Long-term treatment with the antioxidant drug EGb 761 at senescence restored some neurobehavioral effects of chronic ultramild stress exposure seen in young mice.

In this study, we compared the effects of chronic ultramild stress (CUMS) exposure on decision-making behavior in a validated test, and on the stress responsive serotoninergic and dopaminergic systems in four age groups of B6D2F1 female mice (5-6, 11-12, 17-18 and 23-24 months old). The levels of serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5-HIAA) were measured in the brain stem, the cortex, the striatum and the hippocampus; the levels of dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) were measured in the brain stem and the striatum. The influence of a long-term treatment with the extract of Ginkgo biloba leaves EGb 761 (Tanakan) on age- and stress-related changes was also investigated in the two oldest age groups. In the absence of drug treatment, middle-age mice were the least efficient in making a decision, and senescent mice exhibited reduced levels of both 5-HT and DA and their metabolites in all the brain areas examined. CUMS facilitated evaluation and choice behavior in all age groups, but induced age-dependent reduction of hesitation, acceleration of information processing and reduction in serotoninergic neurotransmission. In senescent mice, EGb 761 reduced the impact of stress on evaluation and hesitation, and restored some stress-related neurobehavioral changes that were only seen in young mice, i.e. acceleration of information processing and reduction in brain 5-HIAA levels. Restoration of some plasticity of the serotoninergic systems might contribute to the stress alleviating influence of EGb 761 in old age.

Animal models of Parkinson's disease in rodents induced by toxins: an update.

The development of animal models of Parkinson's disease is of great importance in order to test substitutive or neuroprotective strategies for Parkinson's disease. Such models should reproduce the main characteristics of the disease, such as a selective lesion of dopaminergic neurons that evolves over time and the presence of neuronal inclusions known as Lewy bodies. Optimally, such models should also reproduce the lesion of non-dopaminergic neurons observed in a great majority of patients with Parkinson's disease. From a behavioral point of view, a parkinsonian syndrome should be observed, ideally with akinesia, rigidity and rest tremor. These symptoms should be alleviated by dopamine replacement therapy, which may in turn lead to side effects such as dyskinesia. In this review, we analyze the main characteristics of experimental models of Parkinson's disease induced by neurotoxic compounds such as 6-hydroxydopamine, MPTP and rotenone. We show that, whereas MPTP and 6-hydroxydopamine induce a selective loss of catecholaminergic neurons that in most cases evolves over a short period of time, rotenone infusion by osmotic pumps can induce a chronically progressive degeneration of dopaminergic neurons and also of non-dopaminergic neurons in both the basal ganglia and the brainstem.

Age-dependent effects of a chronic ultramild stress procedure on open-field behaviour in B6D2F1 female mice.

Few studies have been devoted to the interaction between age and stress. However, in view of the age-related changes in various components of the stress responses, the effects of stress may not be constant with age. In this study, we used a dimensional approach to compare open-field behaviour of B6D2F1 female mice, aged 5-6, 11-12, 17-18 and 23-24 months, exposed to a chronic ultramild stress (CUMS) procedure, solely based on nonnociceptive socioenvironmental stressors. Three behavioural dimensions emerged from the principal-component analysis; these were labelled as motor reactivity, exploratory activity, and emotional reactivity. Despite a major effect of age on the three dimensions, we could not conclude that CUMS had any influence as a function the age of the subjects. At all ages, CUMS increased motor activity and had no clear-cut effect on emotional reactivity and exploratory activity. The results are discussed in terms of the influence of the nature of the stressors on behavioural responses to novelty.

Influence of prepartum chronic ultramild stress on maternal pup care behavior in mice.

BACKGROUND: Stress administered to pregnant rodents has been shown to lead to biological and behavioral alterations in both mother and pups. Most of these stress procedures use noxious stressors. Chronicity is obtained by simple repetition of one or two stressors and may be more representative of moderate daily stress experienced during normal life than stress during severe life events. The effects of this procedure were assessed by observing maternal pup-care behavior and testing maternal aggression. METHODS: The subjects included eight controls and eight stressed B6D2F1 females. Chronic ultramild stress was applied from mating to postpartum day (PD) 0. Pup-care behavior was observed on PD 1. Maternal aggression against a male intruder was tested on PD 8, which corresponds to the peak in the display of this behavior. RESULTS: Prenatal stress did not affect basic pup-care behavior, but dramatically impaired defense behavior designed to protect the pups from an external attacker. CONCLUSIONS: The results suggest that gestating females subjected to chronic ultramild stress suffer from a long-lasting decline in recognition of external distress cues either from a resident intruder and/or their own litter. It is assumed these effects are due to the chronicity of the stress rather than its severity.

