07 Mar 2011

Touchscreen technology has come to the rodent world. No, mice are not using iPads just yet; instead, researchers led by Lisa Saksida and Timothy Bussey at the University of Cambridge, U.K., are employing touchscreens to devise versatile tests of animal cognition that mimic tasks used in human studies. In the first application of this technology, the scientists developed a way to measure the attention span of Alzheimer’s disease model mice. In the March 2 Journal of Neuroscience, they report that these animals show the same attention problems as do Alzheimer’s patients. Administration of the AD drug donepezil (trade name Aricept) sharpened the mice’s focus back to normal levels, confirming that these animals display one of the early, non-memory-related symptoms of the disease.

Cholinergic neurons in the basal forebrain produce the neurotransmitter acetylcholine and are known to modulate attention (see, e.g., Bentley et al., 2008). These neurons are particularly vulnerable to the ravages of AD, causing acetylcholine levels to drop in affected brains. Not surprisingly, the anti-cholinesterase inhibitor donepezil, which increases levels of the neurotransmitter, improves attention in people with the disease (see Rockwood et al., 2004 and Foldi et al., 2005).

The Cambridge researchers wondered if the same effect could occur in rodents. First author Carola Romberg tested nine-month-old 3xTgAD mice, which carry mutations in tau, APP, and presenilin-1, and model many of the aspects of early AD, including amyloid plaques, neurofibrillary tangles, and memory problems. She modified a classic rodent task, the 5-Choice Serial Reaction Time Task, to include a touchscreen, making it nearly identical to a human reaction time task (see, e.g., Sahakian and Coull, 1993 and Sahakian et al., 1993). The screen was covered with a black mask containing five holes; in each trial, a random hole would light up for two seconds or less. The mice had to touch the lighted part of the screen with their nose to receive a food reward.

Romberg and colleagues found that the AD mice performed as well as wild-type mice when the light came on for two seconds, a task requiring low attention. When the light stayed on for less than a second, however, the transgenic mice scored more poorly than wild-type, indicating that their attention wandered from the screen more often and caused them to miss the signal. In humans, one of the main measures of lowered attention span is the inability to sustain attention over long periods of time, or reduced vigilance. The AD mice showed this trait as well. When tested on 10 trials in a row, the performance of the transgenic mice dropped rapidly over time, while wild-type mice did as well on the last trial as on the first. Giving the AD mice donepezil an hour before the trial restored their accuracy and vigilance to wild-type levels.

The attention deficit shown by these AD mice is likely to interfere with any memory task, Romberg said, because when you do not pay attention, you learn less. This presents a significant confounding factor for scientists trying to measure memory in mouse models. Romberg suggested it might be better to use an attentional task to measure cognitive decline in AD mice, because there are no confounding factors in this test. She believes that having a mouse model of attention will be useful in other ways, for example, in helping scientists to dissect what other neurotransmitter systems might be involved in attention, as well as in testing new drugs that might sharpen concentration. Romberg would also like to narrow down the brain region involved in this task, and currently is applying donepezil to specific brain regions such as the prefrontal cortex to see which areas control attention.

“Alzheimer’s is not just about memory,” Romberg points out. Many other cognitive domains are affected, she said, and should be studied as well. Romberg believes there is another advantage to the touchscreen task: Because the screen can display anything, it can be used for several other types of learning tasks originally developed for human diagnostics.

This mouse model of attention is exciting, Barbara Sahakian at Cambridge University told ARF. She wrote in an e-mail, “The reason that many animal models of diseases such as AD have been unsuccessful in identifying new treatments is that they have not reproduced the same cognitive dysfunction seen in the human disorder itself.” (See full comment below.) Because this model exhibits a notable symptom of AD, Sahakian said, it could help scientists develop new treatments.—Madolyn Bowman Rogers

Comments

- Barbara Sahakian
  University of Cambridge
- Posted: 07 Mar 2011
- Paper: Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).
I should mention that, of course, I do know Timothy Bussey and Lisa Saksida personally, as they are based at the University of Cambridge, where I work in the Department of Psychiatry. My views on this article are that it is a very exciting and important advance in back translational medicine (1) in that Romberg et al. (2) have developed a mouse model that shows the same form of attentional impairment seen in patients with Alzheimer’s disease. I and my colleagues have shown that this impairment in attention can be improved by treatment with cholinesterase inhibitors (3,4). Indeed, these early results formed the proof-of-concept study for the current symptomatic treatments that are now available for patients with Alzheimer’s disease, including donepezil (Aricept). Romberg et al. have now shown a similar enhancement in performance with donepezil using an "identical" test in mice.

The reason that many "animal models" of diseases such as Alzheimer’s disease have been unsuccessful in identifying new treatments, both symptomatic and neuroprotective, is that they have not reproduced the same cognitive dysfunction seen in the human disorder itself. The ideal animal model should have neurobiology closely aligned to the disease that is being modeled, together with the same symptom profile. This has been very hard to achieve. Romberg et al. now show a model that is closely aligned to the neurobiology and exhibits a prominent symptom of Alzheimer’s disease. This should be a great advantage in leading to new treatment development for Alzheimer’s disease.

A further advance would be in demonstrating that this mouse model also has early episodic memory problems, which are the early symptoms shown by Alzheimer’s patients (5). These memory problems are essential for Alzheimer’s disease early detection, which is crucial to ensure that neuroprotective treatments are given to patients before the damage is done, so that individuals can maintain their mental capital and well-being (6).

See also: Sahakian, B.J. (2011). Benefits and opportunities. Royal Society Brain Waves Project Module 1 Report.

References:

Romberg C, Mattson MP, Mughal MR, Bussey TJ, Saksida LM. Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept). J Neurosci. 2011 Mar 2;31(9):3500-7. PubMed.

Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer's disease. Lancet. 1991 Jul 6;338(8758):50-1. PubMed.

Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, Crockford HA, Crooks M, Hill K, Levy R. Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer's disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology (Berl). 1993;110(4):395-401. PubMed.

Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW. A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson's disease. Brain. 1988 Jun;111 ( Pt 3):695-718. PubMed.

Beddington J, Cooper CL, Field J, Goswami U, Huppert FA, Jenkins R, Jones HS, Kirkwood TB, Sahakian BJ, Thomas SM. The mental wealth of nations. Nature. 2008 Oct 23;455(7216):1057-60. PubMed.

View all comments by Barbara Sahakian

Research Brief: Attention Tests With a Touch of Class—or Maybe Genus

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