Agonistic behavior patterns in mice with streptozotocin-induced diabetes mellitus

To examine the effects of the altered metabolic and hormonal state of diabetes mellitus on rodent social behavior, male Swiss Webster mice made diabetic with streptozotocin were tested in a resident-intruder encounter. Isolated diabetic and control mice were introduced as intruders into the home cages of aggression-trained resident mice. The encounters were videotaped and analyzed for frequencies and durations of agonistic behavior. Diabetic mice responded to the aggression of resident mice with significantly less investigation and aggression and significantly more static defense and escape behaviors than did control mice. Resident mice responded to less aggressive diabetic mice with more aggression and social investigation. Plasma corticosterone levels were significantly higher in diabetic mice compared to controls and positively correlated with submissive behavior in diabetic mice. These findings indicate that social behavior is altered in male diabetic mice and support the hypothesis that elevated pituitary-adrenal cortical activity and/or metabolic changes affect behavior in male diabetic mice.     

Studies of the Interaction between Behavioral Stereotypes and the Effects of Activation of Presynaptic Dopamine Receptors during Extinction and Amnesia in Mice

The involvement of presynaptic dopamine receptors in the retention of a conditioned passive avoidance reflex through extinction and amnesia was studied in C57BL/6J mice selected in a 20-day aggressive conflict test for aggressive and submissive behavioral stereotypes. These experiments showed that in aggressive mice, activation of presynaptic receptors with the agonist (+)3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)3PPP] at a dose of 2 mg/kg degraded learning, significantly decreased the retention time of the acquired conditioned habit in extinction, and increased the effect of an amnesia-inducing treatment. Mice showing submissive behavior in daily confrontations with aggressors responded to administration of (+)3PPP with long-lasting reproduction of the conditioned passive avoidance reaction during extinction and showed no changes in the development of amnesia. These data on the relationship between the effects of activating presynaptic dopamine receptors in reproduction of the memory trace in conditions of trace disruption on the one hand and behavioral status on the other are assessed from the point of view of different basal levels of dopaminergic system operation in aggressive and submissive mice.     

Effects of activation of D1 dopamine receptors on extinction of a conditioned passive avoidance reflex and amnesia in aggressive and submissive mice

The studies reported here demonstrate the relationship between the effect of activation of D1 dopamine receptors on the reproduction of a conditioned passive avoidance reflex during extinction and amnesia and the aggressive and submissive behavioral stereotypes. During extinction, the D1 receptor agonist SKF 38393 at a dose of 5 mg/kg given before acquisition of the conditioned reflex and on test day 12 suppressed the reproduction of the conditioned skill in aggressive mice and improved reproduction in submissive mice. The effects of activation of D1 receptors were also opposite relative to the stereotype in amnesia. In aggressive mice, SKF 38393 significantly decreased the resistance to amnesia characteristic of these animals; in submissive mice, SKF 38393 weakened the amnestic effects of the delay in the “dangerous” sector and restored memory traces. The possible mechanisms of the selectivity of the actions of D1 receptors in mice with alternative behavioral stereotypes in retaining memory traces related to aversive stimulation during extinction and amnesia are discussed. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 55, No. 4, pp. 543–548, July–August, 2005.     

The Effects of Novelty and Behavioral Stereotype on the Development of Amnesia in Mice

The aim of the present study was to analyze the significance of the interaction between the basic behavioral strategy, the extinction of the novelty of information, and the efficacy of amnesia-inducing influences. Using a combination of training to passive avoidance with holding the animal in the unsafe sector of the apparatus, comparative analysis was performed of the reproduction of a memory trace in aggressive and submissive mice of line C57BL/6J with and without six sessions of familiarization with the apparatus. These experiments showed that preliminary habituation prevented the development of amnesia in submissive but not aggressive individuals. The cause of these differences in the effects of preexposure on the development of amnesia involves the selectivity of the process of extinction of information novelty characteristic for the behavioral stereotype.     

糖尿病合并脑缺血再灌注导致学习记忆障碍大鼠模型的建立

目的建立糖尿病合并脑缺血再灌注导致学习记忆障碍大鼠模型。方法Wistar大鼠70只,分为正常对照组,糖尿病 假手术组,脑缺血组,糖尿病 脑缺血组。腹腔注射链脲佐菌素建立糖尿病模型,3d后双侧颈总动脉夹阻再灌注2次。术后1个月用跳台和Morris水迷宫判断其学习记忆能力,取海马组织,HE染色观察CA1区的细胞分布。结果电击后5min模型组的被动回避反应下台潜伏期明显缩短(P<0.01),24h后仍小于其他各组(P<0.05)。模型组学会主动回避反应的训练次数显著多于其他3组(P<0.001)。模型组在目标象限停留的时间最短(P<0.01),游泳的距离也最短(P<0.05)。结论糖尿病合并脑缺血再灌注可在短期内造成学习记忆障碍,糖尿病可加重脑缺血造成的脑损伤。     

Exploration and learning behavior in mice selectively bred for high and low levels of activity

The open-field behavior of mice selectively bred for high and low activity and of unselected controls was studied in detail. The behavior was scored, at 3-sec intervals for 20 min, into one of six categories: air sniffing, rearing, grooming, locomotion, sniffing at objects, and freezing. The selective breeding had been very effective in changing the behavioral profile of the selected mice when compared to the control stock. The inactive mice did not freeze more frequently; instead, their behavior was characterized by more passive exploration (sniffing in particular) which became less pronounced as the observation period progressed. Previous reports in the behavior genetics literature had suggested a relationship between learning and exploratory or emotional behavior. It was hypothesized that the selectively bred mice would also differ with respect to their learning behavior. No differences were found between the active and inactive mice in wheelturn avoidance learning. The inactive mice were significantly slower than the active mice in running through a Lashley III maze, but there were no significant differences in the number of errors made. It was concluded that learning and exploratory behavior are not related in any simple manner in the mouse.     

Behavioral impairments related to cognitive dysfunction in the autoimmune New Zealand black mouse

The possibility that autoimmunological disorders involving neuronal constituents as autoantigens can result in measurable behavioral impairments prompted the behavioral analysis of the New Zealand black (NZB) mouse strain, known to have high levels of brain-reactive antibodies. Sensorimotor competence and performance in tasks requiring learning and memory were assessed in 7-10-month-old NZB and contrasted with those of CFW mice. The NZB mice showed pronounced deficits in performance of passive and active shock avoidance responses. These deficits could not be accounted for by the slight sensorimotor disadvantage of NZB mice relative to CFW mice. No difference between the two mouse strains was seen in passive avoidance behavior at 1.5 months of age. It is concluded that NZB mice display a behavioral deficit related to cognitive dysfunction and that autoimmune mechanisms may be involved in the etiology of this deficit. Such behavioral disturbances produced by an autoimmune mechanism may have relevance for the neurological declines observed in aging, since the incidence of autoimmune disorders increases markedly in old age.     

Sex hormones and behavioral reactions

The paper provides a comparative analysis of the effects of imbalance of gonadal hormones on behavioral processes in rats of both sex. Learning was assesses in active and passive avoidance paradigms, behavior was evaluated in the "open field" test. Hemigonadectomy in male rats or hemiovariectomy in female rats was found to fail to modify the dynamics of acquisition and reproduction of active avoidance and passive reactions as compared to the controls, but to affect the pattern of animal behavior in the "open field" test. Castration of rats of both sex impaired the acquisition and retention of active avoidance performance. Excess of testosterone in male rats significantly inhibited the ability of the animals to form an active avoidance response. Excessive estradiol levels in female rats accelerated the acquisition of active avoidance performance and greatly attenuated extinction of this performance. Gonadal hormonal treatment did not alter the reproducibility of passive avoidance performance. The lack of estrogens resulted in amnesia of passive avoidance performance while that of androgens failed to destroy passive avoidance performance. Excessive estradiol in female rats or its lack in male rats significantly modified the pattern of animal behavior in the "open field" test. The absence of estrogens or their excess did not affect the behavior of rats with exception of individual components.     

Progressive age-related impairment of cognitive behavior in APP23 transgenic mice

Transgenic APP23 mice expressing human APP(751) with the K670N/M671L mutation, were compared at ages 3, 18 or 25 months to non-transgenic littermates in passive avoidance and in a small and large Morris maze. The task in the smaller pool habituated their flight response to the platform. Impairments in passive avoidance and small pool performance in APP23 mice were clearly age-related. In the larger Morris maze APP23 mice at all ages were impaired in latency and distance swum before finding the platform. Identical performance of 18-month APP23 and controls in a visible platform condition indicates that the Morris maze performance deficit was not due to sensory, motor or motivational alterations. At age 3 months both groups initially unexpectedly avoided the visible platform, suggesting that in young mice neophobia may contribute significantly to performance in cognitive tests. In conclusion, APP23 mice exhibit both early behavioral impairment in the large Morris maze as well as impairments in passive avoidance and small pool performance that are marked only in old age.     

An enriched environment mitigates the brain-disruptive effects of prenatal diethylstilbestrol exposure in mice

An enriched environment is known to promote structural changes in the brain and to enhance learning and memory performance in rodents. We previously reported that prenatal exposure to diethylstilbestrol (DES) impaired passive avoidance responses and increased levels of phosphorylated Ca²⁺/calmodulin-dependent protein kinase II (pCaMKII) in the hippocampus of mice. In this study, we examined whether an enriched environment affects the behavioral and neurochemical changes induced in mice prenatally exposed to DES. Male DES-exposed mice were placed in a standard or enriched environment at 3 weeks of age and subjected to behavioral testing after 3 weeks of exposure to these environments. Immunoblot analysis and 5-bromodeoxyuridine (BrdU) immunohistochemistry were then performed. In DES-exposed mice reared in an enriched environment, passive avoidance responses were significantly improved compared to those in mice reared in a standard environment. Moreover, the increase in level of pCaMKII in the hippocampus of DES-exposed mice was reversed by rearing in an enriched environment. Numbers of BrdU-positive cells in the dentate gyrus were significantly increased in normal and DES-exposed mice reared in the enriched environment compared to those in mice reared in the standard environment. These findings suggest that rearing in an enriched environment may mitigate the defects in brain function induced by prenatal exposure to endocrine disrupters such as DES.     

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to streptozotocin (STZ) administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to neurofilament heavy chain (NF-H) and myelin basic protein (MBP). Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pinprick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared with non-diabetic mice. To test whether two neurotrophins nerve growth factor (NGF) and/or neurotrophin-3 (NT-3) known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for 2 weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared with diabetic mice treated with insulin for 2 weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared with control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophin-induced increases in dermal innervation and behavior emphasizes the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy.     

Play is indispensable for an adequate development of coping with social challenges in the rat

In this study, young rats were deprived of early social interactions during weeks 4 and 5 of life. Different behavioral tests were conducted in adulthood to study the behavioral responses of rats lacking early social experiences. Juvenile deprivation resulted in decreased social activity and an altered sexual pattern, but did not affect locomotor activity or the performance in the elevated plus maze. Furthermore, behavioral and neuroendocrine responses of juvenile isolated rats were dramatically altered when they were confronted with territorial aggression. Juvenile deprived rats did not readily display a submissive posture in response to the resident and showed no immobility behavior after being returned to the resident's territory, while their plasma corticosterone and adrenaline concentrations were significantly increased compared to nonisolated controls. In contrast, behavioral responses in the shock prod test were not affected by previous isolation. The results suggest that early social experiences are vital for interactions with conspecifics later in life, i.e., aggression, sexual, and social interactions.     

Behavior of male and female rats with septal lesions: Influence of prior gonadectomy

The influence of gonadectomy at different ages upon the behavioral changes induced by septal lesions in adulthood was examined in male and female rats. In both sexes septal lesions increased emotionality, facilitated acquisition of shuttle avoidance responding, increased escape from light onset, depressed rearing in the open field, increased the number of shocks received during passive avoidance acquisition, but did not affect the number of sessions required to acquire or to extinguish the passive avoidance response. In males prepuberal, but not neonatal or adult gonadectomy attenuated hyperemotionality, but gonadectomy had little influence on other behavioral changes produced by septal lesions. Ovariectomy, either prepuberally or in adulthood, also attenuated hyperemotionality in females with lesions. Adult, but not prepuberal ovariectomy rendered females with septal lesions somewhat hypoactive compared to other female groups. Among animals without lesions, females reared more, entered more squares and were less likely to defecate than males during open field tests. Neonatal, but not prepuberal or adult gonadectomy increased both rearing and activity in males. Females also acquired active avoidance behvior and extinguished passive avoidance behavior more rapidly than males and gonadectomy at any age did not abolish the sex differences in these behaviors. Sex differences in behavior and the effects of gonadectomy were generally similar in controls and in animals with septal lesions, suggesting that differences in septal function are not likely to underly sex differences in these behaviors.     

Behavioral assessment of the Ts65Dn mouse,a model for down syndrome: Altered behavior in the elevated plus maze and open field

The Ts65Dn mouse carries a partial trisomy for mouse chromosome 16 in a region that has high homology to the Down syndrome (DS) region of human chromosome 21 and is, thus, a potential animal model of DS. The focus of the present study was to begin to characterize the behavioral phenotype of this mouse to assess its usefulness as a model of aspects of the DS phenotype. The behavior of Ts65Dn and littermate control mice was assessed in the elevated plus maze, lighted and dark open field, and a step-down passive avoidance task. The behavior of Ts65Dn mice in these tests differed considerably from the nontrisomic controls. In the elevated plus maze, Ts65Dn had more total arm visits than controls, showed a higher percentage of arm visits to the open arms than control mice, and showed no preference for the closed arms. Ts65Dn mice were more active in both open-field situations, regardless of light condition, and ventured into the center of the arena more than controls. Lighting in the open field had moderate effects on the activity of the Ts65Dn mice, but control mice were, as expected, much more active in the dark than the light. The trisomic mice learned and retained the step-down passive avoidance task in the same number of trials as the controls. Overall, these data indicate that Ts65Dn mice are more active than control mice in two testing situations. Most striking is the finding that the Ts65Dn mice were much less responsive to variations in environmental cues to which normal mice are quite sensitive. These data not only begin to characterize systematically the Ts65Dn phenotype, but also raise several interesting issues about the sources of the aberrant behaviors observed in these mice.     

Immunoglobulin-Mediated Neuro-Cognitive Impairment: New Data and a Comprehensive Review

Excessive influx of immunoglobulin (IgG) into the brain has been reported to induce central nervous system (CNS) dysfunction. Depressed patients may exhibit immune activation manifested by elevated inflammatory markers and pro-inflammatory cytokines. The brain and especially the limbic system contain high concentrations of high affinity Fc receptors. We reviewed the literature on this phenomena and present data on the behavioral effects of pooled normal IgG on the brain. Many disease states are associated with depression and we examined whether this may be linked to high IgG influx. Female Balb/C mice were injected intra-cerbroventricularly with human immunoglobulin whole molecule, or human IgG F(ab′)₂ or Fc fragments. Control mice were injected with saline. The four groups were subjected to behavioral (staircase, forced swimming test, and elevated plus maze) and cognitive tests (passive avoidance test). IgG-injected mice exhibited depression-like behavior as reflected by significantly higher immobility time in the forced swimming test (p?<?0.05) and hyperactive behavior as reflected by higher number of stairs climbed in the staircase test compared to controls (p?<?0.01). Fc-fragments-injected mice showed hyperactive behavior as reflected by both higher number of stairs climbed and rearing events in the staircase test compared to controls. The results indicate that high levels of normal IgG in the cerebrospinal fluid can cause hyperactivity and depression-like behavior. The mechanism involved in these CNS manifestations include possibly Fc receptor binding.     

Differential effects of lipopolysaccharide in the social behavior of dominant and submissive mice

Acutely infected animals show a set of non-specific behavioral changes known as sickness behavior. Recent studies have shown that occurrence of sickness behavior is regulated according to a motivational perspective. Thus, the display of sickness behavior may compete with display of other behaviors. In this work, we sought to determine the effects of lipopolysaccharide (LPS) administration (15 microg/mouse i.p.) in the social behavior of dominant and submissive mice. Results showed that social hierarchy influences the expression of sickness behavior. While dominant mice treated with LPS showed an expected reduction in total frequency of behaviors displayed, such decrease did not happen following the same treatment to submissive mice. Similar results occurred regarding social and aggressive behavior. The use of a motivational perspective provides the assumption that, due to their high social ranking, dominant mice were able to prioritize recuperative behavior. Submissive mice, on the other hand, even though treated with LPS, seemed to essentially focus on social defensive behaviors since they remained in the presence of the dominant individuals. Effects of sickness on the hierarchical organization of mice remain to be further investigated.     

Senescence-accelerated mouse (SAM): age-related reduced anxiety-like behavior in the SAM-P/8 strain.

Age-related behavioral changes in the passive avoidance, food neophobia, elevated plus-maze, and water-lick conflict tests were studied using substrains of senescence-accelerated mouse (SAM-P/8 and SAM-R/1) at 2 to 20 months of age. SAM-P/8 mice exhibited a significant impairment of acquisition of passive avoidance compared with SAM-R/1 mice when they were trained repeatedly, and the acquired response in SAM-P/8 mice rapidly diminished in contrast to good retention in SAM-R/1 mice. SAM-P/8 mice showed an age-related decrease in the latency to eat novel food after a 24-h food deprivation as compared with SAM-R/1 mice at 2 to 12 months of age, despite no significant difference in latency to eat familiar food between the two strains. In the elevated plus-maze test, SAM-P/8 mice had apparent increases in the number of entries into open arms and time spent on open arms in comparison to SAM-R/1 mice at 4 through 12 months of age; this difference became obvious with aging, implying age-associated reduced anxiety in the SAM-P/8 strain. In addition, SAM-P/8 mice exhibited a significant increase in punished water drinking compared to SAM-R/1 mice in the water-lick conflict test, although unpunished water intake in SAM-P/8 mice did not differ from that in the SAM-R/1 control. Aged SAM-R/1 mice, 20 months old, exhibited low anxiety-like behavior in the food neophobia and elevated plus-maze tests such as was seen in SAM-P/8 mice, when compared with young (4-month-old) SAM-R/1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Variations in behavior, innate immunity and host resistance to B16F10 melanoma growth in mice that present social stable hierarchical ranks

The present study analyzed the effect of social stable hierarchical dominance/submissive relationships in C57BL/6 mice on behavior, innate immunity, serum corticosterone levels and host resistance to B16F10 melanoma growth. Adult mice (90 days old) kept in pairs since weaning, were analyzed for dominant/submissive ranking in three consecutive days according to the presence or absence of fighting and/or anticipatory submissive responses. Only the pairs of mice where dominant/submissive relationships were clearly stated were employed. Results showed that submissive mice presented in relation to dominants: (1) decreased time spent in the central open-field area; (2) decreased number of entries into the open arms and decreased time spent in the exploration of the open arms of the plus maze; (3) increased time spent in exploration of the plus-maze closed arms; (4) decreased number of entries and in the time spent in the exploration of the third part of the plus-maze open arms; (5) increased number of B16F10 metastasis in the lungs; (6) decreased NK cell cytotoxicity measured in vitro in the peripheral blood and spleen; (7) decreased basal but not in S. aureus induced oxidative burst in both neutrophils and monocytes and (8) similar basal serum levels of corticosterone. The present behavioral findings show that submissive mice, within a stable social hierarchy, present anxiety like-responses a fact that would make than more prone to stressful stimuli. This condition would be responsible for the decreases presently observed on basal neutrophil oxidative burst, NK cell activity and resistance to B16F10 tumor growth. Together the obtained data show that mice that present stable hierarchical relationships display neuro-immune alterations comparable to those reported in mice under a situation of chronic social stress.     

Altered T-lymphocyte response following aggressive encounters in mice

Intermale aggression is a natural form of psychosocial stress that can alter a variety of physiological functions, including immune function. In Experiment 1, daily fighting between pairs of previously isolated male mice differentially altered immunological measures of T-cell responsiveness in dominant and submissive animals. Submissive mice had lower T-cell proliferation and IL-2 production, when compared to dominant, nonfought, or witness mice. Since the fighting behavior often results in wounding of the submissive animal, Experiment 2 used a relatively nonaggressive test to determine whether the immunological differences between dominant and submissive mice were due to wounding or due to the psychosocial state of dominance. Dominant mice had elevated T-cell proliferation and IL-2 production when compared to the other treatment groups. Therefore, it appears that in dominant/submissive pairs of mice a severe physical stress, such as intense fighting, influences the immune system in a different manner than psychological or mild aggressive encounters.