Phase precession in the human hippocampus and entorhinal cortex

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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.     

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.     

Sensory characteristics of the cortical input to the hippocampus: the entorhinal cortex]

Sensory reactions of neurones in the medial entorhinal area were investigated in unanaesthetized rabbits. 54% of the units were multimodal. Different stimuli evoked various response patterns with complex on-off components. Differential coding of pure tones was observed in many cells, which were also sensitive to other sensory modalities. Complete habituation of responses was virtually absent; only partial reduction of the late components was observed in some cases. In 71% of units reactions were stable or incremental (gradual development and increase). It may be concluded that from the entorhinal cortex the hippocampus receives highly differentiated signals of "associative" type, which do not habituate and are of a stable or incremental nature.     

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.     

Inducible and cell-type restricted manipulation in the entorhinal cortex

The entorhinal cortex functions as the gateway to the hippocampal formation. However, its role in formation and consolidation of hippocampus-dependent memory remains relatively unexplored. In this issue of Neuron, Yasuda and Mayford report an elegant cell-type restricted inducible transgenic mouse overexpressing a mutant form of CaM kinase II selectively in superficial layers of medial entorhinal cortex and its upstream regions. These animals display a selective spatial memory deficit during the immediate posttraining period as well as during acquisition in the Morris water maze. Similar to the hippocampus, this time-limited involvement of entorhinal cortex in spatial memory processing suggests a crucial role for hippocampal-entorhinal circuitry in spatial memory formation.     

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.     

Bilateral changes in glutamate uptake,muscarinic receptor binding and acetylcholinesterase level in the rat hippocampus after unilateral entorhinal cortex lesions

This report examines the effects of unilateral electrolytic and knife-cut lesions of entorhinal cortex on glutamate uptake, the muscarinic receptor [³H]QNB binding and acetylcholinesterase (AChE) activity in the dorsal and ventral parts of the ipsi- and contralateral hippocampus of the rat.We found that (1) in unoperated, control rats there are no pre-existing differences in the level of the investigated markers between the right and left hippocampus, (2) both electrolytic and knife-cut lesions of the entorhinal cortex evoke bilateral changes in the investigated markers and (3) the character of the response is dependent on the survival time and on the hippocampal part involved. Four days after operation a substantial reduction in glutamate uptake was found in both the dorsal and ventral parts of the ipsi- and contralateral hippocampus. At the same time there was a drop in muscarinic receptor binding, while AChE activity was not affected. The decrease in glutamate uptake persisted on the 21st postoperative day, whereas muscarinic receptor binding was enhanced, in comparison with the control level, in the ventral part of both the ipsi- and contralateral hippocampus. This overshoot was not so evident on the 30th postoperative day; glutamate uptake at that time reached or even surpassed the control level. Enhancement of AChE activity on the ipsi- and contralateral sides was noted on both the 21st and 30th day after operation.We suggest the following interpretation of these results: (1) glutamatergic projections from the entorhinal cortex to the hippocampus are bilateral, (2) some transneuronal changes probably contribute to the decline in glutamate uptake, particularly on the contralateral side, (3) neuronal depolarization does not seem to be the only mechanism responsible for the decrease in muscarinic receptor binding and (4) some compensatory mechanisms occur in the hippocampus at a later time after the lesion.Moreover, we believe that the use of the contralateral side as a control should be considered with caution in studies with unilaterally lesioned animals.     

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.     

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)     

Spreading of epileptic afterdischarges between entorhinal cortex and hippocampus in acute experiments and the kindling model of epilepsy in the rat--comparing different methods of analysis

Spreading of epileptiform activity in the central nervous system is one of the fundamental problems in epileptology. The patterns of spreading of after-discharges in the hippocampus and entorphinal cortex were studied in acute experiments and using the kindling model of epileptogenesis. Three methods were used to determine the time relations between EEG signals from different brain areas; visual inspections, average amount of mutual information (AAMI) and phase spectrum method. The analysis methods used are adequate for quantification of the degree of coupling between different EEG signals during an afterdischarge, but should be used jointly since different signal features are taken into consideration by different methods. During an afterdischarge only at the beginning the focal area is clearly leading the other brain areas; thereafter the pattern becomes more complex.     

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.     

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.     

14-3-3 expression in denervated hippocampus after entorhinal cortex lesion assessed by culture-derived isotope tags in quantitative proteomics

Activation of astrocytes accompanies many brain pathologies. Reactive astrocytes have a beneficial role in acute neurotrauma but later on might inhibit regeneration. 2D-gel electrophoresis and mass spectrometry were applied to study the proteome difference in denervated hippocampus in wildtype mice and mice lacking intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP-/-Vim-/-) that show attenuated reactive gliosis and enhanced posttraumatic regeneration. Proteomic data and immunohistochemical analyses showed upregulation of the adapter protein 14-3-3 four days postlesion and suggested that 14-3-3 upregulation after injury is triggered by reactive gliosis. Culture-derived isotope tags (CDIT) and mass spectrometry demonstrated that 14-3-3 epsilon was the major isoform upregulated in denervated hippocampus and that its upregulation was attenuated in GFAP-/-Vim-/- mice and thus most likely connected to reactive gliosis.