Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion

Philip W.J. Burnet,Mathieu Di Miceli,Helene M. Savignac,George Tzortzis,Daniel Anthony,Benjamin Gronier,Sherif M. Idriss

doi:10.1016/j.euroneuro.2017.11.001

Abstract

We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.

Highlights

The link between enteric microbiota and brain function is widely accepted, has been considered as ‘a paradigm shift in neuroscience’ (Mayer et al, 2014)
We have previously demonstrated that BimunoTM galacto-oligosaccharides (B-GOSs) intake by adult rats elevated cortical GluN1 subunits and its co-agonist, D-serine (Savignac et al, 2013)
The current study investigated the functional correlates of these alterations by measuring cortical N-methyl-D-aspartate receptors (NMDARs) responses and cognitive flexibility in B-GOSs fed rats, and found increased neuronal responses to iontophoretically applied NMDA, and improved ID/ED set shifting in B-GOSs supplemented animals compared to controls

Summary

Introduction

The link between enteric microbiota and brain function is widely accepted, has been considered as ‘a paradigm shift in neuroscience’ (Mayer et al, 2014). Given that the loss of NMDAR function impairs cellular responses in the rodent cortex (Rompala et al, 2013), we hypothesise that the elevated cortical GluN1 and D-serine following B-GOSs ingestion (Savignac et al, 2013), increases cortical NMDAR-mediated neural activity, and related behaviours In the latter instance, based on existing data, increased cortical NMDAR function in healthy animals may improve attentional set-shifting performance (cognitive flexibility), a prefrontal cortex (PFC)-dependent behaviour often impaired by NMDAR antagonists (Neill et al, 2010; Wallace et al, 2014), or the natural decrease in cortical NMDAR levels during aging (Nicolle and Baxter 2003; Rodefer and Nguyen, 2008). The increase of central NMDAR subunits in the rat brain following B-GOS ingestion, provides a model to test this

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