Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice

Fang

et al. 2017

Front. Aging Neurosci.

Cognitive impairment, functional decline and behavioral symptoms that characterize Alzheimer’s disease (AD) are associated with perturbations of the neuronal network. The typical electroencephalographic (EEG) features in AD patients are increased delta or theta rhythm and decreased alpha or beta rhythm activities. However, considering the role of cross-frequency couplings in cognition, the alternation of cross-frequency couplings in AD patients is still obscure. This study aims to explore the interaction dynamics between different EEG oscillations in AD patients. We recorded the resting eye-closed EEG signals in 8 AD patients and 12 healthy volunteers. By analyzing the wavelet power spectrum and bicoherence of EEG, we found enhanced gamma rhythm power in AD patients in addition to the increased delta and decreased alpha power. Furthermore, an enhancement of the cross-frequency coupling strength between the beta/gamma and low-frequency bands was observed in AD patients compared to healthy controls (HCs). We propose that the pathological increase of ongoing gamma-band power might result from the disruption of the GABAergic interneuron network in AD patients. Furthermore, the cross-frequency overcouplings, which reflect the enhanced synchronization, might indicate the attenuated complexity of the neuronal network, and AD patients have to use more neural resources to maintain the resting brain state. Overall, our findings provide new evidence of the disturbance of the brain oscillation network in AD and further deepen our understanding of the central mechanisms of AD.

Section: Discussioncontrasting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Enhanced Gamma Activity and Cross-Frequency Interaction of Resting-State Electroencephalographic Oscillations in Patients with Alzheimer’s Disease

Fang

et al. 2017

Front. Aging Neurosci.

“…High-frequency electrical stimulation of the nPO elicited hippocampal network oscillations in the theta range, with a current-dependent increase of peak frequency in both WT and TgF344-AD rats under urethane anesthesia, in line with previous findings in rats and mice [ 20 , 24 – 26 ]. Consistent with our recent report on TgF344-AD rats [ 13 ], stimulus-response analysis showed a reduction in hippocampal oscillatory activity with a particularly diminished theta power in both adult and aged TgF344-AD rats compared with their respective WT rats.…”

Section: Resultssupporting

confidence: 90%

“…Normalized time-course power values were then grouped according to genotype and age. Theta phase-gamma amplitude coupling during hippocampal stimulation was assessed using modulation index (MI), as described previously [ 20 , 21 ]. Briefly, the phase containing signal from 3 to 12 Hz, and the amplitude containing signal from 20 to 100 Hz were used to calculate the MI value at each frequency pair for the LFPs recorded during each stimulation.…”

Section: Methodsmentioning

confidence: 99%

Neurophysiological signals as predictive translational biomarkers for Alzheimer’s disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats

et al. 2018

Self Cite

BackgroundTranslational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment.MethodsBrainstem nucleus pontis oralis stimulation-induced hippocampal oscillations were recorded under urethane anesthesia in adult (6-month-old) and aged (12-month-old) TgF344-AD and wild-type rats. Spontaneous cortical activity was monitored in a cohort of freely behaving aged rats implanted with frontal and occipital cortical electroencephalography (EEG) electrodes.ResultsSubcutaneous administration of donepezil significantly augmented stimulation-induced hippocampal theta oscillation in aged wild-type rats and both adult and aged TgF344-AD rats, which have been previously shown to have diminished response to nucleus pontis oralis stimulation. Moreover, in adult TgF344-AD rats, donepezil also significantly increased theta phase-gamma amplitude coupling in the hippocampus during stimulation. However, neither of these effects were significantly changed in adult wild-type rats. Under freely behaving conditions, donepezil treatment had the opposite effect on cortical oscillatory connectivity in TgF344-AD and wild-type rats, and it reduced the occurrence of high-voltage spindle activity in TgF344-AD rats.ConclusionsTogether, these results imply that pharmacologically enhancing cholinergic tone with donepezil could partially reverse oscillatory abnormalities in TgF344-AD rats, which is in line with its clinical effectiveness in AD patients. Therefore, our study suggests good translational opportunities for these neurophysiological signals recorded in TgF344-AD rats, and their application could be considered in drug discovery efforts for developing therapies with disease-modifying potential.

“…Few results are available so far describing CFC in AD mouse models, at the in vivo level (Gurevicius et al, 2013, Ittner et al, 2014, Stoiljkovic et al, 2016. § By linear fitting of PSD log-log plots in the range 30 -100 Hz, we obtained very similar statistical differences between PS2APP and wt mice, at 3 and 6 months of age (data not shown).…”

Section: Accepted Manuscriptmentioning

confidence: 57%

Early hippocampal hyperexcitability in PS2APP mice: role of mutant PS2 and APP

Fontana

Agostini

Murana

et al. 2017

Neurobiology of Aging

Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline.