Granule cells (GCs) of the dentate gyrus use sparse encoding to perform redundancy reduction, pattern separation, and novelty detection. One likely candidate mechanism to enforce low spiking activity is feedforward inhibition, in which the cortical excitatory drive from the perforant path (PP) recruits GABAergic interneurons that then inhibit GCs. Little is known, however, about how PP drive is balanced between GCs versus inhibitory neurons. In simultaneous recordings of GCs and fast-spiking (FS) interneurons from C57BL/6 mice, we find that focal PP stimulation preferentially recruits spiking in FS interneurons over GCs, because GCs require a larger excitatory synaptic current density to reach spike threshold. Blocking inhibition reversed this relationship, revealing a stronger intrinsic coupling between the PP and GCs versus FS interneurons and showing that inhibition can sparsify the output of the dentate gyrus by tightly regulating GC spike probability. Moreover, this regulation is dynamic, because the spiking profile of FS interneurons was frequency tuned, displaying bursting behavior in response to PP stimulation near theta rhythm frequency (ϳ10 Hz). The later spikes in the bursts were part of the feedback inhibitory pathway because they were driven by late EPSCs, were blocked by an inhibitor of synaptic output from GCs, and shared the same frequency dependence as GC spiking. Therefore, the temporal content of signals arriving via the PP determines whether a FS interneuron participates in only feedforward (one spike) or both feedforward and feedback (burst) inhibition.
The dentate gyrus (DG) is a region in the mammalian brain critical for memory encoding with a neuronal architecture and function that deviates considerably from other cortical areas. One of the major differences of the DG compared to other brain regions is the finding that the dentate gyrus generates new principal neurons that are continuously integrated into a fully functional neural circuit throughout life. Another distinguishing characteristic of the dentate network is that the majority of principal neurons are held under strong inhibition and rarely fire action potentials. These two findings raise the question why a predominantly silent network would need to continually incorporate more functional units. The sparse nature of the neural code in the DG is thought to be fundamental to dentate network function, yet the relationship between neurogenesis and low activity levels in the network remains largely unknown. Clues to the functional role of new neurons come from inquiries at the cellular as well as the behavioral level. Few studies have bridged the gap between these levels of inquiry by considering the role of young neurons within the complex dentate network during distinct stages of memory processing. We will review and discuss from a network perspective, the functional role of immature neurons and how their unique cellular properties can modulate the dentate network in memory guided behaviors.
SUMMARY A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, though deficits in the balance contribute to many neurological disorders. We show here that a microRNA (miR-101) is a key orchestrator of this essential feature, shaping the developing network to constrain excitation in the adult. Transient early blockade of miR-101 induces long-lasting hyper-excitability and persistent memory deficits. Using target-site blockers in vivo, we identify multiple developmental programs regulated in parallel by miR-101 to achieve balanced networks. Repression of one target, NKCC1, initiates the switch in GABA signaling, limits early spontaneous activity, and constrains dendritic growth. Kif1a and Ank2 are targeted to prevent excessive synapse formation. Simultaneous de-repression of these three targets completely phenocopies major dysfunctions produced by miR-101 blockade. Our results provide new mechanistic insight into brain development and suggest novel candidates for therapeutic intervention.
Pattern separation is a central concept in current theories of episodic memory: this computation is thought to support our ability to avoid confusion between similar memories by transforming similar cortical input patterns of neural activity into dissimilar output patterns before their long-term storage in the hippocampus. Because there are many ways one can define patterns of neuronal activity and the similarity between them, pattern separation could in theory be achieved through multiple coding strategies. Using our recently developed assay that evaluates pattern separation in isolated tissue by controlling and recording the input and output spike trains of single hippocampal neurons, we explored neural codes through which pattern separation is performed by systematic testing of different similarity metrics and various time resolutions. We discovered that granule cells, the projection neurons of the dentate gyrus, can exhibit both pattern separation and its opposite computation, pattern convergence, depending on the neural code considered and the statistical structure of the input patterns. Pattern separation is favored when inputs are highly similar, and is achieved through spike time reorganization at short time scales (< 100 ms) as well as through variations in firing rate and burstiness at longer time scales. These multiplexed forms of pattern separation are network phenomena, notably controlled by GABAergic inhibition, that involve many celltypes with input-output transformations that participate in pattern separation to different extents and with complementary neural codes: a rate code for dentate fast-spiking interneurons, a burstiness code for hilar mossy cells and a synchrony code at long time scales for CA3 pyramidal cells. Therefore, the isolated hippocampal circuit itself is capable of performing temporal pattern separation using multiplexed coding strategies that might be essential to optimally disambiguate multimodal mnemonic representations.
Pattern separation is a process that minimizes overlap between patterns of neuronal activity representing similar experiences. Theoretical work suggests that the dentate gyrus (DG) performs this role for memory processing but a direct demonstration is lacking. One limitation is the difficulty to measure DG inputs and outputs simultaneously. To rigorously assess pattern separation by DG circuitry, we used mouse brain slices to stimulate DG afferents and simultaneously record DG granule cells (GCs) and interneurons. Output spiketrains of GCs are more dissimilar than their input spiketrains, demonstrating for the first time temporal pattern separation at the level of single neurons in the DG. Pattern separation is larger in GCs than in fast-spiking interneurons and hilar mossy cells, and is amplified in CA3 pyramidal cells. Analysis of the neural noise and computational modelling suggest that this form of pattern separation is not explained by simple randomness and arises from specific presynaptic dynamics. Overall, by reframing the concept of pattern separation in dynamic terms and by connecting it to the physiology of different types of neurons, our study offers a new window of understanding in how hippocampal networks might support episodic memory.
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