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other·neurology, psychiatry, preclinical research, biomedical research·PMC10046559

Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission

Biomolecules · 12 authors, 6 centres

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TL;DR

The central result was that NE-depleted mice showed altered anxiety-, depression-, and cognition-like behaviors, along with changes in sleep patterns, but only when the system was challenged, pointing to NE's role in stress modulation.

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The authors conclude that the NE system is largely constitutively silent and primarily functions during stress. Limitations include the potential for developmental compensatory mechanisms in the knockout model and the inability to distinguish the effects of modularity within NE circuits.

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other

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neurology

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ORIGINAL PAPER

PMC10046559

Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission

Biomolecules

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ABSTRACT

Abstract Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease. Keywords: noradrenaline, depression, anxiety, cocaine sensitization, circadian rhythms, sleep, SV2c

CITATION EXPORT

Elsa Isingrini, Chloé Guinaudie, Léa Perret et al.. Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission. Biomolecules. (2023). https://doi.org/10.3390/biom13030511

AUTHORS

12 · 6 CENTRES

Elsa Isingrini, Chloé Guinaudie, Léa Perret, Elisa Guma, Victor Gorgievski, Ian D Blum, Jessica Colby-Milley, Maryia Bairachnaya, Sébastien Mella, Antoine Adamantidis, Kai-Florian Storch, Bruno Giros

1Department of Psychiatry, Douglas Hospital, Mc Gill University, Montreal, QC H4H 1R3, Canada
2Faculté des Sciences Fondamentales et Biomédicales, Université Paris Cité, INCC UMR 8002, CNRS, F-75006 Paris, France
3Cytometry and Biomarkers Platform, Unit of Technology and Service, Institut Pasteur, Université de Paris, F-75015 Paris, France
4Bioinformatics and Biostatistics Hub Platform, Institut Pasteur, Université de Paris, F-75015 Paris, France
5Zentrum für Experimentelle Neurologie, Department of Neurology, Inselspital University Hospital Bern, 3010 Bern, Switzerland
6Department of Biomedical Research, University of Bern, 3008 Bern, Switzerland