Bidirectional pharmacological perturbations of the noradrenergic system differentially affect tactile detection

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 (

Silence, Solitude, and Serotonin: Neural Mechanisms Linking Hearing Loss and Social Isolation

“…Multiple centralized neuromodulatory systems widely innervate sensory and integrative brain regions, and respond to changes in environmental conditions [ 64 ]. For example, noradrenergic neurons within the locus coeruleus are sensitive to behaviorally important information, such as social context or stress, are affected by social experience, influence connectivity in neural networks related to salience and affect, and alter performance on sensory and cognitive tasks [ 201 , 202 , 203 , 204 , 205 , 206 ]. These kinds of similarities in some of the aspects of how serotonergic, noradrenergic, and other neurochemical systems work have led to the view that these systems may cooperate in regulating integrative neural functions [ 74 , 207 ].…”

The Importance of Accounting for Movement When Relating Neuronal Activity to Sensory and Cognitive Processes

“…How to isolate sensory and cognitive from movement-related neuronal activity The most important consideration in attributing neuronal activity to sensory, cognitive, or motor processes is the behavioral task design. Figure 1A illustrates a common Go/NoGo sensory detection task design (e.g., Ollerenshaw et al, 2012;Pinto et al, 2013;Sachidhanandam et al, 2013;Martins and Froemke, 2015;Yang et al, 2016;Rodenkirch et al, 2019;Banerjee et al, 2020;McBurney-Lin et al, 2020). After a variable intertrial interval, the subject is presented with a stimulus trial (stimulus present) or catch trial (stimulus absent).…”

Physiological and functional heterogeneity in the mouse locus coeruleus

“…Behavior task was controlled by BControl (C. Brody, Princeton University) or custom-based Arduino hardware and software as described previously (Yang et al, 2016, 2021; McBurney-Lin et al, 2020). Video of the left pupil (ipsilateral to LC recording and stimulation) was acquired at 50 Hz using a PhotonFocus camera and StreamPix 5 software, or at 20 Hz using a Basler acA1300-200um camera and Pylon software.…”

“…Tagging was performed during anesthesia (2% isoflurane) and sometimes during awake, non-task performing condition. Mice were trained to perform a go/no-go single-whisker detection task as described previously (McBurney-Lin et al, 2020; Yang et al, 2021) or a variant of this task. Briefly, in the original task, licking to the deflection of the right C2 whisker (go trials) resulted in a water reward (Hit).…”