Mice exhibit stochastic and efficient action switching during probabilistic decision making.

In probabilistic and nonstationary environments, individuals must use internal and external cues to flexibly make decisions that lead to desirable outcomes. To gain insight into the process by which animals choose between actions, we trained mice in a task with time-varying reward probabilities. In our implementation of such a two-armed bandit task, thirsty mice use information about recent action and action­outcome histories to choose between two ports that deliver water probabilistically. Here we comprehensively modeled choice behavior in this task, including the trial-to-trial changes in port selection, i.e., action switching behavior. We find that mouse behavior is, at times, deterministic and, at others, apparently stochastic. The behavior deviates from that of a theoretically optimal agent performing Bayesian inference in a hidden Markov model (HMM). We formulate a set of models based on logistic regression, reinforcement learning, and sticky Bayesian inference that we demonstrate are mathematically equivalent and that accurately describe mouse behavior. The switching behavior of mice in the task is captured in each model by a stochastic action policy, a history-dependent representation of action value, and a tendency to repeat actions despite incoming evidence. The models parsimoniously capture behavior across different environmental conditionals by varying the stickiness parameter, and like the mice, they achieve nearly maximal reward rates. These results indicate that mouse behavior reaches near-maximal performance with reduced action switching and can be described by a set of equivalent models with a small number of relatively fixed parameters.

NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice.

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1-/-Neil2-/- mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1-/-Neil2-/- mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

Individual history of winning and hierarchy landscape influence stress susceptibility in mice.

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, although gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

Chronic pain produces hypervigilance to predator odor in mice.

The adaptive significance of acute pain (to withdraw from tissue-damaging or potentially tissue-damaging external stimuli, and to enhance the salience of the stimulus resulting in escape and avoidance learning) and tonic pain (to enforce recuperation by punishing movement) are well-accepted [1]. Pain researchers, however, generally assert that chronic pain has no adaptive significance, representing instead a pathophysiological state. This belief was recently challenged by the observation [2] that nociceptive sensitization caused by a chronic pain-producing injury reduced predation risk in squid (Doryteuthis pealeii). In that study, injury to an arm (removal of the tip with a scalpel) 6 hours prior led to increased targeting by black sea bass, resulting in decreased survival of the squid in a 30-minute trial featuring free interaction between predator and prey. The surprising finding was that anesthesia during surgery, preventing the chronic nociceptor sensitization associated with such injuries, led to even lower probability of survival. That is, the likely presence of pain increased apparent fitness, and the authors concluded that the chronic pain state and its associated nociceptive sensitization represented an adaptive function. Pain-induced defensive behaviors affecting fitness have also been reported in crustaceans (Gammarus fossarum) [3]. It is, however, currently unknown whether this may also be true in any other species, including in Mammalia.

Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice.

Nest building is an innate behavior in male and female rodents, even when raised in laboratory settings. As such, many researchers provide rodents synthetic and/or natural materials (such as twine, tissue, cotton, paper, and hay) as a gauge of their overall well-being and as an ancillary assessment to predict the possible decline in cognition. Typically, changes in nesting behaviors, such as failure to create a nest, indicate a change in health or welfare. In addition, nesting behavior is sensitive to many environmental and physiological challenges, as well as many genetic mutations underlying pathological disease states. The following protocol describes a nesting behavior paradigm that explores the usage of four types of nesting material. In addition, the protocol utilizes intraclass correlations to demonstrate that inter-rater reliability is higher when nests are constructed out of shredded paper compared to other common nesting materials such as cotton squares, paper twists, and soft cob bedding. The chosen methodology and statistical considerations (i.e., intraclass correlation) for this assay may be of interest for those conducting experiments assessing the quality of living of mice.

Assessment of Mouse Handling Techniques During Cage Changing.

