How Does a Memory Find Its Neurons? Schmidt‐Hieber, Christoph
BioEssays,
November 2018, 2018-11-00, 20181101, 2018-11, Letnik:
40, Številka:
11
Journal Article
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How does the brain store and recall memories? We have long known that a brain region called the hippocampus is critical for processing episodic memories. More recently, targeted manipulation of the ...activity of specific hippocampal neurons in rodents has suggested that memories are encoded by the firing of defined groups of hippocampal neurons, so-called cellular engrams. In the current issue of BioEssays, FranS ca and Monserrat discuss a key question that has puzzled the field for a while: Among the millions of neurons in the mammalian hippocam-pus, how is a subset recruited into a memory engram? 1 Basic neurophysiology teaches us that two factors largely determine whether a neuron is active: On the one hand, each neuron is excited or inhibited by thousands of synaptic inputs that convey information both about the outside world, and about ongoing processing of information in the brain. On the other hand, how these synaptic inputs will affect the activity of a neuron depends on its excitability, which in turn is determined by factors such as its morphological and biophysical properties. A straightforward prediction, then, is that an engram is uniquely associated with a specific memory: A given set of sensory stimuli, let's say the odors, colors, and sounds experienced during memory formation, should recruit a given set of neurons-an engram-that is largely predetermined by synaptic connectivity and excitability. Similarly, activating an engram should recall its associated memory, but not others. Recent experiments in rodents have challenged these straightforward predictions: manipulating the excitability of neurons suggests that there is some redundancy in the hippocampal code, as inhibiting putative future engram cells during memory formation does not inhibit learning of a new memory. 2 Instead, it appears as if the memory could simply be stored in a different population of neurons. From these experiments, one might conclude that hippocampal neurons are stochastically recruited into engrams, and that their initial synaptic wiring plays only a minor role in their selection. 3 How can the straightforward predictions from basic neuro-physiology be reconciled with the seemingly stochastic composition of engrams? FranS ca and Monserrat invoke insights into C. elegans circuits to argue that individual neurons can represent multiple dimensions of both external and internal variables, most of which escape our observation. While we typically test the purely spatial aspect of memories in rodents, we have relatively little experimental control over variables other than physical space, such as an animal's current goal, attention, or more fundamental sensations such as hunger or thirst. Furthermore, the authors argue that once there is some synaptic distance between the primary sensory inputs and the neurons of interest, these dimensions will be increasingly abstract. Finally, they propose that the apparent redundancy of the code can be explained by the insight that while stimulating two non-overlapping populations of engram neurons may have the same behavioral effect, that does not necessarily mean that the same memory was recalled, as recalling even very different memories may evoke the same behavioral output. Thus, they conclude that the wiring and excitability of hippocampal neurons provides a template for memory allocation, and that the seemingly stochastic nature of engrams can be explained by the notion that hippocampal neurons represent multiple, abstract dimensions. This is a timely review on a highly interesting topic, and the authors make some novel and creative points about memory allocation. Further work will be required to show whether the striking temporal dynamics of hippocampal representations, 4 which appears to be at odds with engrams determined by hard wiring, are indeed a consequence of varying attentional levels, or whether additional mechanisms such as synaptic turnover may contribute to engram formation. An important conclusion from their work is that we need better behavioral tasks for animals used in hippocampal research, which are typically rodents. A simple behavior, as tested by a dichotomic go/no-go task, may be the end point of widely different cognitive processes. This redundancy could be reduced if more complex behaviors including multiple choices were tested. More sophisticated behavioral tasks, together with improved control and monitoring of external stimuli and behavioral variables, may therefore disambiguate the effects of stimulating different engrams, and help understand how hippocampal neurons are recruited into memory circuits.
Neurons in the medial entorhinal cortex exhibit a grid-like spatial pattern of spike rates that has been proposed to represent a neural code for path integration. To understand how grid cell firing ...arises from the combination of intrinsic conductances and synaptic input in medial entorhinal stellate cells, we performed patch-clamp recordings in mice navigating in a virtual-reality environment. We found that the membrane potential signature of stellate cells during firing field crossings consisted of a slow depolarization driving spike output. This was best predicted by network models in which neurons receive sustained depolarizing synaptic input during a field crossing, such as continuous attractor network models of grid cell firing. Another key feature of the data, phase precession of intracellular theta oscillations and spiking with respect to extracellular theta oscillations, was best captured by an oscillatory interference model. Thus, these findings provide crucial new information for a quantitative understanding of the cellular basis of spatial navigation in the entorhinal cortex.
Action potentials (APs) are initiated in the proximal axon of most neurons. In myelinated axons, a 50-times higher sodium channel density in the initial segment compared to the soma may account for ...this phenomenon. However, little is known about sodium channel density and gating in proximal unmyelinated axons. To study the mechanisms underlying AP initiation in unmyelinated hippocampal mossy fibers of adult mice, we recorded sodium currents in axonal and somatic membrane patches. We demonstrate that sodium channel density in the proximal axon is approximately 5 times higher than in the soma. Furthermore, sodium channel activation and inactivation are approximately 2 times faster. Modeling revealed that the fast activation localized the initiation site to the proximal axon even upon strong synaptic stimulation, while fast inactivation contributed to energy-efficient membrane charging during APs. Thus, sodium channel gating and density in unmyelinated mossy fiber axons appear to be specialized for robust AP initiation and propagation with minimal current flow.
Dentate gyrus granule cells transmit action potentials (APs) along their unmyelinated mossy fibre axons to the CA3 region.
