Hippocampal seizures differentially modulate locus coeruleus activity and result in consistent time-locked release of noradrenaline in rat hippocampus

The locus coeruleus (LC) is a small brainstem nucleus and is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the regulation of excitability and plasticity of large-scale brain networks. In this study, we performed a detailed assessment of the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation, using state-of-the-art methodology. Action potentials of LC neurons, of which some were identified by means of optogenetics, were recorded in anesthetized rats using a multichannel high-density electrophysiology probe. The seizure-induced change in firing rate differed between LC neurons: 55% of neurons decreased in firing rate during seizures, while 28% increased their firing rate. Topographic analysis of multi-unit activity over the electrophysiology probe showed a topographic clustering of neurons that were inhibited or excited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRABNE2m, in combination with fiber photometry, in both anesthetized and awake rats. Although our neuronal recordings indicated both inhibition and excitation of LC neurons during seizures, a consistent release of noradrenaline was observed. Concentrations of noradrenaline increased at seizure onset and decreased during or shortly after the seizure. In conclusion, this study showed consistent but heterogeneous modulation of LC neurons and a consistent time-locked release of hippocampal noradrenaline during acute hippocampal seizures.