Behavioral Effect of Chemogenetic Inhibition Is Directly Related to Receptor Transduction Levels in Rhesus Monkeys.

Area of Science:

• Neuroscience
• Cognitive Neuroscience
• Primate Research

Background:

• The dorsolateral prefrontal cortex (dlPFC) is crucial for working memory and executive functions.
• Impairments in dlPFC function are observed in neurodegenerative diseases and aging.
• Designer receptors exclusively activated by designer drugs (DREADDs) offer a method for targeted neuronal manipulation.

Purpose of the Study:

• To investigate the impact of inhibitory DREADD activation in the dlPFC on working memory in rhesus monkeys.
• To correlate the extent of DREADD transduction with observed behavioral deficits.
• To validate the use of DREADDs as a tool for studying neuronal function and disruption.

Main Methods:

• Inhibitory DREADDs (hM4Di) were delivered via viral vectors (rAAV5/hSyn-hM4Di-mCherry) to the dlPFC of male rhesus monkeys.
• Neuronal transduction was quantified using stereological analysis of mCherry-immunolabeled neurons.
• Working memory was assessed using a spatial delayed response task following administration of clozapine-N-oxide (CNO) or vehicle.

Main Results:

• CNO administration induced behavioral impairments in spatial working memory tasks only after DREADD transduction.
• A positive correlation was found between the percentage of DREADD-transduced neurons and the magnitude of behavioral deficits.
• Even approximately 3% neuronal transduction in the dlPFC was sufficient to cause significant behavioral disruption.

Conclusions:

• The extent of DREADD transduction directly influences the magnitude of behavioral impairment.
• Validation of DREADD transduction levels is critical for interpreting results and ensuring the reliability of DREADDs in neuroscience research.
• Targeted, even partial, neuronal silencing in distributed areas like the dlPFC can significantly impact cognitive functions such as working memory.