Opposing control of the respiratory brainstem on multiple timescales achieved by noradrenaline and glutamate release from the locus coeruleus

The locus coeruleus (LC) provides widespread noradrenergic (NAergic) modulation throughout the brain to influence a wide range of functions, including breathing. Although both anatomical and physiological evidence supports the involvement of the LC in both the upstream integration and the downstream modulation of breathing, the circuitry behind the latter is unknown. Here, we show that LC neurons in adult male and female mice send projections to the Kӧlliker-Fuse nucleus (KF), a critical site in the control of breathing. Long duration activation of LC neuron terminals in pontine slices induces persistent inhibitory and excitatory NA currents or increases firing rate in postsynaptic KF neurons. Short stimulation on the other hand leads to VGluT2-dependent rapid release of glutamate that may co-occur with slower NAergic transmission in a monosynaptic circuit. Together these results demonstrate that LC neurons can exert flexible, opposing effects on different timescales via glutamatergic and NAergic signaling onto a key respiratory brainstem nucleus. Significance Statement The ability for the LC to co-release fast-acting neurotransmitters and slower-acting neuromodulators provides an increased capacity to differentially and flexibly modulate downstream targets to coordinate cognitive and autonomic functions including breathing, stress and arousal. Here, we demonstrate that LC neurons may co-release glutamate and noradrenaline onto the Kӧlliker-Fuse nucleus (KF), a critical respiratory center, enabling rapid excitation via glutamate and slower opposing modulation via α1- and α2-adrenergic receptors. This multiplexing mechanism may allow the LC to dynamically adjust breathing during diverse behavioral states, stress, or metabolic demand through a single anatomical pathway. Understanding this neuromodulatory gateway has implications for respiratory disorders where LC function is compromised and provides a conserved circuit model for studies on the state-dependent control of breathing.