MORPHOLOGY AND LONG TERM POTENTIATION IN THE HIPPOCAMPUS

这项研究的长期目标是了解神经细胞 活动改变了大脑中的突触连接，并理解 这种改变的连接性和行为学习之间的关系 记忆。使用联想长时程增强(LTP)作为 了解神经元连通性如何随着神经模式的变化而变化 活动的变化，拟议的研究解决了变化的问题 存在的轴棘突触和突触发生与LTP的相关性 成年大鼠的海马体，一种可能突出的大脑结构 与心理健康相关的认知功能障碍。该系统将是 研究了兴奋性内嗅觉皮质(EC)向丘脑的投射 S的CA1锥体细胞远端顶端树突丛。分子。我们的 初步研究表明，成人CA1的树突和突触 美国分子L)的特征与大鼠的轴棘突触相似 齿状回，其中LTP的形态相关性暗示 修改现有的突触；以及2)拥有一些意想不到的 形态特征表明树突正在生长和 突触发生。这些特征包括：丝状足；大，静脉曲张 树突棘；与脊椎相关的相对较高的概率 多聚核糖体；锥体细胞树突内陷 树突和轴突；以及树突的无突触突起。这些 对正常成人CA1S分子的形态观察导致了 假设LTP的形态相关性将不同于 以前在其他海马区获得的那些。明确目标L 描述了EC-CA1突触上LTP的解剖学相关性 测试LTP与那里的增长相关的假设。 特异性目标2描述了EC-CA1突触在 电子显微镜水平，证实锥体细胞树突 参与了在CA1中观察到的异常形态相互作用，S。 分子。《特定目标3》验证了阻断NMDA的假说 受体，可阻止几个海马区LTP的诱导 系统，也防止LTP的解剖学相关性。具体目标L 和3主要使用体外海马片制备，其中 EC-CA1途径的研究可以比体内研究更少含糊，随后 依据：每个锥体突触数量的体视学测定 细胞；功能相关突触特征的量化；以及 与生长相关的连续切片评估与重建 形态特征。使用顺行示踪剂注入EC以 在超微结构水平标记EC-CA1突触，特异性目标2 确定EC轴突突触的突触后元素的类型 在CA1中。金色快速高尔基体法也被用来表征 光镜和电子显微镜观察到了类生长结构 在初步研究中确定了。LTP的解剖学相关性研究 在这里获得的，以及之前在其他海马区的研究 系统，应该允许未来的研究评估结构变化 与海马体相关的行为学习范式。就这样， 对结构修改之间的关系的其他见解 而认知可能会进化。因为海马体显然起着关键作用 在认知、理解活动依赖性突触修饰中的作用 也应该有助于我们更好地了解海马体 功能障碍及其对认知的影响。

The long-term objective of this research is to understand how neural activity modifies synaptic connectivity in brain and to understand the relationship between this altered connectivity and behavioral learning and memory. Using associative long-term potentiation (LTP) as a model for understanding how neuronal connectivity changes as the pattern of neural activity changes, the proposed studies address the question of altered existing axospinous synapses and synaptogenesis as correlates of LTP in the adult rat hippocampus, a brain structure that may figure prominently in mental health-related cognitive dysfunction. The system to be investigated is the excitatory entorhinal cortical (EC) projection to the CA1 pyramidal cell distal apical dendritic tuft in s. moleculare. Our preliminary studies indicate that the dendrites and synapses in adult CA1 s. moleculare l) share features with the axospinous synapses in the dentate gyrus, where the morphological correlates of LTP imply the modification of existing synapses; and 2) possess some unexpected morphological features that suggest ongoing dendritic growth and synaptogenesis. These features include: filopodia; large, varicose dendritic spines; a relatively high probability of spine-associated polyribosomes; invaginations of pyramidal cell dendrites by other dendrites and axons; and synapseless protrusions from dendrites. These morphological observations in normal adult CA1 s. moleculare lead to the hypothesis that the morphological correlates of LTP here will differ from those obtained previously in other hippocampal regions. Specific Aim l characterizes the anatomical correlates of LTP at the EC-CA1 synapses to test the hypothesis that LTP correlates with increased growth there. Specific Aim 2 characterizes the synaptology of the EC-CA1 synapses at the electron microscopic level and confirms that pyramidal cell dendrites participate in the unusual morphological interactions observed in CA1 s. moleculare. Specific Aim 3 tests the hypothesis that blocking the NMDA receptor, which prevents the induction of LTP in several hippocampal systems, also prevents the anatomical correlates of LTP. Specific Aims l and 3 principally use the in vitro hippocampal slice preparation, where the EC-CA1 pathway can be studied less ambiguously than in vivo, followed by: stereological determination of the number of synapses per pyramidal cell; quantification of functionally relevant synaptic features; and serial section evaluation and reconstruction of growth-associated morphological features. Using anterograde tracer injections into the EC to label EC-CA1 synapses at the ultrastructural level, Specific Aim 2 determines the types of postsynaptic elements with which EC axons synapse in CA1. The gold-toned rapid Golgi method is also used to characterize at the light and electron microscopic levels the growth-like structures identified in preliminary studies. The anatomical correlates of LTP obtained here, together with previous studies in other hippocampal systems, should allow future studies to evaluate structural changes in hippocampally relevant behavioral learning paradigms. In this way, additional insight into the relationship between structural modification and cognition may evolve. Because the hippocampus apparently plays a key role in cognition, understanding activity-dependent synaptic modification in the hippocampus should also help us to better understand hippocampal dysfunction and its impact on cognition.