Influence of a chronic ultramild stress procedure on decision-making in mice.

OBJECTIVE: To test the influence of a chronic ultra mild stress (CUMS) procedure, based solely on socio-environmental stressors, on cognitive-behavioural function in mice. DESIGN: Behavioural study. PARTICIPANTS: B6D2F1 mice. INTERVENTIONS: Mice were exposed to various stressors and then tested using a decision-making task. RESULTS: We observed that stress facilitated "choice" behaviour, with an absence of "no choice" behaviour. Stress also facilitated a more rapid capacity to process information, a decrease in the level of evaluation of the choice situation and less hesitation. These stress-related consequences on decision making may be attributed to a higher level of distractability in the stressed mice. CONCLUSIONS: The CUMS model may be useful for the study of stress-related disorders by proposing a new method for assessing gene-environment interactions in cognitive-affective behaviours.

In vivo regulation of cerebral monoamine oxidase activity in senescent controls and chronically stressed mice by long-term treatment with Ginkgo biloba extract (EGb 761).

It is well recognized that Ginkgo biloba extract (EGb 761) exert beneficial effects against various age-related changes and is able to reduce the negative influence of stress. In view of the age-dependent increase in the activity of the B form of monoamine oxidase (MAO-B) and in view of the anti-stress action of EGb 761 hypothetically attributed to an inhibition of monoamine oxidase by this substance, we investigated the effects of long-term treatment with EGb 761 upon in vivo cerebral MAO-A and -B activities of stressed and unstressed 17- and 18-month-old mice. The stress was a 'chronic mild stress' regimen whose behavioral impact is known to be reduced by EGb 761. The results showed that: (1) EGb761 induced reductions in MAO activity in 18-month-old, but not in 17-month-old mice; the older animals having higher basal MAO activity; (2) in unstressed mice, EGb 761 appeared to reduce the age-induced increase in cerebral MAO activity; (3) MAO-A and -B activities of stressed and treated 18-month-old mice did not differ significantly from the levels observed in unstressed and untreated 17-month-old mice. These results may shed light on the anti-stress effects of Ginkgo biloba extract.

5-HT1A autoreceptor desensitization by chronic ultramild stress in mice.

Electrophysiological and biochemical approaches were used to assess possible changes in central 5-HT neurotransmission in mice that had been subjected to chronic ultramild stress for 8 weeks. This treatment produced a significant decrease in the potency of the 5-HT1A agonist ipsapirone to inhibit the electrical activity of serotoninergic neurons in the dorsal raphe nucleus, without modifying 5-HT1A receptor binding in various brain areas. These data demonstrate that chronic ultramild stress triggers a long term and durable functional desensitization of somatodendritic 5-HT1A autoreceptors in mice.

Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging.

A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.

Vocalizations in newborn mice: genetic analysis.

Two kinds of vocalizations are produced by newborn mice: whistles (between 50 and 150 ms in length), having a narrow bandwidth in each strain that ranges from 30 to 90 kHz; and clicks, which are shorter (about 1 ms) and have a larger bandwidth. These vocalizations were individually recorded in 1-day-old pups from seven inbred strains of laboratory mice, at two temperatures (23 +/- 0.5 and 15 +/- 0.5 degrees C). The numbers of clicks and whistles were counted under these two conditions. Moreover, the length and frequencies at the beginning, apex, and end of the whistles were measured during the 15 degrees C condition. Correlations, including several components-additivity, epistasis (between homozygous loci), and maternal environment-were calculated between the characteristics of the whistles during the 15 degrees C condition. Clicks and whistles were also counted from 1 to 8 days of age during the 15 degrees C condition. The numbers of clicks and whistles were age dependent, with a decrease from day 1 to day 8 for the clicks and a consistent production of whistles. A quantitative genetic analysis was also performed on the 1-day-old pups from the Mendelian generations produced by the inbred strains most contrasting for the number of whistles produced in the cold condition: NZB/BINJ and CBA/H. The heterozygous genotype of the mother induced an increment of the number of whistles. Moreover, a significant part of the additive variance was suspected from the first design, and found with the second one, for this variable. Quantitative genetic analysis showed significant dominance and epistasis between homozygous loci and homozygous and heterozygous loci. This points to multigenic correlates for the number of whistles in this population. The significant additive values for all the variables recorded during the 15 +/- 0.5 degrees C condition and for the number of whistles produced during the 23 +/- 0.5 degrees C condition are compatible with an effect that indicates neither directional nor stabilizing selection. This result is examined in the light of the multichannel sensorial process implicated in maternal behavior in mice.

