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Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered prefrontal cortex (PFC) synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.

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Inter-individual variability in behavioral and physiological response has become a well-established phenomenon in animal models of anxiety and other disorders. Such variability is even demonstrated within mouse inbred strains. A recent study showed that adaptive and non-adaptive anxiety phenotypes (measured as habituation and/or sensitization of anxiety responses) may differ within cohorts of 129 mice. This variability was expressed across both anxiety- and activity-related behavioral dimensions. These findings were based however on re-analysis of previously published data. The present study therefore aimed to empirically validate these findings in 129 mice. In addition, we assessed such inter-individuality in two other strains: BALB/c and C57BL/6. Males of three mouse inbred strains (BALB/c, C57BL/6 and 129S2) were behaviorally characterized through repeated exposure to a mild aversive stimulus (modified Hole Board, 4 consecutive trials). Behavioral observations were supplemented with assessment of circulating corticosterone levels. Clustering the individual response trajectories of behavioral and endocrine responses yielded two multidimensional response types of different adaptive value. Interestingly, these response types were displayed by individuals of all three strains. The response types differed significantly on anxiety and activity related behavioral dimensions but not on corticosterone concentrations. This study empirically confirms that adaptive capacities may differ within 129 cohorts. In addition, it extends this inter-individual variability in behavioral profiles to BALB/c and C57BL/6. Whether these two sub-types constitute differential anxiety phenotypes may differ per strain and requires further study.

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Dopaminergic neurotransmission in the striatum has been widely implicated in the reinforcing properties of substances of abuse. However, the striatum is functionally heterogeneous, and previous work has mostly focused on psychostimulant drugs. Therefore, we investigated how dopamine within striatal subregions modulates alcohol-directed behaviour in rats. We assessed the effects of infusion of the dopamine receptor antagonist alpha-flupenthixol into the shell and core of the nucleus accumbens (NAcc) and the dorsolateral striatum (DLS) on responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement. Bilateral infusion of alpha-flupenthixol into the NAcc shell reduced responding for alcohol under both the FR1 (15 µg/side) and the PR schedule (3.75-15 µg/side) of reinforcement. Infusion of alpha-flupenthixol into the NAcc core (7.5-15 µg/side) also decreased responding for alcohol under both schedules. By contrast, alpha-flupenthixol infusion into the DLS did not affect FR1 responding, but reduced responding under the PR schedule (15 µg/side). The decreases in responding were related to earlier termination of responding during the session, whereas the onset and rate of responding remained largely unaffected. Together, these data suggest that dopamine in the NAcc shell is involved in the incentive motivation for alcohol, whereas DLS dopamine comes into play when obtaining alcohol requires high levels of effort. In contrast, NAcc core dopamine appears to play a more general role in alcohol reinforcement. In conclusion, dopaminergic neurotransmission acts in concert in subregions of the striatum to modulate different aspects of alcohol-directed behaviour.

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There is a considerable degree of individual vulnerability for alcohol use disorder (AUD) as only a subpopulation of individuals who regularly consume alcohol develop AUD. It is therefore very important to understand the factors and mechanisms that contribute towards the individual risk for AUD. In this respect, social influences, in particular during development, may be relevant for AUD as disruptions in early social experiences are associated with an increased risk for AUD. Social play, the most prominent form of social behaviour shown by young mammals, is rewarding and considered to be important for social, emotional and cognitive development. Recent studies suggest that early social isolation, effectively depriving animals from social play, increases the risk for addictive behaviour. The aim of this study was therefore to explore the long-term consequences of early social isolation on alcohol consumption and motivation for alcohol. To this end, rats were socially isolated from postnatal days 21-42, followed by 4 weeks of social housing, and voluntary alcohol consumption and operant responding for alcohol were determined in adulthood. We observed enhanced levels of alcohol consumption in adulthood in previously isolated rats, whereas operant responding for alcohol was not altered. The impact of early social isolation was independent of the individual variation in alcohol consumption. These data indicate that social isolation, during a developmental period when social play is highly abundant, enhances the propensity to consume alcohol in adulthood. This implies that early social experience may be a protective factor against excessive alcohol use.

