Ausma Rabe

Fmr1 knockout mouse has a distinctive strain-specific learning impairment.

The Fmr1 gene knockout mouse is a model for the human Fragile X mental retardation syndrome. Fmr1 knockout mice with a C57BL/6-129/OlaHsd hybrid background have been reported to have only a very mild deficiency in learning the Morris water maze task. We compared the effect of this knockout mutation on learning in mice with either an FVB/N-129/OlaHsd hybrid background or a C57BL/6 background. When FVB-129 mice were tested in a cross-shaped water maze task, the knockout mice showed a pronounced deficiency in their ability to learn the position of a hidden escape platform in comparison to normal littermates. In contrast, knockout mice with a C57BL/6 background learned the maze just as well as their normal littermates. Fear conditioning did not reveal differences between knockout and normal mice in either background. These results show that silencing the Fmr1 gene clearly interfered with learning a specific visuospatial task in FVB/N-129 hybrid mice but not in C57BL/6 mice. The strain dependence may model the influence of genetic background in the human Fragile X syndrome.

Intellectual Deficit Associated with Transplacentally Induced Microcephaly in the Rat

Fischer rats injected with methylazoxymethanol late in pregnancy produce young with considerably reduced cerebral hemispheres. They appear normal otherwise. As adults these animals make many more errors in the Hebb-Williams maze than do control animals.

Learning deficit in immature rabbits with aluminum-induced neurofibrillary changes

Abstract Infant rabbits injected into the cisterna magna with 1% aluminum chloride in solution develop widespread neurofibrillary changes. About a half of the animals survive for long periods with little or no overt signs of aluminum toxicity. They do show a statistically significant learning deficit in a water maze.

Acquisition of two-way shuttle-box avoidance after selective hippocampal lesions.

Abstract Rats with lesions in both the anterior and posterior hippocampus (APH) acquired shuttle-box avoidance in fewer trials, with fewer shocks and with a larger proportion of avoidance responses than control animals. Their escape, but not avoidance, latencies were shorter than control latencies throughout training. Although not hyperactive on a jiggle-platform, they showed somewhat greater tendency to spontaneous activity in the shuttle-box than controls. However, neither the shorter escape latencies nor the increased spontaneous activity could account for their superior avoidance learning. Rats with lesions restricted to only the anterior (AH) or the posterior (PH) hippocampus showed no facilitation of avoidance learning over controls. A cortical lesion group was statistically indistinguishable from any other group on any of the measures.

Augmented memory loss in aging mice after one embryonic exposure to alcohol

Prenatal exposure to alcohol can produce behavioral and cognitive deficits even in the absence of dysmorphic facial features. In a mouse model, we tested whether embryonic exposure to alcohol could exacerbate functional loss as animals age. Normal-appearing offspring were selected from litters produced by C57Bl/6J mice that had been gavaged with one teratogenic dose (5.8 g/kg) of ethyl alcohol during organogenesis on the 9th day of gestation. In adulthood, the offspring suffered a deficit in long-term retention, but not acquisition, of a place learning task. Although barely detectable in young adults, the retention deficit was severe in aging mice. These findings demonstrate that the functional deficits resulting from embryonic exposure to alcohol can interact with those of aging.

Premature decline in Morris water maze performance of aging micrencephalic rats

The rat with methylazoxymethanol-induced micrencephaly is a useful animal model of congenital brain defects and associated cognitive impairment. Born with profound morphological and neurochemical alterations in the forebrain, it shows impaired ability to learn mazes. In order to determine how an animal with such a developmentally damaged brain would function in old age, Long-Evans rats 6, 15, and 24 months of age were tested for their ability to learn to locate a hidden platform in the Morris water maze. The performance of micrencephalic rats of all ages was impaired on acquisition, retention, and transfer trials. Moreover, the magnitude of their acquisition deficit increased with age. It remains to be determined whether the premature decline of the micrencephalic rat in learning the task simply reflects a greater impact on an already compromised brain by neuron loss characteristic of aging brains or whether the prenatal insult alters some basic processes resulting in premature aging.

