Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.
A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C , apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.A lthough the molecular basis of aging remains unknown, a large body of evidence indicates that oxidative stress results in DNA damage that subsequently leads to changes in gene expression and organismal aging (1). Genetic modifications or spontaneous mutations in a variety of organisms that result in oxidative stress resistance increase longevity (2-4). In Caenorhabditis elegans, the reduction of metabolic rate through genetic manipulation or environmental changes increases life span (5). Dietary restriction also delays the aging process and extends life span (1), possibly by lowering metabolic rate and thus reducing the production of reactive oxygen species.The hypothalamus plays a key role in regulating metabolism. Consequently, an understanding of the effects of aging on the hypothalamus may provide important insights into the organismal aging process. For example, it has been shown that neuroendocrine regulation of insulin signaling affects longevity in C. elegans (6-8). In mammals, hypothalamic modulation of the neuroendocrine system may regulate the aging process by controlling the production, processing, and degradation of neuroendocrine hormones and neuropeptides.To better understand the molecular processes involved in aging, we have examined changes in gene expression in the aged hypothalamus. To determine whether these age-associated gene expression changes are tissue specific, we also analyzed gene expression in the cortex of young and aged mice. Our results demonstrate that the expression levels of many genes related to neuronal signaling, plasticity, and structure were changed in the aged brain. Moreover, many proteases were up-regulated during the aging process in both hypothalamus and cortex, a number of which are involved in the processing and degradation of neuropeptides. Altered expression of these genes may contribute to age-r...
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