Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches.

Most commonly used behavioral measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal's residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal's performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (NS; Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of NS, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the MWM into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.

Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation.

Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.

Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep.

It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase-amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state.

Hippocampus-retrosplenial cortex interaction is increased during phasic REM and contributes to memory consolidation.

Hippocampal (HPC) theta oscillation during post-training rapid eye movement (REM) sleep supports spatial learning. Theta also modulates neuronal and oscillatory activity in the retrosplenial cortex (RSC) during REM sleep. To investigate the relevance of theta-driven interaction between these two regions to memory consolidation, we computed the Granger causality within theta range on electrophysiological data recorded in freely behaving rats during REM sleep, both before and after contextual fear conditioning. We found a training-induced modulation of causality between HPC and RSC that was correlated with memory retrieval 24 h later. Retrieval was proportional to the change in the relative influence RSC exerted upon HPC theta oscillation. Importantly, causality peaked during theta acceleration, in synchrony with phasic REM sleep. Altogether, these results support a role for phasic REM sleep in hippocampo-cortical memory consolidation and suggest that causality modulation between RSC and HPC during REM sleep plays a functional role in that phenomenon.

An investigation of Hebbian phase sequences as assembly graphs.

Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naïve Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition.