Hippocampal neurons encode information about different types of memory episodes occurring in the same location

Firing patterns of hippocampal complex-spike neurons were examined for the capacity to encode information important to the memory demands of a task even when the overt behavior and location of the animal are held constant. Neuronal activity was recorded as rats continuously alternated left and right turns from the central stem of a modified T maze. Two-thirds of the cells fired differentially as the rat traversed the common stem on left-turn and right-turn trials, even when potentially confounding variations in running speed, heading, and position on the stem were taken into account. Other cells fired differentially on the two trial types in combination with behavioral and spatial factors or appeared to fire similarly on both trial types. This pattern of results suggests that hippocampal representations encode some of the information necessary for representing specific memory episodes.     

The mechanism of rate remapping in the dentate gyrus

Rate remapping is a recently revealed neural code in which sensory information modulates the firing rate of hippocampal place cells. The mechanism underlying rate remapping is unknown. Its characteristic modulation, however, must arise from the interaction of the two major inputs to the hippocampus, the medial entorhinal cortex (MEC), in which grid cells represent the spatial position of the rat, and the lateral entorhinal cortex (LEC), in which cells represent the sensory properties of the environment. We have used computational methods to elucidate the mechanism by which this interaction produces rate remapping. We show that the convergence of LEC and MEC inputs, in conjunction with a competitive network process mediated by feedback inhibition, can account quantitatively for this phenomenon. The same principle accounts for why different place fields of the same cell vary independently as sensory information is altered. Our results show that rate remapping can be explained in terms of known mechanisms.     

Conjunctive spatial and self-motion codes are topographically organized in the GABAergic cells of the lateral septum

The hippocampal spatial code’s relevance for downstream neuronal populations—particularly its major subcortical output the lateral septum (LS)—is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal’s location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior–posterior and dorsal–ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

Calcium imaging of neurons in freely behaving mice reveals how the lateral septum, the main output of the hippocampal place cells, effectively represents information about not only location, but also head direction and self-movement, and may be pivotal in sending this information to downstream brain regions.     

Place cells, neocortex and spatial navigation: a short review

Hippocampal place cells are characterized by location-specific firing, that is each cell fires in a restricted region of the environment explored by the rat. In this review, we briefly examine the sensory information used by place cells to anchor their firing fields in space and show that, among the various sensory cues that can influence place cell activity, visual and motion-related cues are the most relevant. We then explore the contribution of several cortical areas to the generation of the place cell signal with an emphasis on the role of the visual cortex and parietal cortex. Finally, we address the functional significance of place cell activity and demonstrate the existence of a clear relationship between place cell positional activity and spatial navigation performance. We conclude that place cells, together with head direction cells, provide information useful for spatially guided movements, and thus provide a unique model of how spatial information is encoded in the brain.     

Robust path integration in the entorhinal grid cell system with hippocampal feed-back

Animals are able to update their knowledge about their current position solely by integrating the speed and the direction of their movement, which is known as path integration. Recent discoveries suggest that grid cells in the medial entorhinal cortex might perform some of the essential underlying computations of path integration. However, a major concern over path integration is that as the measurement of speed and direction is inaccurate, the representation of the position will become increasingly unreliable. In this paper, we study how allothetic inputs can be used to continually correct the accumulating error in the path integrator system. We set up the model of a mobile agent equipped with the entorhinal representation of idiothetic (grid cell) and allothetic (visual cells) information and simulated its place learning in a virtual environment. Due to competitive learning, a robust hippocampal place code emerges rapidly in the model. At the same time, the hippocampo-entorhinal feed-back connections are modified via Hebbian learning in order to allow hippocampal place cells to influence the attractor dynamics in the entorhinal cortex. We show that the continuous feed-back from the integrated hippocampal place representation is able to stabilize the grid cell code. This research was supported by the EU Framework 6 ICEA project (IST-4-027819-IP).     

Increased attention to spatial context increases both place field stability and spatial memory

The hippocampal formation is critical for the acquisition and consolidation of memories. When recorded in freely moving animals, hippocampal pyramidal neurons fire in a location-specific manner: they are "place" cells, comprising a hippocampal representation of the animal's environment. To explore the relationship between place cells and spatial memory, we recorded from mice in several behavioral contexts. We found that long-term stability of place cell firing fields correlates with the degree of attentional demands and that successful spatial task performance was associated with stable place fields. Furthermore, conditions that maximize place field stability greatly increase orientation to novel cues. This suggests that storage and retrieval of place cells is modulated by a top-down cognitive process resembling attention and that place cells are neural correlates of spatial memory. We propose a model whereby attention provides the requisite neuromodulatation to switch short-term homosynaptic plasticity to long-term heterosynaptic plasticity, and we implicate dopamine in this process.     

