The Locus Coeruleus (LC) is a tiny brain stem nucleus that provides norepinephrine (NE) to most parts of the forebrain and contributes to myriad brain functions, including arousal, sensory processing, nociception, sleep/wake cycles, cognition and stress responses. What remains poorly understood is how such a small structure affects so many distinct processes. Until now, much experimental work has been devoted to determining how LC neurons change their firing properties under various behavioural conditions. These studies have led to the realization that the mode of LC activity matters. For example, a phasic mode with a background firing rate of ~3Hz and strong burst responses to salient stimuli (2-4 spikes at 15Hz) is associated with improved executive function and task engagement. A high tonic mode with background activity of ~6Hz is associated with hypervigilance but greater distractibility during attention tasks and weakened short-burst responses.
A recent hypothesis states that different firing modes of LC promote specific behavioural responses by selectively engaging distinct brain networks. Indeed, human neuroimaging studies have shown that periods of increased arousal, compatible with the phasic mode of LC, are associated with the recruitment of the prefrontal and posterior parietal cortices and with improvements in executive function. In contrast, exposing subjects to prolonged, stressful stimuli, thus mimicking the high tonic LC mode, causes the mobilization of the insula, the amygdala and sensory-motor cortices, compatible with hypervigilance.
Crucially, controlled empirical validation of these observations is difficult because it is impossible to accurately control the levels of LC activity in humans. In my previous work, I found that chemogenetic excitation of LC in mice - which mimics strong and sustained LC activation - leads to the recruitment of networks similar to those that have been reported after stressful stimuli in humans. However, the role of the LC/NE system is not limited to stress, and distinct modes of LC activation can have specific effects on behaviour.
In this Eccellenza proposal, I will focus on understanding how different activation modes of the LC cause changes in brain network dynamics. The proposal is organized into three interconnected projects.
First, I will apply a series of precise and controlled optogenetic manipulations of the LC in mice during anesthetised and awake task-free functional MRI (fMRI) recordings (Project 1). This will provide the first causal evidence that LC firing modes are able to mobilize different brain networks. Using these data, I will study how properties of fMRI signals align with different NE receptor distributions in mice, and test whether there is agreement with changes observed in humans before and after stress induction using an existing dataset (Project 2). This will allow me to establish a translational back-to-back comparison of LC/NE effects on fMRI dynamics in both species. In the third part of the project, I will test how different modes of LC activity change the brain’s ability to encode the saliency of a stimulus. To do so, I will combine LC optogenetics-fMRI with an auditory odd-ball task in awake mice (Project 3). Finally, I will integrate these experimental data into new computational models that are calibrated to mouse data and able to simulate the microcircuit mechanisms through which the LC/NE system regulates network dynamics, thus mechanistically explaining our interventions.
In conclusion, this project will lead to a systematic and analytical description of how the LC/NE system regulates local and global network organization, which is key to understanding how LC promotes distinct behavioural responses.
Last updated:31.10.2022
