Abstract
Understanding the role of the noradrenergic nucleus locus coeruleus (LC) in cognition and behavior is critical: It is involved in several key behavioral functions such as stress and vigilance, as well as in cognitive processes such as attention and decision making. In recent years, the development of viral tools has provided a clear insight into numerous aspects of brain functions in rodents. However, given the specificity of primate brains and the key benefit of monkey research for translational applications, developing viral tools to study the LC in monkeys is essential for understanding its function and exploring potential clinical strategies. Here, we describe a pharmacogenetics approach that allows to selectively and reversibly inactivate LC neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADD). We show that the expression of the hM4Di DREADD can be restricted to noradrenergic LC neurons and that the amount of LC inhibition can be adjusted by adapting the dose of the specific DREADD activator deschloroclozapine (DCZ). Indeed, even if high doses (>0.3 mg/kg) induce a massive inhibition of LC neurons and a clear decrease in vigilance, smaller doses (<0.3 mg/kg) induce a more moderate decrease in LC activity, but it does not affect vigilance, which is more compatible with an assessment of subtle cognitive functions such as decision making and attention.
Highlights
The noradrenergic nucleus locus coeruleus (LC) plays a critical role in various behavioral and cognitive processes including vigilance, arousal, attention and decision making [1–3]
Even if understanding the specific action of NA on distinct receptors located across several brain regions can provide a clear insight into the mechanisms underlying LC functions, the global influence of LC activity remains difficult to extrapolate from a collection of diverse local effects
We have developed a method to reliably and reversibly inactivate LC neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADD)
Summary
The noradrenergic nucleus locus coeruleus (LC) plays a critical role in various behavioral and cognitive processes including vigilance, arousal, attention and decision making [1–3]. Even if single unit recording in behaving animals provided a critical insight into the role of the LC, key advances have been made using manipulations of the noradrenergic system. Reversible manipulations of LC activity and/or noradrenaline (NA) receptors occupation in target regions clearly provided some insight about the causal relation between LC/NA activity and functions such as vigilance, memory or attention [4–8]. Even if understanding the specific action of NA on distinct receptors located across several brain regions can provide a clear insight into the mechanisms underlying LC functions, the global influence of LC activity remains difficult to extrapolate from a collection of diverse local effects. To capture the function of the NA system, it is critical to understand the consequence of the global increase or decrease in LC activity, without any bias in terms of structure or receptor sub-type
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