BACKGROUND Hippocampal oscillations play a critical role in the ontogeny of allocentric memory in rodents. During the critical period for memory development, hippocampal theta is the driving force behind the temporal coordination on neuronal ensembles underpinning spatial memory. While known that hippocampal oscillations are necessary for normal spatial cognition, whether disrupted hippocampal oscillatory activity during the critical period impairs long-term spatial memory is unknown. Here we investigated whether disruption of normal hippocampal rhythms during the critical period have enduring effects on allocentric memory in rodents. OBJECTIVE/HYPOTHESIS We hypothesized that disrupt of hippocampal oscillations via artificial regulation of the medial septum during the critical period for memory development results in long-standing deficits in spatial cognition. METHODS After demonstrating that pan-neuronal medial septum (MS) optogenetic stimulation (465 nm activated) regulated hippocampal oscillations in weanling rats we used a random pattern of stimulation frequencies to disrupt hippocampal theta rhythms for either 1Hr or 5hr a day between postnatal (P) days 21-25. Non-stimulated and yellow light-stimulated (590 nm) rats served as controls. At P50-60 all rats were tested for spatial cognition in the active avoidance task. Rats were then sacrificed, and the MS and hippocampus assessed for cell loss. Power spectrum density of the MS and hippocampus, coherences and voltage correlations between MS and hippocampus were evaluated at baseline for a range of stimulation frequencies from 0.5 to 110Hz and during disruptive hippocampal stimulation. Unpaired t-tests and ANOVA were used to compare oscillatory parameters, behavior and cell density in all animals. RESULTS Non-selective optogenetic stimulation of the MS in P21 rats resulted in precise regulation of hippocampal oscillations with 1:1 entrainment between stimulation frequency (0.5-110Hz) and hippocampal local field potentials. Across bandwidths MS stimulation increased power, coherence and voltage correlation at all frequencies whereas the disruptive stimulation increased power and reduced coherence and voltage correlations with most statistical measures highly significant (p<0.001, following correction for false detection). Rats receiving disruptive hippocampal stimulation during the critical period for memory development for either 1Hr or 5hr had marked impairment in spatial learning as measured in active avoidance test compared to non-stimulated or yellow light-control rats (p<0.001). No cell loss was measured between the blue-stimulated and non-stimulated or yellow light-stimulated controls in either the MS or hippocampus. CONCLUSION The results demonstrated that highly robust regulation of hippocampal oscillations can be achieved with non-selective optogenetic stimulation of the MS in rat pups. A disruptive hippocampal stimulation protocol, which markedly increases power and reduces coherence and voltage correlations between the MS and hippocampus during the critical period of memory development, results in long-standing spatial cognitive deficits. This spatial cognitive impairment is not a result of optogenetic-induced cell loss.

中文翻译：

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在记忆发展的关键时期通过光遗传刺激破坏海马节律损害空间认知

背景海马振荡在啮齿动物异中心记忆的个体发育中起关键作用。在记忆发展的关键时期，海马 theta 是支撑空间记忆的神经元集合的时间协调背后的驱动力。虽然已知海马振荡是正常空间认知所必需的，但关键时期海马振荡活动的中断是否会损害长期空间记忆尚不清楚。在这里，我们调查了关键时期正常海马节律的破坏是否对啮齿类动物的异中心记忆具有持久影响。目标/假设我们假设在记忆发展的关键时期通过人工调节内侧隔破坏海马振荡会导致空间认知的长期缺陷。方法 在证明全神经元内侧隔膜 (MS) 光遗传学刺激（465 nm 激活）调节断奶大鼠的海马振荡后，我们使用刺激频率的随机模式在出生后 (P) 之间每天 1 小时或 5 小时破坏海马 theta 节律第 21-25 天。非刺激和黄光刺激 (590 nm) 大鼠作为对照。在 P50-60 时，所有大鼠都接受了主动回避任务的空间认知测试。然后处死大鼠，并评估 MS 和海马的细胞损失。MS和海马体的功率谱密度，在 0.5 到 110Hz 的刺激频率范围内和破坏性海马刺激期间，在基线评估 MS 和海马之间的相干性和电压相关性。未配对 t 检验和方差分析用于比较所有动物的振荡参数、行为和细胞密度。结果 P21 大鼠 MS 的非选择性光遗传学刺激导致海马振荡的精确调节，刺激频率 (0.5-110Hz) 和海马局部场电位之间的夹带为 1:1。跨带宽 MS 刺激增加了所有频率的功率、相干性和电压相关性，而破坏性刺激增加了功率并降低了相干性和电压相关性，大多数统计测量非常显着（p<0.001，在对错误检测进行校正后）。与非刺激或黄光对照大鼠相比，在 1 小时或 5 小时的记忆发展关键时期接受破坏性海马刺激的大鼠在空间学习方面有明显的损害，如在主动回避测试中所测得的那样 (p < 0.001)。在 MS 或海马中，在蓝色刺激和非刺激或黄色光刺激的对照之间没有测量到细胞损失。结论 结果表明，通过对幼鼠 MS 的非选择性光遗传学刺激，可以实现对海马振荡的高度稳健的调节。一种破坏性的海马刺激方案，在记忆发展的关键时期显着增加功率并降低 MS 和海马之间的相干性和电压相关性，导致长期存在的空间认知缺陷。