Ahnaou A, Rodriguez-Manrique D, Embrechts S, Biermans R, Manyakov N V, Youssef S A, Drinkenburg W H I M
Department of Neuroscience, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Department of Non-Clinical Safety, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Neural Plast. 2020 May 2;2020:1703969. doi: 10.1155/2020/1703969. eCollection 2020.
The aging process eventually cause a breakdown in critical synaptic plasticity and connectivity leading to deficits in memory function. The olfactory bulb (OB) and the hippocampus, both regions of the brain considered critical for the processing of odors and spatial memory, are commonly affected by aging. Using an aged wild-type C57B/6 mouse model, we sought to define the effects of aging on hippocampal plasticity and the integrity of cortical circuits. Specifically, we measured the long-term potentiation of high-frequency stimulation (HFS-LTP) at the Shaffer-Collateral CA1 pyramidal synapses. Next, local field potential (LFP) spectra, phase-amplitude theta-gamma coupling (PAC), and connectivity through coherence were assessed in the olfactory bulb, frontal and entorhinal cortices, CA1, and amygdala circuits. The OB of aged mice showed a significant increase in the number of histone H2AX-positive neurons, a marker of DNA damage. While the input-output relationship measure of basal synaptic activity was found not to differ between young and aged mice, a pronounced decline in the slope of field excitatory postsynaptic potential (fEPSP) and the population spike amplitude (PSA) were found in aged mice. Furthermore, aging was accompanied by deficits in gamma network oscillations, a shift to slow oscillations, reduced coherence and theta-gamma PAC in the OB circuit. Thus, while the basal synaptic activity was unaltered in older mice, impairment in hippocampal synaptic transmission was observed only in response to HFS. However, age-dependent alterations in neural network appeared spontaneously in the OB circuit, suggesting the neurophysiological basis of synaptic deficits underlying olfactory processing. Taken together, the results highlight the sensitivity and therefore potential use of LFP quantitative network oscillations and connectivity at the OB level as objective electrophysiological markers that will help reveal specific dysfunctional circuits in aging-related neurodegeneration studies.
衰老过程最终会导致关键的突触可塑性和连接性受损，进而导致记忆功能缺陷。嗅球（OB）和海马体是大脑中对气味处理和空间记忆至关重要的两个区域，它们通常会受到衰老的影响。我们使用老年野生型C57B/6小鼠模型，试图确定衰老对海马体可塑性和皮质回路完整性的影响。具体而言，我们测量了海马旁回-海马CA1锥体突触处高频刺激的长时程增强（HFS-LTP）。接下来，我们评估了嗅球、额叶和内嗅皮质、CA1以及杏仁核回路的局部场电位（LFP）频谱、相位-振幅θ-γ耦合（PAC）以及通过相干性的连接性。老年小鼠的嗅球中，组蛋白H2AX阳性神经元数量显著增加，这是DNA损伤的一个标志物。虽然发现年轻和老年小鼠之间基础突触活动的输入-输出关系测量没有差异，但在老年小鼠中发现场兴奋性突触后电位（fEPSP）斜率和群体峰电位振幅（PSA）明显下降。此外，衰老伴随着γ网络振荡的缺陷、向慢振荡的转变、嗅球回路中相干性和θ-γ PAC的降低。因此，虽然老年小鼠的基础突触活动未改变，但仅在高频刺激时观察到海马体突触传递受损。然而，神经网络中与年龄相关的改变在嗅球回路中自发出现，这表明嗅觉处理中突触缺陷的神经生理基础。综上所述，这些结果突出了嗅球水平LFP定量网络振荡和连接性的敏感性及其作为客观电生理标志物的潜在用途，这将有助于在衰老相关神经退行性变研究中揭示特定的功能失调回路。
