Other related neurons signal that something is familiar (familiarity neurons); they lose their responsiveness after an image is seen number of times and do not respond to it after that. Yet more neurons signal that something has been seen recently (recency neurons); they respond the first time something is seen and then show reduced activity the next time it is seen. However, the responsiveness of these neurons to the stimulus recovers quickly. Thus if these neurons respond, the stimulus cannot have been seen recently.
Further support to the hypothesis that LTD underlies recognition memory comes from earlier work in which scopolamine (a cholinergic antagonist routinely used as a pre-operative sedative) and lorazepam (an anxiolytic that produces amnesia in high doses) not only prevented the recognition of novelty, but also blocked LTD (lorazepam additionally blocked LTP) and reduced the production of fos, (the product of the immediate early gene c-fos, the activity of which is used as a marker neuronal activity) in slices of perirhinal cortex (Warburton et al 2003; Wan et al 2004).
Thus, in these two examples, a single form of treatment has consistent effects across multiple levels of systems activity. It is in this way, in combination with computer modelling, that the molecular and cellular mechanisms that underlie our memory systems can be investigated.
Visual recognition memory requires a number of judgements other than those based on novelty/familiarity. It also invloves the spatial arrangements of familiar objects or the temporal order in which objects have been seen. These aspects of recognition memory require the integration of multiple pieces of information. Thus, we recognise when familiar furniture has been moved in a room, which requires us to remember not only what individual items are familiar, but where they were before. Similar mechanisms exist for this aspect of recognition memory as for the recognition of individual items. However, in this case there are changes in neuronal activity in the hippocampus and an adjacent region, the postrhinal cortex (POR). The changes are also complex, in that c-fos activity is higher in response to novel arrangements in the POR and the CA1 region of the hippocampus. However, activity is higher in response to familiar arrangements of items in the dendate gyrus and subiculum (Wan et al 1999). This function of the hippocampus may be related to it's role in spatial memory.
Recent evidence suggests that the perirhinal cortex (PRH) is also involved in object arrangement recognition. Using a four object variant of the spontaneous object recognition task, disruption of perirhinal cortex function results in an impairment in the ability of an animal to tell when the positions of two objects have been swapped (object-in-place task: Barker et al 2007). However, such disruption has no effect on the behaviour of an animal when one of a pair of identical items is moved to a new position (object location task). This suggests that the perirhinal cortex not only signals that two non-identical objects are familiar, but their spatial relationship to each other, though not their absolute position.
A third brain region is involved with recognition memory - the medial prefrontal cortex (mPFC). Work here at the MRC centre has confirmed and extended previous work that demonstrated that the mPFC is involved in recency discrimination but not in object location or novelty/familiarity discrimination (Barker et al 2007). Furthermore, it was shown that disruption of mPFC function leads to an impairment in the object-in-place task, suggesting a role for the mPFC in detecting the spatial relationships between objects.
When multiple brain regions have been identified as being involved in the same process, it would seem likely that they operate as a neural network with information being passed between them. Well established anatomical evidence shows that projections connect the hippocampus and the mPFC while there are also anatomical connections between the mPFC and the perirhinal cortex. The perirhinal cortex is also connected to the hippocampus via the entorhinal cortex (see Brown & Aggleton 2001 for review). It is well known that disruption of the fornix (the fibre bundle that forms a major output of the hippocampus to other parts of the limbic system and to the mPFC) or the PRH-POR connection impairs behaviour in the object-in-place task (e.g.Bussey et al 2000). We have also recently shown as part of the above study that disruption of the connection between PRH and mPFC and also results in impairment in this task. So it would appear that a functioning hippocampus, perirhinal and medial prefrontal cortices are necessary for this form of spatial discrimination along with their interconnections.
Blockade of cholinergic transmission with scopolamine prior to memory acquisition impairs performance in spontaneous object recognition tasks. Mounted on the internet with permission of Warburton et al, 2003 Neuron 6; 987-996 © Cell Press Ltd
Disruption of familiarity discrimination has shown that there are multiple neurotransmitter and receptor systems involved in recognition memory. For instance, blockade of perirhinal muscarinic receptors with scopolamine during the acquisition phase of a spontaneous object recognition task, i.e. when the animal is familiarising itself with an object, reduces it's ability to discriminate between the object it's already seen and a new one. It will spend about an equal period of time investigating both novel and familiar objects. However, if scopolamine is administered after the acquisition phase, there is no effect on familarity discrimination (Warburton et al 2003). Thus scoploamine does not make the animal forget but prevents the proper formation and/or consolidation of the memory. Similar results have been seen using lorazepam (Wan et al 2004), a benzodiazapine used as an axiolytic that acts on GABAA receptors, thus implicatingGABAergic transmission in recognition memory.
Scopolamine has also been shown to disrupt memory aquisition in the object-in-place task (Barker and Warburton, 2008) when applied bilaterally to either PRH or mPFC regions. Combined unilateral blockade of muscarinic receptors in these two regions also disrupted this form of memory. Thus, we have shown not only that these regions act together to form a memory network, but that they depend on at least cholinergic neurotransmission.
Long-and short-term recognition memory rely on different glutmatergic transmission mechanisms. Mounted on the internet with permission of Barker et al, 2006 J. Neurosci. 26; 3561-3566 © Society for NeuroscienceIn addition, a further mechanism for long term memory requires the synergistic activation of group I and group II metabotropic glutamate receptors. Blockade of both mGlu5 receptors with MPEP and group II receptors with LY341495 impaired familiarity discrimination at a 24hr but not a 15 min delay between training and trial. Treatment with either antagonist alone had no effect (Barker et al 2006b). Whether the effects of blocking NMDA or mGlu receptors affects the same molecular process is not known, although synergy between these receptors in the generation of LTD has been reported previously (Cho et al 2000). It may be that activation of all three receptor systems is required for the aquisition of long-term object recognition.
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