Stacey L. Germann

Behavioral characteristics of a nervous system-specific erbB4 knock-out mouse

ErbB4 is an important brain receptor for the neuregulin1 growth factor. A conditional knock-out mouse was developed lacking both alleles of the erbB4 gene in neurons/glia, and one allele in other cells. The conditional mutant mice were compared to heterozygous null (one null allele and one wildtype allele in all tissues) and wildtype control (no gene deletion) littermates in a battery of behavioral tests. Conditional mutants displayed a lower level of spontaneous motor activity and reduced grip strength compared to wildtype control mice. Group mean scores of heterozygous nulls were intermediate on these measures. However, heterozygous nulls were delayed in motor development and male heterozygous nulls demonstrated altered cue use in a Morris maze learning and memory task relative to both wildtype control and conditional mutant mice. These findings were interpreted based on more detailed analysis of the behavioral data and considerations of the complex nature and multiple roles of the neuregulin/erbB4 system in the nervous system.

Lifelong feeding of a high aluminum diet to mice.

In three experiments, high aluminum diets (1000 microg Al/g diet) were fed to mice throughout their life span to determine whether neurodegenerative changes were seen with aging. Brain Al concentrations were slightly lower in Al-treated mice than controls. Generally, no increased mortality or gross evidence of neurodegeneration was seen in Al-treated mice. Eighteen and 24 month old Swiss Webster mice fed the high aluminum diet differed from controls on some neurobehavioral tests, but differences were no greater than previously seen with shorter term exposure in younger mice. Both brain Al concentration and susceptibility to oxidative damage, as measured with TBARS, were lower in the Al-treated aged mice than in controls. In addition, Al-treated aged Swiss Webster and C57BL/6J mice showed somewhat enhanced performance in the Morris water maze. Finally, Al treatment did not exacerbate the effect of MPTP treatment on a grip strength measure in either 66 or 235 day old male mice. Swiss Webster and C57BL/6J mice do not appear to provide useful models for studying Al-induced neurodegenerative changes in aging.

Behavioral consequences of ovarian atrophy and estrogen replacement in the APPswe mouse

Cognitive performance was evaluated in a longitudinal study of APPswe2576 transgenic mice (APP) and a wildtype (WT) comparison group. Subgroups of the APP mice were treated with the ovarian toxicant 4-vinylcyclo-hexene diepoxide (VCD) at 60-75 days of age to induce ovarian atrophy and/or given estrogen (estradiol, 4 microg/day) continuously by pellet from 76 days of age. APP mice had a generally poorer radial maze performance than WT at 4.5, 7.5, 10.5 and 15 months of age. In separate tests, APP mice had a slight motor impairment, higher incidence of homecage stereotypy, hyperactivity in an open field and reduced object exploration relative to the WT group. Ovarian atrophy led to better maze performance at 7.5 months. The effect of estrogen on maze performance with aging could not be effectively evaluated due to poor survival (30%) of these mice. No effects of ovarian atrophy or estrogen treatment were identified for amyloid-beta accumulation or plaque formation at 15 months. Long-term longitudinal studies in animal models are needed to explore the consequences of menopause and hormone replacement on Alzheimers disease, but they are complicated by considerations of survival, pre-aging deficits, testing experience and selection of appropriate estrogen treatment levels.

Movement disorders in the Hfe knockout mouse

Abstract The Hfe( - / - ) mouse is a model for human hereditary hemochromatosis (HHH). The accumulation of tissue iron in this condition has led to the suggestion that HHH patients may be at higher risk for neurodegenerative diseases. In this study, adult male Hfe( - / - ) mice and wildtype controls ( n = 12/group) were evaluated for impairment with motor tests (stride length, landing footsplay, rotarod) as well as a general observational battery (Functional Observational Battery, FOB). Hfe( - / - ) mice were characterized by more falls from the rotarod, wider forelimb landing footsplay and hypersensitivity to proximal stimulation. Iron accumulation in brain was not detected by histopathology. These data suggest that a motor syndrome may be associated with HHH that could be further understood through the Hfe( - / - ) mouse model.

Perinatal bupivacaine and infant behavior in rhesus monkeys

To assess the effect of perinatal epidural bupivacaine analgesia on infant behavioral development, bupivacaine (1.2 mg/kg) was administered to term-pregnant rhesus monkeys (treated, n = 11, procedural controls, n = 8) and infant behavior was evaluated for 1 year using a test battery including infant neurobehavioral tests, observation of spontaneous behavior, and structured cognitive testing. No adverse effects of bupivacaine were detected for neonatal neurobehavior, early cognitive abilities, or performance of cognitive tasks by older infants. Bupivacaine infants directed more, shorter fixations at visual stimuli during visual novelty preference testing. Observation of behavior maturation patterns showed that the increase in manipulatory activity that normally occurs at 2 months of age was delayed in bupivacaine infants, and the increase in motor disturbance behaviors that normally occurs at 10 months of age was prolonged. These results are interpreted in terms of life-history and brain maturation landmarks that appear at these ages. The data suggest that epidural bupivacaine does not cause neonatal abnormalities or specific cognitive deficits but can alter the normal course of behavioral development.

Aluminum Effects on Operant Performance and Food Motivation of Mice

Previous studies demonstrated better performance of operant tasks in mice fed excess aluminum (Al) in the diet. The current study examined whether (a) Al leads to impairment of spatial alternation after extended practice, (b) Al enhances performance of an operant task that emphasizes motor learning and ability (differential reinforcement of high rates, DRH), and (c) Al enhances food motivation as reflected in progressive ratio (PR) performance. Male Swiss Webster mice were fed purified diets containing 7 (control), 500, or 1000 microg Al/g diet. Subgroups were fed excess Al diets during development (conception to 35 days postnatal) or as adults (35 days postnatal through the end of testing). Operant training and testing were conducted at 50 days postnatal. Data indicated that extended training of developmentally exposed mice did not lead to performance deficits, that DRH performance of both developmentally and adult-exposed mice was enhanced, and that food motivation (PR task) was significantly greater in the adult-exposed group with a similar trend in the developmentally exposed group. Aluminum may bias performance of food-motivated tasks by influencing food motivation.

Developmental aluminum toxicity in mice can be modulated by low concentrations of minerals (Fe, Zn, P, Ca, Mg) in the diet

Female Swiss Webster mice were fed diets containing 7 (control) or 1000 µg Al/g diet from conception to weaning. Pregnancy weight gain, brith weight, litter size, postnatal mortality, and weaning weight were measured. In different groups, diets low in Fe, Zn, P, or Ca and Mg (CaMg) were used as basal diets, to which Al was added. Relative to controls, who received NRC recommended levels of these nutrients, all diets with marginal essential trace elements impacted development, as demonstrated by effects on birth weight (CaMg, Fe) or weaning weight (Fe, Zn, P). Compared to diets low in Al, the 1000-mg Al/g diet led to reduced weaning weight regardless of the essential element content of the diet. Other end points were influenced by Al only within the basaldiet group; pregnancy weight gain with the low-P diet, litter size with the low-Fe diet, pregnancy completion with the low-Zn diet, and postnatal mortality with the low-CaMg or low-Zn diet. Thus, diets marginal in selected minerals can differentially alter the toxicological profile of developmental Al exposures. A basal diet was also used in which the NRC diet was supplemented with ascorbic acid, which promotes Al absorption. No modification of Al toxicity was seen with ascorbic acid supplementation.