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Preserved auditory salience processing after chemogenetic inhibition of the locus coeruleus noradrenergic neurons in wild-type rats
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  • Anna Kabanova,
  • Mingyu Yang,
  • Nikos Logothetis,
  • Oxana Eschenko
Anna Kabanova
Max-Planck-Institute for Biological Cybernetics
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Mingyu Yang
Max-Planck-Institute for Biological Cybernetics
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Nikos Logothetis
Max-Planck-Institute for Biological Cybernetics
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Oxana Eschenko
Max-Planck-Institute for Biological Cybernetics

Corresponding Author:oxana.eschenko@tuebingen.mpg.de

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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.
27 Oct 2023Submitted to European Journal of Neuroscience
27 Oct 2023Submission Checks Completed
27 Oct 2023Assigned to Editor
28 Oct 2023Review(s) Completed, Editorial Evaluation Pending
13 Mar 20241st Revision Received
18 Mar 2024Submission Checks Completed
18 Mar 2024Assigned to Editor
31 Jul 20242nd Revision Received
02 Aug 2024Submission Checks Completed
02 Aug 2024Review(s) Completed, Editorial Evaluation Pending
02 Aug 2024Assigned to Editor
02 Aug 2024Reviewer(s) Assigned
28 Aug 2024Editorial Decision: Revise Major
29 Aug 20243rd Revision Received
30 Aug 2024Submission Checks Completed
30 Aug 2024Assigned to Editor
30 Aug 2024Review(s) Completed, Editorial Evaluation Pending
30 Aug 2024Reviewer(s) Assigned
09 Sep 2024Editorial Decision: Accept