Using Inhibitory DREADDs to Silence LC Neurons in Monkeys.

Brain Sci

Motivation, Brain and Behavior Team, Institut du Cerveau (ICM), INSERM UMRS 1127, CNRS UMR 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France.

Published: January 2022

AI Article Synopsis

  • Understanding the role of the locus coeruleus (LC) is important for studying behaviors like stress and vigilance, and cognitive processes like attention and decision making.
  • Recent advancements in viral tools have improved our ability to study brain functions in rodents, but similar tools for primate research, especially in monkeys, are necessary for effective translational applications.
  • The described pharmacogenetics approach using DREADD allows for selective and adjustable inactivation of LC neurons, enabling researchers to explore varying effects on cognitive functions and vigilance by modifying dosages of the DREADD activator, deschloroclozapine (DCZ).

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869890PMC
http://dx.doi.org/10.3390/brainsci12020206DOI Listing

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