Rhythmic light flickers have emerged as useful tools to modulate cognition and rescue pathological oscillations related to neurological disorders by entrainment. However, a mechanistic understanding of the entrainment for different brain oscillatory states and light flicker parameters is lacking. To address this issue, we proposed a biophysical neural network model for thalamocortical oscillations (TCOs) and explored the stimulation effects depending on the thalamocortical oscillatory states and stimulation parameters (frequency, intensity, and duty cycle) using the proposed model and electrophysiology experiments. The proposed model generated alpha, beta, and gamma oscillatory states (with main oscillation frequences at 9, 25, and 35 Hz, respectively), which were successfully transmitted from the thalamus to the cortex. By applying light flicker stimulation, we found that the entrainment was state-dependent and it was more prone to induce entrainment if the flicker perturbation frequency was closer to the endogenous oscillatory frequency. In addition, endogenous oscillation would be accelerated, whereas low-frequency oscillatory power would be suppressed by gamma (30–50 Hz) flickers. Notably, the effects of intensity and duty cycle on entrainment were complex; a high intensity of light flicker did not mean high entrainment possibility, and duty cycles below 50% could induce entrainment easier than those above 50%. Further, we observed entrainment discontinuity during gamma flicker stimulations with different frequencies, attributable to the non-linear characteristics of the network oscillations. These results provide support for the experimental design and clinical applications of the modulation of TCOs by gamma (30–50 Hz) light flicker.

No abstract

Background Moderate physical exercise has beneficial effects on the brains of healthy humans and AD patients. Previous reports have suggested that treadmill exercise plays an anti-AD role and improves cognitive ability by promoting amyloid clearance, inhibiting neuronal apoptosis, reducing oxidative stress level, alleviating brain inflammation, and promoting autophagy- lysosome pathway in AD mice. However, few studies have explored the relationship between the ubiquitin-proteasome system and scientific exercise in AD. Objective The current study aimed to investigate the mechanism by which the exercise- regulated E3 ubiquitin ligase improves AD. Methods Both Wildtype and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 12 for each group). WTE and ADE mice were subjected to treadmill exercise for 12 weeks, evaluating the effect of treadmill running on learning and memory ability, Aβ plaque burden, hyper-phosphorylated tau protein and E3 ubiquitin ligase. Results The results indicated that exercise not only restored learning and memory ability, but also reduced Aβ plaque area, inhibited the hyperphosphorylation of Tau protein activated PI3K/ Akt/Hsp70 signaling pathway, and improved ubiquitin-proteasome system function (increased UCHL-1 and CHIP levels, decreased BACE1 levels) in APP/PS1 transgenic mice. Conclusions These findings suggest that exercise may promote the E3 ubiquitin ligase to clear β-Amyloid and hyper-phosphorylated Tau by activating the PI3K/Akt signaling pathway in the hippocampus of AD mice, which is efficient in ameliorating pathological phenotypes and improving learning and memory ability.