Mouse handling during cage changing and health evaluation has traditionally been performed by using forceps. This method was adopted as a biosecurity measure but can adversely affect employee ergonomics and rodent behavior. In this study, we evaluated alternative methods of rodent handling and their potential implications for efficiency, biosecurity, and animal welfare. Study groups included plastic cups, gloved hands, 2 methods of tunnel handling, and forceps. Evaluations included speed of cage change, ATP-based assessment of sanitization, and retrospective analysis of colony health and breeding data. The time to change 14 cages was significantly faster at each time point for the gloved hands and forceps groups as compared with the other methods. Overall speed did not increase significantly with each subsequent study week for any group. ATP levels after sanitization with hydrogen peroxide-peracetic acid mixture differed significantly between gloves and forceps. When ATP level was evaluated on a per-cm² basis, no significant difference between gloves and forceps was detected. Although tunnel and cup handling both increased the time for cage-changing, the tunnel served as both an indirect handling method and a shelter when left within the cage. Retrospective analysis revealed that breeding performance and colony health were similar among groups. Although efficiency is a concern for large-scale implementation of novel handling methods, the tunnel method may prove beneficial for sensitive strains or studies requiring indirect handling. In addition, using gloved hands to directly handle mice during cage changing is efficient and avoids the ergonomic strain associated with forceps. Precautions should be taken when handling mice with gloves, given that the increased contact area carries an increased load of organic debris. Changing gloves between rack sides or before proceeding to the animals belonging to a different investigator minimizes the potential for cross-contamination.

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice.

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions.

Real-time analysis of the behaviour of groups of mice via a depth-sensing camera and machine learning.

Preclinical studies of psychiatric disorders use animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we introduce a method for the real-time analysis of the behaviour of mice housed in groups of up to four over several days and in enriched environments. The method combines computer vision through a depth-sensing infrared camera, machine learning for animal and posture identification, and radio-frequency identification to monitor the quality of mouse tracking. It tracks multiple mice accurately, extracts a list of behavioural traits of both individuals and the groups of mice, and provides a phenotypic profile for each animal. We used the method to study the impact of Shank2 and Shank3 gene mutations-mutations that are associated with autism-on mouse behaviour. Characterization and integration of data from the behavioural profiles of Shank2 and Shank3 mutant female mice revealed their distinctive activity levels and involvement in complex social interactions.

Social hierarchy position in female mice is associated with plasma corticosterone levels and hypothalamic gene expression.

Social hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly higher levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERß and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.

Feeding behaviour, risk-sensitivity and response control: effects of 5-HT2C receptor manipulations.

People, like animals, tend to choose the variable option when given the choice between a fixed and variable delay to reward where, in the variable delay condition, some rewards are available immediately (Laura-Jean et al. 2019 Phil. Trans. R. Soc. B 374, 20180141. ( doi:10.1098/rstb.2018.0141 )). This bias has been suggested to reflect evolutionary pressures resulting from food scarcity in the past placing a premium on obtaining food quickly that can win out against the risks of sometimes sustaining longer delays to food. The psychologies mediating this effect may become maladaptive in the developed world where food is readily available contributing, potentially, to overeating and obesity. Here, we report our development of a novel touchscreen task in mice allowing comparisons of the impact of food delay and food magnitude across species. We show that mice exhibit the typical preference, as shown by humans, for variable over fixed delays to rewards but no preference when it comes to fixed versus variable reward amounts and further show that this bias is sensitive to manipulations of the 5-HT2C receptor, a key mediator of feeding and impulse control. We discuss the data in terms of the utility of the task to model the psychologies and underlying brain mechanisms impacting on feeding behaviours. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

Characterization of behavioral phenotypes in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system.

