Precise and Pervasive Phasic Bursting in Locus Coeruleus during Maternal Behavior in Mice

Abstract

The noradrenergic locus coeruleus (LC) mediates key aspects of arousal, memory, and cognition in structured tasks, but its contribution to naturalistic behavior remains unclear. LC activity is thought to multiplex distinct signals by superimposing sustained ("tonic") firing patterns reflecting global brain states, such as arousal and anxiety, and rapidly fluctuating ("phasic") bursts signaling discrete behaviorally significant events. Manipulations of the LC noradrenergic system broadly impair social behavior, but the temporal structure of LC firing and its relationship to social interaction is unknown. One possibility is that tonic firing may increase in the presence of social partners; it is also possible that phasic bursts may accompany specific social events. We used chronic in vivo electrophysiology and fiber photometry to measure single-unit and population neural activity in LC of freely behaving mice during their interactions with pups. We find that pup retrieval elicits remarkably precise phasic activity in LC that cannot be attributed merely to sensory stimuli, motor activity, or reward. Correlation of LC activity with retrieval events shows that phasic events are most closely related to specific subsequent behaviors. The reliability and magnitude of phasic responses strongly suggest that these events are coordinated across LC and broadcast noradrenaline (NA) release throughout the brain. We also observed slow changes in tonic firing when females performed distinct maternal behaviors such as nest building and pup grooming. We therefore propose that LC signals state changes during sustained interactions and contributes to goal-directed action selection during social behavior with globally broadcast NA release.

Noradrenergic cross-modular reciprocal inhibition within the locus coeruleus

“…GECIs are beginning to be employed to study neuronal activity within the LC (Breton-Provencher et al ., 2022; Dvorkin & Shea, 2022). This approach has not been used to study an inhibitory process such as that seen following activation of α2Rs although a decrease in fluorescence intensity after a phasic excitation associated with maternal pup retrieval has been noted (Dvorkin & Shea, 2022).…”

“…GECIs are beginning to be employed to study neuronal activity within the LC (Breton-Provencher et al ., 2022; Dvorkin & Shea, 2022). This approach has not been used to study an inhibitory process such as that seen following activation of α2Rs although a decrease in fluorescence intensity after a phasic excitation associated with maternal pup retrieval has been noted (Dvorkin & Shea, 2022). The use of calcium imaging to study inhibition is becoming increasingly accepted in tonically active neuronal populations (Favre-Bulle et al ., 2018; Gong et al ., 2020; Vanwalleghem et al ., 2020).…”

The locus coeruleus broadcasts prediction errors across the cortex to promote sensorimotor plasticity

“…However, LC calcium activity also rises prior to locomotion onset, creating the additional possibility of an internally generated movement onset response. Other kinds of movement are also correlated with LC firing, including pup retrievals (Dvorkin and Shea, 2022) and lever pressing (Breton-Provencher et al, 2022). These movement onset responses could also reflect other forms of prediction error, including action prediction errors (Greenstreet et al, 2022) or temporal difference reward prediction errors (in cases where the movement is associated with reward expectation) similar to those documented in the dopaminergic system (Kim et al, 2020).…”

A circuit from the locus coeruleus to the anterior cingulate cortex modulates offspring interactions in mice

“…In response, the dam returns them to the nest in a behavior called 'pup retrieval' [20][21][22][23][24][25] . Recent work from our laboratory shows that a large fraction of LC neurons becomes robustly and precisely active as dams retrieve wayward pups and return them to the nest 26 . We proposed that LC contributes to goal-directed action selection during parental behavior with widespread release of NA 26 .…”

“…Recent work from our laboratory shows that a large fraction of LC neurons becomes robustly and precisely active as dams retrieve wayward pups and return them to the nest 26 . We proposed that LC contributes to goal-directed action selection during parental behavior with widespread release of NA 26 . However, the downstream targets through which LC acts to modulate pup retrieval are unknown.…”