Neuronal ensembles in memory processes.

A neuronal ensemble represents the concomitant activity of a specific group of neurons that could encompass a broad repertoire of brain functions such as motor, perceptual, memory or cognitive states. On the other hand, a memory engram portrays the physical manifestation of memory or the changes that enable learning and retrieval. Engram studies focused for many years on finding where memories are stored as in, which cells or brain regions represent a memory trace, and disregarded the investigation of how neuronal activity patterns give rise to such memories. Recent experiments suggest that the association and reactivation of specific neuronal groups could be the main mechanism underlying the brain's ability to remember past experiences and envision future actions. Thus, the growing consensus is that the interaction between neuronal ensembles could allow sequential activity patterns to become memories and recurrent memories to compose complex behaviors. The goal of this review is to propose how the neuronal ensemble framework could be translated and useful to understand memory processes.

In vivo ephaptic coupling allows memory network formation.

It is increasingly clear that memories are distributed across multiple brain areas. Such "engram complexes" are important features of memory formation and consolidation. Here, we test the hypothesis that engram complexes are formed in part by bioelectric fields that sculpt and guide the neural activity and tie together the areas that participate in engram complexes. Like the conductor of an orchestra, the fields influence each musician or neuron and orchestrate the output, the symphony. Our results use the theory of synergetics, machine learning, and data from a spatial delayed saccade task and provide evidence for in vivo ephaptic coupling in memory representations.

Beyond dimension reduction: Stable electric fields emerge from and allow representational drift.

It is known that the exact neurons maintaining a given memory (the neural ensemble) change from trial to trial. This raises the question of how the brain achieves stability in the face of this representational drift. Here, we demonstrate that this stability emerges at the level of the electric fields that arise from neural activity. We show that electric fields carry information about working memory content. The electric fields, in turn, can act as "guard rails" that funnel higher dimensional variable neural activity along stable lower dimensional routes. We obtained the latent space associated with each memory. We then confirmed the stability of the electric field by mapping the latent space to different cortical patches (that comprise a neural ensemble) and reconstructing information flow between patches. Stable electric fields can allow latent states to be transferred between brain areas, in accord with modern engram theory.

Toward nanoscale localization of memory engrams in Drosophila.

The Mushroom Body (MB) is the primary location of stored associative memories in the Drosophila brain. We discuss recent advances in understanding the MB's neuronal circuits made using advanced light microscopic methods and cell-type-specific genetic tools. We also review how the compartmentalized nature of the MB's organization allows this brain area to form and store memories with widely different dynamics.

On memories, neural ensembles and mental flexibility.

Memories are assumed to be represented by groups of co-activated neurons, called neural ensembles. Describing ensembles is a challenge: complexity of the underlying micro-circuitry is immense. Current approaches use a piecemeal fashion, focusing on single neurons and employing local measures like pairwise correlations. We introduce an alternative approach that identifies ensembles and describes the effective connectivity between them in a holistic fashion. It also links the oscillatory frequencies observed in ensembles with the spatial scales at which activity is expressed. Using unsupervised learning, biophysical modeling and graph theory, we analyze multi-electrode LFPs from frontal cortex during a spatial delayed response task. We find distinct ensembles for different cues and more parsimonious connectivity for cues on the horizontal axis, which may explain the oblique effect in psychophysics. Our approach paves the way for biophysical models with learned parameters that can guide future Brain Computer Interface development.

Cytoelectric coupling: Electric fields sculpt neural activity and "tune" the brain's infrastructure.

We propose and present converging evidence for the Cytoelectric Coupling Hypothesis: Electric fields generated by neurons are causal down to the level of the cytoskeleton. This could be achieved via electrodiffusion and mechanotransduction and exchanges between electrical, potential and chemical energy. Ephaptic coupling organizes neural activity, forming neural ensembles at the macroscale level. This information propagates to the neuron level, affecting spiking, and down to molecular level to stabilize the cytoskeleton, "tuning" it to process information more efficiently.

Recovering object-location memories after sleep deprivation-induced amnesia.

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unknown, however, whether sleep deprivation leads to the loss of information or merely the suboptimal storage of information that is difficult to retrieve. Here, we show that hippocampal object-location memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training, using optogenetic dentate gyrus (DG) memory engram activation or treatment with the clinically approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, the combination of optogenetic DG memory engram activation and roflumilast treatment, 2 days following training and sleep deprivation, made the memory more persistently accessible for retrieval even several days later (i.e., without further optogenetic or pharmacological manipulation). Altogether, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss but instead leads to the suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation. Furthermore, our findings suggest that object-location memories, consolidated under sleep deprivation conditions and thought to be lost, can be made accessible again several days after the learning and sleep deprivation episode, using the clinically approved PDE4 inhibitor roflumilast.

