Noradrenergic input from nucleus of the solitary tract regulates parabrachial activity in mice

The parabrachial complex (PB) is critically involved in aversive processes, and chronic pain is associated with amplified activity of PB neurons in rodent models of neuropathic pain. Here we demonstrate that catecholaminergic input from the caudal nucleus of the solitary tract (cNTScat)—a stress responsive region that integrates intero- and exteroceptive signals—causes amplification of PB activity and their sensory afferents. Using a virally mediated expression of a norepinephrine (NE) sensor, NE2h, and fiber photometry in anesthetized mice, noxious mechanical and thermal stimuli caused prolonged NE transients in PB that far outlast the noxious stimulus. Similar NE transients in PB were evoked by focal stimulation of the superficial cNTS, a region that contains the noradrenergic A2 cell group that projects densely upon PB. In vitro, optical stimulation of cNTScat terminals depolarized PB neurons and increased their frequency of spontaneous excitatory synaptic inputs. A dual opsin approach showed that sensory afferents from the caudal spinal trigeminal nucleus (SpVc) are potentiated by cNTScat terminal activation. This potentiation was coupled with a decrease in the paired pulse ratio, consistent with an cNTScat-mediated increase in the probability of release at SpVc synapses. Together, these data suggest that A2 neurons of the cNTS generate long lasting NE transients in PB which increase excitability and potentiate responses of PB neurons to sensory inputs. These reveal a mechanism through which stressors from multiple modalities may potentiate the aversiveness of nociceptive stimuli. Significance Statement The aversiveness of pain is influenced by many factors, including physiological and emotional stress. We show that the parabrachial nucleus (PB), a key integrative hub for aversive stimuli, experiences prolonged norepinephrine transients following noxious stimulation in mice. These NE transients potentiate sensory input to PB and arise, at least in part, from catecholaminergic projections from the stress-responsive caudal nucleus of the solitary tract (cNTScat). We propose that activity this cNTScat to PB pathway may potentiate the aversiveness of pain in stressful conditions.