Optofluidic control of rodent learning using cloaked caged glutamate.

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned place-preference protocol so as to mediate Pavlovian conditioning.

Interactions Between Odorants and Glutathione Transferases in the Human Olfactory Cleft.

Xenobiotic metabolizing enzymes and other proteins, including odorant-binding proteins located in the nasal epithelium and mucus, participate in a series of processes modulating the concentration of odorants in the environment of olfactory receptors (ORs) and finely impact odor perception. These enzymes and transporters are thought to participate in odorant degradation or transport. Odorant biotransformation results in 1) changes in the odorant quantity up to their clearance and the termination of signaling and 2) the formation of new odorant stimuli (metabolites). Enzymes, such as cytochrome P450 and glutathione transferases (GSTs), have been proposed to participate in odorant clearance in insects and mammals as odorant metabolizing enzymes. This study aims to explore the function of GSTs in human olfaction. Using immunohistochemical methods, GSTs were found to be localized in human tissues surrounding the olfactory epithelium. Then, the activity of 2 members of the GST family toward odorants was measured using heterologously expressed enzymes. The interactions/reactions with odorants were further characterized using a combination of enzymatic techniques. Furthermore, the structure of the complex between human GSTA1 and the glutathione conjugate of an odorant was determined by X-ray crystallography. Our results strongly suggest the role of human GSTs in the modulation of odorant availability to ORs in the peripheral olfactory process.

Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine.

Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self-administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.

Target Interneuron Preference in Thalamocortical Pathways Determines the Temporal Structure of Cortical Responses.

Sensory processing relies on fast detection of changes in environment, as well as integration of contextual cues over time. The mechanisms by which local circuits of the cerebral cortex simultaneously perform these opposite processes remain obscure. Thalamic "specific" nuclei relay sensory information, whereas "nonspecific" nuclei convey information on the environmental and behavioral contexts. We expressed channelrhodopsin in the ventrobasal specific (sensory) or the rhomboid nonspecific (contextual) thalamic nuclei. By selectively activating each thalamic pathway, we found that nonspecific inputs powerfully activate adapting (slow-responding) interneurons but weakly connect fast-spiking interneurons, whereas specific inputs exhibit opposite interneuron preference. Specific inputs thereby induce rapid feedforward inhibition that limits response duration, whereas, in the same cortical area, nonspecific inputs elicit delayed feedforward inhibition that enables lasting recurrent excitation. Using a mean field model, we confirm that cortical response dynamics depends on the type of interneuron targeted by thalamocortical inputs and show that efficient recruitment of adapting interneurons prolongs the cortical response and allows the summation of sensory and contextual inputs. Hence, target choice between slow- and fast-responding inhibitory neurons endows cortical networks with a simple computational solution to perform both sensory detection and integration.

Nasal odorant metabolism: enzymes, activity and function in olfaction.

The nasal tissues have the main consecutive roles of moistening and heating the air entering the respiratory tract and detecting odor via the activation of olfactory receptors in the neuro-olfactory epithelium. Initially, nasal toxicology was investigated to better assess the risk of nasal injuries caused by environmental toxicants or their active metabolites. Later, the characterization of the nasal toxicological barrier was a research concern for the purposes of intranasal drug delivery. Both fields allowed for an increase in our knowledge of the nasal xenobiotic-metabolizing enzymes and transporters that are highly expressed in this tissue. In addition to airborne toxicants or drugs, the main substrates for these proteins are natural volatiles known as odorants that emanate from our daily environment (food, perfume, plants, materials, congeners, etc.). Accordingly, another emerging field of interest has been developed that aims to understand the function of odorant-metabolizing enzymes (OMEs) in olfaction. Early in this field of research, OMEs were suspected to participate in the clearance of odorants from the receptor environment to avoid their saturation and thus maintain the sensitivity of neuronal detection. Other roles of OMEs that could significantly modulate olfaction were also considered, such as the involvement of odorant primary metabolites in the olfactory response. By combining enzymatic, physiological and sensory experimental approaches, recent advances have markedly improved our understanding of the contributions of OMEs to the olfactory process. This review combines recent data from the literature regarding nasal OME identification, localization, and activity and highlights the function of OMEs in olfaction.

