NMDA receptors promote hippocampal sharp-wave ripples and the associated coactivity of CA1 pyramidal cells.

Hippocampal sharp-wave ripples (SWRs) support the reactivation of memory representations, relaying information to neocortex during "offline" and sleep-dependent memory consolidation. While blockade of NMDA receptors (NMDAR) is known to affect both learning and subsequent consolidation, the specific contributions of NMDAR activation to SWR-associated activity remain unclear. Here, we combine biophysical modeling with in vivo local field potential (LFP) and unit recording to quantify changes in SWR dynamics following inactivation of NMDAR. In a biophysical model of CA3-CA1 SWR activity, we find that NMDAR removal leads to reduced SWR density, but spares SWR properties such as duration, cell recruitment and ripple frequency. These predictions are confirmed by experiments in which NMDAR-mediated transmission in rats was inhibited using three different NMDAR antagonists, while recording dorsal CA1 LFP. In the model, loss of NMDAR-mediated conductances also induced a reduction in the proportion of cell pairs that co-activate significantly above chance across multiple events. Again, this prediction is corroborated by dorsal CA1 single-unit recordings, where the NMDAR blocker ketamine disrupted correlated spiking during SWR. Our results are consistent with a framework in which NMDA receptors both promote activation of SWR events and organize SWR-associated spiking content. This suggests that, while SWR are short-lived events emerging in fast excitatory-inhibitory networks, slower network components including NMDAR-mediated currents contribute to ripple density and promote consistency in the spiking content across ripples, underpinning mechanisms for fine-tuning of memory consolidation processes.

TaiNi: Maximizing research output whilst improving animals' welfare in neurophysiology experiments.

Understanding brain function at the cell and circuit level requires representation of neuronal activity through multiple recording sites and at high sampling rates. Traditional tethered recording systems restrict movement and limit the environments suitable for testing, while existing wireless technology is still too heavy for extended recording in mice. Here we tested TaiNi, a novel ultra-lightweight (<2 g) low power wireless system allowing 72-hours of recording from 16 channels sampled at ~19.5 KHz (9.7 KHz bandwidth). We captured local field potentials and action-potentials while mice engaged in unrestricted behaviour in a variety of environments and while performing tasks. Data was synchronized to behaviour with sub-second precision. Comparisons with a state-of-the-art wireless system demonstrated a significant improvement in behaviour owing to reduced weight. Parallel recordings with a tethered system revealed similar spike detection and clustering. TaiNi represents a significant advance in both animal welfare in electrophysiological experiments, and the scope for continuously recording large amounts of data from small animals.

Losing control under ketamine: suppressed cortico-hippocampal drive following acute ketamine in rats.

Systemic doses of the psychotomimetic ketamine alter the spectral characteristics of hippocampal and prefrontal cortical network activity. Using dynamic causal modeling (DCM) of cross-spectral densities, we quantify the putative synaptic mechanisms underlying ketamine effects in terms of changes in directed, effective connectivity between dorsal hippocampus and medial prefrontal (dCA1-mPFC) cortex of freely moving rats. We parameterize dose-dependent changes in spectral signatures of dCA1-mPFC local field potential recordings, using neural mass models of glutamatergic and GABAergic circuits. Optimizing DCMs of theta and gamma frequency range responses, model comparisons suggest that both enhanced gamma and depressed theta power result from a reduction in top-down connectivity from mPFC to the hippocampus, mediated by postsynaptic NMDA receptors (NMDARs). This is accompanied by an alteration in the bottom-up pathway from dCA1 to mPFC, which exhibits a distinct asymmetry: here, feed-forward drive at AMPA receptors increases in the presence of decreased NMDAR-mediated inputs. Setting these findings in the context of predictive coding suggests that NMDAR antagonism by ketamine in recurrent hierarchical networks may result in the failure of top-down connections from higher cortical regions to signal predictions to lower regions in the hierarchy, which consequently fail to respond consistently to errors. Given that NMDAR dysfunction has a central role in pathophysiological theories of schizophrenia and that theta and gamma rhythm abnormalities are evident in schizophrenic patients, the approach followed here may furnish a framework for the study of aberrant hierarchical message passing (of prediction errors) in schizophrenia-and the false perceptual inferences that ensue.