Behavior In CD-1 Mice Research Articles

Comparative study of the effects of adamantane derivatives on the behavior of CD-1 mice with different phenotype of attention stability

The effect of memantine (1 and 10 mg/kg/day), ladasten (50 mg/kg/day) and cyclantane (10 mg/kg/day) on the behavior of CD-1 mice differing in the phenotype of attention stability in the "closed enriched cross maze" test after three days of intraperitoneal administration was studied. It was found that in a subpopulation of mice with an initial attention deficit, these aminoadamantane derivatives partially restored the level of attention. The drugs equally worsened attention in a subpopulation with an initially high attention index by 40–47 % relative to the control, which indicates the absence of selectivity of the effect of these drugs with respect to attention deficit. However, this effect was not accompanied by a change in exploratory and locomotor activity, which makes it possible to make an assumption about the prospects for further study of the pharmacological effects of adamantane derivatives and optimization of their dose and duration of administration.

Memantine Disrupts Motor Coordination through Anxiety-like Behavior in CD1 Mice

Memantine is an FDA approved drug for the treatment of Alzheimer’s disease. It reduces neurodegeneration in the hippocampus and cerebral cortex through the inhibition of extrasynaptic NMDA receptors in patients and mouse models. Potentially, it could prevent neurodegeneration in other brain areas and caused by other diseases. We previously used memantine to prevent functional damage and to retain morphology of cerebellar neurons and Bergmann glia in an optogenetic mouse model of spinocerebellar ataxia type-1 (SCA1). However, before suggesting wider use of memantine in clinics, its side effects must be carefully evaluated. Blockers of NMDA receptors are controversial in terms of their effects on anxiety. Here, we investigated the effects of chronic application of memantine over 9 weeks to CD1 mice and examined rotarod performance and anxiety-related behaviors. Memantine-treated mice exhibited an inability to adapt to anxiety-causing conditions which strongly affected their rotarod performance. A tail suspension test revealed increased signs of behavioral despair. These data provide further insights into the potential deleterious effects of memantine which may result from the lack of adaptation to novel, stressful conditions. This effect of memantine may affect the results of tests used to assess motor performance and should be considered during clinical trials of memantine in patients.

Polyethylene Glycol 3350 Changes Stool Consistency and the Microbiome but not Behavior of CD1 Mice.

Polyethylene Glycol 3350 (PEG3350) is a laxative commonly used to treat constipation in children. The Food and Drug Administration has received reports of increased anxiety, aggression, and obsessive--compulsive behaviors in children administered PEG3350. Thus, we assessed whether daily administration of PEG3350 leads to anxiety-like behavior in mice. Outbred CD-1 IGS mice were administered either a high or a low dose of PEG3350 via daily oral gavage for 2 weeks. As a laxative comparison and control, additional mice were given a high or low dose of magnesium citrate or vehicle (water). Weight and stool consistency were assessed after each gavage to determine laxative effectiveness. Anxiety-like behaviors were assessed using light/dark, open field, and elevated plus maze (EPM) tests at baseline, after 2 weeks of daily gavage, and after a 2 week washout in experiment 1, and after 2 weeks of daily gavage in experiment 2. Stool samples were collected for microbiome analysis in experiment 2 at baseline, after 2 weeks of daily gavage, and after 2 weeks washout. PEG3350 and magnesium citrate significantly changed stool consistency, as well as microbiome alpha and beta diversity. Anxiety-like behaviors were not, however, different in mice administered low or high doses of PEG3350 or magnesium citrate. Although changes in stool consistency and the gut microbiome occurred, administration of PEG3350 did not alter anxiety-like behaviors.

Anxious Behavior of Adult CD1 Mice Perinatally Exposed to Low Concentrations of Ethanol Correlates With Morphological Changes in Cingulate Cortex and Amygdala.

