Partial chemogenetic inhibition of the locus coeruleus due to heterogeneous transduction of noradrenergic neurons preserved auditory salience processing in wild‐type rats.

The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2‐adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus‐transduced rats. The canine adenovirus type 2 (CAV2)–based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell–specific promoter (PRSx8) had high cell‐type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH‐positive LC neurons (range: 9.2–94.4%). Clozapine‐N‐oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di‐expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case‐based immunohistochemistry revealed that virus injections distal (> 150 μm) to the LC core resulted in partial LC transduction, while proximal (< 50 μm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus‐transduced rats. Our results suggest that a residual activity of virus‐non‐transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case‐based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)