Place cells,navigational accuracy,and the human hippocampus.

The hippocampal formation in both rats and humans is involved in spatial navigation. In the rat, cells coding for places, directions, and speed of movement have been recorded from the hippocampus proper and/or the neighbouring subicular complex. Place fields of a group of the hippocampal pyramidal cells cover the surface of an environment but do not appear to do so in any systematic fashion. That is, there is no topographical relation between the anatomical location of the cells within the hippocampus and the place fields of these cells in an environment. Recent work shows that place cells are responding to the summation of two or more Gaussian curves, each of which is fixed at a given distance to two or more walls in the environment. The walls themselves are probably identified by their allocentric direction relative to the rat and this information may be provided by the head direction cells. The right human hippocampus retains its role in spatial mapping as demonstrated by its activation during accurate navigation in imagined and virtual reality environments. In addition, it may have taken on wider memory functions, perhaps by the incorporation of a linear time tag which allows for the storage of the times of visits to particular locations. This extended system would serve as the basis for a spatio-temporal event or episodic memory system.     

A model of grid cells based on a twisted torus topology

The grid cells of the rat medial entorhinal cortex (MEC) show an increased firing frequency when the position of the animal correlates with multiple regions of the environment that are arranged in regular triangular grids. Here, we describe an artificial neural network based on a twisted torus topology, which allows for the generation of regular triangular grids. The association of the activity of pre-defined hippocampal place cells with entorhinal grid cells allows for a highly robust-to-noise calibration mechanism, suggesting a role for the hippocampal back-projections to the entorhinal cortex.     

Coupling of organotypic brain slice cultures to silicon-based arrays of electrodes.

Fetal or early postnatal brain tissue can be cultured in viable and healthy condition for several weeks with development and preservation of the basic cellular and connective organization as so-called organotypic brain slice cultures. Here we demonstrate and describe how it is possible to establish such hippocampal rat brain slice cultures on biocompatible silicon-based chips with arrays of electrodes with a histological organization comparable to that of conventional brain slice cultures grown by the roller drum technique and on semiporous membranes. Intracellular and extracellular recordings from neurons in the slice cultures show that the electroresponsive properties of the neurons and synaptic circuitry are in accordance with those described for cells in acutely prepared slices of the adult rat hippocampus. Based on the recordings and the possibilities of stimulating the cultured cells through the electrode arrays it is anticipated that the setup eventually will allow long-term studies of defined neuronal networks and provide valuable information on both normal and neurotoxicological and neuropathological conditions.     

Bias-free estimation of information content in temporally sparse neuronal activity

Applying information theoretic measures to neuronal activity data enables the quantification of neuronal encoding quality. However, when the sample size is limited, a naïve estimation of the information content typically contains a systematic overestimation (upward bias), which may lead to misinterpretation of coding characteristics. This bias is exacerbated in Ca²⁺ imaging because of the temporal sparsity of elevated Ca²⁺ signals. Here, we introduce methods to correct for the bias in the naïve estimation of information content from limited sample sizes and temporally sparse neuronal activity. We demonstrate the higher accuracy of our methods over previous ones, when applied to Ca²⁺ imaging data recorded from the mouse hippocampus and primary visual cortex, as well as to simulated data with matching tuning properties and firing statistics. Our bias-correction methods allowed an accurate estimation of the information place cells carry about the animal’s position (spatial information) and uncovered the spatial resolution of hippocampal coding. Furthermore, using our methods, we found that cells with higher peak firing rates carry higher spatial information per spike and exposed differences between distinct hippocampal subfields in the long-term evolution of the spatial code. These results could be masked by the bias when applying the commonly used naïve calculation of information content. Thus, a bias-free estimation of information content can uncover otherwise overlooked properties of the neural code.     

The control of seizure-like activity in the rat hippocampal slice

The sudden and transient hypersynchrony of neuronal firing that characterizes epileptic seizures can be considered as the transitory stabilization of metastable states present within the dynamical repertoire of a neuronal network. Using an in vitro model of recurrent spontaneous seizures in the rat horizontal hippocampal slice preparation, we present an approach to characterize the dynamics of the transition to seizure, and to use this information to control the activity and avoid the occurrence of seizure-like events. The transition from the interictal activity (between seizures) to the seizure-like event is aborted by brief (20-50 s) low-frequency (0.5 Hz) periodic forcing perturbations, applied via an extracellular stimulating electrode to the mossy fibers, the axons of the dentate neurons that synapse onto the CA3 pyramidal cells. This perturbation results in the stabilization of an interictal-like low-frequency firing pattern in the hippocampal slice. The results derived from this work shed light on the dynamics of the transition to seizure and will further the development of algorithms that can be used in automated devices to stop seizure occurrence.     

