Neuroscience & Biobehavioral Reviews, Vol. 22, No. 2, pp. 181–193, 1998 ᭧ 1998 Elsevier Science Ltd. All rights reserved Pergamon Printed in Great Britain 0149-7634/98 $32.00 + .00 PII: S0149-7634(97)00005-5 Testing the NMDA, Long-term Potentiation, and Cholinergic Hypotheses of Spatial Learning DONALD PETER CAIN* Department of Psychology and Graduate Program in Neuroscience, University of Western Ontario, London, Ontario N6A 5C2, Canada CAIN, D. P. Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning. NEUROSCI BIOBEHAV REV 22(2), 181–193, 1998.—The problems and issues associated with the use of pharmacological antagonists in studies on learning and memory are considered in a review of the role of N-methyl-d-aspartate (NMDA) receptors, NMDA receptor-mediated long-term potentiation (LTP), and muscarinic receptors in spatial learning in the water maze. The evidence indicates that neither NMDA nor muscarinic receptors, nor NMDA receptor-mediated LTP, are required for spatial learning, although they might normally contribute to it. Detailed behavioral analyses have indicated that the water maze task is more complex than generally has been appreciated, and has a number of dissociable components. Naive rats trained under NMDA or muscarinic antagonism display sensorimotor disturbances that interfere with their ability to acquire the task. Rats made familiar with the general requirements of the task can learn the location of a hidden platform readily under NMDA or muscarinic antagonism. The ability of a rat to acquire the water maze task depends on its ability to apply instinctive behaviors to performance of the task in an adaptive manner. The instinctive behaviors undergo modification as the rat learns the general strategies required in the task. The evidence suggests that at least some of the plastic changes involved in acquiring the task occur in existing neural circuits situated in widespread areas of the brain, including sensory and motor structures in the cortex and elsewhere, and are therefore difficult to distinguish from existing sensorimotor mechanisms. More generally, the findings indicate the difficulty of inferring the occurrence or nonoccurrence of learning from behavior, and the difficulty of causally linking the action of particular receptor populations with the formation of specific memories. ᭧ 1998 Elsevier Science Ltd. All rights reserved. N-Methyl-d-aspartate NMDA Scopolamine Muscarinic receptor Spatial learning Water maze Sensorimotor disturbances Behavior CERTAIN PERIODS in the history of brain research have More recently, behavioral neuroscience has experienced been dominated by a search for the mechanisms of learning a strong resurgence of interest in the engram. Two develop- and memory. Karl Lashley, the father of modern behavioral ments during the 1970s were probably important in this neuroscience, spent much of the period from 1920 to 1950 resurgence. First, Eric Kandel and his colleagues set out searching for the engram in a long series of learning experi- to map the nervous system of Aplysia, a simple invertebrate, ments involving rats and monkeys with brain lesions. For and to identify the neurons and events required for simple Lashley the engram represented the sites of lasting change in forms of behavioral learning (14). Second, Bliss and Lomo the nervous system—presumably specific synapses—that (10) discovered long-term potentiation (LTP), a relatively were associated with particular instances of behavioral learn- long-lasting form of neural plasticity that could be artificially ing, and were necessary for it to occur. His approach of beha- induced in the brain of mammals by electrical stimulation. viorally training rats to discriminate visual stimuli or negotiate The first development showed that detailed knowledge of mazes set the tone of such research for years. Lashley’s con- relevant neural circuitry was beneficial and perhaps even tributions are usually, but incompletely, summed up by the necessary, and that this knowledge, together with electro- ‘‘principle of mass action’’, the conclusion that for complex physiological analysis, could identify the nature and location tasks such as learning to traverse a maze, the amount learned of the engram in a simple animal. The second development and remembered was proportional to the amount of remaining provided a laboratory model of the kind of synaptic plasticity neocortex; the location ofthe damage mattered little. Although that could underlie complex forms of learning in mammals the common view that Lashley failed in his attempts to locate (9). LTP appeared to embody the activity of the ‘‘Hebb the engram for some forms of learning is mistaken (104), the synapse’’, a modifiable synapse that Donald Hebb, Lashley’s perceived negativity of his findings, and the accumulating student, proposed in 1949 as a learning mechanism. evidence for the localization of function in the neocortex, led The idea that the hippocampus was uniquely important many researchers to discredit his conclusions. for engram formation stemmed from the discovery in the * Tel.: +1 519 6792111, ext. 