Locus coeruleus phasic discharge is essential for stimulus-induced gamma oscillations in the prefrontal cortex

Abstract

The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We previously reported that LC microstimulation caused a transient desynchronization of population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest modulation in the gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, an α-adrenoreceptor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the PFC and is essential for mediating sensory information along an ascending noxious pathway. NEW & NOTEWORTHY Our study shows linear relationships between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory information along an ascending noxious pathway.

Distinct ensembles in the noradrenergic locus coeruleus evoke diverse cortical states

“…We tested the hypothesis that activation of LC ensembles was accompanied by the activated cortical state. Such a finding would be wholly consistent with prior studies during urethaneanesthesia or during sleep, which examined cortical spectral power after spontaneous increases in LC multi-unit spiking or after LC stimulation (Carter et al, 2010;Marzo et al, 2014;Neves et al, 2018;Hayat et al, 2020). Here, we examined changes in cortical area 24a local field potential (LFP) power triggered on LC ensemble activation times.…”

“…In order to assess brain state, a single tungsten electrode was placed in cortical area 24a (anterior cingulate cortex) (Paxinos and Watson, 2017) and the mean extracellular field potential (8 kHz lowpass filtered) was recorded in 9 of the 15 rats. Neuronal recordings were made under urethane anesthesia, a widely-used model for studying brain state transitions evoked by LC stimulation (Marzo et al, 2014;Neves et al, 2018). To date, recordings of many LC single units simultaneously in any awake organism with multi-electrode probes has been an intractable problem due to brainstem movement associated with body movement, thus necessitating the use of anesthesia to investigate the relationship between LC ensemble activity and brain state.…”

The Locus Coeruleus Is a Complex and Differentiated Neuromodulatory System

“…To study correlations between evoked LC spiking activity, we applied a single foot shock (5.0 mA, 0.5 ms pulse duration) and measured spike count correlations during the time window of the maximal evoked discharge (50 ms after stimulation; see red spikes in Figure 3A). We used a stimulation intensity that has been shown to elicit a population response (Cedarbaum and Aghajanian, 1978;Devilbiss and Berridge, 2006;Mana and Grace, 1997;Neves et al, 2018;Uematsu et al, 2017;Valentino and Foote, 1987). Mean evoked R SC values were distributed around zero ( Figure 2).…”

Monoaminergic Neuromodulation of Sensory Processing

“…Indeed, simultaneous recordings in the LC and barrel cortex of anesthetized rats combined with dynamical systems modeling showed that activity in the LC was highly predictive of dynamic changes in cortical excitability ( Safaai et al, 2015 ). Moreover, phasic responses in the LC or urethane anesthetized rats were elicited by aversive somatosensory stimuli and modulated the stimulus-induced gamma oscillations in the mPFC, suggesting a corresponding modulation of somatosensory processing ( Neves et al, 2018 ). In awake mice, visual responses have been found to be substantially enhanced during phases when the animals were running compared to no locomotion ( Niell and Stryker, 2010 ).…”