Cell groups reveal structure of stimulus space

An important task of the brain is to represent the outside world. It is unclear how the brain may do this, however, as it can only rely on neural responses and has no independent access to external stimuli in order to “decode” what those responses mean. We investigate what can be learned about a space of stimuli using only the action potentials (spikes) of cells with stereotyped—but unknown—receptive fields. Using hippocampal place cells as a model system, we show that one can (1) extract global features of the environment and (2) construct an accurate representation of space, up to an overall scale factor, that can be used to track the animal's position. Unlike previous approaches to reconstructing position from place cell activity, this information is derived without knowing place fields or any other functions relating neural responses to position. We find that simply knowing which groups of cells fire together reveals a surprising amount of structure in the underlying stimulus space; this may enable the brain to construct its own internal representations.     

New excitement in cognitive space: between place cells and spatial memory

Hippocampal principal neurons-'place cells'-exhibit location-specific firing. Recent work addresses the link between place cell activity and hippocampal memory function. New tasks that challenge spatial memory allow recording from single neurons, as well as ensembles of neurons, during memory computations, and insights into the cellular mechanisms of spatial memory are beginning to emerge.     

Ultrastructure of the cerebral cortex and hippocampus of rats in the early postresuscitation period following total ischemia

The rat frontal brain cortex and CAr hippocampal region were studied on the 4th day after 10-min complete ischemia. It has been established that the number of "dark" osmiophilic neurons was increased. The reparative, destructive and adaptive processes in cells were observed. The most prominent destructive changes were found in CAr hippocampal region, they can be associated with the microcirculatory disturbances. The hypertrophic thread-like mitochondria appear in the nervous and glial cells, with the quantity of lipofuscin granules increasing. Lipofuscin and hypertrophic mitochondria are thought to provide energy exchange in the brain cells during the postischemic period, forming one of the mechanisms of intracellular adaptation to hypoxia.     

Hippocampal Remapping Is Constrained by Sparseness rather than Capacity

Grid cells in the medial entorhinal cortex encode space with firing fields that are arranged on the nodes of spatial hexagonal lattices. Potential candidates to read out the space information of this grid code and to combine it with other sensory cues are hippocampal place cells. In this paper, we investigate a population of grid cells providing feed-forward input to place cells. The capacity of the underlying synaptic transformation is determined by both spatial acuity and the number of different spatial environments that can be represented. The codes for different environments arise from phase shifts of the periodical entorhinal cortex patterns that induce a global remapping of hippocampal place fields, i.e., a new random assignment of place fields for each environment. If only a single environment is encoded, the grid code can be read out at high acuity with only few place cells. A surplus in place cells can be used to store a space code for more environments via remapping. The number of stored environments can be increased even more efficiently by stronger recurrent inhibition and by partitioning the place cell population such that learning affects only a small fraction of them in each environment. We find that the spatial decoding acuity is much more resilient to multiple remappings than the sparseness of the place code. Since the hippocampal place code is sparse, we thus conclude that the projection from grid cells to the place cells is not using its full capacity to transfer space information. Both populations may encode different aspects of space.     

Human mediotemporal EEG characteristics during propofol anesthesia

Evidence for a response-control-related kind of declarative memory during deep propofol anesthesia has recently been reported. Connectivity within the mediotemporal lobe (MTL), and in particular rhinal–hippocampal synchronization within the gamma band, has been shown to be crucial for declarative memory formation. Thus, we analyzed EEG recordings obtained from the scalp, as well as directly from within the hippocampus and from the anterior parahippocampal gyrus, which is covered by rhinal cortex, in patients with unilateral temporal lobe epilepsy during propofol anesthesia, which preceded electrode explantation. For the gamma band a power decrease starting with induction of anesthesia was observed at scalp position Cz, but a power increase was detected at MTL locations. In contrast to prior results for sleep recordings, rhinal–hippocampal coherence did not decrease within the gamma band at deeper levels of anesthesia. These findings may represent an indirect electrophysiological correlate of partially intact declarative memory formation during deep propofol sedation. Furthermore, we investigated how well the plasma propofol level, as well as different stages of anesthesia including the burst suppression phase, could be monitored by different spectral as well as by nonlinear EEG measures. We observed that conventional spectral power measures, most prominently those recorded from mediotemporal locations, are most closely correlated with the plasma propofol level, whereas different stages of anesthesia can be distinguished best by nonconventional spectral as well as nonlinear measures.     