The BTBR T+ Itpr3tf/J (BTBR) mouse strain is a widely used model of autism spectrum disorder (ASD). The BTBR mice display behavior consistent with the three diagnostic categories of ASD. However, the behavioral phenotypes of the BTBR mice in a long-term group housing setting are largely unknown because conventional behavioral tests for ASD model mice are designed for use under simplified artificial conditions over a short observation period. In this study, we applied a newly developed assay system, the Multiple Animal Positioning System (MAPS), to quantify behaviors under group housing conditions over four days of continuous observation. Using MAPS, we showed that in a group housing condition, the BTBR mice exhibited lower activity levels in the dark phase and alteration of social behavior in comparison with the C57BL/6J mice. The phenotypes of the BTBR mice were affected by co-housing with the C57BL/6J mice for four days, but the influence was weak and limited. Our results by MAPS differ from those obtained using conventional behavioral tests. The present study demonstrated that MAPS would be useful for evaluating the usual/natural behaviors of various animal models in detail and under more ethological conditions.

Fitness Consequences of Female Alternative Reproductive Tactics in House Mice (Mus musculus domesticus).

Alternative reproductive tactics (ARTs) are defined as discrete differences in morphological, physiological, and/or behavioral traits associated with reproduction that occur within the same sex and population. House mice provide a rare example of ARTs in females, which can rear their young either solitarily or together with one or several other females in a communal nest. We assessed the fitness consequences of communal and solitary breeding in a wild population to understand how the two tactics can be evolutionarily stable. Females switched between the two tactics (with more than 50% of all females having two or more litters using both tactics), pointing toward communal and solitary breeding being two tactics within a single strategy and not two genetically determined strategies. Communal breeding resulted in reduced pup survival and negatively impacted female reproductive success. Older and likely heavier females more often reared their litters solitarily, indicating that females use a condition-dependent strategy. Solitary breeding seems the more successful tactic, and only younger and likely less competitive females might opt for communal nursing, even at the cost of increased pup mortality. This study emphasizes the importance of analyzing phenotypic plasticity and its role in cooperation in the context of female ARTs.

Rigor and reproducibility in rodent behavioral research.

Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.

Recommended housing densities for research mice: filling the gap in data-driven alternatives.

Space recommendations for mice made in the Guide for Care and Use of Laboratory Animals have not changed since 1972, despite important improvements in husbandry and caging practices. The 1996 version of the Guide put forth a challenge to investigators to produce new data evaluating the effects of space allocation on the well-being of mice. In this review, we summarize many studies published in response to this challenge. We distinguish between studies using ventilated or nonventilated caging systems and those evaluating reproductive performance or general well-being of adult mice. We discuss how these studies might affect current housing density considerations in both production and research settings and consider gaps in mouse housing density research. Additionally, we discuss reliable methods used to monitor and quantify general well-being of research mice. Collectively, this large body of new data suggests that husbandry practices dictating optimal breeding schemes and space allocation per mouse can be reconsidered. Specifically, these data demonstrate that prewean culling of litters has no benefit, trio breeding is an effective production strategy without adversely affecting pup survival and well-being, and housing of adult mice at densities of up to twice current Guide recommendations does not compromise well-being for most strains.-Svenson, K. L., Paigen, B. Recommended housing densities for research mice: filling the gap in data-driven alternatives.

Food avoidance learning based on voluntary wheel running in laboratory mice (Mus musculus).

Mice show a reluctance to eat unfamiliar food, when they first encounter it. This neophobic reaction is conventionally habituated by repeated trials: the mice gradually increase their consumption of the novel food. The new finding reported here is that the consumption remains low in mice that voluntarily run in activity wheels after the novel food access. This effect implies that running yields Pavlovian conditioned flavor aversion, which suppresses, otherwise increasing, consumption of the novel food. In the present research, the effect was demonstrated with a between-group design by pitting experimental mice receiving cheese-running paired treatment against cheese/running unpaired control mice (Experiment 1). The running-based food avoidance in mice was also shown in a differential conditioning paradigm, where one of two novel snacks (chocolate and marshmallow) was paired with running while the other was not, in non-deprived animals (Experiment 2 A) and food-deprived animals (Experiment 2B). These results concord with those previously reported in rats, indicating the generality of the phenomenon.

Behavioural strategies of three wild-derived populations of the house mouse (Mus m. musculus and M. m. domesticus) in five standard tests of exploration and boldness: Searching for differences attributable to subspecies and commensalism.

