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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.
