A factor analysis of behavioral organization in mice]

Laboratory mice with Robertsonian translocation Rb(8,17)1Iem, mice of CBA substrain with the same translocation as well as CBA normal karyotype mice were investigated in several behavioural tests, their results being analysed by means of factor analysis. The genetic differences were revealed in the patterns of factor loadings, in particular in factors "feeding behaviour structure" and "weight loss". The behaviour of mice during logic problem solving (the ability to extrapolate the direction of food stimulus movement was tested) proved to be genotype-dependent in respect to connections with exploratory behaviour indices. Tendencies towards stereotypic or variable (plastic) behaviour patterns were revealed in CBA mice and mice with Rb(8,17)1Iem mice respectively.     

Ethological analyses of the effects of naloxone and the opiate antagonist ICI 154, 129 on social interactions in male house mice

The influences of the mu blocker naloxone and the novel opioid delta receptor antagonist ICI, 154, 129 on videotaped encounters between individually-housed, male Swiss mice and anosmic male ‘standard opponents’ were assessed using a variety of ethological analyses. The effects of drugs were studied on individual elements and on the times allocated by subjects to broad categories of behaviour. Neither of the drugs significantly altered times allocated to broad categories of behaviour. Both doses of both compounds significantly increased the incidences of some ‘fearful’/defensive postures. A more detailed analysis considered the effects of the drugs on the sequences of postures used in the resident's behaviour. This involved the generation of ‘dendrograms’ which provided support for the view that both naloxone and ICI 154, 129 altered the associations between behavioural elements seen in saline controls (especially at higher doses) and that the effects of these antagonists were qualitatively different.     

Characteristics of the brain dopamine system in mice carrying the quaking neurological mutation

Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice with neurological mutation expressed in demyelinization of the brain neurons and constant shaking. It has been shown that apomorphine in a low dose (0.25 mg/kg) produced a more significant decrease in locomotor activity in Qk than in control mice. Qk mice appeared to be less sensitive to the blockade by haloperidol of apomorphine (2.5 mg/kg)-induced climbing. DA1 receptor agonist, SKF-38393 caused less pronounced climbing in Qk mice than in the control. There were no changes in DA level in striatum and n. accumbens, whereas 3,4-dihydroxyphenylacetic acid in n. accumbens and homovanillic acid level in striatum were elevated. It was suggested that the increased DA metabolism and the altered sensitivity of pre- and postsynaptic DA receptors are involved in the shaking behaviour of Qk mice.     

Relation between reactions to pain and the hierarchical rank of animals

Intraspecies experience of domination or subordination in mice is an important factor predetermining their specific behaviour in response to painful stimuli, The significance is emphasized of ethological investigations for studying behavioural reactivity to pain and correct differentiation of responses of "defence-subordination" and "aggression-offence" types. The specificity of diazepam effect on the character of behaviour in response to pain was analysed in animals of different hierarchic rank.     

Food search by mice solving an extrapolation problem after suppression of smell by zinc sulfate

Anosmia induced by intranasal zinc administration to mice capable of solving an extrapolation problem (search for food which disappears from animal sight in definite direction), led to disturbance of normal food searching behaviour. In anosmic mice the percentage of task solutions (correct as well as incorrect) in which the trajectory was the shortest ("goal-directed"), was significantly lower than in controls. At the same time the percentages of correct "goal-directed" choices were equal in both groups. The main differences in the number of correct task solutions were among those trials in which non-goal-directed behaviour was delivered. Thus zinc induced anosmia provokes rather severe deteriorations of food searching behaviour. The investigated group of mice possessing Robertsonian translocation Rb(8, 17) 1 IEM, reveals no disturbance of extrapolation capacity during first 20 s after task presentation. This signifies that this capacity which in this group is higher than in other mice, is not determined by peculiarities of their olfaction.     

