. (2014) 'Hippocampal synaptic plasticity, spatial memory and anxiety.', Nature reviews neuroscience., 15 (3). pp. 181-192. Further information on publisher's website:https://doi.org/10.1038/nrn3677Publisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. AbstractRecent studies with transgenic mice lacking NMDARs in the hippocampus challenge head-on the longstanding hypothesis that hippocampal LTP-like mechanisms underlie the encoding and storage of associative, long-term spatial memories. However, it may not be the synaptic plasticity/memory hypothesis that is wrong. Instead, it may be the role of the hippocampus that needs re-examination. We present an account of hippocampal function which explains its role in both memory and anxiety.3

Delirium is an acute, severe neuropsychiatric syndrome, characterized by cognitive deficits, that is highly prevalent in aging and dementia and is frequently precipitated by peripheral infections. Delirium is poorly understood and the lack of biologically relevant animal models has limited basic research. Here we hypothesized that synaptic loss and accompanying microglial priming during chronic neurodegeneration in the ME7 mouse model of prion disease predisposes these animals to acute dysfunction in the region of prior pathology upon systemic inflammatory activation. Lipopolysaccharide (LPS; 100 μg/kg) induced acute and transient working memory deficits in ME7 animals on a novel T-maze task, but did not do so in normal animals. LPS-treated ME7 animals showed heightened and prolonged transcription of inflammatory mediators in the central nervous system (CNS), compared with LPS-treated normal animals, despite having equivalent levels of circulating cytokines. The demonstration that prior synaptic loss and microglial priming are predisposing factors for acute cognitive impairments induced by systemic inflammation suggests an important animal model with which to study aspects of delirium during dementia.

Controversy revolves around the differential contribution of NR2A- and NR2B-containing NMDA receptors, which coexist in principal forebrain neurons, to synaptic plasticity and learning in the adult brain. Here, we report genetically modified mice in which the NR2B subunit is selectively ablated in principal neurons of the entire postnatal forebrain or only the hippocampus. NR2B ablation resulted in smaller NMDA receptor-mediated EPSCs with accelerated decay kinetics, as recorded in CA1 pyramidal cells. CA3-to-CA1 field LTP remained largely unaltered, although a pairing protocol revealed decreased NMDA receptor-mediated charge transfer and reduced cellular LTP. Mice lacking NR2B in the forebrain were impaired on a range of memory tasks, presenting both spatial and nonspatial phenotypes. In contrast, hippocampus-specific NR2B ablation spared hippocampus-dependent, hidden-platform water maze performance but induced a selective, short-term, spatial working memory deficit for recently visited places. Thus, both hippocampal and extra-hippocampal NR2B containing NMDA receptors critically contribute to spatial performance.

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Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered as crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that GluN1ΔDGCA1 mice, lacking NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory watermaze task as well as Controls, despite impairments on the spatial reference memory radial maze task. In a novel spatial discrimination watermaze paradigm, using two visually identical beacons, GluN1ΔDGCA1 mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform’s actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important role for the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories.

Quick voluntary responses to environmental stimuli are required of people on a daily basis. These movements have long been thought to be controlled via cortical loops involving processing of the stimulus and generation of a suitable response. Recent experiments have shown that in simple reaction time (RT) tasks, the appropriate response can be elicited much earlier (facilitated) when the "go" signal is replaced by a startling (124 dB) auditory stimulus. In the present experiment we combined a startling acoustic stimulus with an established RT paradigm that involved simple and choice RT. In a simple RT condition the prepared voluntary response was elicited at very short latencies following the startle. However, when cortical processing was required prior to responding (choice RT task), the startle did not facilitate the voluntary response, and gave rise to more movement production errors. Since movements requiring ongoing cortical processing following the stimulus are not facilitated by startle, it is unlikely that the startle facilitation is due to increased neural activation. In contrast, it appears more likely that the startle acts as an early trigger for subcortically stored prepared movements since movements that are prepared in advance can be initiated at such short latencies (<60 ms).

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1 À/À mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1À/À mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

A startle stimulus has been shown to elicit a ballistic response in a reaction time (RT) task at very short latencies without involvement of the cerebral cortex (J. Valls-Sole, J. C. Rothwell, F. Gooulard, G. Cossu, & E. Munoz, 1999). The present authors examined the nature of the startle response. A simple RT task was used in which 8 participants performed arm extension movements to 3 target distances (20 degrees, 40 degrees, and 60 degrees ) in a blocked design. An unpredictable startling acoustic stimulus (124 dB) replaced the imperative stimulus in certain trials. The authors verified the presence of a startle response independent from the prepared response by observing electromyographic (EMG) activity in sternocleidomastoid and orbicularis oculi muscles. Findings indicated that when the participant was startled, the intended voluntary response was produced at significantly shorter response latencies. Furthermore, the kinematic variables of the observed response during startle trials for all 3 target distances were mostly unchanged. The EMG characteristics of the responses were not modified, indicating that the response produced was indeed the prepared and intended response.