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT2B-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT2B receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting in vivo properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to ex vivo dopamine neurons were found in mice lacking 5-HT2B receptors. These data support the idea that the chronic 5-HT2B-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αß(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

Odorant Metabolism Analysis by an Automated Ex Vivo Headspace Gas-Chromatography Method.

In the olfactory epithelium (OE), odorant metabolizing enzymes have the dual function of volatile component detoxification and active clearance of odorants from the perireceptor environment to respectively maintain the integrity of the tissues and the sensitivity of the detection. Although emphasized by recent studies, this enzymatic mechanism is poorly documented in mammals. Thus, olfactory metabolism has been characterized mainly in vitro and for a limited number of odorants. The automated ex vivo headspace gas-chromatography method that was developed here was validated to account for odorant olfactory metabolism. This method easily permits the measurement of the fate of an odorant in the OE environment, taking into account the odorant gaseous state and the cellular structure of the tissue, under experimental conditions close to physiological conditions and with a high reproducibility. We confirmed here our previous results showing that a high olfactory metabolizing activity of the mammary pheromone may be necessary to maintain a high level of sensitivity toward this molecule, which is critical for newborn rabbit survival. More generally, the method that is presented here may permit the screening of odorants metabolism alone or in mixture or studying the impact of aging, pathology, polymorphism or inhibitors on odorant metabolism.

Real-time monitoring of the metabolic capacity of ex vivo rat olfactory mucosa by proton transfer reaction mass spectrometry (PTR-MS).

Olfactory mucosa (OM) can metabolise odorant volatile organic compounds through various enzymatic mechanisms to produce odorous or non-odorous metabolites. Preliminary ex vivo studies using headspace-gas chromatography (HS-GC) revealed the formation of metabolites when odorant molecules were injected in the headspace above a fresh explant of rat olfactory mucosa. However, this method did not allow accessing the data during the first 5 min of contact between the odorant and the mucosa; thus limiting the olfactory biological significance. Using a direct-injection mass spectrometry technique with a proton transfer reaction instrument (PTR-MS), we have been able, for the first time, to investigate the first moments of the enzymatic process of the metabolic capacity of ex vivo rat olfactory mucosa in real time. Using ethyl acetate as a model volatile odorous substrate, we demonstrated here for the first time that this odorant could be metabolised by an ex vivo olfactory mucosa within seconds, producing ethanol as metabolite.

When the nose must remain responsive: glutathione conjugation of the mammary pheromone in the newborn rabbit.

In insects, xenobiotic-metabolizing enzymes were demonstrated to regulate pheromones inactivation, clearing them from the olfactory periphery and keeping receptors ready for stimulation renewal. Here, we investigate whether similar processes could occur in mammals, focusing on the pheromonal communication between female rabbits and their newborns. Lactating rabbits emit in their milk a volatile aldehyde, 2-methylbut-2-enal, that elicits searching-grasping in neonates; called the mammary pheromone (MP), it is critical for pups which are constrained to find nipples within the 5 min of daily nursing. For newborns, it is thus essential to remain sensitive to this odorant during the whole nursing period to display several actions of sucking. Here, we show that the MP is enzymatically conjugated to glutathione in newborn olfactory epithelium (OE), in accordance with the high mRNA expression of glutathione transferases evidenced by quantitative reverse transcription-PCR. This activity in the nose is higher than in the liver and in OE of newborns compared with weanlings (no more responsive to the pheromone). Therefore, the results pinpoint the existence of a high level of MP-glutathione conjugation activity in the OE of young rabbits, especially in the developmental window where the perceptual sensitivity toward the MP is crucial for survival.

Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine.

Nicotine is the primary psychoactive component of tobacco. Its reinforcing and addictive properties depend on nicotinic acetylcholine receptors (nAChRs) located within the mesolimbic axis originating in the ventral tegmental area (VTA). The roles and oligomeric assembly of subunit α4- and subunit α6-containing nAChRs in dopaminergic (DAergic) neurons are much debated. Using subunit-specific knockout mice and targeted lentiviral re-expression, we have determined the subunit dependence of intracranial nicotine self-administration (ICSA) into the VTA and the effects of nicotine on dopamine (DA) neuron excitability in the VTA and on DA transmission in the nucleus accumbens (NAc). We show that the α4 subunit, but not the α6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits α4 and α6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that α4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing α4 and α6 subunits, underlies nicotine self-administration and its long-term maintenance.

Threshold for anterior acetabular component overhang correlated with symptomatic iliopsoas impingement after total hip arthroplasty.

Aims: Mechanical impingement of the iliopsoas (IP) tendon accounts for 2% to 6% of persistent postoperative pain after total hip arthroplasty (THA). The most common initiator is anterior acetabular component protrusion, where the anterior margin is not covered by anterior acetabular wall. A CT scan can be used to identify and measure this overhang; however, no threshold exists for determining symptomatic anterior IP impingement due to overhang. A case-control study was conducted in which CT scan measurements were used to define a threshold that differentiates patients with IP impingement from asymptomatic patients after THA. Methods: We analyzed the CT scans of 622 patients (758 THAs) between May 2011 and May 2020. From this population, we identified 136 patients with symptoms suggestive of IP impingement. Among them, six were subsequently excluded: three because the diagnosis was refuted intraoperatively, and three because they had another obvious cause of impingement, leaving 130 hips (130 patients) in the study (impingement) group. They were matched to a control group of 138 asymptomatic hips (138 patients) after THA. The anterior acetabular component overhang was measured on an axial CT slice based on anatomical landmarks (orthogonal to the pelvic axis). Results: The impingement group had a median overhang of 8 mm (interquartile range (IQR) 5 to 11) versus 0 mm (IQR 0 to 4) for the control group (p < 0.001). Using receiver operating characteristic curves, an overhang threshold of 4 mm was best correlated with a diagnosis of impingement (sensitivity 79%, specificity 85%; positive predictive value 75%, negative predictive value 85%). Conclusion: Pain after THA related to IP impingement can be reasonably linked to acetabular overhang if it exceeds 4 mm on a CT scan. Below this threshold, it seems logical to look for another cause of IP irritation or another reason for the pain after THA before concluding that impingement is present.

Ultrasound-guided fasciotomy in forearm chronic exertional compartment syndrome: Preliminary results in 12 cases.

INTRODUCTION: Forearm chronic exertional compartment syndrome is a rare condition in athletes and musicians who perform repeated prolonged forced gripping movements. It mainly affects young men, and presents with cramp-like pain, beginning on the anteromedial side of the forearm and progressively extending to the entire circumference, and may be associated with muscle weakness and neurologic symptoms. The objective of this study was to report preliminary results of ultrasound-guided fasciotomy in the treatment of forearm chronic exertional compartment syndrome. MATERIAL AND METHODS: A single-center retrospective observational study was conducted. Forearm chronic exertional compartment syndrome was diagnosed on clinical presentation and pathological intramuscular pressure measurement, defined as >30 mmHg at 1 min after effort. The series comprised 7 men, with bilateral involvement. Mean age was 30 years. All patients were motorcyclists. The mean preoperative intramuscular pressure at 1 min after effort was 60.75 mmHg (range: 30-81 mmHg). The main study endpoint was change in pain on visual analogic scale. Secondary endpoints comprised patient satisfaction, change in competitive sports level, and time to return to sport. Complications were noted. RESULTS: Six patients (12 forearms) were evaluated. Mean follow-up was 22.5 months (range: 3-48 months). Mean pain rating was 7.3/10 (range: 6-9) preoperatively, and 0/10 postoperatively. All patients were satisfied with the procedure. Mean time to return to sports was 25.5 days (range: 21-30 days). No patients decreased their competitive sports level after the procedure. One patient presented a postoperative hematoma, not requiring surgery. CONCLUSION: Ultrasound-guided fasciotomy in the treatment of Forearm chronic exertional compartment syndrome is an innovative technique with promising preliminary results. LEVEL OF EVIDENCE: IV; retrospective cohort.

