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

Abstract

Background: 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. Methods: We applied a comprehensive profiling approach in adult male Tph2-/- 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. Results: In classical procedures, Tph2-/- rats presented an unexpected normal cognitive profile. Under the complex and experimenter-free conditions of their home-cage, the same Tph2-/- 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 Tph2-/- rats showed strong social disorganization with disrupted social networks and hierarchical structure, which may arise from communication deficits and cognitive blunting. Conclusions: 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.

Tryptophan Hydroxylase 2 Knockout Male Rats Exhibit a Strengthened Oxytocin System, Are Aggressive, and Are Less Anxious

“…As 5-HT regulates the aggression in both sexes, enhanced serotonergic activity could inhibit intermale aggression, while hindering 5-HT signaling will stimulate aggression. , 5-HT transporter knockout rats exhibit less aggression, more prosocial behaviors with a high sensitivity to social stimuli . In our case, Tph2 –/– rats had outburst aggressive behaviors almost immediately when housed together with another rat in a novel environment (data not shown), as reported Tph2 –/– rats have more dense social networks, a more unstable hierarchy, and normal social memory . Therefore, we propose that Tph2 –/– rats have a deficit in updating environmental information, leading to disrupted transmission of social information like hierarchy and social network.…”

“…9 In our case, Tph2 −/− rats had outburst aggressive behaviors almost immediately when housed together with another rat in a novel environment (data not shown), as reported Tph2 −/− rats have more dense social networks, a more unstable hierarchy, and normal social memory. 14 Therefore, we propose that Tph2 −/− rats have a deficit in updating environmental information, leading to disrupted transmission of social information like hierarchy and social network. At the same time, we noticed that Tph2 −/− rats spent more time on social contact with their assigned partner, but in an 'antisocial' manner with increased mounting behavior.…”

TPH2 knockout male rats are aggressive, show less anxiety, and exhibit an altered oxytocin system

“…Serotonin transporter knockout rats exhibit less aggression, more prosocial behaviors with a high sensitivity to social stimuli (Homberg & Lesch, 2011). In our case, Tph2 -/- rats had outburst aggressive behaviors almost immediately when housed together with another rat in a novel environment (Supplementary Fig1), as reported Tph2 -/- rats have more dense social networks, a more unstable hierarchy and normal social memory (Alonso et al, 2021). Therefore, we propose that Tph2 -/- rats have a deficit in updating environmental information, leading to disrupted transmission of social information like hierarchy and social network etc.…”

Is SARS-CoV-2 a Risk Factor of Bipolar Disorder?—A Narrative Review

“…These results may indicate serotonergic hyperactivity in the manic phase and hypoactivity in the depressive phase [ 239 ]. Studies in mice have also shown that serotonin deficiency causes aggressive and overly sexual behavior similar to that of patients in the manic phase [ 240 ].…”