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RATIONALE: A bidirectional relationship between alcohol use disorder (AUD) and deficits in impulse control and decision making has been suggested. However, the mechanisms by which neurocognitive impairments predispose to, or result from AUD remain incompletely understood. OBJECTIVES: The aim of this study is to gain more insight in the effects of alcohol exposure on decision making and impulse control. We used two modified versions of the rat gambling task (rGT) that differ in the net gain and the punishment magnitude associated with the different response options. METHODS: In experiment 1, we assessed the effects of acute alcohol treatment (0-0.8 g/kg) on rGT performance. In experiment 2, we determined the effects of alcohol on rGT acquisition (15 sessions, 0.6 g/kg). Next, these animals were challenged with alcohol (0-1.0 g/kg) prior to rGT sessions. RESULTS: Acute alcohol treatment suppressed baseline performance in both rGT versions but only modestly altered decision making. Treatment with alcohol during acquisition increased risky choices in the rGT version that involved larger punishment and blunted the reduction in win-shift behavior during acquisition in both rGT versions. Moreover, rats treated with alcohol during acquisition showed an increase in premature and perseverative responding upon subsequent alcohol challenges (0-1.0 g/kg) and were less sensitive to the behavioral suppressant effects of alcohol. CONCLUSIONS: Our results show that repeated alcohol exposure alters decision making during rGT acquisition and reduces the ability to adjust choice behavior on the basis of feedback. In addition, repeated alcohol exposure unmasks its behavioral disinhibitory effects in the rGT. Impaired responsiveness to choice feedback and behavioral disinhibition may contribute to the development of AUD.

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BACKGROUND: An important risk for atherosclerosis is a low level of HDL cholesterol. Baseline HDL cholesterol is under complex genetic and environmental control. Here we report on results of male mice from a consomic strain survey and the parental inbred strains for baseline circulating total cholesterol concentration, which is almost the same as HDL cholesterol in chow fed mice. The consomic strains have been derived from C57BL/6J (host strain) and A/J (donor strain) inbred lines. The work contributes to the value of the mouse as an animal model for studying the genetic background of differences in baseline circulating total and HDL cholesterol levels. RESULTS: The consomic strain survey suggested that mouse chromosomes 1, 7, 9, 14, 16, 17, 19, X, and Y contained at least one quantitative trait locus that is involved in baseline circulating total cholesterol concentration. All consomic lines, for which there is evidence that the substituted chromosome contains a quantitative trait locus, increase compared to the host strain baseline circulating total cholesterol concentration. Since there is evidence that 'body weight', 'age at blood sampling', 'time of the day blood was collected', and 'season' influence this phenotype, additional statistical analyses (with these variables as covariates) were performed. Now there is only evidence for quantitative trait loci on chromosomes 1, 8, 12, and Y. Taken the present results together with previous consomic strain surveys there is evidence that all mouse chromosomes carry quantitative trait loci that control baseline circulating total cholesterol levels. There was however little agreement between the present consomic strain results and previous sets of data. This might be explained by seasonal effects and differences in methodological variables such as age of the mice, fasting versus non-fasting, percentage of dietary fat, unanesthetized versus anesthetized mice, and the daily light-dark cycle. CONCLUSIONS: The present findings, when compared with previous consomic strain surveys, clearly illustrate the complexity of the genetic-environmental architecture for the regulation of baseline circulating total cholesterol levels in mice. Different data can be obtained from different labs and it underscores that animal geneticists should present as accurate a picture as possible of the laboratory mouse's environment.