Perinatal ethanol (EtOH) exposure is associated with high incidence of behavioral disorders such as depression and anxiety. The cerebral areas related with these consequences involve the corticolimbic system, in particular the prefrontal cortex, hippocampus, amygdala, and cingulate cortex, although the latter has not been thoroughly studied yet. Different animal models of prenatal or perinatal EtOH exposure have reported morphofunctional alterations in the central nervous system, which could explain behavioral disorders along life; these results focus on youth and adolescents and are still controversial. In the light of these inconclusive results, the aim of this work was to analyze adult behavior in CD1 mice perinatally exposed to low concentrations of EtOH (PEE) during gestation and lactation, and describe the morphology of the cingulate cortex and amygdala with a view to establishing structure/function/behavior correlations. Primiparous CD1 female mice were exposed to EtOH 6% v/v for 20 days prior to mating and continued drinking EtOH 6% v/v during pregnancy and lactation. After weaning, male pups were fed food and water ad libitum until 77 days of age, when behavioral and morphological studies were performed. Mouse behavior was analyzed through light–dark box and open field tests. Parameters related to anxious behavior and locomotor activity revealed anxiogenic behavior in PEE mice. After behavioral studies, mice were perfused and neurons, axons, serotonin transporter, 5HT, CB1 receptor (CB1R) and 5HT1A receptor (5HT1AR) were studied by immunofluorescence and immunohistochemistry in brain sections containing cingulate cortex and amygdala. Cingulate cortex and amygdala cytoarchitecture were preserved in adult PEE mice, although a smaller number of neurons was detected in the amygdala. Cingulate cortex axons demonstrated disorganized radial distribution and reduced area. Serotonergic and endocannabinoid systems, both involved in anxious behavior, showed differential expression. Serotonergic afferents were lower in both brain areas of PEE animals, while 5HT1AR expression was lower in the cingulate cortex and higher in the amygdala. The expression of CB1R was lower only in the amygdala. In sum, EtOH exposure during early brain development induces morphological changes in structures of the limbic system and its neuromodulation, which persist into adulthood and may be responsible for anxious behavior.

Proprioceptive stimuli and habit formation: Interresponse time mediated behavior in CD-1 mice

The consolidation of behavioral sequences into relatively ballistic habits is thought to involve the formation of stimulus – response associations. Typically, the stimuli in these associations are assumed to be exteroceptive, i.e., external to the organism. However, responses, themselves, also possess stimulus properties that can mediate behavior. Indeed, these “proprioceptive cues” have long been hypothesized to underlie habit formation (Hull, 1934a, 1934b). One such stimulus involves the time durations between responses – a stimulus termed interresponse time (IRT). We hypothesize that IRTs can come to serve as stimuli that differentially control response elements during habit formation. To examine this hypothesis we report on two experiments that asked whether CD-1 mice utilize IRTs to structure behavior in a two-choice environment. In experiment 1, eight mice were exposed to a free-operant concurrent variable-interval (VI) 30-s VI 60-s reinforcement schedule. We found that switch and stay responses were differentially correlated with IRT durations. In Experiment 2 we directly and differentially reinforced stay/switch responses based on IRT durations in a two-lever procedure. For four of the subjects, the probability of receiving reinforcement after switch responses was proportional to IRT duration. For five of the subjects, these reinforcement probabilities were inversely proportional to IRT duration. Regardless, all of our subjects learned to emit IRT-mediated switching behavior that matched the reinforcement contingencies. Together, Experiments 1 and 2 provide the first evidence of which we are aware that IRTs can come to control sequential choice behavior in mice.

Bisphenol S Alters the Lactating Mammary Gland and Nursing Behaviors in Mice Exposed During Pregnancy and Lactation.

High doses of estrogenic pharmaceuticals were once prescribed to women to halt lactation. Yet, the effects of low-level xenoestrogens on lactation remain poorly studied. We investigated the effects of bisphenol S (BPS), an estrogen receptor (ER) agonist, on the lactating mammary gland; the arcuate nucleus, a region of the hypothalamus important for neuroendocrine control of lactational behaviors; and nursing behavior in CD-1 mice. Female mice were exposed to vehicle, 2 or 200 µg BPS/kg/d from pregnancy day 9 until lactational day (LD) 20, and tissues were collected on LD21. Tissues were also collected from a second group at LD2. BPS exposure significantly reduced the fraction of the mammary gland comprised of lobules, the milk-producing units, on LD21, but not LD2. BPS also altered expression of Esr1 and ERα in the mammary gland at LD21, consistent with early involution. In the arcuate nucleus, no changes were observed in expression of signal transducer and activator of transcription 5, a marker of prolactin signaling, or ERα, suggesting that BPS may act directly on the mammary gland. However, observations of nursing behavior collected during the lactational period revealed stage-specific effects on both pup and maternal nursing behaviors; BPS-treated dams spent significantly more time nursing later in the lactational period, and BPS-treated pups were less likely to initiate nursing. Pup growth and development were also stunted. These data indicate that low doses of BPS can alter lactational behaviors and the maternal mammary gland. Together, they support the hypothesis that pregnancy and lactation are sensitive to low-dose xenoestrogen exposures.

Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice.

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.

Leucine blocks lipopolysaccharide-induced depression-like behavior by interfering with kynurenine influx into the brain.

Inflammation activates the tryptophan-kynurenine metabolism pathway. Circulating kynurenine is transported into the brain at the vascular blood–brain barrier (BBB) by the large amino-acid transporter LAT-1, where it is further metabolized into neurotoxic metabolites responsible for depressive symptoms. LAT-1 transports tryptophan, kynurenine and the amino acid leucine. We sought to competitively inhibit kynurenine blood-to-brain transport with leucine in order to attenuate lipopolysaccharide-induced depression-like behavior in CD-1 mice. Given that the concentration of circulating kynurenine is 100 fold less than kynurenine, we hypothesized that leucine should inhibit kynurenine more than tryptophan transport. We had already demonstrated that inflammation increases luminal-to-abluminal transport of tryptophan using an in vitro model of BBB transport. Here we show that lipopolysaccharide-treated mice (0.83 mg/kg, ip) develop depression-like behavior at 24 h (reduced sucrose preference and increased forced swim test immobility; p p p p

Preference for high-fat diet is developed by young Swiss CD1 mice after short-term feeding and is prevented by NMDA receptor antagonists

Obesity is a worldwide epidemic that is increasing at an alarming rate. One of its causes is the increased availability and consumption of diets rich in fat. In the present study, we investigated the effects of short-term consumption of a high fat diet (HFD) on dietary preferences in Swiss CD1 mice and its relation in time to specific metabolic effects. Mice that were weaned 21days postpartum and fed a chow diet for one week were afterward subjected to a diet preference test for 5days, exposed to both a regular diet (RD) and HFD. We found that mice did not show any preferences. In a second experiment, two groups of mice that were weaned 21days postpartum and subjected to a chow diet for one week were fed either RD or HFD for 18days, and a diet preference test was performed for 5days. After this short-term consumption of HFD, mice preferred HFD, while mice subjected to RD did not show any preference. Importantly, no differences in blood glucose levels were found between the groups prior to and after the experiments. The results support our hypothesis that the preference for HFD is not a spontaneous behavior in CD1 mice, but it can be observed after short-term consumption; additionally, this preference develops before metabolic effects appear. Finally, this preference for HFD could not be observed when the mice were i.p. injected daily with low doses of the NMDA receptor antagonists, ketamine, ifenprodil or MK-801 during the HFD feeding period. These data suggest that acquisition of dietary preference for HFD is a NMDA receptor-dependent learning process.

The glycolytic metabolite methylglyoxal induces changes in vigilance by generating low-amplitude non-REM sleep

Methylglyoxal (MG), an essential by-product of glycolysis, is a highly reactive endogenous α-oxoaldehyde. Although high levels of MG are cytotoxic, physiological doses of MG were shown to reduce anxiety-related behavior through selective activation of γ-aminobutyric acid type A (GABAA) receptors. Because the latter play a major role in sleep induction, this study examined the potential of MG to regulate sleep. Specifically, we assessed how MG influences sleep-wake behavior in CD1 mice that received intracerebroventricular injections of either vehicle or 0.7 µmol MG at onset of darkness. We used electroencephalogram (EEG) and electromyogram (EMG) recordings to monitor changes in vigilance states, sleep architecture and the EEG spectrum, for 24 h after receipt of injections. Administration of MG rapidly induced non-rapid eye movement sleep (NREMS) and, concomitantly, decreased wakefulness and suppressed EEG delta power during NREMS. In addition, MG robustly enhanced the amount and number of episodes of an unclassified state of vigilance in which EMG, as well as EEG delta and theta power, were very low. MG did not affect overall rapid eye movement sleep (REMS) in a given 24-h period, but significantly reduced the power of theta activity during REMS. Our results provide the first evidence that MG can exert sleep-promoting properties by triggering low-amplitude NREMS.

