Constitutive depletion of brain serotonin differentially affects rats' social and cognitive abilities

<strong>Background</strong> Central serotonin is an essential neuromodulator for mental disorders. It appears a promising transdiagnostic marker of distinct psychiatric disorders and a common modulator of some of their key behavioral symptoms. We aimed to identify the behavioral markers of serotonergic function in rats and compare them to human deficits. <strong>Methods</strong> We applied a comprehensive profiling approach in adult male <em>Tph2^−/−</em> rats constitutively lacking central serotonin. Under classical and ethological testing conditions, we tested each individual’s cognitive, social and non-social abilities and characterized the group organization (i.e. social network, hierarchy). Using unsupervised machine learning, we identified the functions most dependent on central serotonin. <strong>Results</strong> In classical procedures, <em>Tph2^−/−</em> rats presented an unexpected normal cognitive profile. Under the complex and experimenter-free conditions of their home-cage, the same <em>Tph2^−/−</em> rats presented drastic changes in their daily life. Brain serotonin depletion induced compulsive aggression and sexual behavior, hyperactive and hypervigilant stereotyped behavior, reduced self-care and body weight, and exacerbated corticosterone levels. Group-housed <em>Tph2^−/−</em> rats showed strong social disorganization with disrupted social networks and hierarchical structure, which may arise from communication deficits and cognitive blunting. <strong>Conclusions</strong> Serotonin depletion induced a profile reminiscent of the symptomatology of impulse control and anxiety disorders. Serotonin was necessary for behavioral adaptation to dynamic social environments. In classical testing conditions, our animal model challenged the concept of an essential role of serotonin in decision-making, flexibility, and impulsivity, although developmental compensations may have occurred. These contrasting findings highlight the need to generalize the evaluation of animal models’ multidimensional functions within the complexity of the social living environment.