Correction: The odorant metabolizing enzyme UGT2A1: Immunolocalization and impact of the modulation of its activity on the olfactory response.

[This corrects the article DOI: 10.1371/journal.pone.0249029.].

Dopamine Neuron Activity and Stress Signaling as Links Between Social Hierarchy and Psychopathology Vulnerability.

BACKGROUND: Social status in humans, generally reflected by socioeconomic status, has been associated, when constrained, with heightened vulnerability to pathologies including psychiatric diseases. Social hierarchy in mice translates into individual and interdependent behavioral strategies of animals within a group. The rules leading to the emergence of a social organization are elusive, and detangling the contribution of social status from other factors, whether environmental or genetic, to normal and pathological behaviors remains challenging. METHODS: We investigated the mechanisms shaping the emergence of a social hierarchy in isogenic C57BL/6 mice raised in groups of 4 using conditional mutant mouse models and chemogenetic manipulation of dopamine midbrain neuronal activity. We further studied the evolution of behavioral traits and the vulnerability to psychopathological-like phenotypes according to the social status of the animals. RESULTS: Higher sociability predetermined higher social hierarchy in the colony. Upon hierarchy establishment, higher-ranked mice showed increased anxiety and better cognitive abilities in a working memory task. Strikingly, the higher-ranked mice displayed a reduced activity of dopaminergic neurons within the ventral tegmental area, paired with a decreased behavioral response to cocaine and a decreased vulnerability to depressive-like behaviors following repeated social defeats. The pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signaling in dopamine-sensing brain areas that resulted in decreased dopaminergic activity promoted accession to higher social ranks. CONCLUSIONS: Dopamine activity and its modulation by the stress response shapes social organization in mice, potentially linking interindividual and social status differences in vulnerability to psychopathologies.

Modulation of the mouse prefrontal cortex activation by neuronal nicotinic receptors during novelty exploration but not by exploration of a familiar environment.

Organization of locomotor behavior is altered in mice knockout for the ß2 subunit of the nicotinic receptor-ß2-/- mice-during novelty exploration. We investigated the neuronal basis of this alteration by measuring activation of the immediate early gene c-fos in the brains of wild-type (WT) and ß2-/- mice after exploration of a novel or a familiar environment. Results show 1) no constitutive difference between WT and ß2-/- mice in c-fos gene expression in any brain region, 2) novelty exploration triggered activation of the hippocampus and the reward circuit while exploration of a familiar environment produced increased activation in the amygdala, and 3) in ß2-/- mice, exploration of novelty, but not familiarity, induced an increase in activation in the prelimbic prefrontal cortex (PFC) compared with WT mice. c-Fos immunoreactivity after different stages of learning in a maze increased similarly in the prelimbic area of both WT and ß2-/- mice, while their performance differed. In WT mice, exploration of a novel environment triggered an increase in c-Fos expression in the reward circuit and the hippocampus, while in ß2-/- mice, the amygdala and the motor cortex were additionally activated. We also highlight the role of nicotinic receptors during activation of the PFC, specifically during free exploration of a novel environment.

Dopaminergic and prefrontal dynamics co-determine mouse decisions in a spatial gambling task.

The neural mechanisms by which animals initiate goal-directed actions, choose between options, or explore opportunities remain unknown. Here, we develop a spatial gambling task in which mice, to obtain intracranial self-stimulation rewards, self-determine the initiation, direction, vigor, and pace of their actions based on their knowledge of the outcomes. Using electrophysiological recordings, pharmacology, and optogenetics, we identify a sequence of oscillations and firings in the ventral tegmental area (VTA), orbitofrontal cortex (OFC), and prefrontal cortex (PFC) that co-encodes and co-determines self-initiation and choices. This sequence appeared with learning as an uncued realignment of spontaneous dynamics. Interactions between the structures varied with the reward context, particularly the uncertainty associated with the different options. We suggest that self-generated choices arise from a distributed circuit based on an OFC-VTA core determining whether to wait for or initiate actions, while the PFC is specifically engaged by reward uncertainty in action selection and pace.

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed considerable heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in nicotine consumption even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified ß4-containing nicotinic acetylcholine receptors of IPN neurons as molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate for individual variabilities and adaptations in nicotine consumption.

Ciprofibrate regulation of rat hepatic bilirubin glucuronidation and UDP-glucuronosyltransferases expression.

Synthetic fibrates are hypolipidemic drugs known to stimulate hepatic peroxisome proliferation and bilirubin glucuronidation. This study was designed to estimate the effects of ciprofibrate simultaneously on rat hepatic bilirubin glucuronoconjugation and on hepatic expression of UGT1A1, UGT1A2 and UGT1A5, all of which belong to the bilirubin cluster. Hepatic bilirubin glucuronidation activity and UDP-glucuronosyltransferase expression (RT-PCR and Western blotting) were measured after a single-dose ciprofibrate treatment (5 mg/kg by gastric intubation) in 36-h time course experiments. Ciprofibrate regulation of PPARα and UGT1A5 mRNA expression was also investigated in rat hepatocytes. Bilirubin conjugation activity was induced by ciprofibrate, reaching a maximum level (2.4×) 24 h after the treatment. UGT1A1 and UGT1A5 mRNA expression was induced 1.5 times by ciprofibrate, with UGT1A5 reaching the basal level of UGT1A1. Although UGT1A2 mRNA was induced approximately threefold by ciprofibrate, its expression level remained low in comparison with basal or induced levels of UGT1A1 and UGT1A5 mRNA. In the 36-h time course experiment, bilirubin conjugation activity as well as UGT1A5 and PPARα mRNA expression presented a biphasic induction profile. Although a similar level of induction was observed in primary cultured hepatocyte experiments, such biphasic variation was not observed for both UGT1A5 and PPARα, and the induction of UGT1A5 mRNA expression by ciprofibrate required de novo protein synthesis. A single dose of ciprofibrate significantly induces rat liver bilirubin conjugation as well as UGT1A1, UGT1A5 and PPARα expression. The induction mechanism may involve PPARα, at least regarding UGT1A5 regulation.

Social Determinants of Inter-Individual Variability and Vulnerability: The Role of Dopamine.

Individuals differ in their traits and preferences, which shape their interactions, their prospects for survival and their susceptibility to diseases. These correlations are well documented, yet the neurophysiological mechanisms underlying the emergence of distinct personalities and their relation to vulnerability to diseases are poorly understood. Social ties, in particular, are thought to be major modulators of personality traits and psychiatric vulnerability, yet the majority of neuroscience studies are performed on rodents in socially impoverished conditions. Rodent micro-society paradigms are therefore key experimental paradigms to understand how social life generates diversity by shaping individual traits. Dopamine circuitry is implicated at the interface between social life experiences, the expression of essential traits, and the emergence of pathologies, thus proving a possible mechanism to link these three concepts at a neuromodulatory level. Evaluating inter-individual variability in automated social testing environments shows great promise for improving our understanding of the link between social life, personality, and precision psychiatry - as well as elucidating the underlying neurophysiological mechanisms.