Elucidating the neurochemical basis of LTP induction and maintenance in vivo

项目摘要 蓝斑（LC）中含有去甲肾上腺素（NE）的神经元细胞被认为与多巴胺（DA）共释放。 它的许多投射，包括进入海马体。通过DA和NE的释放，LC被认为是主要的 通过维持长时程增强（LTP）（一种不可或缺的机制）， 记忆巩固的机制。了解LC调节记忆的机制， 对海马记忆电路和动力学的研究至关重要。然而，由于其 由于结构相似，很难确定DA和NE各自在LTP维持中的确切作用。在 体内微透析在过去传统上用于测量细胞中分子的紧张性细胞外浓度 但是由于采样探针的尺寸和低时空分辨率而对组织造成的损伤使得实时 对紧张性神经递质浓度及其生物学功能的追踪是有问题的。我们的实验室已经开发出- 最先进的伏安技术能够实时测量神经递质的紧张浓度， 高空间分辨率。我们假设，通过改变体内应用的伏安波形，并通过开发一种 新的基于人工智能的后处理管道，可以可靠地分析非常相似的分析物，如DA和NE。 解决了通过准确的神经递质鉴定和药理学操作，我们的目标是确定特异性神经递质， NE和DA对海马LTP的影响。此外，我们假设LC的电刺激将导致 增加海马DA和NE释放和增强LTP诱导相比，没有刺激。的能力 基于它们的伏安信号来解析各个分析物一直是电化学中未解决的问题， 能够跟踪它们对海马中LTP诱导和维持的相对实时贡献， 精度更好地理解LTP的诱导和维持机制对于获得 增加对记忆电路和生理学的理解。

PROJECT SUMMARY Norepinephrine (NE)-containing neuronal cells in the locus coeruleus (LC) are thought to co-release dopamine (DA) from many of its projections, including into the hippocampus. Through DA and NE release, the LC is thought to play a major role in modulating hippocampal memory encoding through the maintenance of long-term potentiation (LTP), an integral mechanism for memory consolidation. Understanding the mechanisms by which the LC modulates memory is of fundamental importance to investigations into hippocampal memory circuitry and dynamics. However, because of their structural similarity, it has been difficult to ascertain the precise roles that DA and NE each have on LTP maintenance. In vivo microdialysis has been traditionally used in the past to measure tonic extracellular concentrations of molecules in the brain, but damage to tissue because of the size of the sampling probe and low spatiotemporal resolution make real-time tracking of tonic neurotransmitter concentrations, and their biological functions, problematic. Our lab has developed state- of-the-art voltammetric techniques capable of measuring tonic concentrations of neurotransmitters in real-time with very high spatial resolution. We hypothesize that by altering the voltammetric waveform applied in vivo and by developing a novel artificial intelligence based post-processing pipeline, very similar analytes such as DA and NE can be reliably resolved. Through accurate neurotransmitter identification and pharmacologic manipulation, we aim to ascertain the specific effects NE and DA have on hippocampal LTP. Additionally, we hypothesize that electrical stimulation of the LC will lead to increased hippocampal DA and NE release and enhanced LTP induction compared to no stimulation. The ability to resolve individual analytes based on their voltammetric signals has been an unsolved problem in electrochemistry and will enable tracking of their relative real-time contributions to LTP induction and maintenance in the hippocampus with high accuracy. A greater understanding of LTP induction and maintenance mechanisms is of vital importance to garnering an increased understanding of memory circuitry and physiology.