Age-related morphological changes in the hippocampus in two mouse strains.

The granule cell number (nGR) in the dentate gyrus (DG) has been reported to vary considerably among inbred strains of mice, thus providing proof of some genetically associated components to this variation. Furthermore, several authors have described age-related morphological changes in the DG in both humans and animals, but there is no general agreement in the literature about the occurrence of such changes. The purpose of this study was to investigate for strain differences in hippocampal structure changes in old C57BL/6J (B) and DBA/2J (D) mice as compared with younger ones. The nGR in the DG, as well as other structural parameters of the hippocampus, were determined in female B and D mice of 4 and 24 months. The two-way analysis of variance indicated a significant interaction between 'strain' and 'age' for the nGR, suggesting that this parameter changes differently with age in B and D mice. This finding indicates that these strains could present a differential susceptibility in granule cell aging raising the possibility that age effects on the granule cell population in the DG could be influenced by some hereditary factors.

Effect of long-term treatment with EGb 761 on age-dependent structural changes in the hippocampi of three inbred mouse strains.

Female mice of the inbred strains C57BL/6J, BALB/cJ and DBA/2J were used to determine the possible existence of a genetically-based differential susceptibility to the effects of treatment with an extract of Ginkgo biloba (EGb 761). Timm's silver-sulphide staining method was used to visualize and determine changes in the areas of the hippocampal structures of aged subjects, and more specifically on the projection fields of the mossy fibers which appear to decrease as a function of ageing. Experiments were begun when the animals were 15 months old. Treated animals received EGb 761 (50 mg/kg/day, p.o.) for 7 months in their drinking water. Inter-strain differences existed for the areas of the whole regio inferior, stratum pyramidale, stratum lacunosum moleculare and hilus (CA4) and for the projection field of intra- and infrapyramidal mossy fibers (iipMF) in the CA3 region of the hippocampus. Chronic treatment with EGb 761 significantly increased the projection field of iipMF and significantly reduced the area of the stratum radiatum, as compared with control mice. No differential sensitivity to EGb 761 existed among the mouse strains tested. Antioxydint properties of EGb 761 may explain its neuroprotective and neurotrophic actions on the hippocampus, and might explain certain improvements in memory and other cognitive functions in both humans and experimental animals.

Hippocampal mossy fiber changes in mice transgenic for the human copper-zinc superoxide dismutase gene.

The copper-zinc superoxide dismutase (SOD-1) gene, located on chromosome 21 and triplicated in Down's syndrome (DS), is suspected to be involved in the neuropathology observed in Alzheimer's disease (AD), DS and physiological aging. In order to explore the effect of an overproduction of SOD-1 in the mouse hippocampus, we investigated the Timm-stained mossy fiber (MF) innervation in the hippocampus of transgenic mice for the human SOD-1 gene (hSOD-1 mice). The results showed a decrease of the MF projection area in the hSOD-1 mice overexpressing the SOD-1 protein. These findings suggest that free radicals could play a role in this particular synaptic loss.

Locomotor and exploratory activity in three inbred strains of mice from young adulthood to senescence.

Nine variables measuring activity and exploratory behavior were collected for nine independent groups of three inbred strains of mice (BALB/c, C57BL/6, and DBA/2) at three ages (150, 400, and 750 days). An analysis of variance measuring differences of performances and a covariance analysis estimating the evolution of scores with age shows that (1) some variables are unaffected by age; (2) a strain-age interaction is observed for some variables; (3) some groups do not exhibit any age-related change for certain variables; and (4) the level of ability of age-related behavior varies across groups. These data argue for rejection of a general factor of aging and suggest that we are dealing with two distinct phenotypes: performance, and age-related modification of the performance, which therefore are not linked.