A Hydrophilic Peptide Comprising 18 Amino Acid Residues of the Prosaposin Sequence Has Neurotrophic Activity In Vitro and In Vivo

Abstract: Prosaposin, a 517-amino-acid glycoprotein, not only acts as the precursor of saposin A, B, C, and D but also possesses neurotrophic activity to rescue hippocampal CA1 neurons from ischemic damage in vivo and to promote neurite extension of neuroblastoma cells in vitro. Recently, the trophic activity of prosaposin on human neuroblastoma cells has been shown to reside in the NH₂-terminal hydrophilic sequence (LIDNNRTEEILY) of the human saposin C. Here we show that prosaposin, saposin C, and a peptide comprising the 18-amino-acid sequence (18-mer peptide; LSELIINNATEELLIKGL) located in the NH₂-terminal hydrophilic sequence of the rat saposin C-domain promoted survival and neurite outgrowth of cultured rat hippocampal neurons in a dose-dependent manner. Moreover, infusion for 7 days of the 18-mer peptide into the lateral ventricle of gerbils, starting either 2 h before or immediately after 3 min of forebrain ischemia, protected ischemia-induced learning disability and hippocampal CA1 neuronal loss. Thus, we ascribe the in vitro and in vivo trophic actions of prosaposin on hippocampal neurons to the linear 18-mer sequence and raise the possibility that this peptide can be used as an agent for the treatment of forebrain ischemic damage.     

The Role of “Outward-Journey Information” in Homing Experiments with Pigeons: New Data on Ontogeny of Navigation and General Survey

Potentially, homing from distant areas can be based on two different principles of navigation: (1) A path-integration mechanism records and integrates an animal's motions during the outward trip; it is independent of location-specific stimuli. (2) Site localization, by contrast, is performed by deducing the animal's position in relation to home from such stimuli. Hence the first mechanism entirely depends on an uninterrupted flow of “outward-journey information”. The second mechanism may but need not be independent of stimuli recorded during the outward journey. Homing of pigeons is evidently based on site localization. Empirical findings do not support the idea that in experiments using passive displacement path integration is involved in addition or alternatively. Also, there is no reason to assume that very young pigeons transitionally, for only few weeks, apply such a method (as has been concluded by Wiltschko & Wiltschko 1982, 1985, etc.). It is shown that very young pigeons require local olfactory signals for initial homeward orientation as do older birds (Fig. 1). They are not generally better at homeward orientation than older inexperienced pigeons and show similar deviations from home and preferences for a particular compass direction (Table 1, Fig. 2). Olfactory signals appear to be gathered, as good as conditions allow, during any stage of a homing experiment. No fundamental difference can be recognized between olfactory “outward-journey information”, “release-site information”, etc. Signals received at different times and sites before release may contribute by varying proportions to the initial-orientation patterns observed under varying circumstances.     

Na^＋／Ca^2＋交换抑制剂在大鼠海马缺氧损伤中的作用

本文以大鼠离体海马脑片和分散培养的海马神经元为标本,分别采用微电极记录技术和激光扫描共聚焦显微镜动态监测单个神经元［Ｃａ２＋］ｉ的方法,研究Ｎａ＋／Ｃａ２＋交换抑制剂Ｂｅｎｚａｍｉｌ对缺氧后海马脑片损伤以及海马神经元［Ｃａ２＋］ｉ变化的影响。结果显示,预先用Ｂｅｎｚａｍｉｌ（５０μｍｏｌ）灌流的海马脑片缺氧后ＰＶ持续时间较对照组显著延长,提示其可延缓海马不可逆缺氧损伤的发生;共聚焦测［Ｃａ２＋］ｉ实验进一步发现,急性缺氧可诱导海马神经元［Ｃａ２＋］ｉ迅速升高,而Ｂｅｎｚａｍｉｌ（２０μｍｏｌ）能显著抑制缺氧引起的［Ｃａ２＋］ｉ升高。上述结果表明,抑制神经元Ｎａ＋／Ｃａ２＋交换活动可提高海马脑片抗缺氧能力,其作用机制可能与抑制缺氧所致神经元［Ｃａ２＋］ｉ升高有关,由此推测Ｎａ＋／Ｃａ２＋交换体参于大鼠海马脑区缺氧损伤,它可能是导致缺氧后神经元［Ｃａ２＋］ｉ升高的重要途径之一