Low frequency hippocampal-cortical activity drives brain-wide resting-state functional connectivity: An optogenetic functional MRI study

Abstract

The hippocampus, including the dorsal dentate gyrus (dDG), and cortex engage in bidirectional communication. We propose that low frequency activity in hippocampal-cortical pathways underlies brain-wide resting-state connectivity to mediate distinct cognitive functions and integrate sensory information. Since the DG primarily receives cortical terminal projections and acts as a bridge for cortico-hippocampal-cortical network communication, we examined how spatiotemporally specific activity initiated in the dDG influences cortical activity and subsequent brain-wide resting-state functional connectivity by combining optogenetic, cell-specific stimulation of CaMKIIα-expressing excitatory neurons (i.e., dDG granule cells) and large-scale functional MRI (fMRI) detection. Low (0.5-2 Hz), but not high (40 Hz), frequency stimulation of dDG excitatory neurons evoked robust cortical and subcortical fMRI responses. Subsequent local field potential (LFP) recordings revealed that only low frequency stimulation evoked strong LFP responses in bilateral V1, corroborating the fMRI results, though all tested stimulation frequencies evoked LFP responses in dDG. LFP latency measurements indicate that the first evoked responses occurred in the ipsilateral dDG and propagated to the ipsilateral V1 polysynaptically (9.5±1.3ms, p < 0.001), before reaching contralateral V1 via monosynaptic interhemispheric callosal connections (4.0±1.5ms, p < 0.01). In addition, interhemispheric resting-state fMRI (rsfMRI) connectivity was enhanced in dorsal hippocampus (dHP), primary visual (V1), primary auditory (A1) and primary somatosensory (S1) cortices during and after low, but not high, frequency stimulation. We further observed an increase in infra-slow (<0.1 Hz) rsfMRI BOLD activity in dHP, V1, A1 and S1 during and after low frequency stimulation. Subsequent LFP recordings revealed an increase in slow oscillations in dorsal hippocampus and visual cortex, interhemispheric visual cortical connectivity, and hippocampal-cortical connectivity. Visually-evoked fMRI responses in visual regions were also increased during and after low frequency dDG stimulation. In addition, after low frequency dDG stimulation, long-term but not short-term memory was improved in novel-object recognition test compared to sham. Our results indicate that low frequency activity propagates in hippocampal-cortical pathway, drives interhemispheric cortical rsfMRI connectivity, mediates visual processing and coordinates long-term memory.