Low-frequency hippocampal–cortical activity drives brain-wide resting-state functional MRI connectivity

Significance The hippocampus with its dense reciprocal axonal projections to and from cortex is widely believed to mediate numerous cognitive functions. However, it is unknown whether and how specific hippocampal–cortical activity contributes to the brain-wide functional connectivity. Here, we use optogenetics and fMRI to examine how excitatory neural activity initiated in the dorsal dentate gyrus of the hippocampus propagates and modulates resting-state fMRI (rsfMRI) connectivity. We discover its robust propagation brain-wide at low frequency (1 Hz), which enhances interhemispheric rsfMRI connectivity and cortical and subcortical visual responses. Our findings highlight the important role of slow hippocampal–cortical oscillatory activity in driving brain-wide rsfMRI connectivity and mediating sensory processing. The hippocampus, including the dorsal dentate gyrus (dDG), and cortex engage in bidirectional communication. We propose that low-frequency activity in hippocampal–cortical pathways contributes to brain-wide resting-state connectivity to integrate sensory information. Using optogenetic stimulation and brain-wide fMRI and resting-state fMRI (rsfMRI), we determined the large-scale effects of spatiotemporal-specific downstream propagation of hippocampal activity. Low-frequency (1 Hz), but not high-frequency (40 Hz), stimulation of dDG excitatory neurons evoked robust cortical and subcortical brain-wide fMRI responses. More importantly, it enhanced interhemispheric rsfMRI connectivity in various cortices and hippocampus. Subsequent local field potential recordings revealed an increase in slow oscillations in dorsal hippocampus and visual cortex, interhemispheric visual cortical connectivity, and hippocampal–cortical connectivity. Meanwhile, pharmacological inactivation of dDG neurons decreased interhemispheric rsfMRI connectivity. Functionally, visually evoked fMRI responses in visual regions also increased during and after low-frequency dDG stimulation. Together, our results indicate that low-frequency activity robustly propagates in the dorsal hippocampal–cortical pathway, drives interhemispheric cortical rsfMRI connectivity, and mediates visual processing.

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