Although the initiation and propagation of APs are fundamental steps during ...neural computation, little is known about the
site of AP initiation and the speed of propagation in mossy fibre axons. To address these questions, we performed simultaneous
somatic and axonal whole-cell recordings from granule cells in acute hippocampal slices of adult mice at â¼23°C. Injection
of short current pulses or synaptic stimulation evoked axonal and somatic APs with similar amplitudes. By contrast, the time
course was significantly different, as axonal APs had a higher maximal rate of rise (464 ± 30 V s â1 in the axon versus 297 ± 12 V s â1 in the soma, mean ± s.e.m. ). Furthermore, analysis of latencies between the axonal and somatic signals showed that APs were initiated in the proximal
axon at â¼20â30 μm distance from the soma, and propagated orthodromically with a velocity of 0.24 m s â1 . Qualitatively similar results were obtained at a recording temperature of â¼34°C. Modelling of AP propagation in detailed
cable models of granule cells suggested that a â¼4 times higher Na + channel density (â¼1000 pS μm â2 ) in the axon might account for both the higher rate of rise of axonal APs and the robust AP initiation in the proximal mossy
fibre axon. This may be of critical importance to separate dendritic integration of thousands of synaptic inputs from the
generation and transmission of a common AP output.
Neural stem cells in various regions of the vertebrate brain continuously generate neurons throughout life. In the mammalian hippocampus, a region important for spatial and episodic memory, thousands ...of new granule cells are produced per day, with the exact number depending on environmental conditions and physical exercise. The survival of these neurons is improved by learning and conversely learning may be promoted by neurogenesis. Although it has been suggested that newly generated neurons may have specific properties to facilitate learning, the cellular and synaptic mechanisms of plasticity in these neurons are largely unknown. Here we show that young granule cells in the adult hippocampus differ substantially from mature granule cells in both active and passive membrane properties. In young neurons, T-type Ca2+ channels can generate isolated Ca2+ spikes and boost fast Na+ action potentials, contributing to the induction of synaptic plasticity. Associative long-term potentiation can be induced more easily in young neurons than in mature neurons under identical conditions. Thus, newly generated neurons express unique mechanisms to facilitate synaptic plasticity, which may be important for the formation of new memories.
The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and have been proposed to form the ...neural basis of a cognitive map of space that supports these mnemonic functions. However, the direct influence of place cell activity on spatial navigation behavior has not yet been demonstrated. Using an ‘all-optical’ combination of simultaneous two-photon calcium imaging and two-photon optogenetics, we identified and selectively activated place cells that encoded behaviorally relevant locations in a virtual reality environment. Targeted stimulation of a small number of place cells was sufficient to bias the behavior of animals during a spatial memory task, providing causal evidence that hippocampal place cells actively support spatial navigation and memory.
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•Two-photon optogenetics in VR enables targeted manipulation of place cell ensembles•Activating specific place cell ensembles drives their spatially associated behavior•Place cell stimulation inhibits endogenous place code expression and triggers remapping•Direct evidence for a causal role of place cells in spatial navigation
Selective stimulation of a small number of hippocampal place cells in mice provides causal evidence that hippocampal place cells actively support spatial navigation and memory.
Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model ...system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation.
Abstract
Episodic memory formation and recall are complementary processes that rely on opposing neuronal computations in the hippocampus. How this conflict is resolved in hippocampal circuits is ...unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarisation upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the synaptic response to novelty may bias granule cell population activity, which can drive downstream attractor networks to a new state, favouring the switch from recall to new memory formation when faced with novelty. Such a novelty-driven switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.
Although dendritic signal processing has been extensively investigated in hippocampal pyramidal cells, only little is known about dendritic integration of synaptic potentials in dentate gyrus granule ...cells, the first stage in the hippocampal trisynaptic circuit. Here we combined dual whole-cell patch-clamp recordings with high-resolution two-photon microscopy to obtain detailed passive cable models of hippocampal granule cells from adult mice. Passive cable properties were determined by direct fitting of the compartmental model to the experimentally measured voltage responses to short and long current pulses. The data are best fit by a cable model with homogenously distributed parameters, including an average specific membrane resistance (R(m)) of 38.0 kohms cm2, a membrane capacitance (C(m)) of 1.0 microF cm(-2), and an intracellular resistivity (R(i)) of 194 ohms cm. Computational analysis shows that signal propagation from somata into dendrites is more efficient in granule cells compared with CA1 pyramidal cells for both steady-state and sinusoidal voltage waveforms up to the gamma frequency range (f50% of 74 Hz). Similarly, distal synaptic inputs from entorhinal fibers can efficiently depolarize the somatic membrane of granule cells. Furthermore, the time course of distal dendritic synaptic potentials is remarkably fast, and temporal summation is restricted to a narrow time window in the range of approximately 10 ms attributable to the rapid dendritic charge redistribution during transient voltage signals. Therefore, the structure of the granule cell dendritic tree may be critically important for precise dendritic signal processing and coincidence detection during hippocampus-dependent memory formation and retrieval.
The transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional ...focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function.
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•Forebrain cholinergic neuron subsets originate from septal NKX2-1+ve progenitors•Septal Nkx2-1 deletion causes widespread loss of forebrain cholinergic neurons•Severe deficits in learning and memory in septal Nkx2-1 conditional mutant mice•Hippocampal network activity alterations in the absence of embryonic septal NKX2-1
NKX2-1 is a highly conserved patterning gene in the developing forebrain, mutations in which can lead to a spectrum of disorders including cognitive deficiencies. Using genetic fate mapping and intersectional deletion, Magno et al. demonstrate a requirement for embryonic septal NKX2-1 in forebrain cholinergic system development and learning and memory.
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