Preserved auditory salience processing after chemogenetic inhibition of
the locus coeruleus noradrenergic neurons in wild-type rats
Abstract
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. In the present study, we
compared the effects of chemogenetic and pharmacological suppression of
noradrenergic transmission on the ASR and PPI in wild-type adult male
rats. Clonidine (0.05 mg/kg, i.p.), an alpha2-adrenoreceptor agonist,
strongly reduced the ASR amplitude. We confirmed a high cell-type
specificity (94.4 ± 3.1%) of the canine adenovirus type 2 (CAV2)-based
vector carrying a gene cassette for expression of inhibitory designer
receptors (hM4Di) and noradrenergic cell-specific promoter (PRSx8).
Clozapine-N-Oxide (CNO; 1 mg/kg, i.p), a hM4Di actuator, caused the
firing cessation of hM4Di-expressing LC neurons but did not affect the
ASR. A case-based immunohistochemistry revealed heterogeneous virus
transduction of DbH-positive LC neurons (range: 9.2 – 94.4%). The
virus injections distal (> 150µm) to the LC core resulted
in partial LC transduction, while proximal (< 50µm) injections
caused neuronal loss due to virus neurotoxicity. Overall, complete
inhibition of the entire population of LC neurons was rarely achieved;
therefore, the activity of virus-unaffected LC neurons might have been
sufficient for mediating an unaltered behavioral response to startling
sounds. Our results highlight the importance of a case-based assessment
of the efficiency of virus transduction for targeted cell populations
and consider it when interpreting behavioral effects in experiments
employing chemogenetic modulation.