David Dupret

Spatial Relational Memory Requires Hippocampal Adult Neurogenesis

The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

Adult hippocampal neurogenesis is involved in anxiety-related behaviors

Adult hippocampal neurogenesis is a unique example of structural plasticity, the functional role of which has been a matter of intense debate. New transgenic models have recently shown that neurogenesis participates in hippocampus-mediated learning. Here, we show that transgenic animals, in which adult hippocampal neurogenesis has been specifically impaired, exhibit a striking increase in anxiety-related behaviors. Our results indicate that neurogenesis plays an important role in the regulation of affective states and could be the target of new treatments for anxiety disorders.

The reorganization and reactivation of hippocampal maps predict spatial memory performance

The hippocampus is an important brain circuit for spatial memory and the spatially selective spiking of hippocampal neuronal assemblies is thought to provide a mnemonic representation of space. We found that remembering newly learnt goal locations required NMDA receptor–dependent stabilization and enhanced reactivation of goal-related hippocampal assemblies. During spatial learning, place-related firing patterns in the CA1, but not CA3, region of the rat hippocampus were reorganized to represent new goal locations. Such reorganization did not occur when goals were marked by visual cues. The stabilization and successful retrieval of these newly acquired CA1 representations of behaviorally relevant places was NMDAR dependent and necessary for subsequent memory retention performance. Goal-related assembly patterns associated with sharp wave/ripple network oscillations, during both learning and subsequent rest periods, predicted memory performance. Together, these results suggest that the reorganization and reactivation of assembly firing patterns in the hippocampus represent the formation and expression of new spatial memory traces.

Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence

We found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence.

Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus

During adulthood, new neurons are continuously added to the mammalian dentate gyrus (DG). An increasing number of studies have correlated changes in rates of dentate neurogenesis with memory abilities. One study based on subchronic treatment with the toxin methylazoxymethanol acetate (MAM) has provided causal evidence that neurogenesis is involved in hippocampal‐dependent trace conditioning. In contrast, spatial learning is not impaired following MAM treatment. We hypothesized that this was due to the small residual number of new cells produced following MAM treatment. In the present experiment, we attempted to achieve a higher level of reduction of adult‐generated cells following MAM treatment in young and aged rats. We found only a partial reduction of adult‐generated cells in the DG. More importantly, independently of the age of the animals, MAM treatment at a dose necessary to reduce neurogenesis altered the overall health of the animals. In conclusion, the behavioural results obtained following subchronic treatment with high doses of MAM in adulthood must be interpreted with extreme caution.

Dynamic Reconfiguration of Hippocampal Interneuron Circuits during Spatial Learning

Summary In the hippocampus, cell assemblies forming mnemonic representations of space are thought to arise as a result of changes in functional connections of pyramidal cells. We have found that CA1 interneuron circuits are also reconfigured during goal-oriented spatial learning through modification of inputs from pyramidal cells. As learning progressed, new pyramidal assemblies expressed in theta cycles alternated with previously established ones, and eventually overtook them. The firing patterns of interneurons developed a relationship to new, learning-related assemblies: some interneurons associated their activity with new pyramidal assemblies while some others dissociated from them. These firing associations were explained by changes in the weight of monosynaptic inputs received by interneurons from new pyramidal assemblies, as these predicted the associational changes. Spatial learning thus engages circuit modifications in the hippocampus that incorporate a redistribution of inhibitory activity that might assist in the segregation of competing pyramidal cell assembly patterns in space and time.

Memory trace replay: the shaping of memory consolidation by neuromodulation

Highlights • Memory trace replay results from lingering excitability and synaptic plasticity.• The balance of replay mechanisms may be determined by neuromodulation.• Acetylcholine release can shape the direction of replay in sharp wave ripples.• Dopamine release can dictate which cell assemblies are replayed.

Spectrally resolved fast transient brain states in electrophysiological data

The brain is capable of producing coordinated fast changing neural dynamics across multiple brain regions in order to adapt to rapidly changing environments. However, it is non-trivial to identify multiregion dynamics at fast sub-second time-scales in electrophysiological data. We propose a method that, with no knowledge of any task timings, can simultaneously identify and describe fast transient multiregion dynamics in terms of their temporal, spectral and spatial properties. The approach models brain activity using a discrete set of sequential states, with each state distinguished by its own multiregion spectral properties. This can identify potentially very short-lived visits to a brain state, at the same time as inferring the states properties, by pooling over many repeated visits to that state. We show how this can be used to compute state-specific measures such as power spectra and coherence. We demonstrate that this can be used to identify short-lived transient brain states with distinct power and functional connectivity (e.g., coherence) properties in an MEG data set collected during a volitional motor task.

Hippocampal Offline Reactivation Consolidates Recently Formed Cell Assembly Patterns during Sharp Wave-Ripples

Summary The ability to reinstate neuronal assemblies representing mnemonic information is thought to require their consolidation through offline reactivation during sleep/rest. To test this, we detected cell assembly patterns formed by repeated neuronal co-activations in the mouse hippocampus during exploration of spatial environments. We found that the reinstatement of assembly patterns representing a novel, but not a familiar, environment correlated with their offline reactivation and was impaired by closed-loop optogenetic disruption of sharp wave-ripple oscillations. Moreover, we discovered that reactivation was only required for the reinstatement of assembly patterns whose expression was gradually strengthened during encoding of a novel place. The context-dependent reinstatement of assembly patterns whose expression did not gain in strength beyond the first few minutes of spatial encoding was not dependent on reactivation. This demonstrates that the hippocampus can hold concurrent representations of space that markedly differ in their encoding dynamics and their dependence on offline reactivation for consolidation. Video Abstract

Recoding a cocaine-place memory engram to a neutral engram in the hippocampus

The hippocampus provides the brains memory system with a subset of neurons holding a map-like representation of each environment experienced. We found in mice that optogenetic silencing those neurons active in an environment unmasked a subset of quiet neurons, enabling the emergence of an alternative map. When applied in a cocaine-paired environment, this intervention neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior.