Spatial representation along the proximodistal axis of CA1

CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part.     

Locomotion-related oscillatory body movements at 6-12 Hz modulate the hippocampal theta rhythm

The hippocampal theta rhythm is required for accurate navigation and spatial memory but its relation to the dynamics of locomotion is poorly understood. We used miniature accelerometers to quantify with high temporal and spatial resolution the oscillatory movements associated with running in rats. Simultaneously, we recorded local field potentials in the CA1 area of the hippocampus. We report that when rats run their heads display prominent vertical oscillations with frequencies in the same range as the hippocampal theta rhythm (i.e., 6-12 Hz). In our behavioral set-up, rats run mainly with speeds between 50 and 100 cm/s. In this range of speeds, both the amplitude and frequency of the "theta" head oscillations were increasing functions of running speed, demonstrating that the head oscillations are part of the locomotion dynamics. We found evidence that these rhythmical locomotor dynamics interact with the neuronal activity in the hippocampus. The amplitude of the hippocampal theta rhythm depended on the relative phase shift with the head oscillations, being maximal when the two signals were in phase. Despite similarity in frequency, the head movements and LFP oscillations only displayed weak phase and frequency locking. Our results are consistent with that neurons in the CA1 region receive inputs that are phase locked to the head acceleration signal and that these inputs are integrated with the ongoing theta rhythm.     

Simulation of the hippocampal theta rhythm

Centre of Theoretical and Computational Neuroscience, University of Plymouth, UK Basing on the hypothesis about the mechanisms of the theta rhythm generation, the article presents mathematical and computational models of theta activity in the hippocampus. The problem of the theta rhythm modeling is nontrivial because the slow theta oscillations (about 5 Hz) should be generated by a neural system composed of frequently firing neural populations. We studied a model of neural pacemakers in the septum. In this model, the pacemaker follows the frequency of the external signal if this frequency does not deviate too far from the natural frequency of the pacemaker, otherwise the pacemaker returns to the frequency of its own oscillations. These results are in agreement with the experimental records of medial septum neurons. Our model of the septal pacemaker of the theta rhythm is based on the hypothesis that the hippocampal theta appears as a result of the influence of the assemblies of neurons in the medial septum which are under control of pacemaker neurons. Though the model of the pacemaker satisfies many experimental facts, the synchronization of activity in different neural assemblies of the model is not as strong as it should be. Another model of the theta generation is based on the anatomical data about the existence of the inhibitory GABAergic loop between the medial septum and the hippocampus. This model shows stable oscillations at the frequency of the theta rhythm in a broad range of parameter values. It also provides explanation to the experimental data about the variation of the frequency and the amplitude of the theta rhythm under different external stimulations of the system. The role of the theta rhythm for information processing in the hippocampus is discussed.     

A computational study on altered theta-gamma coupling during learning and phase coding

There is considerable interest in the role of coupling between theta and gamma oscillations in the brain in the context of learning and memory. Here we have used a neural network model which is capable of producing coupling of theta phase to gamma amplitude firstly to explore its ability to reproduce reported learning changes and secondly to memory-span and phase coding effects. The spiking neural network incorporates two kinetically different GABA(A) receptor-mediated currents to generate both theta and gamma rhythms and we have found that by selective alteration of both NMDA receptors and GABA(A,slow) receptors it can reproduce learning-related changes in the strength of coupling between theta and gamma either with or without coincident changes in theta amplitude. When the model was used to explore the relationship between theta and gamma oscillations, working memory capacity and phase coding it showed that the potential storage capacity of short term memories, in terms of nested gamma-subcycles, coincides with the maximal theta power. Increasing theta power is also related to the precision of theta phase which functions as a potential timing clock for neuronal firing in the cortex or hippocampus.     

Interactions between electrical activities of the sensomotor cortex and the hippocampus during 'animal hypnosis' in rabbits

The electrical activity of the left and right sensorimotor cortex and left and right dorsal hippocampus (CA3 fields) was recorded during "animal hypnosis" in rabbits. The "animal hypnosis" produced asymmetry in the spectral power of the hippocampal electrical activity due to an increase in the power of delta 1, delta 2, and theta 1 components in the left-hippocampus and decrease in the spectral power in the same ranges in the right-hippocampus. Hemispheric asymmetry in the electrical activity during the "animal hypnosis" was also expressed in the indices of coherence between the sensorimotor cortex and hippocampus. EEG coherence between the left sensorimotor cortex and left hippocampus in the delta 1, theta 1, and theta 2 ranges was higher than that between the right-side structures.     

Mechanisms of the regulation and functional significance of the theta rhythm. Roles of serotonergic and noradrenergic systems

The evidence for the role of serotonergic and noradrenergic effects on the septohippocampal theta oscillations obtained by the author and her colleagues are reviewed. Analysis of neuronal activity in the medial septal area or hippocampus and hippocampal EEG simultaneously recorded in awake rabbits exposed to different kinds of brainstem influences led to the following conclusions. 1. Serotonergic median raphe nucleus and noradrenergic locus ceruleus act as functional antagonists in theta regulation: the former structure restricts the theta rhythm generation, whereas the latter enhances this process. 2. Both transmitter systems control sensory reactions of septal and hippocampal neurons through up and down regulation of the theta activity. 3. When continuous theta activity induced by various experimental manipulations is recorded, responsiveness of septohippocampal neurons to sensory stimulation is strongly reduced. These findings provide support for the view that the theta oscillations act as an active filter in the information selection and registration. Interaction of different transmitter systems in the theta rhythm control as well as attention and memory is discussed.     

Animal model of Alzheimer’s disease: characteristics of EEG and memory

We studied the effects of aggregated amyloid β-peptide Aβ_25–35 on spatial memory and the spectral-correlational characteristics of EEG of both the dorsal hippocampus and the frontal cortex both in adult and aged rats at the early stage of Aβ_25–35 action. Spatial memory was characterized using a novel cognitive test. A decrease in low-frequency theta band oscillations in the dorsal hippocampus and the frontal cortex was observed. The mean coefficient of EEG cross-correlation between these structures was significantly reduced at the early stage of Aβ_25–35 action both in adult and aged rats. In addition, we found that one month after Aβ_25–35 injection spatial memory was impaired. These results suggest that the decrease in low-frequency theta band oscillations and the weakening of binding between the dorsal hippocampus and the frontal cortex under the action of Aβ_25–35 may be an underlying cause of the typical memory breakdown associated with the Alzheimer’s disease.     

Speed controls the amplitude and timing of the hippocampal gamma rhythm

Cortical and hippocampal gamma oscillations have been implicated in many behavioral tasks. The hippocampus is required for spatial navigation where animals run at varying speeds. Hence we tested the hypothesis that the gamma rhythm could encode the running speed of mice. We found that the amplitude of slow (20-45 Hz) and fast (45-120 Hz) gamma rhythms in the hippocampal local field potential (LFP) increased with running speed. The speed-dependence of gamma amplitude was restricted to a narrow range of theta phases where gamma amplitude was maximal, called the preferred theta phase of gamma. The preferred phase of slow gamma precessed to lower values with increasing running speed. While maximal fast and slow gamma occurred at coincident phases of theta at low speeds, they became progressively more theta-phase separated with increasing speed. These results demonstrate a novel influence of speed on the amplitude and timing of the hippocampal gamma rhythm which could contribute to learning of temporal sequences and navigation.     

Theta band zero-lag long-range cortical synchronization via hippocampal dynamical relaying

Growing evidence suggests that synchronization among distributed neuronal networks underlie functional integration in the brain. Neural synchronization is typically revealed by a consistent phase delay between neural responses generated in two separated sources. But the influence of a third neuronal assembly in that synchrony pattern remains largely unexplored. We investigate here the potential role of the hippocampus in determining cortico-cortical theta synchronization in different behavioral states during motor quiescent and while animals actively explore the environment. To achieve this goal, the two states were modeled with a recurrent network involving the hippocampus, as a relay element, and two distant neocortical sites. We found that cortico-cortical neural coupling accompanied higher hippocampal theta oscillations in both behavioral states, although the highest level of synchronization between cortical regions emerged during motor exploration. Local field potentials recorded from the same brain regions qualitatively confirm these findings in the two behavioral states. These results suggest that zero-lag long-range cortico-cortical synchronization is likely mediated by hippocampal theta oscillations in lower mammals as a function of cognitive demands and motor acts.     

电刺激大鼠右后背海马诱导前背海马神经网络癫痫样电活动

本文旨在探讨单侧海马(hippocampus,HPC)内神经网络与HPC癫痫发生的关系及其细胞机制。实验在45只SSprague-Dawley大鼠上完成。急性强直电刺激大鼠右侧后背HPC CAl基树突区(acute tetanizatio of the posterior dorsal hippocampus,ATPDH;60Hz,2s,0.4-0.6mA)诱发HPC癫痫模型,同步记录同侧前背HPC CAl顶树突区单位放电和基树突区深部电图。结果,ATPDH可以沿长铀向前1．8mm处对前背MIC神经网络产生下述效应：(1)同步或非同步原发性单位与深部电图后放电,在同步性后放电锁时(time-lock)关系明显。非同步性后放电的深部电图癫痫样电活动具有宽频带特征(5-90Hz);(2)原发性单位后放-后抑制效应可以引发低频原发性电图后放电,长时程爆发式单位放电可以诱发高频原发性电图后放电;(3)短束原发性电图后放电也可以诱发原发性单位后放电;(4)原发性电图后放电和神经元单位放电的抑制效应具有明显可塑性特征。以上结果提示,重复施加ATPDH可以引起前背HPC癫痫相关性病理生理性神经网络的重建;而单个神经元与神经网络的异常电活动之间具有明显的互动作用和突触传递可塑性特征;沿HPC长铀内在抑制性通路的过度活动也可以诱发电图癫痫样电活动,导致HPC网络癫痫的发生。     

