Whole-brain afferent input mapping to functionally distinct brainstem noradrenaline cell types

Abstract

The locus coeruleus (LC) is a small region in the pons and the main source of noradrenaline (NA) to the forebrain. While traditional models suggested that all LC-NA neurons project indiscriminately throughout the brain, accumulating evidence indicates that these cells can be heterogeneous based on their anatomical connectivity and behavioral functionality and exhibit distinct coding modes. How LC-NA neuronal subpopulations are endowed with unique functional properties is unclear. Here, we used a viral-genetic approach for mapping anatomical connectivity at different levels of organization based on inputs and outputs of defined cell classes. Specifically, we studied the whole-brain afferent inputs onto two functionally distinct LC-NA neuronal subpopulations which project to amygdala or medial prefrontal cortex (mPFC). We found that the global input distribution is similar for both LC-NA neuronal subpopulations. However, finer analysis demonstrated important differences in inputs from specific brain regions. Moreover, sex related differences were apparent, but only in inputs to amygdala-projecting LC-NA neurons. These findings reveal a cell type and sex specific afferent input organization which could allow for context dependent and target specific control of NA outflow to forebrain structures involved in emotional control and decision making.

Keywords: Afferent input anatomy; Brain-wide circuits; Locus coeruleus; Neuromodulation; Noradrenaline.