Animal populations adopting a commensal way of life, e. g. house mice in buildings and stores, are subject to different selection pressures than those living in a non-commensal environment. This may radically influence their behaviour. This study investigated the effects of a commensal way of life on exploratory behaviour in mice. The focal population was non-commensal Mus musculus musculus from Northern Iran. To assess the effect of commensal way of life on exploratory behaviour, it was compared with commensal M. m. musculus from the Czech Republic and to assess the effect of subspecies, it was compared to non-commensal M. m. domesticus from Eastern Syria. We compared their behaviour in five tests of exploratory behaviour and boldness: an open field test with 1) free exploration and 2) forced exploration, 3) hole-board test, 4) test of vertical activity and 5) elevated plus maze. We detected a significant effect of population on behaviour in all five tests. M. m. domesticus was generally bolder and more active than M. m. musculus. Commensal mice were characterized by a higher level of vertical activity (climbing, rearing, jumping). These results suggest that the specific selection pressures of the commensal lifestyle select mice for higher affinity towards elevated places.

The impact of environmental interventions among mouse siblings on the heritability and malleability of general cognitive ability.

General cognitive ability can be highly heritable in some species, but at the same time, is very malleable. This apparent paradox could potentially be explained by gene-environment interactions and correlations that remain hidden due to experimental limitations on human research and blind spots in animal research. Here, we shed light on this issue by combining the design of a sibling study with an environmental intervention administered to laboratory mice. The analysis included 58 litters of four full-sibling genetically heterogeneous CD-1 male mice, for a total of 232 mice. We separated the mice into two subsets of siblings: a control group (maintained in standard laboratory conditions) and an environmental-enrichment group (which had access to continuous physical exercise and daily exposure to novel environments). We found that general cognitive ability in mice has substantial heritability (24% for all mice) and is also malleable. The mice that experienced the enriched environment had a mean intelligence score that was 0.44 standard deviations higher than their siblings in the control group (equivalent to gains of 6.6 IQ points in humans). We also found that the estimate of heritability changed between groups (55% in the control group compared with non-significant 15% in the enrichment group), analogous to findings in humans across socio-economic status. Unexpectedly, no evidence of gene-environment interaction was detected, and so the change in heritability might be best explained by higher environmental variance in the enrichment group. Our findings, as well as the 'sibling intervention procedure' for mice, may be valuable to future research on the heritability, mechanisms and evolution of cognition.This article is part of the theme issue 'Causes and consequences of individual differences in cognitive abilities'.

Of mice and mental health: facilitating dialogue and seeing further.

The science of mental life is critical for understanding both how we function, and impairments in our functioning. However, understanding the causal mechanisms underlying mental health disorders and developing new treatments are challenges too great to be solved by any individual approach. There is a growing awareness that translational research-from laboratory to patient and back again to animal models-will be critical for the improved understanding and treatment of mental health disorders. The motivation and intention to pursue translational approaches is therefore strong in mental health research, but critically, opportunities for interaction between basic scientists and clinicians are relatively limited, and vary depending on the institution in which researchers are working. This has promoted the development of a 'culture gap' between basic and clinical scientists that limits interaction and sharing of knowledge. Here, we provide 14 examples of contemporary translational research and call for an increased collaborative approach to mental health research that spans clinical diagnoses, levels of analysis and bridges between basic to clinical mental health sciences, including, but not limited to, psychology and neuroscience. What is needed is an inclusive and integrated approach, bringing together scientists working at all levels of enquiry with clinicians providing insights on what works (and what does not). To stimulate the much-needed innovation in therapeutic techniques, an analysis of component parts is critical. Our approach suggests simplifying complex behaviours into distinct psychological components. Asking collaboratively driven scientific questions about dysfunction will also benefit our fundamental understanding of mental life.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Addictive behaviour in experimental animals: prospects for translation.

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas-the impact of drug-associated conditioned stimuli-or drug cues-on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.