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BACKGROUND: Alcohol is one of the most commonly used psychoactive substances. Prolonged alcohol use can result in alcohol use disorder (AUD), characterized by excessive and compulsive alcohol consumption. Importantly, however, the development of AUD only happens in a minority of individuals who consume alcohol. To understand the individual vulnerability for AUD, models that capture both the individual variability in alcohol consumption and the transition from casual to compulsive alcohol use are essential. METHODS: Individual variability in voluntary alcohol intake and the preference for alcohol were assessed under continuous alcohol access (CAA) and intermittent-every-other-day alcohol access (IAA) schedules in the home cage using outbred Lister Hooded rats. Subsequently, the reinforcing properties of alcohol were tested in an operant setting. In subsequent experiments, we performed a quinine adulteration experiment to assess inflexible alcohol consumption and blood alcohol levels (BALs) were assessed after voluntary alcohol consumption. RESULTS: We found marked individual differences in alcohol consumption and preference under both access schedules, whereby subgroups of high- and low-alcohol-drinking rats (HD and LD) could be identified. HD with IAA increased their alcohol intake over days in the first month, whereas LD did not. Moreover, when alcohol access time was extended from 7 to 24 h/d for rats with IAA, alcohol intake profoundly increased in HD with IAA, whereas LD with IAA maintained low levels of alcohol intake. Furthermore, HD earned more alcohol than LD under both fixed ratio and progressive ratio schedules of reinforcement. We further found that HD continued their intake of a quinine-adulterated alcohol solution to a larger extent than LD and HD showed higher BALs after 30 minutes of alcohol consumption. CONCLUSIONS: These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD.

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Various protocols to induce chronic stress in rodents are being used to determine the effects and underlying mechanisms of prolonged stress experience. Recently, a novel chronic social stress (CSS) protocol has been developed for mice where social instability in adolescence and early adulthood is induced. This protocol has been shown to cause an increase in HPA-axis activity and acute avoidance behaviour in the elevated plus maze. The aim of the present study was to investigate the effect of this CSS protocol on habituation to an initially novel environment in CD1 mice, since it has been shown that initially high avoidance behaviour in mice can still be followed by rapid habituation, pointing towards an adaptive response. One group of male mice, the CSS group, was exposed to the CSS protocol for 7 weeks and we compared their behavioural and physiological responses with male mice that were housed in a stable social group, the SH group. The results reveal a decrease in body weight gain and fur condition, changes in adrenal weight and decreased GR mRNA expression in the CA1 and the dentate gyrus of the hippocampus in chronically stressed CD1 animals. Irrespective of such evidence for a significantly stressful effect of the protocol, CD 1 mice, after termination of the stress procedure, revealed habituation profiles that matched those of control animals. We conclude that the physiological and central-nervous effects caused by a CSS procedure as used in this experiment fall within the coping capacities of CD1 mice at the behavioural level.

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Corticosteroid hormones, released after stress, are known to influence neuronal activity and produce a wide range of effects upon the brain. They affect cognitive tasks including decision-making. Recently it was shown that systemic injections of corticosterone (CORT) disrupt reward-based decision-making in rats when tested in a rat model of the Iowa Gambling Task (rIGT), i.e., rats do not learn across trial blocks to avoid the long-term disadvantageous option. This effect was associated with a change in neuronal activity in prefrontal brain areas, i.e., the infralimbic (IL), lateral orbitofrontal (lOFC) and insular cortex, as assessed by changes in c-Fos expression. Here, we studied whether injections of CORT directly into the IL and lOFC lead to similar changes in decision-making. As in our earlier study, CORT was injected during the final 3 days of the behavioral paradigm, 25 min prior to behavioral testing. Infusions of vehicle into the IL led to a decreased number of visits to the disadvantageous arm across trial blocks, while infusion with CORT did not. Infusions into the lOFC did not lead to differences in the number of visits to the disadvantageous arm between vehicle treated and CORT treated rats. However, compared to vehicle treated rats of the IL group, performance of vehicle treated rats of the lOFC group was impaired, possibly due to cannulation/infusion-related damage of the lOFC affecting decision-making. Overall, these results show that infusions with CORT into the IL are sufficient to disrupt decision-making performance, pointing to a critical role of the IL in corticosteroid effects on reward-based decision-making. The data do not directly support that the same holds true for infusions into the lOFC.

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When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto (WKY), Fawn Hooded (FH), Brown Norway (BN) and Lewis (LE), were investigated in different tests related to pain and nociception. During Pavlovian fear conditioning, the LE and WKY showed a significantly longer duration of freezing behaviour than the FH and BN. Additionally, differences in c-Fos expression in subregions of the prefrontal cortex and amygdala between rat strains during retrieval and expression of conditioned fear were found. For example, the BN did not show recruitment of the basolateral amygdala, whereas the WKY, FH and LE did. During the hot plate test, the WKY and LE showed a lower thermal threshold compared to the BN and FH. In a follow-up experiment, the two most contrasting strains regarding behaviour during the hot plate test and Pavlovian fear conditioning (i.e. FH and WKY) were selected and the hot plate test, Von Frey test and somatosensory-evoked potential (SEP) were investigated. During the Von Frey test, the WKY showed a lower mechanical threshold compared to the FH. When measuring the SEP, the FH appeared to be less reactive to increasing stimulus intensities when considering both peak amplitudes and latencies. Altogether, the combined results indicate various differences between rat strains in Pavlovian fear conditioning, nociception related behaviours and nociceptive processing. These findings demonstrate the necessity of using multiple rat strains when using tests including noxious stimuli and suggest that the choice of rat strains should be considered. When selecting a strain for a particular study it should be considered how this strain behaves during the tests used in that study.

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Buprenorphine is commonly used as (part of) postoperative analgesic treatment with dosage dependent side-effects such as pica behaviour. No strict consensus exists about the optimal dosing interval of buprenorphine, as its duration of action has been described as being in the range of 6-12 h. In this study, dosing intervals of 8 h (thrice-a-day) and 12 h (twice-a-day) for buprenorphine in a multimodal analgesic strategy (concurrent administration of a non-steroidal anti-inflammatory drug) were compared on food intake, weight and side-effects (gnawing on plastic Petri dishes and growth rate, indicative of pica behaviour) in rats. The food intake and weight of both intervals were comparable, as the animals from the twice-a-day group did not lose more weight or consumed less food during the analgesic period. The rats from the thrice-a-day group suffered from more side-effects, as the growth rate was decreased and more plastic was gnawed on. It is recommended to carefully evaluate analgesic and side-effects when using buprenorphine. When side-effects are observed, the possibility of increasing the dosing interval of buprenorphine should be explored. In this study, increasing the dosing interval of buprenorphine in a multimodal analgesic regimen resulted in reduced unwanted side-effects, without increasing weight loss or decreasing food intake. Although this is suggestive of provision of comparable analgesia, future studies including more pain-related readout parameters to assess the effect of the dosing interval on analgesic efficacy are recommended.

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Emotional states are known to affect cognitive processes. For example highly anxious individuals interpret ambiguous stimuli more negatively than low anxious people, an effect called negative judgement bias. Recently, the measurement of judgement bias has been used to try and indicate emotional states in animals. In the present experiment a potential test for judgement bias in mice was examined. Mice were trained with two distinct odour cues (vanilla or apple) predicting either a palatable or an unpalatable almond piece. Subsequently their reaction to mixtures of both odours, the ambiguous stimuli, was investigated. Mice of the BALB/cJ and 129P3/J inbred mouse strains (high initial anxiety and low initial anxiety phenotypes respectively) were tested. While BALB/cJ mice showed odour association learning and showed intermediate reactions to the ambiguous cues, 129P3/J mice did not discriminate between the cues. Additionally BALB/cJ mice that were tested under more aversive white light conditions revealed a higher latency to approach the almond piece than mice tested under less aversive red light conditions. The ambiguous stimulus however was interpreted as negative under both test conditions. Brain c-Fos expression levels (a marker for neuronal activity) differed between the BALB/c/J and 129P3/J in the lateral amygdala and the prelimbic cortex, indicating differences in ambiguous information processing between the strains. The behavioural results suggest that the present judgement bias test might be used to assess emotional states in at least BALB/c mice, however further research on both behaviour and on the involved brain mechanisms is necessary to confirm this idea.

