Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.
Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.
复制标题
AppNL-G-F/NL-G-F 小鼠自然睡眠期间海马 - 内侧前额叶皮层回路中表达小白蛋白的中间神经元功能的改变和相关网络振荡。
DOI：
10.1016/j.nbd.2023.106151
复制
发表时间：
2023
影响因子：
6.1
通讯作者：
Brady ES
中科院分区：
文献类型：
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作者：
Brady ES
在阿尔茨海默病 (AD) 的早期阶段，肽淀粉样蛋白-β (Aβ) 的积累会损害突触并扰乱神经元活动，导致与认知相关的神经元振荡受到破坏。这被认为主要是由于中枢神经系统突触抑制受损，特别是通过表达小白蛋白（PV）的中间神经元，而这对于产生几个关键振荡至关重要。这一领域的研究主要是在小鼠模型中进行的，这些模型过度表达 AD 相关基因的人源化突变形式，从而产生夸张的病理学结果。这促进了在内源水平表达这些基因的敲入小鼠系的开发和使用，例如本研究中使用的 AppNL-G-F/NL-G-Fmouse 模型。这些小鼠似乎模拟了 Aβ 诱导的网络损伤的早期阶段，但目前缺乏对这些损伤的深入表征。因此，我们使用 16 个月大的 AppNL-G-F/NL-G-F 小鼠，分析了清醒行为、快速眼动 (REM) 和非快速眼动 (NREM) 睡眠期间海马体和内侧前额叶皮层 (mPFC) 中的神经元振荡，以评估网络功能障碍的程度。在清醒行为、快速眼动睡眠或非快速眼动睡眠期间，海马体或前额叶皮层中的伽马振荡没有发生变化。然而，在 NREM 睡眠期间，发现 mPFC 纺锤体的功率增加，而海马尖波波纹的功率降低。后者伴随着表达 PV 的中间神经元活动同步性的增加（使用双光子 Ca2+ 成像测量），以及表达 PV 的中间神经元密度的降低。此外，虽然检测到 mPFC 和海马体的局部网络功能发生变化，但这些区域之间的远程通信似乎完好无损。总而言之，我们的结果表明，这些 NREM 睡眠特异性损伤代表了淀粉样蛋白病引起的回路崩溃的早期阶段。
In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-Fmouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-Fmice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.