Trajectory encoding in the hippocampus and entorhinal cortex

We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.     

Grid alignment in entorhinal cortex

The spatial responses of many of the cells recorded in all layers of rodent medial entorhinal cortex (mEC) show mutually aligned grid patterns. Recent experimental findings have shown that grids can often be better described as elliptical rather than purely circular and that, beyond the mutual alignment of their grid axes, ellipses tend to also orient their long axis along preferred directions. Are grid alignment and ellipse orientation aspects of the same phenomenon? Does the grid alignment result from single-unit mechanisms or does it require network interactions? We address these issues by refining a single-unit adaptation model of grid formation, to describe specifically the spontaneous emergence of conjunctive grid-by-head-direction cells in layers III, V, and VI of mEC. We find that tight alignment can be produced by recurrent collateral interactions, but this requires head-direction (HD) modulation. Through a competitive learning process driven by spatial inputs, grid fields then form already aligned, and with randomly distributed spatial phases. In addition, we find that the self-organization process is influenced by any anisotropy in the behavior of the simulated rat. The common grid alignment often orients along preferred running directions (RDs), as induced in a square environment. When speed anisotropy is present in exploration behavior, the shape of individual grids is distorted toward an ellipsoid arrangement. Speed anisotropy orients the long ellipse axis along the fast direction. Speed anisotropy on its own also tends to align grids, even without collaterals, but the alignment is seen to be loose. Finally, the alignment of spatial grid fields in multiple environments shows that the network expresses the same set of grid fields across environments, modulo a coherent rotation and translation. Thus, an efficient metric encoding of space may emerge through spontaneous pattern formation at the single-unit level, but it is coherent, hence context-invariant, if aided by collateral interactions.     

Phase precession in the human hippocampus and entorhinal cortex

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Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCK_B antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCK_B antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.     

Quantitative estimations of the entorhinal cortex in Alzheimer's disease

OBJECTIVE: To detect and quantify structural parameters in the entorhinal cortex (EC) of potential use in Alzheimer's disease (AD). STUDY DESIGN: We estimated by stereologic tools the total volume of the EC and subfields EI and ER, the number of neurons and the volume-weighted mean soma volume of layer II neurons. EC morphometric parameters were also assessed in both control and AD cases. RESULTS: In AD, EC volume decreased by 35%, while total number of neurons reached 51%. Also, neuron density had a significant decrease mainly due to change in the EI subfield (31% decrease). The EC showed a decrease in size and a morphology more elliptic and irregular. Moreover, layer II neurons soma size (volume, area, and 1-dimensional parameters) were more rounded. Thus the EC decreases in size and neuron number in AD and minor changes in number per volume were noted. CONCLUSION: These quantitative data can be of value in volumetric MRI studies in AD patients.     

Theta oscillations decrease spike synchrony in the hippocampus and entorhinal cortex

Oscillations and synchrony are often used synonymously. However, oscillatory mechanisms involving both excitation and inhibition can generate non-synchronous yet coordinated firing patterns. Using simultaneous recordings from multiple layers of the entorhinal–hippocampal loop, we found that coactivation of principal cell pairs (synchrony) was lowest during exploration and rapid-eye-movement (REM) sleep, associated with theta oscillations, and highest in slow wave sleep. Individual principal neurons had a wide range of theta phase preference. Thus, while theta oscillations reduce population synchrony, they nevertheless coordinate the phase (temporal) distribution of neurons. As a result, multiple cell assemblies can nest within the period of the theta cycle.     

Ageing of the human entorhinal cortex and subicular complex.