Voluntary Wheel Running Does Not Attenuate Lps Induced Sickness Behavior In Cd-1 Mice

Voluntary Wheel Running Does Not Attenuate Lps Induced Sickness Behavior In Cd-1 Mice

Modulation of anxiety by acute blockade and genetic deletion of the CB 1 cannabinoid receptor in mice together with biogenic amine changes in the forebrain

The CB 1 cannabinoid receptor has been implicated in the control of fear and anxiety. We investigated the effects of genetic and pharmacological blockade of the CB 1 cannabinoid receptor on the behaviour of CD1 mice using three different ethological models of fear and anxiety (elevated T-maze and plus-maze and open field test of emotionality). Furthermore, we measured tissue levels of noradrenalin (NA), dopamine (DA), serotonin (5-HT) and their metabolites in several forebrain regions, i.e. prefrontal cortex, hippocampus, septum, dorsal and ventral striatum to examine the relationship between CB 1 receptor manipulation and monoaminergic neurotransmission. The major findings can be summarized as follows: The CB 1 receptor antagonist SR141617A (rimonabant) modulated anxiety in a dose-dependent manner. At a dose of 3 mg/kg i.p., the compound consistently increased anxiety parameters in all of the three different anxiety tests applied, while a lower dosage of 1 mg/kg had no such effect. The neurochemical evaluation of the mice administered 3 mg/kg SR141617A revealed increases in the concentrations of DOPAC and 5-HIAA in the dorsal striatum, elevated DA levels in the hippocampus and reduced dopamine turnover in the septum. Furthermore, these animals had a higher HVA/DA turnover in the frontal cortex. CB 1 receptor knockout mice as well as mice treated with the selective CB 1 receptor antagonist AM251 (3 mg/kg; i.p.) did not display any significant alterations in anxiety-related behaviour as measured with the elevated plus-maze and open field test of emotionality, respectively. Our findings support the general idea of a SR141617A-sensitive receptive site that is different from the ‘classical’ CB 1 receptor and that has a pivotal role in the regulation of different psychological functions. However, with regard to its functional significance in terms of anxiety our findings suggest that under physiological conditions this receptive site seems to be involved in the control of anxiolysis rather than anxiogenesis as suggested previously.

Effects of acute hypergravity exposure and parity on maternal behavior in CD-1 mice

We assessed the behavioral response to acute hypergravity exposure in lactating mother mice, Mus musculus of the outbred CD-1 strain. Primiparous or terziparous dams were exposed with their litters to a centrifugal force equivalent to 2G hypergravity for 1 h daily from postnatal day 2 (P2) to P9. We made detailed behavioral observations before, during and after the rotation on selected days to identify elements of the maternal behavioral repertoire vulnerable to 2G challenge. Licking and nest building were reduced during rotation while mothers sniffed and snouted their pups more. Nursing and total time in physical contact with pups were relatively stable. The effects of rotation were most pronounced on P2, dams appearing to habituate to the treatment with repeated exposure. Dam parity had a limited effect on the behavioral response to rotation, primiparous mothers tending to spend longer nursing their pups during the rotation and showing a greater tendency to lick and nest-build in post-rotation. Differences between parity groups diminished over days. Body weight was decreased in rotated primiparous dams and their pups gained less weight than stationary controls. Ultrasonic vocalization (USV) rates recorded on P2, P5 and P9 seemed to indicate delayed behavioral development in rotated pups.

The Role of Muscle Larvae of Trichinella spiralis in the Behavioral Alterations of the Mouse Host

The effects of early and encysted muscle larvae of Trichinella spiralis on the open-field behavior of CD-1 mice were studied. Chemotherapy with fenbendazole prior to encystment of larvae prevented the development of behavioral changes in mice. The chemotherapeutic destruction of encysted muscle larvae restored the ambulatory activity of mice to normal levels. The study suggests that muscle larvae are the etiological agents of behavioral alterations in the mouse host.