3 proje3ctions, and direct perforant path projections to hippocampal area CA3. These studies will allow us to determine the effects of novelty and neuromodulatory systems on LTP induction in the primary synaptic systems of the hippocampus, and address the role of neuromodulators and novelty detection in processes of memory storage that may be relevant to both memory disorders and current models of hippocampal information processing.