Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long-Evans rats.

Reaching tasks are popular tools for investigating the neural mechanisms of motor skill learning and recovery from brain damage in rodents, but there is considerable unexplained variability across studies using these tasks. We investigated whether breeder, batch effects, experimenter, time of year, weight and other factors contribute to differences in the acquisition and performance of a skilled reaching task, the single pellet retrieval task, in adult male Long-Evans hooded rats. First, we retrospectively analyzed task acquisition and performance in rats from different breeding colonies that were used in several studies spanning a 3 year period in our laboratory. Second, we compared reaching variables in age-matched rats from different breeders that were trained together as a batch by the same experimenters. All rats had received daily training on the reaching task until they reached a criterion of successful reaches per attempt. We found significant breeder-dependent differences in learning rate and final performance level. This was found even when age-matched rats from different breeders were trained together by the same experimenters. There was also significant batch-to-batch variability within rats from the same breeder trained by the same experimenter. Other factors, including weight, paw preference and the experimenter, were not as strong or consistent in their contributions to differences across studies. The breeder and batch effects found within the same rat strain may reflect genetic and environmental influences on the neural substrates of motor skill learning. This is an important consideration when comparing baseline performance across studies and for controlling variability within studies.

Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism.

Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing Aß accumulation. Similarly, intrahippocampal injections of an anti-Aß antibody reduced Aß levels and normalized mTOR activity, indicating that high Aß levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted Aß is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the Aß-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the Aß-induced mTOR hyperactivity. Taken together, our data show that Aß accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which Aß exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.

CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease.

Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-ß (Aß) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aß and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aß-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.

Remodeling the brain with behavioral experience after stroke.

BACKGROUND AND PURPOSE: Behavioral experience can drive brain plasticity, but we lack sufficient knowledge to optimize its therapeutic use after stroke. METHODS: We outline recent findings from rodent models of cortical stroke of how experiences interact with postinjury events to influence synaptic connectivity and functional outcome. We focus on upper extremity function. RESULTS: After unilateral cortical infarcts, behavioral experiences shape neuronal structure and activity in both hemispheres. Experiences that matter include interventions such as skill training and constraint-like therapy as well as unguided behaviors such as learned nonuse and behavioral compensation. Lateralized behaviors have bihemispheric influences. Ischemic injury can alter the sensitivity of remaining neocortical neurons to behavioral change and this can have positive and negative functional effects. CONCLUSIONS: Because experience is ongoing in stroke survivors, a better understanding of its interaction with brain reorganization is needed so that it can be manipulated to improve function and prevent its worsening.

The vermicelli handling test: a simple quantitative measure of dexterous forepaw function in rats.

Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta [Whishaw IQ, Coles BL. Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 1996;77:135-48]. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment.

Motor skill training, but not voluntary exercise, improves skilled reaching after unilateral ischemic lesions of the sensorimotor cortex in rats.

BACKGROUND AND PURPOSE: Exercise and rehabilitative training each have been implicated in the promotion of restorative neural plasticity after cerebral injury. Because motor skill training induces synaptic plasticity and exercise increases plasticity-related proteins, we asked if exercise could improve the efficacy of training on a skilled motor task after focal cortical lesions. METHODS: Female young and middle-aged rats were trained on the single-pellet retrieval task and received unilateral ischemic sensorimotor cortex lesions contralateral to the trained limb. Rats then received both, either, or neither voluntary running and/or rehabilitative training for 5 weeks beginning 5 days postlesion. Motor skill training consisted of daily practice of the impaired forelimb in a tray-reaching task. Exercised rats had free access to running wheels for 6 h/day. Reaching function was periodically probed using the single-pellet retrieval task. RESULTS: In young adults, motor skill training significantly enhanced skilled reaching recovery compared to controls. However, exercise did not significantly enhance performance when administered alone or in combination with skill training. There was also no major benefit of exercise in older rats. Additionally, there were no effects of exercise in a measure of coordinated forelimb placement (the foot-fault test) or in immunocytochemical measures of several plasticity-related proteins in the motor cortex. CONCLUSIONS: In young and middle-aged animals, exercise did not improve motor skill training efficacy following ischemic lesions. Practicing motor skills more effectively improved recovery of these skills than did exercise. It remains possible that an alternative manner of administering exercise would be more effective.

The brain metabolic enhancer methylene blue improves discrimination learning in rats.

Methylene blue (MB) is a metabolic enhancer that has been demonstrated to improve memory retention when given post-training in low doses in a variety of tasks in rats, including inhibitory avoidance, spatial memory (in both normal and metabolically-impaired subjects), object recognition, and habituation to a familiar environment. MB has been also shown to improve memory retention of extinction of fear conditioning in the rat. No experiments have been conducted to determine the effects of MB on more complex learning such as in discrimination tasks that require repeated days of training. This study examined the effects of daily MB on spatial discrimination memory in a baited holeboard maze. Following three days of discrimination training, subjects treated daily with post-training MB (1 mg/kg) reliably discriminated between rewarded (baited) and non-rewarded (unbaited) trials as indicated by a greater number of correct responses on rewarded trials than non-rewarded trials during the last three days of discrimination training. No such discrimination effects were observed in the saline-treated control group during the same training period. To determine whether the memory-enhancing effects of MB are associated with an increase in metabolic energy capacity in the brain, cytochrome c oxidation was measured in brains from rats treated with 1 mg/kg MB or saline for three days. The number of daily injections was chosen based on the behavioral data which revealed group differences three days after the beginning of MB treatment. Brain cytochrome oxidase activity in the MB-treated group was approximately 70% higher than in saline-treated rats. The findings suggest that repeated post-training MB may improve memory consolidation between days of learning by an induction in the enzyme cytochrome oxidase, leading to increased metabolic capacity in brain regions requiring more energy during discrimination learning.

Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition.

Genetic and behavioral studies in humans and mouse mutants have implicated the gene encoding neuregulin-1 (Nrg-1) as a candidate susceptibility gene for schizophrenia. We examined the behavior of mice heterozygous for a mutation in neuregulin-1's immunoglobulin (Ig)-like domain (Ig-nrg-1 mice). We found that these animals displayed behaviors related to a schizophrenia-like phenotype, such as clozapine suppression of open-field and running wheel activity and impaired latent inhibition. Contrary to findings with other nrg-1 mutants, Ig-nrg-1 mice did not exhibit significantly elevated locomotion relative to littermate controls. These results suggest that Ig-Nrg-1's contribute to some - but not all - aspects of the schizophrenia-like phenotype of nrg-1 mutants, and further support nrg-1 as a candidate gene for schizophrenia.