Multidimensional description of behavioural phenotypes: Role of serotonin in individual profiles of behaviour
Final Report Abstract
Considering a continuum between normality and pathology, a promising approach towards modelling human mental diseases is to study inter-individual differences and the spontaneous expression of maladapted behavior prior to the identification of their specific biological markers. In rats it has been shown, studying one function at a time, that hyposerotonergia can be responsible for poor decision-making, higher cognitive inflexibility, higher cognitive risk taking and a higher level of aggression, which are core symptoms of most psychiatric diseases. In line with the search for endophenotypes (heritable biological markers of neurocognitive traits) of mental and neurological disorders, we wanted to evaluate the role of hyposerotonergia in the concomitant expression of those behaviours so that individual rats presenting such poor multi-dimensional profile be better risk models for studying human mental and neurological disorders. First we established the behavioural profile of two genetically different strains of rats, on classical strain used in biomedical research, the Wistar Han (WH) and the Dark Agouti (DA) rats which are the background strain of transgenic rats used in the second part of the study. We showed that WH rats were indeed different from the strain of the DA rats at specific cognitive and social levels. We could recommend the use of the WH to model reward sensitivity and impulsivity and the DA strains to study compulsivity and anxiety-related behaviours. Interestingly rats with poor-decision-making abilities were comparable between strains and had similar socio-cognitive phenotypes. The conservation of this subpopulation of rats with extreme, poor behavioural profiles between strains confirmed their translational potential (between strains and species) and their suitability for the evaluation of the concomitant effects of a congenital lack of serotonin (A) or an acute decrease of brain serotonin (B) on the expression of their profile. Next, we evaluated the behavior profile in rats completely depleted of central serotonin due to the genetic deletion of the tryptophan hydroxylase 2 (TPH2), rate limiting enzyme of serotonin synthesis in the brain. Although serotonin is known to be a critical modulator of animal’s sociocognitive abilities, the cognitive and social abilities of TPH2-deficient rats were well preserved when tested outside their home cages in classical mazes. However, their social abilities and social network dynamics were impaired in natural and complex environment of tests, where the lack of central serotonin could have been compensated for. Next we investigated if a mild acute decrease in central serotonin would more realistically affect performances in decision-making, cognitive flexibility and social recognition memory using a novel rat model of inducible serotonin depletion, the TetO-shTph2 rats (tetO). And indeed, the acute decrease of central serotonin induced: poor-decision making normal motivation for reward, normal cognitive flexibility levels, risk aversion (probability) in poor decision makers (PDMs), normal social preference but delayed social recognition in PDMs. In this study, combining inter-individual, inter strain and dimensional approaches with the use of sophisticated transgenic rat models, we have contributed to the identification of a direct although complex and volatile link between hyposerotonergia and the concomitant expression of socio-cognitive deficits which is the core of psychiatric disorders.
Publications
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(2019) Interindividual and inter-strain differences in cognitive and social abilities of Dark Agouti and Wistar Han rats
Alonso L, Peeva P, Bader M, Winter Y, Alenina N, Rivalan M
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Targeted Manipulation of Brain Serotonin – RNAi-mediated Knockdown of Tryptophan hydroxylase 2 in the Rat. ACS Chemical Neuroscience. 2019
Matthes S, Mosienko V, Popova E, Rivalan M, Bader M, Alenina N
