Pupil diameter is often treated as a noninvasive readout of activity in the locus coeruleus (LC). However, how accurately it can be used to index LC activity is not known. To address this question, we established a graded relationship between pupil size changes and LC spiking activity in mice, where pupil dilation increased monotonically with the number of LC spikes. However, this relationship exists with substantial variability such that pupil diameter can only be used to accurately predict a small fraction of LC activity on a moment-by-moment basis. In addition, pupil exhibited large session-to-session fluctuations in response to identical optical stimulation in the LC. The variations in the pupil–LC relationship were strongly correlated with decision bias-related behavioral variables. Together, our data show that substantial variability exists in an overall graded relationship between pupil diameter and LC activity, and further suggest that the pupil–LC relationship is dynamically modulated by brain states, supporting and extending our previous findings (Yang et al., 2021).

No abstract

No abstract

12The brain neuromodulatory systems heavily influence behavioral and cognitive processes. 13Previous work has shown that norepinephrine (NE), a classic neuromodulator mainly derived from 14 the locus coeruleus (LC), enhances neuronal responses to sensory stimuli. However, the role of 15 the LC-NE system in modulating perceptual task performance is not well understood. In addition, 16 systemic perturbation of NE signaling has often been proposed to specifically target the LC in 17 functional studies, yet the assumption that localized (specific) and systemic (nonspecific) 18 perturbations of LC-NE have the same behavioral impact remains largely untested. In this study, 19we trained mice to perform a head-fixed, quantitative tactile detection task, and administered an 20 α2 adrenergic receptor agonist or antagonist to pharmacologically down-or up-regulate LC-NE 21 activity, respectively. We addressed the outstanding question of how bidirectional perturbations 22 of LC-NE activity affect tactile detection, and tested whether localized and systemic drug 23 treatments exert the same behavioral effects. We found that both localized and systemic 24 suppression of LC-NE impaired tactile detection by reducing motivation. Surprisingly, while locally 25 activating LC-NE enabled mice to perform in a near-optimal regime, systemic activation impaired 26 approaches may induce compensatory plasticity changes (Acheson et al., 1980; Harik et al., 1981; 53 Valentini et al., 2004) and mask the effects specific to LC-NE. More recent studies employed 54 acute, reversible perturbations including pharmacological, electrical, chemogenetic, and 55 optogenetic stimulations. Among these approaches, pharmacology facilitates translational 56 comparison between animal and human studies. The inhibitory α2 adrenergic receptors (ARs) 57 are highly expressed in the LC, but only sparsely expressed, if at all, in neighboring brainstem 58 regions (McCune et al., 1993;Nicholas et al., 1993). Targeting α2 ARs is considered a specific 59 manner to perturb LC-NE activity (e.g., (Neves et al., 2018)). Agonizing α2 ARs suppresses LC-60 NE signaling by hyperpolarizing LC neurons and reducing NE release in downstream areas 61 (

The brain neuromodulatory systems heavily influence behavioral and cognitive processes.Previous work has shown that norepinephrine (NE), a classic neuromodulator mainly derived from the locus coeruleus (LC), enhances neuronal responses to sensory stimuli. However, the role of the LC-NE system in modulating perceptual task performance is not well understood. In addition, systemic perturbation of NE signaling has often been proposed to specifically target the LC in functional studies, yet the assumption that localized (specific) and systemic (nonspecific) perturbations of LC-NE have the same behavioral impact remains largely untested. In this study, we trained mice to perform a head-fixed, quantitative tactile detection task, and administered an α2 adrenergic receptor agonist or antagonist to pharmacologically down-or up-regulate LC-NE activity, respectively. We addressed the outstanding question of how bidirectional perturbations of LC-NE activity affect tactile detection, and tested whether localized and systemic drug treatments exert the same behavioral effects. We found that both localized and systemic suppression of LC-NE impaired tactile detection by reducing motivation. Surprisingly, while locally activating LC-NE enabled mice to perform in a near-optimal regime, systemic activation impaired . CC-BY-NC-ND 4.