Mechanisms and optogenetic control of rhythm slowing associated with Alzheimer’s disease: some views from dynamical modeling

This paper aims to explain and expand the dynamic mechanisms underlying the interesting but controversial experimental phenomena in the optogenetic regulation of Alzheimer’s disease (AD) from the dynamical modeling perspective. First, we are fortunate to find a medial septum GABAergic (MSGABA) neuron model that perfectly reproduces the in vitro experimental results in mice, including the positive correlation of neuronal firing rate to the injection current, immediate or delayed spike responses as well as different response probabilities to the optogenetic stimulations. Then, we further propose a larger cornu ammonis 1-MSGABA (CA1-MS) circuit model, trying to provide some more generalized dynamical views, not just matching some in vivo experimental results. The results not only verify the pacing effect of MSGABA neurons on hippocampal \(\theta \) $\theta$ rhythm, but also suggest that the increased conductances of several potassium channels can cause or rescue the AD-related rhythm slowing phenomena, including the increased \(\theta \) $\theta$ band power, the decreased \(\gamma \) $\gamma$ band power and the firing rate. More importantly, in terms of the optional stimulus parameters and the restored power levels, 40 and 80Hz optogenetic stimulations are the most suitable choices for restoring the low and high \(\gamma \) $\gamma$ band powers, respectively. It is also noteworthy that both periodic and Poisson optogenetic stimulations rescue the rhythm slowing, whereas the random arrhythmic stimulation does not, indicating the importance of the intrinsic rhythm of the stimulation pulse. These modeling results fill the gap in optogenetic dynamical modeling research of AD, reveal more comprehensive regulatory mechanisms, and are expected to provide some possible theoretical guidances for the diagnosis and treatment of AD.