Effects of hippocampal lesions and duration of sensory input on spontaneous alternation.
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The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotide directed against the alpha subunit of different Gi-proteins (anti-Gialpha1, anti-Gialpha2, anti-Gialpha3) on amnesia induced by morphine was evaluated in the mouse passive avoidance test. The administration of morphine (6 - 10 mg kg(-1) i.p.) immediately after the training session produced amnesia that was prevented by PTX (0.25 microg per mouse i.c.v.) administered 7 days before the passive avoidance test. Anti-Gialpha1 (6.25 microg per mouse i.c.v.) and anti-Gialpha3 (12.5 microg per mouse i.c.v.), administered 18 and 24 h before the training session, prevented the morphine amnesia. By contrast, pretreatment with anti-Gialpha2 (3.12 - 25 microg per mouse i.c.v.) never modified the impairment of memory processes induced by morphine. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by Gi1 and Gi3 protein subtypes in the transduction mechanism involved in the impairment of memory processes produced by morphine.
The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.
The extracellular matrix glycoprotein tenascin-C is widely expressed during development and repair, making it surprising that few abnormalities have been found in transgenic mice lacking this molecule. We have therefore re-examined the transgenic mice described by Saga et al. [Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. (1992) Genes Dev., 6 1821-1831] in which tenascin-C was knocked-out by homologous recombination, focusing on two aspects of the nervous system likely to reveal any abnormalities that might follow the loss of tenascin-C. First, we have determined the pattern of myelin and distribution of oligodendrocyte precursor cells in those areas, such as the optic nerve and retina where local concentrations of tenascin-C have been proposed to act as barriers to oligodendrocyte precursor migration and so prevent inappropriate myelination. Secondly, we have examined the behaviour of the mice in a number of well-characterized tests, e.g. beam-walking, passive avoidance and the Morris water maze. We find no abnormalities of myelination or oligodendrocyte precursor distribution in adult mice, showing that local concentrations of tenascin-C are not the sole mechanism responsible for the pattern of myelination in these regions of CNS. However, we do find a number of behavioural abnormalities in these mice and show that hyperlocomotion and deficits in coordination during beam walking can be ascribed to tenascin-C deficiency. The effects on coordination are, however, not seen on a 129 genetic background. Taken together, these results significantly extend the phenotype associated with tenascin-C deficiency but argue against a role in myelination.
Numerous animal models of early stress are currently being developed because early stress results in long-term disruptions of neuronal functions and the development of long-term behavioral disorders. These models should allow to study the concept of vulnerability applied to psychiatric disorders. The fundamental importance of the bond between the mother and the offsprings, in all mammalian species, for the development of the new-born, point to the great interest of animal models of mother/pups separation. Long periods of deprivation tend to result in anxiety, depressive-like behaviors and drug addiction in adult rats. Neurobiological studies have shown that several neuronal systems, in particular neuropeptidergic systems in the limbic structures of the brain, are disrupted, possibly due to the effects of early stress on neurodevelopment. Models evaluating the impact of early environmental factors should help to improve the prevention and prediction of psychiatric disorders and to develop new therapeutic strategies.
Mildly stressful early life experiences can potentially impact a broad range of social, cognitive, and physiological functions in humans, nonhuman primates, and rodents. Recent rodent studies favor a maternal-mediation hypothesis that considers maternal-care differences induced by neonatal stimulation as the cause of individual differences in offspring development. Using neonatal novelty exposure, a neonatal stimulation paradigm that dissociates maternal individual differences from a direct stimulation effect on the offspring, we investigated the effect of early exposures to novelty on a diverse range of psychological functions using several assessment paradigms. Pups that received brief neonatal novelty exposures away from the home environment showed enhancement in spatial working memory, social competition, and corticosterone response to surprise during adulthood compared with their home-staying siblings. These functional enhancements in novelty-exposed rats occurred despite evidence that maternal care was directed preferentially toward home-staying instead of novelty-exposed pups, indicating that greater maternal care is neither necessary nor sufficient for these early stimulation-induced functional enhancements. We suggest a unifying maternal-modulation hypothesis, which distinguishes itself from the maternal-mediation hypothesis in that (i) neonatal stimulation can have direct effects on pups, cumulatively leading to long-term improvement in adult offspring; and (ii) maternal behavior can attenuate or potentiate these effects, thereby decreasing or increasing this long-term functional improvement.
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The behavioral correlates of vitamin A and B 6 dietary deficiency in young adult rats (Experiment 1) and middle-aged, retired breeder rats (Experiment 2) were examined. Male and female rats received either vitamin A deficient, vitamin B6 deficient, or normal control diets for two and a half months. Body weight, eating, and drinking of water and adulterated fluids were monitored. Pyridoxine deficiency generally had greater effects on consummatory behavior and weight gain than vitamin A deficiency, but this effect was influenced by the rats' age and sex. Wheel running, (Experiment 1), increased above control levels in both the vitamin delete groups. Vitamin A and B 6 deplete diets may affect behavior before an animal displays classical physical signs. Furthermore, such behavioral changes are not restricted to young, rapidly growing male rats; instead, their character is influenced by both the sex and age of the animal.
Eight, 20, and 31 month old male C57BL/6N mice were exposed to three 24-hour restraint sessions per week, or to a nontreatment condition. All mice received five 2-minute open field tests after 5 and after 6 weeks of treatment. The activity of restrained mice tended to be greater than that of nonrestrained animals. In general, 8 month old mice were more active than older subjects. Age related activity decrements were prominent in the first series of open field tests, while restraint effects were most pronounced in the second series.
The open-field behavior of old rabbits (32-50 months) was compared to that of young-controls (3 months). Old rabbits engaged in less grooming and rearing behaviors and were more active than young controls. The old rabbits demonstrated a pattern of ambulation which did not indicate a preference for any particular area of the open-field. In contrast, young rabbits exhibited a very stereotypic pattern of exploration in the open-field, engaging in relatively low levels of ambulation confined to the area near the sides of the open-field. Old rabbits fed a diet which included 860 ppm nimodipine showed behaviors in the open-field which closely approximated those of the young-controls. Nimodipine-treated rabbits made fewer crossings and more rears and grooms than the old controls. These results indicate that very specific aging-related changes occur in the open-field behaviors of rabbits, and that nimodipine effectively reverses these aging-associated changes. These data are consistent with previous studies that have shown improvements in open-field behaviors by old rats receiving nimodipine.
Electromyographic recordings from the mystacial pad of rats were used to assess the effect of unilateral vibrissa contact on the bilateral movement of the vibrissae. A first group of animals was trained to whisk freely in air and served to establish the baseline variability in bilateral symmetry. We observed that the electromyogram (EMG) activity across the two mystacial pads was rhythmic and synchronous to within 2 ms on a whisk-by-whisk basis; this value is small in comparison with the approximately 50 ms required for protraction during the whisk cycle. A second group of animals was trained to use their vibrissae to contact a sensor that was located on one side of the head. The average EMG activity across the two pads was synchronous at the time of vibrissa contact, albeit with higher variability than for the case of free whisking. In contrast, the average amplitude of the activity on the contact vs noncontact side of the face was transiently greater, by 25% or approximately 10 degrees, at the time of contact. These data show that the amplitude of the vibrissae on the two sides of the face can be controlled independently, while the timing of vibrissa movement is largely synchronous.
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Current understanding of the functional roles of individual dopamine D1-like [D1, D5] and D2-like [D2L/s, D3, D4] receptor subtypes remains incomplete. In particular, the lack of pharmacological agonists and antagonists able to distinguish between D1 and D5 receptors means that any differential roles in the regulation of behavior are poorly understood. Mutant mice with targeted gene deletion ("knockout") of individual dopamine receptor subtypes offer an important alternative approach to resolving these functional roles. In congenic D1 mutants examined ethologically, progressive increases in specific topographies of behavior over wildtypes were considerably greater than those in D1 mutants on a mixed genetic background; D1 knockout appears to influence the neuronal substrate(s) of habituation to disrupt sculpture of the changing topography of behavior from initial exploration through to quiescence. Similarly, the D1 receptor appears to regulate specific topographies of orofacial movement in the mouse as these are "sculpted" in a time-dependent manner. Although the well-recognized role of the D1-like family in regulating several aspects of behavioral topography has been assumed to involve primarily D1 receptors, this presumption may require modification to accommodate a subtle but not negligible role for their D5 counterparts as evidenced in the phenotype of congenic D5 mutants.
Zinc deprivation from day 110 to 150 of gestation in rhesus monkeys resulted in rash, alopecia, anorexia, decreased feed efficiency, and low plasma zinc in the mothers. Infants of the dams that had been deprived of zinc during gestation displayed a more rapid postnatal growth rate than infants of the control mothers. Infants of the zinc-deprived dams played and explored less than the control infants. They also associated with their mothers a greater percentage of the time and were less active. This study has shown that third trimester maternal zinc deprivation in nonhuman primates can impair behavioral development of offspring.
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Mature-young 5-mo.-old and aged 25-mo.-old rats (N=28 of each age group) at the same level of motivation were given forced-correct-response training trials on a 14 unit T-maze by blocking off all wrong turns. During later test trials in the maze, when the 14 culs-de-sac were open, aged rats made significantly fewer errors than mature-young rats. The effect of distribution of test trials were relatively minor, but comparison of distributed practice groups with control groups not given forced-correct-response training also indicated a strong differential age effect of training procedure on the reduction of errors during test trials. The deleterious effect of age on learning and problem solving is not immutable.