Comparison of interval timing behaviour in mice following dorsal or ventral hippocampal lesions with mice having δ-opioid receptor gene deletion

Mice with cytotoxic lesions of the dorsal hippocampus (DH) underestimated 15 s and 45 s target durations in a bi-peak procedure as evidenced by proportional leftward shifts of the peak functions that emerged during training as a result of decreases in both ‘start’ and ‘stop’ times. In contrast, mice with lesions of the ventral hippocampus (VH) displayed rightward shifts that were immediately present and were largely limited to increases in the ‘stop’ time for the 45 s target duration. Moreover, the effects of the DH lesions were congruent with the scalar property of interval timing in that the 15 s and 45 s functions superimposed when plotted on a relative timescale, whereas the effects of the VH lesions violated the scalar property. Mice with DH lesions also showed enhanced reversal learning in comparison to control and VH lesioned mice. These results are compared with the timing distortions observed in mice lacking δ-opioid receptors (Oprd1^−/−) which were similar to mice with DH lesions. Taken together, these results suggest a balance between hippocampal–striatal interactions for interval timing and demonstrate possible functional dissociations along the septotemporal axis of the hippocampus in terms of motivation, timed response thresholds and encoding in temporal memory.     

A 4 Hz oscillation adaptively synchronizes prefrontal, VTA, and hippocampal activities

Network oscillations support transient communication across brain structures. We show here, in rats, that task-related neuronal activity in the medial prefrontal cortex (PFC), the hippocampus, and the ventral tegmental area (VTA), regions critical for working memory, is coordinated by a 4 Hz oscillation. A prominent increase of power and coherence of the 4 Hz oscillation in the PFC and the VTA and its phase modulation of gamma power in both structures was present in the working memory part of the task. Subsets of both PFC and hippocampal neurons predicted the turn choices of the rat. The goal-predicting PFC pyramidal neurons were more strongly phase locked to both 4 Hz and hippocampal theta oscillations than nonpredicting cells. The 4 Hz and theta oscillations were phase coupled and jointly modulated both gamma waves and neuronal spikes in the PFC, the VTA, and the hippocampus. Thus, multiplexed timing mechanisms in the PFC-VTA-hippocampus axis may support processing of information, including working memory.     

Hippocampal Theta Modulation of Neocortical Spike Times and Gamma Rhythm: A Biophysical Model Study

The hippocampal theta and neocortical gamma rhythms are two prominent examples of oscillatory neuronal activity. The hippocampus has often been hypothesized to influence neocortical networks by its theta rhythm, and, recently, evidence for such a direct influence has been found. We examined a possible mechanism for this influence by means of a biophysical model study using conductance-based model neurons. We found, in agreement with previous studies, that networks of fast-spiking GABA -ergic interneurons, coupled with shunting inhibition, synchronize their spike activity at a gamma frequency and are able to impose this rhythm on a network of pyramidal cells to which they are coupled. When our model was supplied with hippocampal theta-modulated input fibres, the theta rhythm biased the spike timings of both the fast-spiking and pyramidal cells. Furthermore, both the amplitude and frequency of local field potential gamma oscillations were influenced by the phase of the theta rhythm. We show that the fast-spiking cells, not pyramidal cells, are essential for this latter phenomenon, thus highlighting their crucial role in the interplay between hippocampus and neocortex.     

Differential pharmacological properties of GABAA/benzodiazepine receptor complex in dorsal compared to ventral rat hippocampus

Several studies have indicated a functional differentiation across the septotemporal axis of rat hippocampus. Our previous results have shown that the alpha 1 beta 2 gamma 2-GABAA receptor subtype dominates in dorsal hippocampus (DH), while the alpha 2 beta 1 gamma 2-subtype prevails in ventral hippocampus (VH). We therefore studied possible differences in the pharmacological properties and receptor binding parameters of the GABAA receptor subtypes between DH and VH, by examining: (1)(a) the specific binding of [3H]-flunitrazepam (Benzodiazepine sites agonist) by using quantitative autoradiography, (b) the kinetic parameters of [3H]-flunitrazepam specific binding, by using the "wipe off" technique and (2) the competitive displacement of [3H]-flunitrazepam binding by using zolpidem (selective agonist of the alpha 1-subtype) and L-655,708 (selective inverse agonist of the alpha 5-subtype) and the enhancement of [3H]-flunitrazepam binding by using etomidate (selective positive modulator of the beta 2-subunit), in an autoradiographical saturation kinetic study. Our results showed in VH compared to DH: (A) lower level of [3H]-flunitrazepam binding, apparently due to weaker binding affinity (higher KD value), since no differences in the Bmax value could be detected, (B) higher IC50 values for zolpidem and lower IC50 values for L-655,708 and (C) higher EC50 values for etomidate. In conclusion, the lower binding for zolpidem and etomidate and the higher binding for L-655,708 observed in VH support the evidence that the alpha 1 beta 2 gamma 2-GABAA receptor subtype dominates in DH and the alpha 5-subtype prevails in VH. Further, our results suggest differential pharmacological effects of the benzodiazepines in DH compared to VH, with the sedative effects being more potent in the dorsal hippocampus.     

