Here 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.

SummaryThe 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

SummaryTheta oscillations reflect rhythmic inputs that continuously converge to the hippocampus during exploratory and memory-guided behavior. The theta-nested operations that organize hippocampal spiking could either occur regularly from one cycle to the next or be tuned on a cycle-by-cycle basis. To resolve this, we identified spectral components nested in individual theta cycles recorded from the mouse CA1 hippocampus. Our single-cycle profiling revealed theta spectral components associated with different firing modulations and distinguishable ensembles of principal cells. Moreover, novel co-firing patterns of principal cells in theta cycles nesting mid-gamma oscillations were the most strongly reactivated in subsequent offline sharp-wave/ripple events. Finally, theta-nested spectral components were differentially altered by behavioral stages of a memory task; the 80-Hz mid-gamma component was strengthened during learning, whereas the 22-Hz beta, 35-Hz slow gamma, and 54-Hz mid-gamma components increased during retrieval. We conclude that cycle-to-cycle variability of theta-nested spectral components allows parsing of theta oscillations into transient operating modes with complementary mnemonic roles.

The hippocampus provides the brain’s 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. This intervention applied in a cocaine-paired environment neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior.

The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult mammalian brain that become functionally integrated into existing neural circuits. To what extent this form of plasticity contributes to memory functions remains to be elucidated. Using mapping of activity-dependent gene expression, we visualized in mice injected with the birthdating marker 5-bromo-2 -deoxyuridine the recruitment of new neurons in a set of controlled water maze procedures that engage specific spatial memory processes and require hippocampal-cortical networks. Here, we provide new evidence that adult-generated hippocampal neurons make a specific but differential contribution to the processing of remote spatial memories. First, we show that new neurons in the DG are recruited into neuronal networks that support retrieval of remote spatial memory and that their activation is situation-specific. We further reveal that once selected, new hippocampal neurons are durably incorporated into memory circuits, and also that their recruitment into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. We find that initial spatial training during a critical period, when new neurons are more receptive to surrounding neuronal activity, favors their subsequent recruitment upon remote memory retrieval. We therefore hypothesize that new neurons activated during this critical period become tagged so that once mature, they are preferentially recruited into hippocampal networks underlying remote spatial memory representation when encountering a similar experience.immediate early gene ͉ learning ͉ memory consolidation ͉ neurogenesis ͉ plasticity N ew neurons are generated throughout adult life in discrete regions of the mammalian brain, including the dentate gyrus (DG) of the hippocampus. Some of these newborn neurons become integrated into preexisting hippocampal circuits, raising the possibility that they may thereby contribute to behaviorally relevant neuronal assemblies. Supporting this idea, the increasing number of reports that have used correlative and invasive approaches indicates the existence of a functional link between hippocampal-dependent learning and adult hippocampal neurogenesis (1-5). Recently, it was found that new cells contribute to the functional activity patterns elicited in the hippocampus in response to performing memory tasks that solicit hippocampal networks (4, 6, 7).To date, the nature of the specific contributions of adultgenerated neurons to memory processing remains largely unknown. During the second week after birth, new hippocampal cells enter a period during which they show enhanced synaptic plasticity, their functional maturation occurs, and their ultimate survival is determined (8, 9). At this age, depletion of new neurons leads to memory impairment in several hippocampaldependent tasks (1, 3). Based on these observations, we sought to examine in mice injected with the birthdating marker 5-bromo-2Ј-deoxyuridine (BrdU) the contribu...

SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit.

SummaryRetrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior.

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