Comparison of the Effects of Chlorpromazine,Dextroamphetamine and Methylphenidate on the Behaviour and Functioning of Hyperactive Children

Chlorpromazine, dextroamphetamine and methylphenidate were significantly superior to placebo in producing overall improvement in the behaviour of hyperactive children. Chlorpromazine was effective for the majority of the children, but reduced only hyperactivity, having no demonstrable effect on distractibility, aggressivity or excitability. Both stimulants produced more goal-oriented behaviour and reduced distractibility. Methylphenidate was the most effective of the drugs in prpducing exceptional improvement. All three active drugs had to be discontinued in a few of the children because of side effects. Not all hyperactive children were benefited by the drugs.No background variables (with the exception of mother-child relationship) were found in the present studies to predict favourable response to the drugs.Methylphenidate became our drug of choice for this group of hyperactive children.     

Modulation of behavior of mice of different genotypes by serotonin antibodies

The effect of active immunization with conjugated serotonin-protein on the "open-field" behaviour and passive avoidance conditioning was studied in genetically different mice strains (C57BL/6 and BALB/c). The obtained immunophysiological effects of serotonin antibodies depended on genetically determined characteristics of animal behaviour. Serotonin antibodies altered rearing and crossings of the "open-field" center and retention of passive avoidance learning in C57BL/6 mice. The active immunization with conjugated serotonin-protein of BALB/c mice resulted in modulation of the "open-field" latency and both training and testing of passive avoidance behaviour.     

Effect of psychotropic preparations on the behavior of inbred mice under emotional stress]

The effect of phenazepam and sydnocarb in doses of 0.05, 0.07 and 0.1 mg/kg or 6, 12 and 24 mg/kg, respectively, on the behaviour of C57BL/6, CBA and BALB/c mice, was studied in the "open field" test. Interlinear difference in the reaction of inbred animals to emotional stress and its phenazepam or sydnocarb correction were established.     

A computer ethological-pharmacological analysis of the intraspecific behavior of primates

Experiments were performed on primates (Cercopithecus sabeus, Macaca maurus, Cebus apella). Possibility to formalize the structure of normal and pathological monkey behaviour was shown by computerized technique. Rigid dominant-subordinate structures (linear type) were demonstrated on Macaca maurus, Cercopithecus sabeus, Cebus apella. These structures display some variants of normal relationship between monkeys. Raising in isolation from conspecifics determines behavioural disadaptation and pathological behaviour, e.g. "timid-defensive" syndrome. Model of "timid-defensive" syndrome in isolated primates seems to be useful for psycho-pharmacological research, for assessment of anxiolytic and antidepressive properties of drugs.     

Rhodanese and ALA-S in mammary tumor and liver from normal and tumor-bearing mice.

1. Basal levels and allyl-isopropylacetamide (AIA) or veronal induced levels of delta-amino-levulinate synthetase (ALA-S), cytoplasmic and mitochondrial rhodanese were determined in tumor (T) and liver of both normal mice (NM) and T-bearing mice (TBM). 2. Rhodanese tumoral mitochondrial levels were higher than the hepatic normal mitochondrial fraction, while the cytoplasmic activity was nearly equal in all sources. 3. In neither case was the activity of tumoral ALA-S and rhodanese altered by any of the porphyrinogenic drugs. 4. Mitochondrial and cytoplasmic rhodanese activity was also measured in tumor and liver of TBM at different intervals after transplantation. We concluded that the behaviour of rhodanese is a property inherent to the tissue and not one attained with time.     

Effects of chronic buspirone treatment on female mice exposed to the long-lasting psychoemotional influence

The effects of chronic treatment (30 days) with the 5-HT1A receptor partial agonist buspirone (0.05, 1 and 10 mg/kg i.p.) on the behaviour of C57BL/6J female mice exposed to long-lasting psychoemotional influence were studied. The influence involved forced living of each female with an aggressive male separated with a perforated transparent partition in the same cage and daily female's presence during 10-min intermale confrontations behind a partition caused by introducing of another male to the aggressive male. Chronic buspirone injection (in all used doses) did not affect the behaviour of females estimated in the "partitions" and "open field" tests at the end of the drug treatment. The anxiolytic effect of buspirone only at the dose of 1 mg/kg on the female's plus-maze behaviour was revealed. In the Porsolt, test buspirone in the dose of 1 mg/kg caused a slight increase in the duration of immobility indicating a slight pro-depressive effect. Thus, chronic buspirone treatment of females exposed to the long-lasting psychoemotional impact has a different effect on their behaviour depending on the dose and test conditions.     

Conditional gene expression in the respiratory epithelium of the mouse

Transgenic mouse models mediating conditional temporal and spatial regulation of gene expression to the respiratory epithelium were developed utilizing the reverse tetracycline transactivator (rtTA) expressed under the control of SP-C and CCSP promoters. Luciferase activity was detected in the lungs of fetal and adult double transgenic mice but was not detected in other tissues or in single transgenic mice. In adult mice, maximal luciferase activity was detected 16h after the administration of doxycycline in the drinking water, or 2h after the injection of doxycycline. Activation of the transgene was observed after the administration of doxycycline in food pellets. After prolonged exposure to doxycycline, luciferase activity decreased slowly following removal of doxycycline, suggesting the importance of tissue pools which maintained expression of the transgene. In SP-C-rtTA mice, exposure of the pregnant dam to doxycycline induced luciferase activity in fetal lung tissue as early as E10.5. Luciferase activity was maintained in the lung tissue of pups during the period of lactation when the mother received doxycycline in the drinking water. In the CCSP-rtTA mice, luciferase was not detected in the absence of doxycycline. In the SP-C-rtTA mice, luciferase activity was detected in the absence of doxycycline but was enhanced approximately 10-fold by administration of drugs. The SP-C-rtTA and CCSP-rtTA activator mice control the expression of transgenes in the developing and mature respiratory epithelium, and will be useful for the study of gene function in the lung.     

Effect of fenazepam on the ACTH content of the blood plasma in inbred mice under stress exposure

The influence of phenazepam on plasma ACTH level before and after exposure to stress in the "open field" test was investigated in C57BL/6, BALB/c and F1(C57BL/6 X BALB/c) mice. The differences in the dose-dependent drug effect on the hormone level between strains were studied. A correlation between ACTH level and a characteristic animal behaviour has been established for different strains.     

Hand-preference training in the mouse reveals key elements of its learning and memory process and resolves the phenotypic complexity in the behaviour.

Handedness in the mouse comprises 2 different behaviours. Some strains have a conditional behaviour, in that the mice learn a direction of hand preference in response to reaching for food, whereas other strains have an innate or constitutive behaviour, and prior experience has no measurable effect on their hand preference. However, hybrids from different strains have revealed both recessive and dominant forms of constitutive hand preference. We proposed that kinetic parameters of the learning process would resolve this genetic heterogeneity as well as the phenotypic complexity in the behaviour. We conducted and report here a detailed kinetic analysis of hand-preference training in the C57BL/6J strain. It revealed elements of the fundamental process of learning and long-term memory that underlies the behaviour by documenting consolidation of memory, blocking of this consolidation by an inhibitor of protein synthesis, retention of memory, and speed of learning in response to training reaches. Furthermore, speed of learning is clearly described by 2 parameters that we call "capacity" (or maximum amount of learned preference) and "ability" (or number of training reaches to achieve half the capacity). These 2 kinetic parameters can vary independently among genetically different strains that learn a preference, and we used them to demonstrate that the respective recessive and dominant forms of constitutive hand-preference may be the consequence of a true null or loss of function and a gain of function, possibly a memory regulator, in the learning process. The quantitative measures provide a sensitive and selective method to establish the fundamental learning process underlying mouse hand preference and to demonstrate empirically how genes and contextual environment shape its phenotypic complexity.     

Genetic variation in heroin-induced changes in behaviour: effects of B6 strain dose on conditioned reward and locomotor sensitization in 129-B6 hybrid mice

Substantial interindividual variability exists in the propensity to develop opiate addiction. Genetic variation in opiate reward may contribute to this variability. A large body of evidence indicates genetic variation in mice for several effects of opiate drugs. The present study examined heroin-induced place conditioning and locomotor sensitization in the two strains of mice employed most frequently in the generation of transgenic animals, C57BL/6J (B6) and 129X1/sVJ (129), as well as in groups of B6-129 hybrid mice, differing in their amount of B6 genetic background. Four pairings of 100 microg/kg of heroin elicited robust place conditioning and locomotor sensitization in B6 controls and in N(10) congenic B6-129 hybrid mice. In comparison, the identical treatment produced no locomotor sensitization and induced place aversion in 129 controls. No heroin-induced changes in the behaviour of N(3) congenic B6-129 hybrid mice or F5-8 non-congenic B6-129 hybrid mice were observed. The expression of place conditioning was not facilitated in any group by the administration of a heroin-priming injection prior to testing. These data indicate that genetic variation exists in mice for the rewarding and locomotor-sensitizing effects of heroin and that the capacity of heroin to induce conditioned reward and locomotor sensitization can be modulated in a B6 strain dose-dependent manner in B6-129 hybrid mice. Thus, strain differences in heroin responsiveness should be considered when examining transgenic lines on B6-129 backgrounds for opiate-induced changes in behaviour that may be relevant for addiction.     

Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver

Background

The liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates.

Principal findings

By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group.

Conclusion

Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver.     

四君子汤对免疫抑制小鼠肝脏细菌易位的影响

目的观察四君子汤对免疫抑制小鼠免疫功能及肝脏细菌易位的影响,探讨神经-内分泌-代谢-微生态-免疫网络之间的关系。方法应用氢化可的松制备小鼠免疫功能抑制模型,造成肝脏细菌易位;观察四君子汤对小鼠吞噬细胞功能的影响和细菌易位的控制,同时设自然恢复组和正常对照组进行比较。结果氢化可的松灌喂3d后,小鼠吞噬细胞的吞噬功能明显下降,肝脏出现大量细菌易位;经四君子汤治疗6h后,小鼠吞噬细胞吞噬功能显著提高。肝脏细菌易位明显减少。结论四君子汤能有效地控制免疫抑制小鼠肝脏细菌易位。     

Relationship between the sequelae of zoosocial isolation and individual characteristics of the animal

The changes were studied of various psychophysiological characteristics of mice behaviour, arising after prolonged solitary isolation in cages. The qualitative specificity of such changes is non-uniform and depends on the animals' individual characteristics (spontaneously aggressive or nonaggressive after isolation). Two types of the consequences of isolation are singled out: 1) General changes (non-specific) arising in all groups of mice; 2) Special changes (specific), typical of a certain group of animals only. In the group of aggressive mice there is a difference between aggression enhanced by isolation, and that which developed in the course of isolation. The most substantial qualitative changes in behaviour takes place in the latter case. It has been suggested that only individual approach makes it possible to determine exactly the qualitative aspects of social isolation consequences.     

Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice

In order to assess the androgenic activity of synthetic progestins currently used as "antiandrogens" for the treatment of prostate cancer in men, the effect of a series of these compounds has been studied in mice on the growth of the androgen-sensitive Shionogi tumor. Female mice (DD/S strain) were inoculated subcutaneously with 10(6) viable cells and divided into groups who received, respectively, the synthetic "progestins" medroxyprogesterone acetate (MPA), megestrol acetate (MEG), cyproterone acetate (CPA) or chlormadinone acetate (CMA), compared with the non-steroidal antiandrogen Flutamide (Flu), each administered at the twice-daily dose of 250 micrograms. Each synthetic "progestin" exerted a marked stimulatory effect on the growth of the tumor. The most impressive effect on growth was observed with MPA. In fact, in MPA-treated mice, tumor size was 17 times larger than control at 4.92 +/- 0.36 cm2/mouse 21 days after inoculation. CPA, CMA and MEG also stimulated the growth of this androgen-sensitive tumor, the percentages of stimulation of tumor size being 3.1-, 3.2- and 11.0-fold above control, respectively, on day 21, while Flu had no significant stimulatory effect. The present data clearly show that all the above-mentioned progestins have variable levels of stimulatory activity on the growth of the androgen-sensitive Shionogi tumor and indicate that such drugs are unlikely to be recommendable for the treatment of prostate cancer.     

Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury

Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat‐related activities. The heat‐shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of reactive oxygen species‐induced p53 target genes Pig1, Pig8, and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP‐15. In contrast to Hsp110‐ or Hsp70i‐deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild‐type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement in contextual and cued fear conditioning tests and beam balance in wild‐type mice that were treated with Celastrol or BGP‐15 following TBI compared to TBI‐treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI.