Complex neuromodulatory processes in the locus coeruleus neuron-astrocyte network

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The locus coeruleus (LC) in the brainstem innervates most brain areas with synapses that release the chemical neurotransmitter noradrenaline (NA) to control behaviors like memory, anxiety, pain sensation or breathing. It is thought that the LC is a `simple' brain circuit in which spontaneous action potential (`spike') discharge is synchronous to facilitate rhythmic NA release in the target areas. However, recent in vivo studies indicate that the LC is rather a complex network capable of generating different spike `burst' patterns within neuron clusters that receive from other brain areas synaptic input involving diverse neurotransmitters. Accordingly, such presumptive `LC modules' may express different neurotransmitters receptors, e.g. for glutamate, dopamine or endogenous opioids that are all pivotal for brain cell communication. Astrocytic glial cells in the vicinity of the neurons might contribute to complex LC activities as in other brain areas. Indeed, there is evidence that LC neurons are excited by lactate released from adjacent astrocytes. All this indicates that the LC is NOT a simple circuit. The proposed research aims at testing the Overarching Hypothesis: The LC is a complex neuromodulatory network in which neurotransmitters and neuron-astrocyte interactions shape spike burst output patterns and thus the efficacy of pulsed NA release. We are qualified for this research based on our previous extensive in vitro studies of spontaneously active neuron-astrocyte networks, e.g. in the spinal cord, hippocampus, cortex or breathing center. For this, we combine pharmacological manipulations with electrophysiological recording of local field potentials (LFP) and membrane potential from an individual cell plus imaging of signaling factors. For example, we image changes of intracellular calcium or membrane potential with chemical dyes and, since several years, with genetically-engineered fluorescent protein sensors. Regarding the proposed research, we reported recently that LC neurons in newborn rat brain slices spontaneously generate phase-locked, non-synchronous spikes. Moreover, spikes in single neurons overlap to form bell-shaped LFP bursts and this LC population burst pattern changes profoundly in response to glutamate or activators of ionotropic glutamate receptor (iGluR) subtypes. Our preliminary findings show that activation of opioid and NA receptor subtypes transforms the LC burst pattern in different fashion. Here, we will identify mechanisms by which (i) neurotransmitter receptors modulate LC activity and (ii) lactate released from astrocytes stimulates LC neurons. Our research will show that the LC has intrinsic mechanisms for adapting its discharge pattern under the influence of specific neurotransmitters and signals from astrocytes. This complex behavior is likely pivotal to enable this small brain structure to affect specifically the different activities of numerous target brain areas that are involved in distinct behaviors.