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The object recognition task (ORT) allows assessing learning and memory processes in rodents. In this study, two areas in which knowledge about the ORT could be extended were addressed; i.e. generality to species and strains, and intervening variables including housing and estrous cycle. Regarding generality to species and strains, the ORT performance of golden hamsters was assessed. The hamsters showed sufficient exploration times, object recognition performance, and a retention-interval dependent decline similar to rats and mice. Subsequently, we tested three mouse strains which have not been described before in the ORT; i.e. OF1, NMRI, and SJL mice. OF1 and NMRI strains performed equally well, whereas the SJL strain showed low exploration times and no memory retention. Therefore, the SJL strain is unsuited for ORT experiments using a 1h retention interval and a fixed (3 min) trial duration. Furthermore, the sensitivity to a pharmacological memory deficit model (scopolamine) was tested in three rat strains. Each strain showed a dose dependent relationship, but the least effective dose of scopolamine differed among the three strains, the effect being greater in the order of Wistar, Long-Evans, Hooded Lister rats. Finally, to investigate potential intervening variables in the ORT, the effects of housing conditions and estrous cycle were investigated with rats. Single housing resulted in absolute higher performance than social housing. Furthermore, females in pro-estrus/estrus showed better performance compared to females in met-estrus/di-estrus. Taken together, object recognition appears to be a common ability of rodent species, but different strains have different memory capacities and sensitivities to scopolamine, individual housing leads to higher performance, and performance of females is dependent on the estrous cycle phase. Thus, rodent species, strain, housing, and estrous cycle should be taken into consideration in ORT studies.

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In both humans and rats high levels of anxiety impair decision-making in the Iowa gambling task (IGT) in male subjects. Expression of the immediate early gene c-fos as marker of neural activity in rat studies indicated a role of the medial prefrontal cortex (prelimbic and infralimbic region; mPFC) in mediating the relationship between anxiety and decision-making. To delineate this relationship further and assess the underlying neurobiology in more detail, we inactivated in the present study the mPFC in male rats using a mixture of the GABA-receptor agonists muscimol and baclofen. Rats were exposed to the elevated plus maze (EPM) to measure effects on anxiety and to the rodent version of the IGT (r-IGT). Inactivation led to increased levels of anxiety on the EPM, while not affecting general activity. The effect in the r-IGT (trials 61-120) was dependent on levels of performance prior to inactivation (trial 41-60): inactivation of the mPFC hampered task performance in rats, which already showed a preference for the advantageous option, but not in rats which were still choosing in a random manner. These data suggest that the mPFC becomes more strongly involved as rats have learned task-contingencies, i.e., choose for the best long-term option. Furthermore they suggest, along with the data of our earlier study, that both anxiety and decision-making in rats are mediated through a neural circuitry including at least the mPFC. The data are discussed in relation to recent data of rodent studies on the neural circuitry underlying decision-making.

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Co-species housing of mice and rats is common practice at most breeding facilities and research laboratories, neglecting the possible effects on the animals. We investigated physiological as well as behavioral stress-reactivity in mice and rats which were either derived from a co-species or species-separated housing condition at the breeding facilities. The animals were kept under the housing condition they were used to or assigned to the opposite one. Co-species housing had a significant impact on acute stress reactivity in mice and rats but only if they were used to this housing condition throughout their lives. Moreover, the stress-effects appeared to be long lasting. Assigning animals, derived from a species-separated housing condition, to co-species housing led to chronic stress in mice and affected experimental behavior of rats. Our findings led to the conclusion that co-species housing in mice and rats should be avoided, supporting the recommendations by the U.S. National Institutes of Health (NIH) and the Dutch Ministry of Health, Welfare and Sport (VWS). In order to support the interpretation, facilitate the reproducibility and comparability and subsequently the generalizability of experimental results, breeding facilities should at least provide detailed information about their housing conditions.

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The replicability of results derived from studies in rodents might be influenced by stress caused by inappropriate housing conditions. Here we compared the experimental behaviour and stress response (circulating corticosterone level and adrenal tyrosine hydroxylase activity) of individually-housed male and female inbred mice with that of animals housed in social groups. All mice were behaviourally tested in the modified hole board test (mHB). Male C57BL/6, BALB/c and A mice housed in groups of 3 were compared with individually-housed mice. In a subsequent experiment female C57BL/6 and BALB/c mice were housed under similar conditions. To exclude the possible effects of within-cage order of testing, only one individual per group was behaviourally tested. Neither male nor female mice housed individually showed stronger signs of stress than their socially-housed counterparts. However, we observed a within-cage order effect on the hormonal stress response (corticosterone) in socially-housed female C57BL/6 mice. No effects of individual housing on behaviour in the mHB were found.

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