Project Summary / Abstract
Systems neuroscience has viewed the brainstem noradrenergic nucleus, Locus Coeruleus (LC), as the
source of a global arousal signal, which modulates cognitive functions by altering operations throughout
the entire central nervous system. This is achieved, presumably, by this small collection of only ~1,600
neurons in rodents spiking synchronously. Recently, however, the first large-scale recordings of many
LC single units simultaneously in anesthetized rats demonstrated that LC population activity consists
of a nuanced pattern of distinct ensembles that are independently active. In parallel, chemogenetic and
optogenetic manipulations of the LC in behaving rodents revealed that the LC contains subsets of
neurons that provide forebrain circuit-specific neuromodulation of specific cognitive functions. These
recent advances compel the field to record LC ensembles in behaving animals. However, this requires
surmounting the obstacle of brainstem movement in behaving animals which has heretofore limited LC
recordings to multi-unit activity or one single unit. Here, we will establish the feasibility of ultra-flexible
multi-electrode probes, called ‘nanoelectronic threads’ (NETs), for months-long LC ensemble
recordings in unanesthetized rats. As a proof-of-concept study demonstrating the feasibility of NETs,
we recorded ~150 single units simultaneously in the visual cortex of freely moving rats for up to four
months. In this project, we aim to implant 512 electrodes in the LC of the head-fixed behaving rat and
record 100s of LC single units simultaneously, along with ongoing arousal/behavioral state (pupil size,
locomotion, orofacial movements, etc.). By increasing the number of units recorded by orders of
magnitude, this project will be transformational for LC research. Our approach will be broadly useful to
neuroscientists recording in other brainstem and subcortical structures in which recording many single
units is difficult. Our overall goal is to use this R34 to establish the method, which will enable a
subsequent Targeted Brain Circuits Project R01 submission focused on the role of LC ensemble activity
in the circuit basis of cognitive rigidity that is precipitated by chronic, months-long stress.
