Memory loss is one of the most devastating symptoms of Alzheimer’s disease (AD). But are all of these memories gone forever, or are some of them just irretrievable? And how can we find out? In today’s PLoS Biology, Richard Morris and colleagues at Edinburgh University, Scotland, describe a new type of water maze test that can distinguish memory storage from memory retrieval problems in rats. The technique may be useful to study memory loss in animal models of disease.
Hanging over the field of amnesia research has been the question of whether memory problems are due to truly lost memories or simply poor recollection. To eliminate the latter possibility, research must show that memories are really retrieved and not a result of relearning. Many experiments that test animal memory have trouble distinguishing between these two possibilities. For example, does that rat really recall a mild foot shock or has its memory actually been wiped and it has relearned to avoid it? By adapting the classic Morris water maze, first author Livia de Hoz and colleagues have designed a test that distinguishes retrieval from relearning. The test may open the flood gates for investigation into how the hippocampus and cortex cooperate to store and retrieve memories.
The key to the test is a simple hint. De Hoz and colleagues trained animals to find and climb to safety on a hidden platform in the water maze. After induction of amnesia—a partial or complete hippocampal lesion—they retested the animals before and after briefly showing them the platform again. The idea is to remind the animals of the existence of the platform but not to teach them of its location.
The results were definitive. After partial hippocampal lesions, rats searched aimlessly around the tank until they got the hint, then they began to search more locally, where the platform was originally. The key observation was that even though the hint can come in the opposite quadrant of the tank, the rats still searched the original locale (see image). The results suggest that their memories can indeed be retrieved and the rats are not just relearning the platform position. The results also indicate that the lesions caused retrieval rather than storage problems. In contrast, animals with complete lesions wandered aimlessly around the tank even after getting the hint, which is what would be expected in a case where memories just cannot be retrieved.
Image credit: © De Hoz et al.
Rats trained to find the hidden platform (red dot) in the water maze cannot remember where it is after partial hippocampal lesion (left animal track), but after getting a hint--the platform is briefly raised either in its original location or in the opposite quadrant of the tank (yellow dot)--the animals begin to search more locally. The fact that they search in the original quadrant, irrespective of where the hint is, suggests that they are truly remembering the location and not just relearning.
The authors further eliminated the possibility that the animals were relearning rather than remembering by training them in a totally new environment. While the sham-operated control animals could learn the position of a new platform, those with hippocampal lesions could not.
While the test may or may not be directly applicable to animal models of AD, as the authors write, “the findings open a potential avenue of research into the neural dynamics of memory reactivation and retrieval.” In particular, these findings offer a new means to explore the relationship of the hippocampal-cortex axis to memory. For example, does the hippocampus mediate links between different cortical regions before memories are consolidated, as has been suggested (see review by Squire and Alvarez, 1995), or is it itself the site of long-term storage (see discussion by Moscovitch and Nadel, 1998)? Answers to these questions may help us understand the role the hippocampus may play in Alzheimer’s-related memory losses (see, for example, Eustache et al., 2004).—Tom Fagan
- Squire LR, Alvarez P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol. 1995 Apr;5(2):169-77. PubMed.
- Moscovitch M, Nadel L. Consolidation and the hippocampal complex revisited: in defense of the multiple-trace model. Curr Opin Neurobiol. 1998 Apr;8(2):297-300. PubMed.
- Eustache F, Piolino P, Giffard B, Viader F, De la Sayette V, Baron JC, Desgranges B. 'In the course of time': a PET study of the cerebral substrates of autobiographical amnesia in Alzheimer's disease. Brain. 2004 Jul;127(Pt 7):1549-60. PubMed.
- de Hoz L, Martin SJ, Morris RG. Forgetting, reminding, and remembering: the retrieval of lost spatial memory. PLoS Biol. 2004 Aug;2(8):E225. PubMed.