Genetics and senescence. I. Age-related changes in activity and exploration in three inbred strains of mice.

Exploratory, locomotor and ambulatory activities were measured in nine independent groups of three inbred strains of mice (BALB/cBy, C57BL/6J and DBA/2J), at three different ages (150 days, 400 days and 750 days). The results show that for two of the three variables, the age-related changes present different patterns as a function of strain. The genetic and/or environmental correlates of the reactivity to aging may thus depend on the behavioral trait under study.

A note on the genetics of a unilateral senile cataract in mice.

Unilateral cataracts were investigated in 750 day-old BALB/c, C57BL/6 and DBA/2 mice, and the six reciprocal crosses between these strains. This abnormality of the lens appears to be inherited additively in the cross DBA/2xBALB/c (with incomplete penetrance in DBA/2 and F1 mice) but as a completely recessive character in the cross DBA/2xC57BL/6. The mode of inheritance may depend on the genetic background against which this phenotype is expressed, unless this abnormality is inherited as a threshold character. Aged DBA/2 mice may constitute a useful model for senile unilateral cataract, probably caused by early uveitis.

Differences in patterns of pup care in Mus musculus domesticus. VIII. Effects of previous experience and parity in XLII inbred mice.

An improvement in two variables of a retrieving test has been shown in eight inbred strains of mice following the second parturition. To test the possible contribution of presence at birth and/or caregiving to a cohabitation effect, retrieval behavior was measured in four groups of XLII inbred mice: one group of biparas, and three groups of primiparas; one without any previous maternal experience, one previously exposed to parturition and caregiving by an alien female, and one exposed to a female with her newborn litter. The two variables do not discriminate between the groups in the same way. The scores on one variable (first retrieval latency) fit into an increasingly complex hierarchy of cohabitational environment with parturient females. The second variable (move away from the pups) discriminates between those primiparas who had a cohabitational experience including both birth and caregiving and those that did not. Dissimilarities between the actions of these two variables are discussed in the light of genetic and ethological mechanisms.

Differences in patterns of pup care in mice. V--Pup ultrasonic emissions and pup care behavior.

Newborn mice, like all newborn rodents, are able to emit high frequency signals, in particular when they are put out of the nest. Moreover, it is known that in this situation retrieving behaviors are induced in the foster mother, which are likely to reveal stable differences across inbred strains of mice. The question that arises is whether these differences are causally linked to differences in the pup rate of signalling and/or to the capacity of the females of these strains to perceive them. To provide insights into this question, the behavior of 8 inbred strains of mice was observed: A/J, BALB/c, CBA/H, C57BL/6, C57Br, DBA, NZB and XLII. Pup ultrasonic calls of each of these strains, emitted in the same conditions as a retrieving test, were recorded and tabulated. Auditory sensitivities of females belonging to these strains were determined by auditory evoked potentials recorded in the inferior colliculus. These two variables were analysed in relation to scores of females of these strains on three variables of a retrieving test. Results show that the presence of other factors than auditory cues must be taken into account to describe differences across strains in retrieving performances. This conclusion has been confirmed by results obtained using cross-fostering procedure. Female mice unable to utilize ultrasonic information may use other sensory channels. Furthermore, female mice capable of perceiving ultrasounds may also be able to use different sensory modalities in different situations.

Early development in mice: I. Genotype and post-natal maternal effects.

The co-actions of genetic effects and the post-natal maternal rearing environment on the development of weight, 9 reflex responses, and survival have been tested by the cross-fostering method in two inbred mice strains--CBA/H and NZB. Pups of the two strains were not treated differentially by the mothers and experimental handling did not systematically affect pup development. Comparisons of unfostered, infostered, and cross-fostered pups show (1) in 16 cases out of 34, reflex development was affected by the pup strain, and in 10 cases out of 34 by the foster mother strain; (2) survival is only affected by the pup strain; (3) weight development is affected by strain of both the pup and the mother as well as their interactions. The adopted pups' scores were situated outside the range of the two non-adopted groups for certain reflexes as well as for weight. Two non-exclusive hypotheses are proposed: the mother strain can affect pup development (1) either through differences in stimulation provided by the mothers (2) or through differences in milk composition.