In vitro hippocampal gamma oscillation power as an index of in vivo CA3 gamma oscillation strength and spatial reference memory

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Abstract

Neuronal synchronisation at gamma frequencies (30–100 Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various in vitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro.

Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3.

The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay.

The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory.

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Research highlights

► CA3 gamma oscillation strength in freely moving mice correlates with CA3 gamma oscillation strength in hippocampal slice models. ► CA3 gamma oscillation strength correlates with performance in spatial reference memory tasks. ► In vitro CA3 gamma oscillation strength can be used as a neurophysiological index of spatial reference memory.

Introduction

To understand the mechanisms underlying learning and memory, and to develop nootropics, several in vitro neurophysiological markers have been identified that correlate with prior behavioural performance. Long-term potentiation (LTP) of synaptic strength in the hippocampus is used as index for hippocampal memory capacity (Whitlock, Heynen, Shuler, & Bear, 2006), but dissociations between LTP and learning have also been reported (Bach et al., 1995, Bannerman et al., 2008, Bikbaev et al., 2008). The hippocampal slow-afterhyperpolarization amplitude covaries with spatial learning ability (Tombaugh, Rowe, & Rose, 2005) but the causality in this relationship is unclear (Matthews, Linardakis, & Disterhoft, 2009).

Synchronisation of neuronal firing at frequencies in the gamma band (30–100 Hz) due to shared recurrent inhibitory inputs (Csicsvari et al., 2003, Fisahn et al., 1998, Sohal et al., 2009) has been implicated in cognitive functions, including attentional selection (Jensen et al., 2007, Vidal et al., 2006), feature binding (Herrmann et al., 2004, Vidal et al., 2006), working memory (Fuchs et al., 2007) and long-term memory (Bikbaev et al., 2008, Fell et al., 2001, Herrmann et al., 2004, Jensen et al., 2007, Jutras et al., 2009).

The hippocampus displays high- and low-frequency gamma oscillations that are driven by gamma generators in the entorhinal cortex and area CA3 respectively (Bragin et al., 1995, Colgin et al., 2009) and may be associated with different aspects of spatial information processing (Colgin et al., 2009). Spatial memory tasks increase gamma synchronisation in area CA3 (Montgomery & Buzsaki, 2007), which is involved in spatial memory (Kesner, 2007, Montgomery and Buzsaki, 2007, Steffenach et al., 2002), suggesting that the capacity of the CA3 network to generate gamma oscillations is a useful index for the ability to store and/or retrieve spatial information.

Although reduced hippocampal gamma oscillations have been associated with impaired spatial memory (Fuchs et al., 2007), normal brain ageing (Vreugdenhil & Toescu, 2005) and Alzheimer disease (Driver et al., 2007), this relationship could be an epiphenomenon introduced by experimental manipulation. Instead of testing differences between experimental groups, we took advantage of the natural intrinsic variability in cognitive performance in normal inbred mice, in order to determine correlations between performance in different memory tasks, CA3 gamma oscillations recorded in vivo and in vitro. In this way we could also address the question whether spontaneous small-amplitude gamma oscillations and kainate-induced large-amplitude gamma oscillations recorded in vitro (Pietersen, Patel, Jefferys, and Vreugdenhil, 2009) provide good models for gamma oscillations recorded in the same area in vivo.

Our results indicate that the capacity of area CA3 to generate gamma oscillations in vitro correlates with the gamma oscillation strength recorded in vivo, and with performance in spatial reference memory tasks supporting the use of in vitro hippocampal gamma oscillation strength as an index for spatial learning ability.

Section snippets

Animals

Forty eight adult (>3 months) male C57bl/6J mice (B&K Universal Ltd., Hull, UK) were kept in groups of four under standard conditions, with normal chow ad libitum and a 12-h light cycle starting at 6 am. The behavioural testing was done between 3 pm and 6 pm. Mice were placed in a dim, red light-lit room for 1 h before testing in a specially designated behavioural testing room. Behavioural tests were performed on two groups of 24 mice. Testing sequence was: Barnes circular platform acquisition and

Results

Our main aim here was to determine the degree of correlation between reference memory and CA3 gamma oscillations, recorded both in vivo with electrodes implanted in area CA3 and ex vivo, in hippocampal brain slices. To this end, cognitive performance was assessed in all animals.

Discussion

Using a multi-stage assessment of behaviour, in vivo CA3 LFPs and in vitro gamma oscillations in the same individual mice, we have demonstrated correlations between spatial reference memory and the strength of gamma oscillations recorded in slices, and that the strength of the gamma oscillations recorded in vitro correlates with the gamma oscillation strength recorded in freely moving mice.

Acknowledgments

We thank the Medical Research Council for support (Grant # 68131) and Dr. Alan White for the statistical advice.

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