Serotonin drives aggression and social behaviors of laboratory male mice in a semi-natural environment.

Aggression is an adaptive social behavior crucial for the stability and prosperity of social groups. When uncontrolled, aggression leads to pathological violence that disrupts group structure and individual wellbeing. The comorbidity of uncontrolled aggression across different psychopathologies makes it a potential endophenotype of mental disorders with the same neurobiological substrates. Serotonin plays a critical role in regulating impulsive and aggressive behaviors. Mice lacking in brain serotonin, due to the ablation of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in serotonin synthesis, could serve as a potential model for studying pathological aggression. Home cage monitoring allows for the continuous observation and quantification of social and non-social behaviors in group-housed, freely-moving mice. Using an ethological approach, we investigated the impact of central serotonin ablation on the everyday expression of social and non-social behaviors and their correlations in undisturbed, group-living Tph2-deficient and wildtype mice. By training a machine learning algorithm on behavioral time series, "allogrooming", "struggling at feeder", and "eating" emerged as key behaviors dissociating one genotype from the other. Although Tph2-deficient mice exhibited characteristics of pathological aggression and reduced communication compared to wildtype animals, they still demonstrated affiliative huddle behaviors to normal levels. Altogether, such a distinct and dynamic phenotype of Tph2-deficient mice influenced the group's structure and the subsequent development of its hierarchical organization. These aspects were analyzed using social network analysis and the Glicko rating methods. This study demonstrates the importance of the ethological approach for understanding the global impact of pathological aggression on various aspects of life, both at the individual and group levels. Home cage monitoring allows the observation of the natural behaviors of mice in a semi-natural habitat, providing an accurate representation of real-world phenomena and pathological mechanisms. The results of this study provide insights into the neurobiological substrate of pathological aggression and its potential role in complex brain disorders.

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

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.

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

Central serotonin appears a promising transdiagnostic marker of psychiatric disorders and a modulator of some of their key behavioral symptoms. In adult male Tph2 -/- rats, constitutively lacking central serotonin, we tested individual's cognitive, social and non-social abilities and characterized group's social organization under classical and ethological testing conditions. Using unsupervised machine learning, we identified the functions most dependent on serotonin. Although serotonin depletion did not affect cognitive performances in classical testing, in the home-cage it induced compulsive aggression and sexual behavior, hyperactive and hypervigilant stereotyped behavior, reduced self-care and exacerbated corticosterone levels. This profile recalled symptoms of impulse control and anxiety disorders. Serotonin appeared essential for behavioral adaptation to dynamic social environments. Our animal model challenges the essential role of serotonin in decision-making, flexibility, impulsivity, and risk-taking. These findings highlight the importance of studying everyday life functions within the dynamic social living environment to model complexity in animal models.

A Comparative Study of the Physiological and Socio-Economic Vulnerabilities to Heat Waves of the Population of the Metropolis of Lyon (France) in a Climate Change Context.

Increases in the frequency and intensity of heat waves are direct consequences of global climate change with a higher risk for urban populations due to the urban heat island effect. Reducing urban overheating is a priority, as is identifying the most vulnerable people to establish targeted and coordinated public health policies. There are many ways of understanding the concept of vulnerability and multiple definitions and applications exist in the literature. To date, however, nothing has been done on the territory of this study, the metropolis of Lyon (France). The objective is thus to construct two vulnerability indices: physiological, focusing on the organism's capacities to respond to heat waves; and socio-economic, based on the social and economic characteristics and capacities of the community. To this end, two complementary methodologies have been implemented: the AHP (Analytic Hierarchy Process) and the PCA (Principal Component Analysis) with Varimax rotation, respectively. The results were then spatialized to the smallest demographic census unit in France. The areas highlighted differed due to conceptual and methodological differences: the highest physiological vulnerabilities are in the center while the socio-economic ones are in the eastern periphery of the urban area. The location of these areas will enable prevention campaigns to be carried out, targeted according to the publics concerned.

Inter-individual and inter-strain differences in cognitive and social abilities of Dark Agouti and Wistar Han rats.

Healthy animals displaying extreme behaviours that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Using a Rat Gambling Task, healthy individuals spontaneously making poor decisions (PDMs) were found to co-express a combination of other cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in Dark Agouti (DA) and Wistar Han (WH) rats, 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to extract key discriminative traits between DA and WH strains, relevant for biomedical research. We have compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats at the strain and at the individual level. Here we found that the naturally occurring PDM's profile was consistent between both rat lines. Then, although the PDM individuals did not take more risks in probability discounting task, they seemed to be of higher social ranks. Finally and despite their similarities in performance, WH and DA lines differed in degree of reward sensitivity, impulsivity, locomotor activity and open space-occupation. The reproducibility and conservation of the complex phenotypes of PDMs and GDMs (good decision makers) in these two genetically different strains support their translational potential. Both strains, present large phenotypic variation in behaviours pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.

Habenular CB1 Receptors Control the Expression of Aversive Memories.

Expression of aversive memories is key for survival, but the underlying brain mechanisms are not fully understood. Medial habenular (MHb) axons corelease glutamate and acetylcholine onto target postsynaptic interpeduncular (IPN) neurons, but their role in aversive memories has not been addressed so far. We found that cannabinoid type 1 receptors (CB1R), key regulators of aversive responses, are present at presynaptic terminals of MHb neurons in the IPN. Conditional deletion of CB1R from MHb neurons reduces fear-conditioned freezing and abolishes conditioned odor aversion in mice, without affecting neutral or appetitively motivated memories. Interestingly, local inhibition of nicotinic, but not glutamatergic receptors in the target region IPN before retrieval, rescues these phenotypes. Finally, optogenetic electrophysiological recordings of MHb-to-IPN circuitry revealed that blockade of CB1R specifically enhances cholinergic, but not glutamatergic, neurotransmission. Thus, presynaptic CB1R control expression of aversive memories by selectively modulating cholinergic transmission at MHb synapses in the IPN.