Poor Decision Making and Sociability Impairment Following Central Serotonin Reduction in Inducible TPH2-Knockdown Rats

Author:

Alonso Lucille123,Peeva Polina4,Fernández-del Valle Alquicira Tania12,Erdelyi Narda1,Gil Nolskog Ángel2,Bader Michael2456,Winter York12ORCID,Alenina Natalia45ORCID,Rivalan Marion127ORCID

Affiliation:

1. Institut für Biologie, Humboldt-Universität zu Berlin, 10099 Berlin, Germany

2. Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany

3. Univ. Bordeaux, CNRS, IINS, UMR 5297, F-33000 Bordeaux, France

4. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany

5. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany

6. Institute for Biology, University of Lübeck, 23562 Lübeck, Germany

7. NeuroPSI—Paris-Saclay Institute of Neuroscience, CNRS—Université Paris-Saclay, F-91400 Saclay, France

Abstract

Serotonin is an essential neuromodulator for mental health and animals’ socio-cognitive abilities. However, we previously found that a constitutive depletion of central serotonin did not impair rat cognitive abilities in stand-alone tests. Here, we investigated how a mild and acute decrease in brain serotonin would affect rats’ cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knockdown of tryptophan hydroxylase 2 (TPH2), we achieved a 20% decrease in serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making, cognitive flexibility, and social recognition memory were tested in low-serotonin (Tph2-kd) and control rats. Our results showed that the Tph2-kd rats were more prone to choose disadvantageously in the long term (poor decision making) in the Rat Gambling Task and that only the low-serotonin poor decision makers were more sensitive to probabilistic discounting and had poorer social recognition memory than other low-serotonin and control individuals. Flexibility was unaffected by the acute brain serotonin reduction. Poor social recognition memory was the most central characteristic of the behavioral network of low-serotonin poor decision makers, suggesting a key role of social recognition in the expression of their profile. The acute decrease in brain serotonin appeared to specifically amplify the cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity the Tph2-kd rat model offers to study inter-individual susceptibilities to develop cognitive impairment following mild variations of brain serotonin in otherwise healthy individuals. These transgenic and differential approaches together could be critical for the identification of translational markers and vulnerabilities in the development of mental disorders.

Funder

Deutsche Forschungsgemeinschaft

Deutsche Forschungsgemeinschaft to the Center of Excellence NeuroCure DFGEXC 257

EU H2020 MSCA ITN projects ‘‘Serotonin and Beyond’’ to Natalia Alenina and Michael Bader

Publisher

MDPI AG

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