Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. However, the molecular mechanisms underlying long-term spatial memory are poorly understood. In this study, we show that mitogen-activated protein kinase (MAPK, also called ERK) is activated in the dorsal, but not the ventral, hippocampus of rats after training in a spatial memory task, the Morris water maze. The activation was expressed as enhanced phosphorylation of MAPK in the pyramidal neurons of the CA1/CA2 subfield. In contrast, no increase in the percentage of phospho-MAPK-positive cells was detected in either the CA3 subfield or the dentate gyrus. The enhanced phosphorylation was observed only after multiple training trials but not after a single trial or after multiple trials in which the location of the target platform was randomly changed between each trial. Inhibition of the MAPK/ERK cascade in dorsal hippocampi did not impair acquisition, but blocked the formation of long-term spatial memory. In contrast, intrahippocampal infusion of SB203580, a specific inhibitor of the stress-activated MAPK (p38 MAPK), did not interfere with memory storage. These results demonstrate a MAPK-mediated cellular event in the CA1/CA2 subfields of the dorsal hippocampus that is critical for long-term spatial memory.
Declarative memories are thought to be initially stored in the hippocampus, and then transferred to the neocortex. This is a key feature of the standard model of consolidation and is supported by studies reporting a requirement for activity within the neocortex for recall of remote, but not recent, hippocampal-dependent memories. New evidence from our and other laboratories, however, suggests that, for trace fear conditioning, memories are stored in the rodent medial prefrontal cortex and in the hippocampus from the time of training. Consistent with this, we show that activity in the medial prefrontal cortex is necessary for retrieval of recent and remote memories, suggesting that information stored in this neocortical structure from the time of training is necessary for memory recall.
Objective: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. Methods:We studied 658 elderly participants without dementia from a prospective, communitybased study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability.Results: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. Conclusions:Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology. Neurology Memory decline is frequent among the elderly and it is most often attributed to dysfunction and atrophy of the hippocampus and related mesial temporal lobe structures.1-3 Subclinical brain infarcts are present in about one-third of older adults, and are associated with a 2-fold risk of dementia and a steeper decline in age-associated cognitive function. 4 -6 However, the effects of subclinical brain infarcts on hippocampal integrity and age-related memory decline are not well understood. Memory deficits have been described following brain infarcts. Cortical infarcts can result in diverse deficits depending on size and location of lesion and can produce cognitive decline in multiple domains, including perceptual speed and memory. 7,8 Subcortical infarcts can result in executive dysfunction, 9 although strategic thalamic or limbic system infarcts can result in memory loss. 10,11 Clinically, it can be difficult to differentiate between cognitive decline due to
Activation of intracellular second messenger cascades has been linked to learning and memory in various organisms. Identification of down-stream targets of these second messengers that play a role in learning and memory is an active area of research. Recently, it has been reported that increases in intracellular calcium can activate a cysteine-dependent aspartate-directed protease (caspase) cascade in mice. Using an antibody that selectively recognizes activated caspase-3, we detected the presence of this enzyme in hippocampal neurons. Inhibition of caspase activity in the hippocampus blocked long-term, but not short-term, spatial memory. These results suggest that a caspase-mediated cellular event(s) in hippocampal neurons is critical for long-term spatial memory storage.
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