Neuronal mechanisms mediating long-lasting changes in signal processing also influence neurovascular coupling in the rat hippocampus

Abstract

To investigate how altered neural signal processing influences fMRI-BOLD responses in the hippocampus, we performed simultaneous in vivo electrophysiology and BOLD-fMRI in male Wistar rats during electrical stimulation of the perforant pathway. By defining input activity via applied pulses and measuring output activity through population spikes, we were able to identify qualitative and quantitative changes in signal processing once the relationship between input and output changed. An initial series of three low-intensity stimulations (LIS) induced clear, consistent BOLD responses. However, following a high-intensity stimulation (HIS) that triggered brief neuronal after-discharges, subsequent series of three identical LIS resulted in significantly attenuated BOLD responses. Electrophysiological data revealed that while total neuronal activity remained stable across all LIS, only the initial LIS induced long-lasting changes in signal processing (persisting beyond 1 minute) and transiently increased gamma band activity. By contrast, after HIS, these changes were reversed and could no longer be re-induced, coinciding with the absence of further increases in gamma band activity. Pharmacological experiments using MK801 and isoflurane further demonstrated that the mechanisms underlying long-lasting changes in signal processing also enhance LIS-induced BOLD responses. These findings suggest that positive fMRI-BOLD responses reflect functionally relevant changes in neural network properties—such as long-lasting modifications in signal processing—rather than simple increases in total neuronal output. Significance Statement An increase in BOLD fMRI signal in a specific brain region is generally interpreted as reflecting increased neuronal activity, with larger increases taken to indicate higher levels of activity. Here, we show that identical inputs can elicit stronger BOLD responses when they also induce long-lasting changes in local network properties, even when the overall activity of principal neurons remains similar. This suggests that the BOLD response is better understood as an indicator of functionally relevant changes in local network processing rather than a purely quantitative measure of neuronal activity.