Right-pawed Mice Research Articles

Differential responses of stressful elements to predatory exposure in behavior-lateralized mice

BackgroundPredatory stress as a psychological stressor can elicit the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which is involved in the dialogue of the neuroimmunoendocrine network. The brain has been proven to regulate the activity of the HPA axis by way of lateralization. In the present study, we probed the pivotal elements of the HPA circuitry including CRH, GR and a multifunctional cytokine in behavior-lateralized mice to determine their changes when the animals were subjected to predator exposure.MethodsBehavior-lateralized mice were classified into left-pawed and right-pawed mice through a paw-preference test. Thereafter, mice in the acute stress group received a single 60-min cat exposure, and mice in the chronic group received daily 60-min cat exposure for 14 consecutive days. The plasma CS and TNF-α were determined by ELISA, the hypothalamic CRH mRNA and hippocampal GR mRNA were detected by real-time PCR, and the hippocampal GR protein was detected by western blot analysis.ResultsThe results revealed that the levels of plasma CS were significantly elevated after chronic predatory exposure in both right-pawed and left-pawed mice; the right-pawed mice exhibited a higher plasma CS level than the left-pawed mice. Similarly, the acute or chronic cat exposure could induce the release of plasma TNF-α, and the left-pawed mice tended to show a higher level after the acute stress. Chronic stress significantly upregulated the expression of hypothalamic CRH mRNA in both left-pawed and right-pawed mice. Normally, the left-pawed mice exhibited a higher GR expression in the hippocampus than the right-pawed mice. After the cat exposure, the expression of GR in both left-pawed and right-pawed mice was revealed to be greatly downregulated.ConclusionOur findings indicate that predatory stress can invoke a differential response of stressful elements in behavior-lateralized mice. Some of these responses shaped by behavioral lateralization might be helpful for facilitating adaption to various stimuli.

Predator exposure-induced cerebral interleukins are modulated heterogeneously by behavioral asymmetry

Predator exposure is a naturalistic stressor that is likely to elicit a stressful response pattern similar to those experienced in the real world. As a consequence of stress, HPA hormonal activity and the alteration of mediators such as cytokines may result. Behavioral asymmetry, as assessed by paw preference, exerted effects on immune responses and peripheral cytokine production, observed after exposure to the physical stimuli. Thus, we hypothesized that behavioral asymmetry can modulate mouse brain interleukins and HPA activity after exposure to an internally generated psychological stress source. To determine the impact of behavioral asymmetry, mice were divided into left- and right-pawed groups by paw preference. Then, the mice received either a single 60-min or a daily 60-min predator exposure (cat exposure) for 14 consecutive days. After receiving predator exposure, trunk blood was collected and brain tissues, including the cerebral cortex, hippocampus and hypothalamus, were separated. Plasma corticosterone (CS) was detected by EIA, and IL-1β and IL-6 levels in the cortex, hippocampus and hypothalamus, were quantified by ELISA. The results revealed that predator stress, in particular chronic stress, could enhance plasma CS concentration and could alter IL-1β and IL-6 concentrations in the cortex, hippocampus and hypothalamus. Simultaneously, predator stress-induced CS and brain interleukin levels were modulated by behavioral asymmetry. The left-pawed mice showed a decreased variation in CS, less than right-pawed mice, and both left-pawed and right-pawed mice displayed heterogeneous direction and intensity of changes for IL-1β and IL-6 in the cortex, hippocampus and hypothalamus after predator exposure. From these results, it can be concluded that the alteration of cytokines depends on the characteristics of the stressor. Furthermore, the asymmetric cytokine responses within the brain to a natural, psychological stressor may be involved in the immunomodulation of behavioral asymmetry. These findings likely reflect the flexibility in reactivity patterns of a population in response to various insults.

Dynamics of motor asymmetry profiles in striped field mouse (Apodemus agrarius pall.) populations

The ratios between individuals with different signs of motor asymmetry (right-pawed, left-pawed, and ambidextrous) were estimated in two urban populations of striped field mice. Right-pawed mice were prevailing in both populations. An increase in the stress of regulatory system (stress index) in mice from these populations was accompanied by a shift of the asymmetry profile towards a greater proportion of left-pawed mice. The ratio between the numbers of right-pawed and non-right-pawed animals varied with time with a period close to that of the population dynamics. Apparently, the changes in the asymmetry profiles reflected population rearrangement: dominance of animals with a specific set of physiological, ecological, and behavioral characteristics gave way to an increased proportion of animals with a different set of characteristics. Qualitative differences between right- and left-pawed animals are evidenced by the specific characteristics of behavior and humoral immunity found in animals differing in motor lateralization.