Artificial Theta Stimulation Impairs Encoding of Contextual Fear Memory

Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4–12 Hz) and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.     

Theta returns

Recent physiological studies have implicated theta - a high-amplitude 4-8 Hz oscillation that is prominent in rat hippocampus during locomotion, orienting and other voluntary behaviors - in synaptic plasticity, information coding and the function of working memory. Intracranial recordings from human cortex have revealed evidence of high-amplitude theta oscillations throughout the brain, including the neocortex. Although its specific role is largely unknown, the observation of human theta has begun to reveal an intriguing connection between brain oscillations and cognitive processes.     

Individual typological characteristics of higher nervous performance and asymmetry of hippocampus and amygdala electrical activity in dogs

Electrical activity of the frontal cortex, dorsal hippocampus, basolateral amygdala and lateral hypothalamus of both hemispheres was recorded in nine dogs in the state of quiet wakefulness without any stimulation. Individual typological features of higher nervous activity were assessed by the animal performance under conditions of free choice of the reinforcement mode: either high probable but of low alimentary quality, or with low probability but more valuable. Mean values of the maxima of crosscorrelation function between electrical activity of the investigated structures of two hemispheres were used as a basis for assessment of conditions for interaction between left and right formations. For the hippocampus and amygdala, in some dogs these conditions were the best in the theta and beta 2 ranges, in other animals--in the theta and alpha bands. In phlegmatic dogs, spectral densities in the theta range were higher in the left hippocampus than in the symmetrical structure, in sanguine animals spectral densities in the theta and beta 2 ranges in the hippocampus and amygdala were higher in the right hemisphere than in the left one. Thus, the hemispheric asymmetry of electrical activity of the limbic formations seems to be an important factor, which determines the individual typological features of the higher nervous activity in dogs.     

Membrane and network theta-rhythm generation in hippocampal slices

The hippocampal rhythms observed in vivo are the result of a complex interplay between cellular and synaptic properties within the hippocampus, and extra-hippocampal tonic as well as periodic inputs. For the stable rhythm to occur, the hippocampal circuitry should have the potential to oscillate at the specific frequencies. The in vitro studies revealed multiple mechanisms supporting the generation of the theta rhythm, which is the main operational mode of the hippocampus. In the hippocampus and related structures cellular membranes can oscillate at theta rhythm when they are depolarized to near-threshold membrane potentials; membranes are also adjusted to resonate with the external signal applied at theta frequency. Synaptically connected hippocampal network alone can generate theta rhythm when a necessary tonic excitation is provided. Finally, rhythmic inputs in theta range from the septum and entorhinal cortex have a propensity to synchronize oscillations in the whole hippocampal formation and associated structures to operate in a unified mode of activity. Based on the results obtained in slices and slice cultures, the present review shows this multilevel hierarchy, which serves to guarantee easy occurrence and reliable maintenance of the theta rhythm in the hippocampus.     

The typological characteristics of higher nervous activity in dogs and the maxima of the cross-correlation function between the electrical activities of the frontal cortex and the brain limbic systems]

Electrical activity of the frontal cortex, dorsal hippocampus, basolateral amygdala and lateral hypothalamus was recorded in eight dogs with chronically implanted electrodes. Mean values of the maxima of crosscorrelation function (MCCF) between electrical potentials in the theta, alpha and beta-2 ranges were used as a basis for assessment of conditions for interaction between these structures. Typological features of the higher nervous activity were assessed by the animal performance under conditions of free choice of the reinforcement mode of a conditioned stimulus: either high probable but of low alimentary quality or with low probability but more valuable. The mean MCCF values in the theta range were higher than in the other ranges. The brain structure which had the high MCCF in the theta-range, at least, with two of the structures under study was considered as "dominant". It was shown that hippocampus was the dominant structure for melancholic dogs, the frontal cortex was in phlegmatics. The hypothalamus was shown to be the "dominant structure" in both sanguine and choleric animals, but, for the most part, its activity was correlated with different structures. Thus, conditions for interaction between the frontal cortex, hippocampus, amygdala and hypothalamus seem to be an important factor, which determines typological features of the higher nervous activity of dogs.