Distinct brain networks for remote episodic memory depending on content and emotional experience.

Memories of life episodes are the heart of individual stories. However, modelling episodic memory is a major challenge in both humans and animals when considering all its characteristics. As a consequence, the mechanisms that underlie the storage of old nontraumatic episodic memories remain enigmatic. Here, using a new task in rodents that models human episodic memory including odour/place/context components and applying advances behavioural and computational analyses, we show that rats form and recollect integrated remote episodic memories of two occasionally encountered complex episodes occurring in their daily life. Similar to humans, the information content and accuracy of memories vary across individuals and depend on the emotional relationship with odours experienced during the very first episode. We used cellular brain imaging and functional connectivity analyses, to find out the engrams of remote episodic memories for the first time. Activated brain networks completely reflect the nature and content of episodic memories, with a larger cortico-hippocampal network when the recollection is complete and with an emotional brain network related to odours that is critical in maintaining accurate and vivid memories. The engrams of remote episodic memories remain highly dynamic since synaptic plasticity processes occur during recall related to memory updates and reinforcement.

GABAergic Interneurons with Nonlinear Dendrites: From Neuronal Computations to Memory Engrams.

GABAergic interneurons (INs) are a highly diverse class of neurons in the mammalian brain with a critical role in orchestrating multiple cognitive functions and maintaining the balance of excitation/inhibition across neuronal circuitries. In this perspective, we discuss recent findings regarding the ability of some IN subtypes to integrate incoming inputs in nonlinear ways within their dendritic branches. These recently discovered features may endow the specific INs with advanced computing capabilities, whose breadth and functional contributions remain an open question. Along these lines, we discuss theoretical and experimental evidence regarding the potential role of nonlinear IN dendrites in advancing single neuron computations and contributing to memory formation.

The use of the Emotional-Object Recognition as an assay to assess learning and memory associated to an aversive stimulus in rodents.

BACKGROUND: Emotionally salient experiences induce the formation of explicit memory traces, besides eliciting automatic or implicit emotional memory in rodents. This study aims at investigating the implementation of a novel task for studying the formation of limbic memory engrams as a result of the acquisition- and retrieval- of fear-conditioning - biased declarative memory traces, measured by animal discrimination of an "emotional-object". Moreover, by using this new method we investigated the potential interactions between stimulation of cannabinoid transmission and integration of emotional information and cognitive functioning. NEW METHOD: The Emotional-Object Recognition task is composed of 3 following sessions: habituation; cued fear-conditioned learning; emotional recognition. Rats are exposed to Context "B chamber" for habituation and cued fear-conditioning, and tested in Context "A chamber" for emotional-object recognition. RESULTS: Cued fear-conditioning induces a reduction in emotional-object exploration time during the Emotional-Object Recognition task in controls. The activation of cannabinoid signalling impairs limbic memory formation, with respect to vehicle. COMPARISON TO EXISTING METHODS: The Emotional-Object Recognition test overcomes several limitations of commonly employed methods that explore declarative-, spatial memory and fear-conditioning in a non-integrated manner. It allows the assessment of unbiased cognitive indicators of emotional learning and memory. CONCLUSIONS: The Emotional-Object Recognition task is a valuable tool for investigating whether, and at what extent, specific drugs or pathological conditions that interfere with the individual affective/emotional homeostasis, can modulate the formation of emotionally salient explicit memory traces, thus jeopardizing control and regulation of animal behavioural strategy.

Distinct memory engrams in the infralimbic cortex of rats control opposing environmental actions on a learned behavior.

Conflicting evidence exists regarding the role of infralimbic cortex (IL) in the environmental control of appetitive behavior. Inhibition of IL, irrespective of its intrinsic neural activity, attenuates not only the ability of environmental cues predictive of reward availability to promote reward seeking, but also the ability of environmental cues predictive of reward omission to suppress this behavior. Here we report that such bidirectional behavioral modulation in rats is mediated by functionally distinct units of neurons (neural ensembles) that are concurrently localized within the same IL brain area but selectively reactive to different environmental cues. Ensemble-specific neural activity is thought to function as a memory engram representing a learned association between environment and behavior. Our findings establish the causal evidence for the concurrent existence of two distinct engrams within a single brain site, each mediating opposing environmental actions on a learned behavior.