In mice, production of plasma IL-1 and IL-6 in response to MPTP is related to behavioral lateralization

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces dopaminergic neuron death in substantia nigra and dopamine loss in striatum, similar to those observed in Parkinson disease. Given MPTP can also induce alterations in brain cytokines and in peripheral immune parameters, we hypothesize that MPTP can induce an elevation of plasma cytokines. We have previously shown that cytokine production depends on behavioral lateralization in certain conditions. Therefore, we further postulate that the MPTP-induced plasma cytokines are related to behavioral lateralization. To answer these questions, C57BL/6J male mice, selected for paw preference, were injected with 25 mg/kg MPTP ip for five consecutive days and were decapitated at day 1, day 3, or day 14 after the last injection. Striatal DA and DOPAC concentration were measured by HPLC and plasma levels of IL-1β and IL-6 were quantified by ELISA. The results showed that after MPTP treatment, striatal DA content was dramatically decreased, IL-1β levels increased on day 3, while IL-6 levels increased on day 14. Interestingly, behavioral lateralization influenced DA/DOPAC ratio as well as plasma IL-1β and IL-6 levels. In left-pawed mice, MPTP induced a higher decrease of DA/DOPAC ratio than in right-pawed mice. The increase of IL-1β was observed in left-pawed but not in right-pawed mice. The elevation of IL-6 was higher in right-pawed mice than in left-pawed mice. These results have clearly demonstrated our hypotheses, that MPTP can induce increase of plasma IL-1β and IL-6 levels in mice, and this effect is shaped by behavioral lateralization.

Callosal agenesis affects consistency of laterality in a paw preference task in BALB/cCF mice

We tested the hypothesis that the ontogenetic development of the corpus callosum (CC) affects the consistency of laterality in a paw preference task. Adult male mice (55 normal and 29 acallosal) of the BALB/cCF strain were initially tested (twice; inter-test interval: 72 h) in an unbiased setup in which both forepaws could easily perform a reaching movement. In a subsequent test, animals were placed in a biased setup that favored the use of the non-preferred paw. Acallosal and normal mice were strongly lateralized in the unbiased setup. Additionally, while normal mice did not present a populational bias favoring one of the paws, acallosal mice presented a significant bias favoring the left paw. In the biased setup, left- and right-pawed normal mice were equally consistent (approximately 65% of the animals, in both groups, used the preferred paw of the initial two tests, in spite of the bias). Conversely, while left-pawed acallosal mice were as consistent (65%) as normal mice, only 20% of right-pawed mice were consistent. These results suggest that the development of the CC affects consistency of laterality in a side-dependent manner. These results are discussed considering the role of the CC in the establishment of behavioral lateralization.

Brain interleukin asymmetries and paw preference in mice

The two sides of the brain are differently involved in the modulation of immune responses as demonstrated by lesion and behavioral approaches. To study the interactions between cerebral cortex cytokines and brain lateralization, three groups of BALB/c mice were selected on the basis of their performance in the paw preference test (left-pawed, ambidextrous and right-pawed) and the levels of interleukin-1β and interleukin-6 were measured in the two cerebral cortices after an intraperitoneal saline or lipopolysaccharide. Generally, right cortices had higher interleukin-1β and interleukin-6 levels than left cortices for both saline and lipopolysaccharide-treated mice. A strong correlation between the levels of interleukin-1β and interleukin-6 in right and left cortices and behavioral lateralization was observed. For the saline-treated mice: in their left cortices, interleukin-1β levels were higher for ambidextrous mice than for right-pawed mice ( P<0.05); in their right cortices, interleukin-6 levels were higher for ambidextrous mice than for right-/left-pawed mice, and right-pawed mice have higher levels of interleukin-6 than left-pawed mice ( P<0.01). In their left cortices, interleukin-6 levels are higher for left-pawed mice than for both ambidextrous and right-pawed mice ( P<0.01). In their left cortices, interleukin-6 levels are higher for left-pawed mice than for both ambidextrous and right-pawed mice ( P<0.01). The quadratic curve equations showed that the levels of interleukin-1β and interleukin-6 in the right/left cortices had a highly significant correlation with paw preference scores in both normal and lipopolysaccharide-treated mice. In conclusion, the present report demonstrated that the basal levels of interleukin-1β and interleukin-6 were higher in the right cortex than left cortex in mice. There was a strong correlation between the levels of interleukin-1β and interleukin-6 and behavioral lateralization, and cytokine asymmetries had a strong correlation with the direction and the intensity of behavioral lateralization.

Cytokine Stress Responses Depend on Lateralization in Mice

In mice, lateralization as assessed by paw preference represents a behavioral trait linked to immune reactivity and stress susceptibility. Right-pawed mice are more reactive to stress than left-pawed animals when brain metabolism, activation of the corticoid axis, and depression of lymphoproliferation are studied. Since stress responses include cytokine production, we address the possibility that lateralization influences the production of cytokines - especially interleukin (IL)-1 - responsible for depression of lymphoproliferation and activation of the corticoid axis. Increased plasma IL-1 level that may be considered as a stress marker, was observed in right- but not in left-pawed mice submitted to a 4 h-restraint. Likewise, plasma levels were greater in right- than in left-pawed animals 2 h after the administration of a low dose of lipopolysaccharides (LPS). By contrast, there was no lateralization effect in restraint-induced plasma level of IL-6 or in the LPS-induced increase in plasma IL-10. Prazosin, an f 1/ f 2 adrenoreceptor antagonist, drastically increased plasma IL-10 induced by LPS, reduced plasma levels of IL-1 and abolished the effect of lateralization observed after LPS alone. This suggests that f -adrenergic modulation of IL-1 production depends on lateralization through mechanisms that need further investigation.

Lateralization and Catecholaminergic Neuroimmunomodulation: Prazosin, an α1/α2-Adrenergic Receptor Antagonist, Suppresses Interleukin-1 and Increases Interleukin-10 Production Induced by Lipopolysaccharides

Objective: The brain has previously been shown to asymmetrically modulate neurochemical, neuroendocrine and immune responses to lipopolysaccharides (LPS). As these responses are reversed by a chemical sympathectomy, it can be hypothesized that the asymmetry in the functioning of the sympathetic nervous system may be one of the mechanisms by which the brain hemispheres asymmetrically modulate immune reactivity. Methods: The effects of prazosin, an α1/α2-adrenergic receptor antagonist, on the production of interleukin (IL)-1β and IL-10 induced by LPS was studied in mice selected for their paw preference. Results: Two hours after intraperitoneal injection of 5 µg of LPS, plasma levels of IL-1β were higher in right-pawed mice as compared to left-pawed or ambidextrous animals. No lateralization effect was observed for LPS-induced plasma IL-10 levels. Prazosin, 10 mg/kg, injected intraperitoneally half an hour before LPS, reduced plasma levels of IL-1β and abolished the effect of lateralization. By contrast, prazosin drastically increased plasma levels of IL-10 in response to LPS and the production of corticosterone in untreated controls. Conclusions: These results suggest that the catecholaminergic modulation of immune reactivity depends on lateralization. This work further demonstrates that prazosin is endowed with anti-inflammatory properties that may be considered side effects of this drug, which is widely prescribed in the treatment of hypertension.

Strain-Dependent Association between Lateralization and Lipopolysaccharide- Induced IL-1β and IL-6 Production in Mice

Objective: The brain modulates the immune system in an asymmetrical way, as shown by the association between paw preference and immune response in the mouse. We predicted that the production of cytokines, which are one of the molecular pathways for brain-immune interactions, should be linked to lateralization in a strain-dependent manner. Methods: We therefore measured plasma levels of interleukin (IL)-1β and IL-6 after an intraperitoneal injection of lipopolysaccharide (LPS) in two strains of mice (C3H and BALB/c) that were selected for their different profiles of cytokine production. Results: Plasma levels of IL-1β and IL-6 increased after LPS injection in both strains and this increase was dependent on paw preference in BALB/c but not in C3H mice. Increased levels of IL-1β were observed in left-pawed and ambidextrous but not in right-pawed mice. For IL-6, the LPS-induced increase was higher in ambidextrous than in left- and right-pawed animals. Conclusion: Cytokines may represent one of the factors responsible for interindividual differences in brain-immune interactions.