Age-dependent changes in the entorhinal cortex (EC) and subicular complex (SC) were studied in 30 brains of patients who died between 14 and 86 years of age, without CNS impairment, as determined by macro- and microscopic examination. The brains were fixed in 10% formalin and embedded in paraffin. Three series of coronal EC and SC sections (7 microns) were stained by Nissl, PAS or hematoxylin-eosin. Using neuronal count and Kariometry, age-dependent modifications were studied in layers II, III and V of the lateral area of the EC; in the pyramidal layer of the subiculum (S), and in layer II of the presubiculum (PS). All EC layers studied presented a slight (11-20%) although significant reduction up to 35 years, but from 35 to 75 years the decrease was not significant. After 75 years the neuronal loss increased slightly. The nuclear area decreased up to the age of 40-45 years, (10-18%) and augmented from this age up to 75 years (10-14%). During the last period of life, the nuclear area did not change. From 30-60 years, pyramidal layer in the S showed a significant neuronal loss (30%), thereafter, neuronal reduction was less. At early years, the nuclear area decreased insignificantly (15%), and from 35 years up to the most advanced age studied, it increased significantly (13%). In the PS, layer II manifested a cell loss throughout the lifespan (32.9%) and the changes in the nuclear area did not reach statistical significance due to the dispersions of its values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiological study of connections between the entorhinal cortex and the neocortex

In acute experiments in rabbits immobilized by d-tubocurarine, stimulation of the entorhinal area with rectangular electric impulses led to the appearance of evoked potentials (EP) with a latent period of 6–12 msec in the occipital, temporal, parietal, and cingular areas of the neocortex. The amplitude of the positive response component was 500 µV, and its duration 25–50 msec. The negative component was not always discernible. When rhythmic stimulation was used, these EPs followed stimulation frequencies not exceeding 20 per sec. Stimulation of the medial parts of the entorhinal area with a frequency of one to three per sec was accompanied by recruitment of the EP in the occipital and temporal neocortex areas. Nembutal depressed the amplitude of the neocortex EP appearing in response to stimulation of the entorhinal cortex. With the aid of double stimulation it could be established that, after conditioning stimulation of the entorhinal area, the positive component of the primary response (PR) evoked by stimulation of the contralateral sciatic nerve in the projection zone of the somatosensory cortex is strengthened during the first 50 msec, and subsequently after 80–120 msec. In these cases, the negative component was depressed. These findings are discussed with a view to the influence of limbic structures on the neocortex.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 2, No. 1, pp. 73–78, January–February, 1970.     

Inducible and selective erasure of memories in the mouse brain via chemical-genetic manipulation

Rapid and selective erasures of certain types of memories in the brain would be desirable under certain clinical circumstances. By employing an inducible and reversible chemical-genetic technique, we find that transient alphaCaMKII overexpression at the time of recall impairs the retrieval of both newly formed one-hour object recognition memory and fear memories, as well as 1-month-old fear memories. Systematic analyses suggest that excessive alphaCaMKII activity-induced recall deficits are not caused by disrupting the retrieval access to the stored information but are, rather, due to the active erasure of the stored memories. Further experiments show that the recall-induced erasure of fear memories is highly restricted to the memory being retrieved while leaving other memories intact. Therefore, our study reveals a molecular genetic paradigm through which a given memory, such as new or old fear memory, can be rapidly and specifically erased in a controlled and inducible manner in the brain.     

Demonstration of olfactory projections and responses within the entorhinal cortex in rats

An electrophysiological study was performed in rat entorhinal cortex. The results confirmed anatomical data on its connections with olfactory structures. Unit analysis has shown that neurons respond to odours. This area thus appears as an important structure for olfactory projections, possibly relaying these informations to the hippocampus.     

Comparison of the effects of serotonin in the hippocampus and the entorhinal cortex

Among the molecular, cellular, and systemic events that have been proposed to modulate the function of the hippocampus and the entorhinal cortex (EC), one of the most frequently cited possibilities is the activation of the serotonergic system. Neurons in the hippocampus and in the EC receive a strong serotonergic projection from the raphe nuclei and express serotonin (5-HT) receptors at high density. Here we review the various effects of 5-HT on intrinsic and synaptic properties of neurons in the hippocampus and the EC. Although similar membrane-potential changes following 5-HT application have been reported for neurons of the entorhinal cortex and the hippocampus, the effects of serotonin on synaptic transmission are contrary in both areas. Serotonin mainly depresses fast and slow inhibition of the principal output cells of the hippocampus, whereas it selectively suppresses the excitation in the entorhinal cortex. On the basis of these data, we discuss the possible role of serotonin under physiological and pathophysiological circumstances.     

CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory

To investigate the role of the entorhinal cortex in memory at a molecular level, we developed transgenic mice in which transgene expression was inducible and limited to the superficial layers of the medial entorhinal cortex, pre- and parasubiculum. We found that expression of a constitutively active mutant form of CaMKII in these structures disrupted spatial memory formation. Immediate post-training activation of the transgene disrupted previously established memory while transgene activation 3 weeks following the training was ineffective. These results demonstrate that, similar to the hippocampus, the entorhinal cortex plays a time-limited role in spatial memory formation but is not a final cortical repository of long-term memory. Moreover, these results suggest that the indiscriminate activation of CaMKII is able to disrupt preexisting memories, possibly by altering the pattern of synaptic weight changes that are thought to form the basis of the memory trace.     

Microcircuits of functionally identified neurons in the rat medial entorhinal cortex

Extracellular recordings have elucidated spatial neural representations without identifying underlying microcircuits. We labeled neurons juxtacellularly in medial entorhinal cortex of freely moving rats with?a friction-based, pipette-stabilization system. In a linear maze novel to the animals, spatial firing of superficial layer neurons was reminiscent of grid cell activity. Layer 2 stellate cells showed stronger theta modulation than layer 3 neurons, and both fired during the ascending phase of field potential theta. Deep-layer neurons showed little or no activity. Layer 2 stellate cells resided in hundreds of small patches. At the dorsomedial entorhinal border, we identified larger (putative parasubicular) patches, which contained polarized head-direction selective neurons firing during the descending theta phase. Three axon systems interconnected patches: centrifugal axons from superficial cells to single large patches, centripetal axons from large-patch cells to single small patches, and circumcurrent axons interconnecting large patches. Our microcircuit analysis during behavior reveals modularity of entorhinal processing. VIDEO ABSTRACT:     

Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex

The extensive connections of the entorhinal cortex with the hippocampus and the neocortex point to this region as a major interface in the hippocampal-neocortical interactions underlying memory. We asked whether hippocampal-dependent recall of spatial memory depends on the entorhinal cortex, and, if so, which parts are critical. After training in a Morris water maze, rats received fiber-sparing lesions in the dorsolateral band of the entorhinal cortex, which mediates much of the visuospatial input to the dorsal hippocampus. These lesions entirely disrupted retention and retarded new learning. Spatial memory was spared by lesions in the ventromedial band, which connects primarily with ventral hippocampus, but these lesions reduced defensive behavior on an elevated plus maze, mirroring the effects of damage to ventral hippocampus. The results suggest that the functional differences between dorsal and ventral hippocampus reflect their connectivity with modules of the entorhinal cortex that are differently linked to the rest of the cortex.     

Analysis of excitatory microcircuitry in the medial entorhinal cortex reveals cell-type-specific differences

Medial entorhinal cortex (MEC) plays an important role in physiological processes underlying navigation, learning, and memory. Excitatory cells in the different MEC layers project in a region-specific manner to the hippocampus. However, the intrinsic microcircuitry of the main excitatory cells in the superficial MEC layers is largely unknown. Using scanning photostimulation, we investigated the functional microcircuitry of two such cell types, stellate and pyramidal cells. We found cell-type-specific intralaminar and ascending interlaminar feedback inputs. The ascending interlaminar inputs display distinct organizational principles depending on the cell-type and its position within the superficial lamina: the spatial spread of inputs for stellate cells is narrower than for pyramidal cells, while inputs to pyramidal cells in layer 3, but not in layer 2, exhibit an asymmetric offset to the medial side of the cell's main axis. Differential laminar sources of excitatory inputs might contribute to the functional diversity of stellate and pyramidal cells.