Biology subjects

Rivalan, M.

Publications and source records attributed to Rivalan, M..

9 recordsLinked to original sources

bioRxiv2024

Serotonin drives aggression and social behaviours of laboratory mice in a semi-natural environment

Aggression is an adaptive social behaviour crucial for the stability and prosperity of social groups. When uncontrolled, aggression leads to pathological violence that disrupts group structure and individual well-being. 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 the regulation of impulsive and aggressive behaviours, and mice lacking brain serotonin, due to the ablation of a rate-limiting enzyme of serotonin synthesis (Tryptophan hydroxylase 2, TPH2), are a potential model of pathological aggression. Home cage monitoring allows for the continuous observation and quantification of social and non-social behaviours in group-housed, freely-moving mice. Using an ethological approach, we investigated the impact of central serotonin ablation on everyday expression of social and non-social behaviours and their correlations in undisturbed, group-living Tph2-deficient and wildtype mice. By training a machine learning algorithm on behavioural time series, "allogrooming", "struggling at feeder" and "eating" emerged as key behaviours dissociating one genotype from the other. Although Tph2-deficient mice showed characteristics of pathological aggression and decreased communication compared to wildtype animals they still showed affiliative behaviours to normal levels. Altogether, such distinct and dynamic phenotype of Tph2-deficient mice influenced the groups structure and the dynamic of its hierarchical organization which emerged later. 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 different aspects of life both at the individual and the group level. Home cage monitoring allows the observation of the natural behaviours of the mice in a semi-natural habitat and provides 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 their potential role in complex brain disorders.

neuroscience↗

bioRxiv2024

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 of brain serotonin would affect rats cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knock-down of tryptophan hydroxylase 2 (TPH2), we achieved 20% decrease of serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making in the Rat Gambling Task and the Probability Discounting Task, 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 on the long term (poor decision making) 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 expression of their profile. The acute decrease of brain serotonin appeared to specifically amplify cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity 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.

neuroscience↗

bioRxiv2023

Binge Feeding Promotes Appetite via Modulating Olfactory Flavor Representation

Binge eating commonly leads to overeating, but the exact mechanism is unclear. While it is known that experiencing flavor contributes to satiety, the interactions between flavor, feeding rate, and food intake remain unknown. Here, we demonstrate a novel feeding rate-dependent feedback loop between olfactory flavor representation in the anterior olfactory (piriform) cortex (aPC) and food intake. Using miniscopes for in vivo calcium imaging in freely foraging mice, we identified specific excitatory neuronal responses to food and water during slow feeding. Switching to binge feeding transformed these specific responses into unspecific global suppression of neuronal activity. Food consumption was predicted by the degree of suppression of neuronal activity in the aPC during binge feeding. Also, food deprivation enhanced neuronal activity suppression. We confirmed the hypothesis that aPC suppression promotes food intake with closed-loop optogenetics experiments. Together, we show that olfactory sensory representation in the aPC reciprocally interacts with consummatory behavior to enhance food intake.

neuroscience↗

bioRxiv2023

Development and Application of Home Cage Monitoring in Laboratory Mice and Rats: a Systematic Review

Traditionally, in biomedical animal research, laboratory rodents are individually examined in test apparatuses outside their home cages at selected time points. However, the outcome of such tests can be influenced by the novel environment, the time of day, separation from the social group, or the presence of an experimenter. Moreover, valuable information may be missed when the animals are only monitored in short periods. These issues can be overcome by longitudinal monitoring mice and rats in their home cages. To shed light on the development of home cage monitoring (HCM) and the current state of the art, a systematic review was carried out on 521 publications retrieved through PubMed and Web of Science. Both the absolute ([~] x26) and relative ([~] x7) number of HCM-related publications increased from 1974 to 2020. In both mice and rats, there was a clear bias towards males and individually housed animals, but during the past decade (2011-2020), an increasing number of studies used both sexes and group housing. More than 70 % of the studies did not involve a disease model, but the percentage of studies using disease models increased since the 2000s. In most studies, animals were kept for short (up to 4 weeks) length periods in the HCM systems; intermediate length periods (4-12 weeks) increased in frequency in the years between 2011 and 2020. Before the 2000s, HCM techniques were predominantly applied for less than 12 hours, while 24-hour measurements have been more frequently since the 2000s. The systematic review demonstrated that manual monitoring is decreasing but still relevant. Until (and including) the 1990s, most techniques were applied manually but have been progressively replaced by automation since the 2000s. Independent of the publication year, the main behavioral parameters measured were locomotor activity, feeding, and social behaviors; the main physiological parameters were heart rate and electrocardiography. External appearance-related parameters were rarely examined in the home cages. Due to technological progress and application of artificial intelligence, more refined and detailed behavioral parameters could be investigated in the home cage in recent times. Over the period covered in this study, techniques for HCM of mice and rats has improved considerably. This development is ongoing and further progress and validation of HCM systems will extend the applications to allow for continuous, longitudinal, non-invasive monitoring of an increasing range of parameters in group-housed small rodents in their home cages.

animal behavior and cognition↗

bioRxiv2021

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

BackgroundCentral 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. MethodsWe applied a comprehensive profiling approach in adult male Tph2-/- rats constitutively lacking central serotonin. Under classical and ethological testing conditions, we tested each individuals 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. ResultsIn 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. ConclusionsSerotonin 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.

animal behavior and cognition↗

bioRxiv2020

A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions.

Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency (GPIBD). Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol (GPI) anchor pathway exhibit cognitive impairments, motor delay, and often epilepsy. Thus far, the pathophysiology underlying the disease remains unclear, and suitable rodent models that mirror all symptoms observed in human patients have not been available. Therefore, we used CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, Pigv:c.1022C>A (p.A341E), at a site that is conserved in mice. Mirroring the human pathology, mutant Pigv341E mice exhibited deficits in motor coordination, cognitive impairments, and alterations in sociability and sleep patterns, as well as increased seizure susceptibility. Furthermore, immunohistochemistry revealed reduced synaptophysin immunoreactivity in Pigv341E mice, and electrophysiology recordings showed decreased hippocampal synaptic transmission that could underlie impaired memory formation. In single-cell RNA sequencing, Pigv341E-hippocampal cells exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction in Abl1 transcript levels in several cell clusters suggested a link to the signaling pathway of GPI-anchored ephrins. We also observed elevated levels of Hdc transcripts, which might affect histamine metabolism with consequences for circadian rhythm. This new mouse model will not only open the doors to further investigation into the pathophysiology of GPIBD, but will also deepen our understanding of the role of GPI-anchor-related pathways in brain development. Significance statementInherited GPI-anchor biosynthesis deficiencies (IGDs) explain many cases of syndromic intellectual disability. Although diagnostic methods are improving, the pathophysiology underlying the disease remains unclear. Furthermore, we lack rodent models suitable for characterizing cognitive and social disabilities. To address this issue, we generated the first viable mouse model for an IGD that mirrors the condition in human patients with a behavioral phenotype and susceptibility to epilepsy. Using the new model, we obtained neurological insights such as deficits in synaptic transmission that will facilitate understanding of the pathophysiology of IGDs.

neuroscience↗

bioRxiv2020

Two-dimensional reward evaluation in mice

When choosing among multi-attribute options, integrating the full information may be computationally costly and time-consuming. So-called non-compensatory decision rules only rely on partial information, for example when a difference on a single attribute overrides all others. Such rules may be ecologically more advantageous, despite being economically suboptimal. Here we present a study that investigates to what extent animals rely on integrative rules (using the full information) versus non-compensatory rules when choosing where to forage. Groups of mice were trained to obtain water from dispensers varying along two reward dimensions: volume and probability. The mices choices over the course of the experiment suggested an initial reliance on integrative rules, later displaced by a sequential rule, in which volume was evaluated before probability. Our results also demonstrate that while the evaluation of probability differences may depend on the reward volumes, the evaluation of volume differences is seemingly unaffected by the reward probabilities.

animal behavior and cognition↗

bioRxiv2019

Loss of Piccolo function in rats induces Pontocerebellar Hypoplasia type 3-like phenotypes

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3), although a causal relationship is lacking. We have characterized recently generated knockout (Pclogt/gt) rats. Analysis revealed a dramatic reduction in brain size compared to wildtype (Pclowt/wt) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell (GC) layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber (MF) afferents from pontine neurons and the expression of the 6 GABAA receptor subunit at the MF-GC synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers (CFs). Ultrastructural and functional studies revealed a reduced size of MF boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together these data suggest that loss of Piccolo function in patients with PCH3 could be causal for many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder.\n\nSignificance StatementPontocerebellar Hypoplasia type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the Piccolo gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo knockout rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with PCH3 are also exhibited by these Piccolo deficient animals.

neuroscience↗

bioRxiv2019

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

BackgroundHealthy animals showing extreme behaviours spontaneously that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Healthy poor decision makers (PDMs) identified using a Rat Gambling Task, co-express a combination of 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 the Dark Agouti (DA) and Wistar Han (WH), 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to discuss how the key traits of each strain could be relevant for biomedical research.\n\nMethodsWe compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats using several tests. We analysed the results at the strain and the individual level.\n\nResultsPrevious findings in WH rats were reproduced and could be generalized to DA. Each PDM of either strain displayed a similar, naturally occurring, combination of behavioural traits, including possibly higher social rank, but no deficits in probability-based decision-making. A Random forest analysis revealed interesting discriminating traits between WH and DA.\n\nConclusionThe reproducibility and conservation of the socio-cognitive and behavioural phenotypes of GDM (good decision maker) and PDM individuals in the two genetically different strains of WH and DA support a good translational validity of these phenotypes. Both DA and WH rat strains present large phenotypic variations in behaviour pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.

animal behavior and cognition↗