Interleukin-1-Induced Sickness Behavior Depends on Behavioral Lateralization in Mice

Neveu, P. J., R.-M. Bluthé, S. Liè GE, S. Moya, B. Michaud and R. Dantzer. Interleukin-1-induced sickness behavior depends on behavioral lateralization in mice. Physiol Behav 63(4) 587–590, 1998. Inter-individual differences in brain-immune interactions have been demonstrated previously in mice using lateralization as a behavioral trait of population heterogeneity. Lipopolysaccharide (LPS), which is known to induce neurochemical, neuroendocrine, and immune responses depending on lateralization, is also able to induce sickness behavior, via the production of interleukin-1 (IL-1). The objective of this study was to determine whether lateralization can influence the behavioral response to LPS and to IL-1. To test this hypothesis, adult female C3H mice, previously selected for paw preference in a food reaching task, were injected intraperitoneally (i.p.) with 0.75 μg LPS or 0.75 μg recombinant IL-1β. Sickness induced by these molecules was measured by depressed social behavior, increased immobility, loss of body weight, and reduced food intake during the 6 h following injection. LPS-induced sickness was similar in right- and left-pawed mice. In contrast, IL-1-induced sickness behavior was dependent on behavioral lateralization. IL-1-induced depression of social investigation was more pronounced in right-pawed mice than in left-pawed animals. Likewise, IL-1-induced immobility was more important in right-pawed mice. There was a similar trend for food intake to be lower and loss of body weight to be higher in right-pawed mice than in left-pawed animals. These results demonstrate that right-pawed mice are more sensitive to IL-1-induced sickness than left-pawed animals. They extend our previous data showing a greater susceptibility to stress of right-pawed animals. The existence of inter-individual differences in the reactivity to stress or immune activation may be useful to study the mechanisms of the various strategies used by an individual in response to environmental aggressions.

Differential prolactin responsiveness to stress in left- and right-pawed mice

Behavioral laterality has been shown to be related to immunological and endocrinological responsiveness in mice. The current study extended these findings by examining the pituitary hormone prolactin, and its response to stress, in left- and right-pawed mice. In two experiments, mice were tested on two measures of behavioral laterality, the Collins paw preference test and the Lateral Paw Preference (LPP) test. Circulating PRL levels were then measured in all subjects under baseline and stressed conditions. In Experiment 1, the PRL stress response was related to Collins paw preference in interaction with coat-color among females of a genetically heterogeneous group. Left-pawed black females showed a significant increase in PRL, while right-pawed black females did not. Among agouti mice, left-pawed females showed a significant decrease, while right-pawed did not. Experiment 2 used a genetically homogeneous group of agouti CM mice. Again there were effects of Collins paw preference among females, with the right-pawed showing a significant increase in PRL following stress. In neither experiment were there effects of LPP. In neither experiment were there lateralized differences among males. These results indicate lateralized regulation of PRL among females, similar to that previously observed for ACTH regulation.

Genetic variation in paw preference (handedness) in the mouse.

Lateralization of paw preference in laboratory mice in a single-paw reaching task has been used as a model system for left- and right-hand usage. Given a set number of paw reaches for food from a centrally placed food tube, an individual mouse will exhibit a reliable number of left and right paw reaches. Within any single inbred strain, there are approximately equal numbers of left-pawed and right-pawed mice. Nevertheless, significant strain differences have been reported for the degree of lateralization of paw preference. We report here a systematic survey of paw preference in 12 inbred strains of the mouse in which the degree of lateralization falls into two groups of weakly lateralized and highly lateralized paw preference. The genetic inference is that a single major gene may control some function, and alternate alleles at this locus are expressed as weakly and highly lateralized paw preference. Reciprocal crosses indicate the trait is additive with no maternal or X-linked effects. The direction of paw preference has previously appeared to be genetically neutral, but in some strains there is evidence of significant deviation of the numbers of mice to the left and right of equal paw usage, independent of degree of lateralization, and this suggests that direction of left-right paw usage may be a separate genetic trait in the mouse model.