Neuromodulatory and astrocyte influences on hippocampal place cell plasticity

项目摘要/摘要 星形胶质细胞在回路功能中的作用，特别是在神经可塑性方面，一直是 被探索过，但仍有争议。研究神经可塑性的一个很好的大脑区域是海马体，因为 它的神经元代表认知上相关的世界维度，这些维度在 行为上相关的态度。海马体包含代表脑内位置的位置细胞 环境，并显示与行为相关的重组重组，例如，在奖励 地点。这发生在小鼠的目标导向学习(GOL)任务中。多巴胺(DA)是一种有益的 候选神经调节剂影响与奖励相关的重新映射，因为已知它会影响 放置单元的稳定性。海马区DA的来源最近被证明是该基因座 蓝斑(LC)，也释放去甲肾上腺素(NE)。LC在GOL中的作用尚不清楚。 学习过程中从LC释放的NE和DA可以直接作用于神经元，但也可以 影响星形胶质细胞。皮质星形胶质细胞对去甲肾上腺素有反应，钙水平有很大变化，但这 还没有在海马体中进行检测。这些钙反应可能会导致 神经网络功能。这项提案将审查1)LC预测对 大鼠海马神经元和星形胶质细胞钙离子的变化 星形胶质细胞钙，3)LC对奖赏相关部位细胞重新定位的影响，4)LC是否 对场所细胞的影响需要完整的星形胶质细胞钙。我假设LC活动导致放置细胞 通过其对星形胶质细胞钙水平的影响而向奖励区移动。我会检查这些的 在清醒的、行为正常的小鼠中使用双光子钙成像的问题。更好地理解 神经调节、星形胶质细胞功能和神经可塑性之间的关系将产生新的 有关电路功能和病理学的理论。

Project Summary/Abstract The role of astrocytes in circuit function, particularly with respect to neural plasticity, has been explored but is debated. One excellent brain area to study neural plasticity is the hippocampus, since it has neurons that represent cognitively relevant dimensions of the world that change in a behaviorally relevant manner. The hippocampus contains place cells that represent locations in the environment, and show reorganized restructuring relevant to behavior, for example at a reward location. This occurs during goal-oriented learning (GOL) tasks in mice. Dopamine (DA) is a good candidate neuromodulator to influence reward-related remapping, since it is known to affect the stability of place cells. The source of DA in the hippocampus was recently shown to be the locus coeruleus (LC), which also releases norepinephrine (NE). The role of the LC during GOL is unknown. NE and DA released from the LC during learning could act directly on neurons, but it could also influence astrocytes. Astrocytes in cortex respond to NE with large changes in calcium levels, but this has not been examined in the hippocampus. These calcium responses may cause alterations in neural network function. This proposal will examine 1) the activity of LC projections to the hippocampus and astrocyte calcium during GOL 2) the relationship between LC axon activity and astrocyte calcium, 3) the LC’s effect on reward-related place cell remapping, 4) and whether the LC’s effect on place cells requires intact astrocyte calcium. I hypothesize that LC activity causes place cell shifts toward the reward zone via its effects on astrocyte calcium levels. I will examine these questions using two-photon calcium imaging in awake, behaving mice. A better understanding of the relationship between neuromodulation, astrocyte function, and neural plasticity will generate new theories about circuit function and pathology.