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Abstract

Aims: Many visceral and higher-order brain functions depend on noradrenergic neurotransmission. Our understanding of how the evolutionary preserved and seemingly undifferentiated brainstem nucleus Locus Coeruleus (LC) modulates anatomically and functionally distinct brain networks underlying diverse bran functions remains elusive. We study interactions between the LC and its diverse forebrain targets with a focus on the mechanisms of differentiated neuromodulation of the functionally diverse neural circuits.
Methods: We use a multi-modal methodology to characterize the noradrenergic effects at different spatial and temporal scales. We combine the whole-brain imaging using fMRI with extracellular recordings in the LC and in its forebrain targets. We experimentally modulate the LC activity and/or neurotransmission within selective noradrenergic pathways and monitor the local, global, and behavioral consequences of such interventions.
Results: The LC neurons respond to salient events. The LC stimulation prior presentation of a salient acoustic cue attenuated startle response. Spontaneous or elicited LC activation cases rapid change of ongoing brain state. The net effect of LC activation depends on the amount of NE released and post-synaptic processing. A mild, high-frequency LC stimulation produced thalamo-cortical activation and hippocampal suppression. Stronger LC activation caused thalamic activation, but cortical suppression as revealed by BOLD responses.
Conclusions: The LC activation in response to salient stimuli potentiates broadcasting within thalamo-cortical sensory pathways, while suppresses potentially competing networks, thus reducing interference. Emerging view on heterogeneous LC organization proposes the existence of functional modules within LC neuronal population. The functionally distinct LC assemblies may provide a complex, differentiated and possibly target-specific neuromodulation in the forebrain.