Heterogeneous properties of locus coeruleus cortical projection neurons

Daniel John Chandler

doi:10.17918/00000599

The brainstem nucleus locus coeruleus (LC) innervates the entire central nervous system and is the primary source of norepinephrine (NE) to the neocortex. While classically considered a homogenous modulator of forebrain activity by virtue of highly widespread and divergent axons, recent behavioral and pharmacological evidence suggest this nucleus may execute distinct operations within functionally distinct cortical regions. To test the hypothesis that LC is more functionally organized than previously recognized, we compared the distributions of neurons in LC projecting to orbitofrontal (OFC), medial prefrontal (mPFC), anterior cingulate cortices (ACC) to those projecting to primary motor cortex (M1) through a variety of anatomical, molecular, and electrophysiological assays. Here we show that each of these cortical regions is innervated by a distinct subset of LC neurons with minimal overlap between groups. Moreover, cells projecting to OFC and mPFC were found to contain enriched mRNAs related to synaptic excitability and transmission relative to those innervating M1. Finally, through the use of whole cell patch clamp, we demonstrate that these same populations of cells are characterized by a greater level of spontaneous tonic discharge. This set of studies is the first to identify such unique molecular and physiological properties within subsets of terminal field-specific LC neurons and supports the idea that LC projections to the neocortex are organized according to the functional role of their target circuitry. Such an arrangement may have behavioral significance insofar as PFC projection neurons have lower thresholds of activation and higher basal discharge rates than M1 projection cells thus prompting greater and asynchronous NE release and more robust noradrenergic modulatory actions in decision-making circuits relative to movement generating circuits. This may facilitate decision making prior to movement generation. Perturbations in the functional anatomy and physiology described here may be related to neuropsychiatric conditions associated with dysregulation of the LC-noradrenergic system such as attention deficit hyperactivity disorder. Furthermore, these findings challenge the classical view of LC as a relatively homogenous modulator of forebrain activity and provide the basis for a renewed scientific interest in this region of the brain.

Heterogeneous properties of locus coeruleus cortical projection neurons

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Heterogeneous properties of locus coeruleus cortical projection neurons

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