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as the theta rhythm, which is hypothesized to allow rapid transitions between encoding and retrieval.

Glutamate Receptors

The ► NMDA receptor is a major target for glutamate in the brain and its role in ► long-term potentiation is thought to be related to mnemonic encoding. It is no surprise that NMDA blockade using compounds such as AP5, ► ketamine, or MK-801, either intrahippocampal or intracerebral in rats impairs spatial learning using the Morris water maze, without affecting perceptual or motivational processes. For example, a degree of selectivity is suggested by the lack of impairment on a nonspatial discrimination task following AP5 infusion (McNamara and Skelton 1993). ► Metabotropic glutamate receptor agents can also modulate spatial learning. For examples, an mGluR5 allosteric modulator enhances spatial learning in the rat, probably by enhancing LTP and LTD, and an mGluR2 receptor antagonist can impair spatial learning when infused into the nucleus accumbens. Although they are likely to play a role, the function of AMPA and kainate receptors in specific modulation of glutamatergic activity during spatial memory tasks is not well understood; similarly for the influence of NMDA receptor subunits. Aging, at least in mice, is known to be associated with changes in NMDA subunit expression which may contribute to memory decline with aging (Zhao et al. 2009).

Cholinergic Receptors

Studies employing lesions of the cholinergic cell groups in the basal forebrain nucleus basalis magnocellularis or medial septum, pharmacological blockade of acetylcho-line receptors, age-related decreases in ► acetylcholine activity, and ► microdialysis to index acetylcholine release provide compelling converging evidence for the important role of the acetylcholine system in spatial memory. However, it is now generally accepted that cholinergic modulation can also influence visual attention, altering cue processing (e.g., Muir et al. 1993), and thus it is important that these additional effects are taken into account. In humans, fMRI and positron emission tomography (► PET) have confirmed the effects of cholinergic enhancement with ► physostigmine on stimulus-driven shifts in ► attention, which can reduce demands on working memory processes in the ► prefrontal cortex.

Within the hippocampus, microdialysis in the rat clearly shows a positive relationship between acetylcho-line and spatial learning and memory performance, and in humans it is predicted that patients with cholinergic dysfunction (e.g., ► Alzheimer's disease) or volunteers administered scopolamine will be impaired on tasks of spatial memory via alteration of hippocampal activity based on the proposal that acetylcholine activity dynamics modulates hippocampal-based encoding of new information (Hasselmo 2006). Using a virtual reality-based spatial memory task based on the Morris water maze, deficits in hippocampal activation following scopolamine (0.4 mg s. c.) have been demonstrated in healthy volunteers (Anto-nova et al. 2009). The task requires the movement (using a trackball) to a platform in a virtual reality arena surrounded by abstract images (see Fig. 1). The memory for place is assessed by removing the platform and asking the volunteer to move to the platform location from the same starting point with different environmental cues (viewpoint-dependent or egocentric condition), or from different starting points with the same environment cues (viewpoint-independent or allocentric condition). Using a different task of spatial navigation (Gron et al. 2006), the ► acetylcholinesterase inhibitor and nicotinic cholinergic receptor agonist, ► galantamine (4 mg b.i.d. for 7 days), has been shown to modulate neural activity in a group of ten patients with ► mild cognitive impairment (these patients have an increased risk for developing clinically defined Alzheimer's disease). Using one-sample t-tests galantamine was shown to decrease activity in the supplementary motor area and increase activity in a network of regions known to be associated with this task in young healthy volunteers: occiptotemporal junction, fusiform gyrus, posterior cingulate, parahippocampal gyrus, and hippocampus. While the task depended in part on spatial memory, the use of egocentric or allocentric frames of

Spatial Memory in Humans. Fig. 1. A screenshot of the arena task used by Parslow et al. (2005) reproduced with kind permission from Professor Robin Morris. The goal of the task is to move toward the pole, at first with the pole visible and subsequently after removal of the pole. Changes in the starting position and background environment allow the control of the frames of reference likely to be used in spatial memory recall.

reference was not controlled and the role of motivational and decision-making processes in the completion of such tasks is poorly understood.

