Low frequency stimulation of hippocampus evoked large-scale cortical and subcortical responses: an optogenetic functional MRI study

Abstract

It has been tacitly assumed that the hippocampus exerts an influence on the cortex and subcortex. Recent studies have indicated that cortical activity may be entrained by hippocampal theta-beta oscillations. It has also been suggested that hippocampal-cortical interactions can be altered by slow oscillations. However, the effects of low frequency stimulation in the hippocampus on the widespread and large-scale cortical and subcortical activities remain largely unexplored. In addition, most of the previous studies used electrical stimulation which stimulated non-specific cell populations. Hence, optogenetic functional magnetic resonance imaging (ofMRI) is used to provide whole brain 4D coverage and address the issue of non-specific neuronal stimulation. As the hippocampus consists mainly of type II calmodulin-dependent protein kinase (CamKIIα) expressing neurons, CamKIIα-channelrhodopsin-encoding virus was injected into the dorsal dentate gyrus of adult male Sprague-Dawley rats. Optic fiber was implanted to the same site of virus injection. Low frequency stimulations (0.5, 1 and 2Hz) were used to determine the spatiotemporal dynamics of the widespread and large-scale cortical and subcortical activity. All low frequency stimulations resulted in the recruitment of various cortical and subcortical responses, including the bilateral visual cortex (VC), bilateral superior colliculus (SC) and bilateral lateral geniculate nucleus (LGN). The strength and spatial extend of these cortical and subcortical responses increased with an increase in stimulation frequency (from 0.5Hz to 2 Hz). Subsequently, intracortical local field potential (LFP) recordings were performed at two locations, namely bilateral VC. Various frequency stimulations (0.5, 1, 2, 10 and 20Hz) were used to determine the temporal dynamics of the bilateral VC activities. Only low frequency stimulation evoked strong LFP responses in the bilateral VC, which coincides with the ofMRI results. Latency measurements of the evoked responses showed that the response was first evoked in the ipsilateral VC and then in the contralateral VC. This indicates that such cortical recruitment has a multi-synaptic basis of activity propagation. In summary, these results suggest that low frequency stimulation in the hippocampus enables the widespread and large-scale recruitment of the cortex and subcortex. This study also highlights the possibilities of utilizing ofMRI in studying the underlying mechanisms of the widespread and large-scale neural circuits and brain networks.