Using mutant mice lacking norepinephrine and rats treated with drugs that block some norepinephrine receptors (beta blockers), the research team found that this neurotransmitter is critical for retrieving intermediate-term contextual and spatial memories, but not for the formation or long-term consolidation of emotional memories, as previously hypothesized by others.
Mice and rats went through learning tasks that employ different brain regions: the hippocampus, which governs spatial and contextual memories; and the amygdala, which is important for emotional learning and memory in general.
The results of their tests ran counter to currently held hypotheses that suggest that stress hormones like norepinephrine are responsible for enhanced memory formation during emotionally arousing times. "Indeed, we set out to test that hypothesis with our norepinephrine-deficient mice," says Thomas. "We expected to see a difference in amygdala-dependent behaviors between the mutants and controls if it were emotional memory, in general, that was being affected by the absence of norepinephrine. But we didn't see that. Instead, we found a specific impairment in hippocampus-dependent contextual memory retrieval."
Using rats given beta blockers and a swimming navigation task in a water maze, which relies on the hippocampus but not the amygdala, the researchers sought to determine if norepinephrine was also necessary for spatial memories. The tests indicated that norepinephrine is critical for a period of time after a memory is formed, but is not critical in recalling older memories. "There are probably other mechanisms important for retrieving memories for the longer term that are independent of norepinephrine," says Thomas.
This line of research may have relevance to human learning and memory. Patients suffering from post-traumatic stress disorder have recurrent intrusive memories; that is, they experience traumatic events from the past in their minds. Evidence from studies in other labs suggests that in PTSD there might be hyper-signaling by norepinephrine. "Perhaps that's one reason why PTSD patients experience these recurrent intrusive memories," says Thomas.
Depression may include the opposite problem in that there's often difficulty in memory retrieval, and this could be due, in part, to dysfunction of the adrenergic system. In addition, beta-blockers, which are used to treat heart failure and hypertension (among other ailments) block the same norepinephrine receptors important for memory retrieval. Therefore, when treating heart disease, the use of beta blockers that do not cross into the brain may help to avoid memory-related side effects, suggest the researchers.
Other Penn researchers collaborating on this work are Charles F. Murchison, Xiao-Yan Zhang, Wei-Ping Zhang, Ming Ouyang, and Anee Lee. The research was supported in part by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, and the Mental Retardation and Developmental Disabilities Research Center at the Children's Hospital of Philadelphia. The authors have no competing financial interest in this work.
Embargoed copies of the Cell paper can be obtained at:
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