Other Neurotransmitters g-Aminobutyric acid ► (GABA) receptors control the flow of excitation through the brain. Within the hippocampus, GABA receptors are categorized as ► GABAA and GABAB, which have differential distribution and control of neuronal activity. Expression of the a5 subunit of the GABAA receptor is enriched in pyramidal cells of the hippocampus, thus the knockout mouse can be considered a model of hippocampal GABAA functionality. Performance is improved in the a5 subunit knockout mouse after administration of a full ► inverse agonist of the a5 subunit on the delayed match-to-place Morris water maze task, in which the platform is moved between trials. Do-pamine systems have previously been associated with the learning aspects of spatial memory tasks, with degeneration of the nigrostriatal dopamine system associated with learning deficits in the Morris water maze. Long-term effects on the consolidation of aspects of spatial memory, including object displacement tasks impaired after intra-accumbens injection of dopamine D1 and D2 antagonists, as well as improvements with ► levodopa, highlight a role for the striatal dopamine system. However, in terms of normal aging, analysis of impaired performance on the Morris water maze with age, in relation to hippocampal receptor density, showed no associations with dopamine D1 receptors. Serotonin1A receptor binding sites were, however, increased in poor performers in keeping with the proposed role of 5-HT1A receptors in encoding and consolidation of spatial memory rather than retrieval. Interestingly, 5-HT1B knockout mice appear protected against age-related hippocampal memory decline. However, a selective role in spatial memory has been questioned by 5-HT release being associated more closely with motor behavior and feeding behavior during spatial memory tasks rather than task performance. To date, there are no studies in humans that test other agents against spatial memory tasks.

Conclusions

Spatial memory describes a collection of functions associated with spatial information processing including navigation and localizing of objects. Egocentric and allo-centric frames of reference have been proposed for spatial processing, but are likely to interact in many situations. Nonetheless, separable functional neuroanatomy appears plausible for egocentric (parietal lobes) and allocentric (hippocampal region/striatum) memory tasks, with the latter emerging recently in functional imaging investigations using virtual reality. In keeping with the research in experimental animals, the hippocampal and proximal medial temporal lobe structures have a central role in spatial memory processing in humans. Predictions from hippocampal neuropharmacology of important neuro-transmitters in spatial memory processing imply a degree of opportunity for enhancement in human populations although this remains largely unexplored. A positive association between cholinergic activity and spatial memory in healthy volunteers (using scopolamine) and patients with mild cognitive impairment (using galantamine) is a strong indicator for the scope of behavioral modulation possible with the correct target compounds. Further work with GABAergic agents, particularly a5 inverse agonists, dopaminergic, and serotonergic compounds is required to validate predictions from experimental animals.

Cross-References

► Human Long-Term Memory

► Human Short-Term and Working Memory

► Short-Term and Working Memory in Humans

References

Aguirre GK, D'Esposito M (1997) Environmental knowledge is subserved by separable dorsal/ventral neural areas. J Neurosci 17(7):2512-2518 Antonova E, Parslow D, Brammer M, Simmons A, Dawson G, Morris R (2009) Scopolamine disrupts hippocampal activity during allo-centric spatial memory in humans: an fMRI study using a virtual reality analogue of Morris water maze (submitted) Burgess N (2008) Spatial cognition and the brain. Ann N Y Acad Sci 1124:77-97

De Leonibus E, Oliverio A, Mele A (2005) A study on the role of the dorsal striatum and the nucleus accumbens in allocentric and egocentric spatial memory consolidation. Learn Mem 12(5):491-503 Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL, Fried I (2003) Cellular networks underlying human spatial navigation. Nature 425(6954):184-188 Goodale MA, Milner AD (1992) Separate visual pathways for perception and action. Trends Neurosci 15(1):20-25 Gron G, Brandenburg I, Wunderlich AP, Riepe MW (2006) Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Neurobiol Aging 27(1):78-87 Hasselmo ME (2006) The role of acetylcholine in learning and memory.

Curr Opin Neurobiol 16(6):710-715 Maguire EA, Frackowiak RS, Frith CD (1997) Recalling routes around London: activation of the right hippocampus in taxi drivers. J Neurosci 17(18):7103-7110 McNamara RK, Skelton RW (1993) The neuropharmacological and neu-rochemical basis of place learning in the Morris water maze. Brain Res Brain Res Rev 18(1):33-49 Moscovitch M, Rosenbaum RS, Gilboa A, Addis DR, Westmacott R, Grady C, McAndrews MP, Levine B, Black S, Winocur G, Nadel L (2005) Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory. JAnat 207(1):35-66

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