Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications

Abstract

Key points The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task‐related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC‐NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I‐INs) located in the peri‐LC. We also observe that inhibition of peri‐LC I‐INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri‐LC I‐INs and LC‐NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri‐LC I‐INs. Abstract Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task‐related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC‐NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation‐pause profile observed in animals. The activity was referred to as phasic‐like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory–inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I‐INs) in the medial part of the peri‐LC that exerted feedforward inhibition of LC‐NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri‐LC I‐INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri‐LC I‐INs and LC‐NA neurons. These observations demonstrate functional roles of peri‐LC I‐INs in integrating inputs of the frontal cortex onto LC‐NA neurons and gating the phasic LC output.

Locus Coeruleus Malfunction Is Linked to Psychopathology in Prodromal Dementia With Lewy Bodies

“…cortical pathways recently disentangled by Bari's group (Bari et al, 2020). Moreover, both projections from the LC to cortical regions and back-projections are fundamental, such as the connection from the prefrontal cortex to the LC for LC-activity guided attentional behavior, as recently demonstrated in a study by Kuo et al (2020). Recent evidence indicates dynamic interplay between the amygdala and hippocampus in emotional memory-processing guided by arousal-driven LC activity (Jacobs et al, 2020), which can be compromised by LC dysfunction.…”

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

“…Whether all these neuronal subtypes make direct connections with LC-NE neurons, as well as their function in LC modulated behaviors, remains unresolved. Nonetheless, the neuronal subtype that has received the most attention is the LC-GABA population, which forms inhibitory synapses on LC-NE neurons (Aston- Jin et al, 2016;Breton-Provencher and Sur, 2019;Kuo et al, 2020;Figure 2A).…”

“…Whether all these neuronal subtypes make direct connections with LC-NE neurons, as well as their function in LC modulated behaviors, remains unresolved. Nonetheless, the neuronal subtype that has received the most attention is the LC-GABA population, which forms inhibitory synapses on LC-NE neurons ( Aston-Jones et al, 2004 ; Jin et al, 2016 ; Breton-Provencher and Sur, 2019 ; Kuo et al, 2020 ; Figure 2A ). Tracing experiments indicate that these LC-GABA neurons receive inputs from largely the same brain regions as LC-NE neurons, with only several regions exhibiting preferential projections to either LC-GABA or LC-NE neurons ( Breton-Provencher and Sur, 2019 ; Figures 2B,C ).…”

“…A subpopulation of LC-GABA neurons are active simultaneously with LC-NE neurons, reflecting coincident inputs to both LC-NE and LC-GABA populations ( Breton-Provencher and Sur, 2019 ). Coincident inputs to LC-NE and LC-GABA neurons play a critical role in controlling the phasic activity of LC-NE neurons ( Kuo et al, 2020 ) and resultant transient increases in arousal in response to salient sensory stimuli ( Breton-Provencher and Sur, 2019 ). Based on retrograde labeling, LC-GABA neurons would receive preferential, or non-coincident, inputs from several brain regions, suggesting that these regions can exert inhibitory control of LC-NE activity ( Breton-Provencher and Sur, 2019 ; Figure 2C ).…”

Precise and pervasive phasic bursting in locus coeruleus during maternal behavior

“…We were not able to definitively identify the location of the cell bodies of the RI neurons, however, the apparently reciprocal firing pattern during pup retrieval raises the possibility that RI correspond to GABAergic neurons in and around LC that have been proposed to exert inhibitory control of LC-NA [31][32][33][34] . Many of our recording sessions yielded multiple simultaneously recorded neurons (Fig.…”