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2014-4-9

A team of researchers -- SOMA Shogo (Special Researcher, JSPS, and Graduate School of Medicine), SUEMATSU Naofumi (Special Researcher, JSPS, and Graduate School of Frontier Biosciences, OU), SHIMEGI Satoshi (Associate Professor, Graduate School of Medicine and Graduate School of Frontier Biosciences) -- conducted research into the relationship between cognitive decline in advanced aging and/or Alzheimer's disease. It has been well established for some 30 years that a decreased level of acetylcholine (ACh) is a cause of such cognitive decline (a hypothesis referred to as the cholinergic hypothesis). While the cholinergic hypothesis explains the loss of short-term memory which in AD generally progresses into at least one additional cognitive deficit (apraxia or agnosia, for example), it has not been clear whether this hypothesis fully explains deficits of well-learned tasks, i.e., memory retrieval of actions which have been mastered and repeatedly performed over a length of time.

Thus, this team trained rats to memorize an association between lever manipulations and a reward. The rats were able to learn the task within 10 days and after that they repeatedly practiced the task for an additional 30 days, making the actions performed into long-term well-learned task. The researchers then administered scopolamine (SCOP) to the rats. (SCOP is a muscarinic acetylcholine [ACh] receptor [mAChR] antagonist.) Within 30 minutes of SCOP being administered, the rats ceased to manipulate any levers although they seemed to be curious about the levers. However, 3 hours later, the rats had recovered and were able to successfully complete the tasks they had been taught although with some impairment of associative memories.

Their research shows a strong relationship between a blockade of mAChR and loss of ability to recall well-trained memories. In short, a deficit of ACh in the brain is not the sole determinant involved in the impairment of cognitive function in humans in advanced aging or AD.


Abstract

Acetylcholine (ACh) is known to play an important role in memory functions, and its deficit has been proposed to cause the cognitive decline associated with advanced age and Alzheimer’s disease (the cholinergic hypothesis). Although many studies have tested the cholinergic hypothesis for recently acquired memory, only a few have investigated the role of ACh in the retrieval process of well-trained cognitive memory, which describes the memory established from repetition and daily routine. To examine this point, we trained rats to perform a two-alternative forced-choice visual detection task. Each trial was started by having the rats pull upward a central-lever, which triggered the presentation of a visual stimulus to the right or left side of the display monitor, and then pulling upward a stimulus-relevant choice-lever located on both sides. Rats learned the task within 10 days, and the task training was continued for a month. Task performance was measured with or without systemic administration of a muscarinic ACh receptor (mAChR) antagonist, scopolamine (SCOP), prior to the test. After 30 min of SCOP administration, rats stopped manipulating any lever even though they explored the lever and surrounding environment, suggesting a loss of the task-related associative memory. Three hours later, rats were recovered to complete the trial, but the rats selected the levers irrespective of the visual stimulus, suggesting they remembered a series of lever-manipulations in association with a reward, but not association between the reward and visual stimulation. Furthermore, an m1-AChR, but not nicotinic AChR antagonist caused a similar deficit in the task execution. SCOP neither interfered with locomotor activity nor drinking behavior, while it influenced anxiety. These results suggest that the activation of mAChRs at basal ACh levels is essential for the recall of well-trained cognitive memory.

 

To learn more about this research, please read the full research report entitled “Blockade of muscarinic receptors impairs the retrieval of well-trained memory” at this page of the Frontiers in Aging Neuroscience website.


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Graduate School of Medicine
Graduate School of Frontier Biosciences

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