4628; Fax: +1 519 6613961; E-mail: [email protected] 181 182 CAIN 1950s that human patients with hippocampal removals movement by visual and other sensory input, climbing experienced severe disturbances in learning and memory onto and standing on the platform), there must be pre- (87). Later, based on animal research, O’Keefe and Nadel existing neural circuits that the rat brings to the water maze (71) proposed that the hippocampus served as a spatial map. task for its successful acquisition (51,100,102,104,117), in Their hypothesis was supported by the finding that indivi- addition to engrams that might be formed by neuroplastic dual complex spike cells in the hippocampus, called place processes during training. cells, fired when an animal was in a specific location within Successful acquisition of the water maze task requires an an environment (70). This suggested that place cells coded animal to navigate efficiently from any starting point in the spatial locations in the environment, giving anatomical and pool to a specific location containing the hidden platform. functional support to the hypothesis that the hippocampus Whishaw and Mittleman (115) showed that normal rats served as a spatial map that was crucial for spatial learn- made use of a number of different spatial navigation ing—the learning of a location in the environment in strategies in acquiring the water maze task, and that these relation to cues in that environment. The fact that damage strategies were considerably more complex than had been to the hippocampus or related structures severely disrupted thought. They suggested that ‘‘some deficits in spatial acquisition of tasks that required spatial information was navigation that follow brain damage may be as easily consistent with their hypothesis (65,69). attributed to the loss of search strategies as to the loss of a Further impetus for the idea that the hippocampus might hypothetical subsystem of memory’’ (p. 428). This general be important for engram formation came from research approach led to an extensive series of experiments, the showing that LTP occurred most readily in the hippo- conclusion of which was that muscarinic antagonists disrupt campus. Although hippocampal LTP has been theoretically a sensorimotor subsystem important for the selection of linked to various kinds of learning, it has been most closely behavioral strategies required to solve the water maze linked to spatial learning (15,63,64). LTP at most hippo- task, and do not prevent spatial learning per se campal synapses was found to be dependent on activity at N- (109,110,117,118). The question whether experimental methyl-d-aspartate (NMDA) receptors (17,34,64), and treatments affect the selection of behavioral strategies for NMDA receptor antagonists were found to severely disrupt acquiring the water maze task, or even basic sensory acquisition of spatial learning tasks (63,64). This suggested processing or motor control mechanisms, is important for that NMDA receptor-mediated LTP in the hippocampus understanding drug and lesion effects. established the engram for spatial learning. The relevance of this question is that all conclusions This review will evaluate the hypothesis that NMDA about the neural mechanisms of learning, conceived of as receptor-mediated LTP in the hippocampus is necessary changes in conduction through specific neural circuits, are for establishing the engram for spatial learning. The number inferences from observable behavior. For inferences about of laboratory tasks that could potentially involve aspects of spatial learning to be valid, the behavioral changes cannot spatial learning for their acquisition is large, so the discus- have resulted from the disruptive effects of an experimental sion will focus on selected studies involving the water maze. treatment on the mechanisms involved in producing the This task requires a rat or mouse to swim in a circular pool instinctive behaviors required to perform the task. Under- of water 1–2 m in diameter until it finds and climbs onto a standing the effects of treatments on instinctive behaviors, small platform hidden just beneath the surface, which as well as on the engram, is vital for arriving at a useful and provides the only refuge. This task is well suited for the complete understanding of learning and memory (102,104). study of spatial learning because it requires the animal to The difficulty of knowing whether experimental treat- learn to swim to a specific location using visual cues in the ments have affected pre-existing neural circuits that produce room (61,71,96). Normal rats learn to do this quickly, but instinctive behavior, or the engram, or both, is a very diffi- rats given NMDA antagonists or hippocampal lesions do cult problem for even the simplest forms of learning. A poorly on this task (63–65). further complication is the fact that instinctive behaviors In addition to a hypothesized role for NMDA receptor- themselves can be modified by experience. There are mediated hippocampal LTP in spatial learning, there is evi- many examples of this from a large variety of species.