Bidirectional pharmacological perturbations of the noradrenergic system differentially affect tactile detection

Abstract

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.

Locus coeruleus spiking differently correlates with S1 cortex activity and pupil diameter in a tactile detection task

“…Recent optogenetic and pharmacological work has shown that activating the LC–NE system enhances detection/discrimination sensitivity ( Gelbard-Sagiv et al, 2018 ; Rodenkirch et al, 2019 ; McBurney-Lin et al, 2020 ). Thus, LC–NE acting on early sensory areas (i.e., primary sensory thalamus, primary sensory cortex) likely affects perceptual decision making ( McBurney-Lin et al, 2019 ).…”

Locus Coeruleus Norepinephrine Neurons Facilitate Orbitofrontal Cortex Remapping and Behavioral Flexibility

“…Since we observed that LC-NE activity diverged in response to reward or error and that the magnitude of this difference correlated with learning, we next wanted to examine how manipulating the activity of these neurons altered reversal behavior in the maze task. Pharmacological agents selective for alpha-2 (α2) adrenergic receptors were directly infused into the LC on reversal sessions to transiently silence (clonidine, α2-agonist) or enhance (idazoxan, α2-antagonist) LC activity through an autoreceptor-dependent mechanism (Figure 2A, B) 40,41 . Mice were assigned to one of three treatment groups: clonidine, idazoxan, or control (saline) and received a cannula infusion, according to their group, on each reversal day (R1-R4) before the maze task (Figure 2C).…”

“…On days of infusion (Fig. 2B), 600 nl of 0.9% sodium chloride (Hospira, St. Jude Pharmacy), α2-antagonist idazoxan hydrochloride (5 mg/ml, adapted from 68 , Sigma, I6138), or α2-agonist clonidine hydrochloride (5 mM, adapted from 40 , Sigma, C7897) were infused bilaterally (200 nl/min, 2 min wait) using a dual-syringe (5 μl, Hamilton, 87931) microinjection pump (KD Scientific, 14-831-211) and plastic tubing (P1 Technologies, 8F023X041P01) immediately before the maze task. Testing prior to experiments determined drug dosages that did not cause gross impairments in behavior.…”

Control and coding of pupil size by hypothalamic orexin neurons

“…To suppress LC function, we used two manipulations with different modes of action: local, stereotaxic-guided LC infusion of clonidine and systemic injection of the LC norepinephrine-depleting toxin DSP4 ( N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine hydrochloride). The rationale for this was based on previous publications showing that clonidine suppresses LC noradrenergic neurons by activating the inhibitory α2-adrenoceptor 34 – 37 , while DSP4 treatment selectively degrades the LC noradrenergic function to 10–30% of its normal value 38 . In the clonidine experiments (Extended Data Fig.…”