The respiratory control system is plastic. It has a working memory and is capable of retaining how respiratory stimuli affect breathing by regulating synaptic strength between respiratory neurons. For example, repeated airway obstructions trigger a form of respiratory plasticity that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This form of respiratory plasticity is known as long-term facilitation (LTF) and requires noradrenaline released onto XII motoneurons. However, the brainstem regions responsible for this form of LTF remain unidentified. Here, we used electrophysiology, neuropharmacology and immunohistochemistry in adult rats to identify the brainstem regions involved in mediating LTF. First, we show that repeated airway obstructions induce LTF of XII motoneuron activity and that inactivation of the noradrenergic system prevents LTF. Second, we show that noradrenergic cells in the locus coeruleus (LC), which project to XII motoneurons, are recruited during LTF induction. Third, we show that targeted inactivation of noradrenergic LC cells during LTF induction prevents LTF. And lastly, we show that the nucleus tractus solitarius (NTS), which has known projections to the LC, is critical for LTF because its inactivation prevents LTF. Our results suggest that both the LC and NTS are involved in mediating apnea-induced LTF, and we hypothesize that a NTS → LC → XII circuit mechanism mediates this form of respiratory motor plasticity.

The respiratory control system can augment respiratory output following repetitive challenges. For example, repeated airway obstructions can trigger a form of respiratory memory that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This augmentation in respiratory motor output is known as long-term facilitation (LTF) and can be elicited by repeated apneas or bouts of hypoxia. We demonstrate that LTF can be triggered in the absence of repeated apneas or hypoxia by intermittently stimulating locus coeruleus (LC) neurons, or through pharmacological activation of the neurotrophic machinery in XII motoneurons. We used pharmacological and optogenetic approaches to elicit LTF and show that this is mediated by α1-adrenergic receptor-binding at the XII motor pool. We also use optical LC inhibition to reaffirm the importance of the LC in mediating apnea-induced LTF. Lastly, we show that neurotrophic signaling agonists or antagonists applied to XII motoneurons can also be used to elicit or prevent LTF expression, respectively, and acts co-operatively with noradrenaline. These results suggest LTF can be triggered by multiple hypoxia-independent triggers and is mediated by the release of noradrenaline from the LC onto α1-adrenergic receptors on XII motoneurons to trigger plasticity via activation of neurotrophic signaling cascades.

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery), or reintroduction of the reinforcement (i.e., reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction, however, the role and source of endogenous NA in these effects is unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopisn, is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery), or reintroduction of the reinforcement (i.e., reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction, however, the role and source of endogenous NA in these effects is unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopisn, is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery), or reintroduction of the reinforcement (i.e., reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction, however, the role and source of endogenous NA in these effects is unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopisn, is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.