Infantile Handling Eliminates Reversal Learning Deficit in Rats Prenatally Exposed to Alcohol

Prenatal exposure to ethanol results in learning deficits and alters physiological response to stress. Neonatal handling and stimulation. on the other hand, produce long-lasting physiological and behavioral changes in response to stress. To determine whether early handling, consisting of daily separation and tactile stimulation for the first 3 weeks, can modify fetal alcohol effects on learning ability of young adult rats, offspring of rats chronically exposed to ethanol throughout pregnancy and control animals were trained in a T-maze to learn a position response and then to reverse the learned response. The nonhandled, ethanol-treated rats were deficient on reversal, but the ethanol-treated rats that were handled during the first 3 weeks of postnatal development showed no deficit in learning to reverse their previously learned responses. Postnatal handling had no effect on acquisition in alcohol-treated rats. Neither reversal nor acquisition was affected by infantile handling in pair-fed or normal control animals. Early handling may have eliminated the reversal deficit in the ethanol-treated offspring by altering their physiological and behavioral reactivity to stress.

Effect of selective hippocampal lesions in the rat on acquisition, performance, and extinction of bar pressing on a fixed ratio schedule

SummaryRats with bilateral anterior and posterior hippocampal lesions (APH), anterior hippocampal lesions (AH), and controls were trained on CRF for water, and then switched to FR-20. Both hippocampal groups adapted more readily than controls to the FR-20 schedule and maintained significantly higher rates for 45 days. There were no significant differences on FR-20 between the lesion groups. Following FR-20, the rates of all groups were equalized by training on FR-30. During subsequent extinction, the APH group made significantly more responses than both the AH and control groups, while AH and control groups were indistinguishable. The acquisition results were interpreted as indicating increased emotional reactivity to delay of anticipated reward in both hippocampally lesioned groups. The extinction results suggested that APH, but not AH, lesions also result in increased perseveration.

Long-term running alleviates some behavioral and molecular abnormalities in Down syndrome mouse model Ts65Dn

Running may affect the mood, behavior and neurochemistry of running animals. In the present study, we investigated whether voluntary daily running, sustained over several months, might improve cognition and motor function and modify the brain levels of selected proteins (SOD1, DYRK1A, MAP2, APP and synaptophysin) in Ts65Dn mice, a mouse model for Down syndrome (DS). Ts65Dn and age-matched wild-type mice, all females, had free access to a running wheel either from the time of weaning (post-weaning cohort) or from around 7 months of age (adult cohort). Sedentary female mice were housed in similar cages, without running wheels. Behavioral testing and evaluation of motor performance showed that running improved cognitive function and motor skills in Ts65Dn mice. However, while a dramatic improvement in the locomotor functions and learning of motor skills was observed in Ts65Dn mice from both post-weaning and adult cohorts, improved object memory was seen only in Ts65Dn mice that had free access to the wheel from weaning. The total levels of APP and MAP2ab were reduced and the levels of SOD1 were increased in the runners from the post-weaning cohort, while only the levels of MAP2ab and α-cleaved C-terminal fragments of APP were reduced in the adult group in comparison with sedentary trisomic mice. Hence, our study demonstrates that Ts65Dn females benefit from sustained voluntary physical exercise, more prominently if running starts early in life, providing further support to the idea that a properly designed physical exercise program could be a valuable adjuvant to future pharmacotherapy for DS.

Relationship of Down’s Syndrome to Alzheimer’s Disease

Down’s syndrome (DS), or trisomy 21, is a major known cause of mental retardation, occurring in 1 of every 1000 live births.1 Alzheimer’s disease (AD) is a progressive dementing disorder, with characteristic brain pathology, that affects about 10% of people over 65 years of age.2 3 The presence of Alzheimer-type pathology in the brains of almost all people 35 years and older with DS has been the cornerstone for the widely held view that people with DS will develop AD not only at a much younger age, but also in much larger numbers than will people without DS.4-7 Because of this relationship between DS and AD, it has been widely assumed that knowledge about almost any aspect of one of these conditions will illuminate the other.8-11 For example, the similarity of the morphological and neurochemical abnormalities in AD and DS has led to the proposition that aging DS brains may serve as a model for the pathogenesis of brain abnormalities in AD.12 13 In addition, since DS is a genetic disorder with many features of premature aging,14 it has been expected that the study of DS will contribute important information about the role of genetics and aging in the etiology of AD.15-19