癫癎发作对大鼠海马感觉门控的影响

目的：观察癫癎发作对大鼠海马感觉门控的影响。方法：采用青霉素诱导的大鼠癫癎发作模型，将探测电极植入大鼠海马的CA1区，连续7天，记录大鼠海马的听觉诱发电位；采用条件—测试模式的双短音刺激（S1、S2），刺激间隔是500ms，观察大鼠癫癎发作前后S1和S2波的峰—峰值、潜伏期和N40的测试刺激／条件刺激（T／C）比的变化，并与对照组进行比较。结果：与生理盐水对照组相比，实验组大鼠第一天癫癎发作后S2的峰—峰值增大，差异有显著意义（P=0．043）。反复癫癎发作一周，实验组第二天以后每天癫癎发作后总的趋势是：S1的峰—峰值减小，与对照组相比差异有显著意义（P=0．01），N40的T／C比在癫癎发作后增大，差异具有显著意义（P=0．028）。结论：癫癎发作对大鼠海马感觉门控具有急性和潜在的慢性损害作用。     

Sensitization and hippocampal type 2 theta in the rat

Previous research has consistently demonstrated that there are two types of theta which can be recorded from the hippocampus of a variety of species. Type 1 theta occurs during voluntary movements such as walking, running and rearing while type 2 theta occurs during alert immobility. Large amplitude irregular activity (LIA) occurs during more automatic behaviors such as grooming and chewing as well as during non-alert immobility. Type 2 theta can be readily elicited in the unrestrained guinea pig and rabbit. While spontaneous type 2 theta rarely occurs in the rat, short trains of type 2 theta have been observed during conditioning. The purpose of the present study was to examine the relationship between type 2 theta and inescapable shock when the temporal characteristics of the conditioning stimulus (CS) were varied. Three conditioning paradigms (delay, trace, random) were utilized. Type 2 theta production increased over time as a function of the number of shocks and was not due to conditioning. There were no differences in the three groups in the occurrence of type 2 theta during CS presentations or during the inter-stimulus intervals. Previously neutral sensory stimulation also produced type 2 theta after conditioning in all groups. The inescapable shocks placed the rat in a high state of arousal which subsequently sensitized the animal to produce type 2 theta. The data was used to support the hypothesis that a state of arousal is a necessary precursor for the production of type 2 theta.     

Behavioral correlates of hippocampal type 2 theta in the rat

Previous research has indicated that there are two types of theta activity which can be recorded from the hippocampus in most rodents. One type (type 1) of theta is correlated with voluntary movements while the second (type 2) occurs during immobility. A third waveform termed LIA (Large Amplitude Irregular Activity) occurs during more automatic behaviors, e.g., grooming, shivering or immobility. In the rabbit and guinea pig type 2 theta can readily be elicited in unrestrained animals. However, type 2 theta is rarely seen in the unrestrained rat. The purpose of the present study was to determine the stimulus conditions that are necessary for the elicitation of type 2 theta in the rat. In the present study 20 unrestrained rats were observed in the presence of a cat or a ferret. Movements by the cat or ferret produced theta in immobile rats. Sensory stimuli which did not ordinarily produce type 2 theta would reliably do so in the presence of the cat or ferret. It is hypothesized that type 2 theta in the unrestrained immobile rat occurs during sensory processing but only when the animal is in a high state of "arousal."     

A circadian rhythm of hippocampal theta activity in the mouse

Hippocampal theta activity dominates the cortical EEG of the mouse during certain behaviors. We have therefore been able to study the circadian distribution of hippocampal theta activity by means of chronic EEG implantation and computerized EEG state scoring. Observations in six mice indicate consistent and significant circadian patterns of theta-dominated EEG, both during wakefulness (theta-dominated wake, or TDW) and during sleep (REM sleep). The probability of REM rises gradually to a maximum during the sleep period and then falls abruptly at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two episodes of each coincide remarkably, as do their circadian distributions. The probability of TDW rises to a very high level at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two halves of a single circadian rhythm of theta probability. This concept would be relevant in interpreting the abnormally phase-advanced pattern of REM sleep observed in human depressives.     

Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing

Hippocampal theta activity is the result of the concerted activity of a group of nuclei located in the brain stem and the caudal diencephalic area, which are together referred to as the synchronizing ascending system. Serotonin is recognized as the only neurotransmitter able to desynchronize the hippocampal electroencephalographic. A theory has been developed in which serotonin, acting on medial septal neurons, modulates cholinergic/GABAergic inputs to the hippocampus and, thus, the cognitive processing mediated by this area. However, few studies have addressed the relationship between serotonin modulation of theta activity and cognition. In this review, we present a summary and analysis of the data relating serotonin and its theta activity modulation with cognition, and we also discuss the few works relating serotonin, theta activity and cognition as well as the theories regarding the serotonin regulation of memory processes organized by the hippocampus. We propose that serotonin depletion induces impairment of the relays coding the frequency of hippocampal theta activity, whereas depletion of the relays in which frequency is not coded induces improvements in spatial learning that are related to increased expression of high-frequency theta activity.     

The dynamics of hippocampal sensory gating during the development of morphine dependence and withdrawal in rats

The effects of morphine on hippocampal sensory gating (N40) during the development of morphine dependence and withdrawal were investigated in the double click auditory evoked potential (EP) suppression paradigm. Rats were made dependent upon morphine hydrochloride by a series of injections (every 12 h) over 6 days, followed by withdrawal after stopping morphine administration. Hippocampal gating was examined during the development of dependence and withdrawal. Moreover, the DA antagonist haloperidol was used to assess the contribution of dopamine to hippocampal gating induced by morphine. Our results showed that the morphine-treated rats exhibited significantly disrupted hippocampal gating during the development of morphine dependence and this disrupted gating was partially reversed by haloperidol pretreatment. In contrast, there was significantly enhanced hippocampal gating at the fifth and sixth days of withdrawal. The dynamics of hippocampal gating during the development of morphine dependence and withdrawal suggests the interaction between the hippocampus and opioids.     

Lesions of the vestibular system disrupt hippocampal theta rhythm in the rat

The hippocampus has a major role in memory for spatial location. Theta is a rhythmic hippocampal EEG oscillation that occurs at approximately 8 Hz during voluntary movement and that may have some role in encoding spatial information. We investigated whether, as part of this process, theta might be influenced by self-movement signals provided by the vestibular system. The effects of bilateral peripheral vestibular lesions, made > or = 60 days prior to recording, were assessed in freely moving rats. Power spectral analysis revealed that theta in the lesioned animals had a lower power and frequency compared with that recorded in the control animals. When the electroencephalography (EEG) was compared in epochs matched for speed of movement and acceleration, theta was less rhythmic in the lesioned group, indicating that the effect was not a result of between-group differences in this behavior. Blood measurements of corticosterone were also similar in the two groups indicating that the results could not be attributed to changes in stress levels. Despite the changes in theta EEG, individual neurons in the CA1 region of lesioned animals continued to fire with a periodicity of approximately 8 Hz. The positive correlation between cell firing rate and movement velocity that is observed in CA1 neurons of normal animals was also maintained in cells recorded from lesion group animals. These findings indicate that although vestibular signals may contribute to theta rhythm generation, velocity-related firing in hippocampal neurons is dependent on nonvestibular signals such as sensory flow, proprioception, or motor efference copy.     

Differential effects of escapable and inescapable footshock on hippocampal theta activity.

Three groups of rats were exposed to escapable shock, inescapable shock, or no shock using procedures known to induce learned helplessness effects. Twenty-four hours later, hippocampal electroencephalograms were recorded from freely moving subjects. A 5-s probe shock was delivered after 15 min, and recording continued. Frequency analyses revealed no differences between the pretreatment groups during the first recording segment. Immediately after the probe shock, however, trains of immobility-related theta activity were observed in both the escapable-and no-shock groups. No such activity was observed in the inescapable-shock group. Because immobility followed the probe shock in all groups, this relative impairment was not due to differential motor activity. These results offer in vivo support for in vitro findings suggesting that hippocampal activity is sensitive to event contingencies and is involved in stress-induced learning deficits.     

Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating

Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural network is not well understood. The present study used EEG and MEG to assess sensory gating and volumetric MRI to measure hippocampal volume to investigate relationships between them in 22 normal controls and 22 patients with schizophrenia. In the schizophrenia group, anterior but not posterior hippocampal volume was smaller, and both the P50 and M50 gating ratios were larger (worse) than in controls. Independent of group, left-hemisphere M50 gating ratio correlated negatively with left anterior hippocampal volume, and right-hemisphere M50 gating ratio correlated negatively with right anterior hippocampal volume. Schizophrenia diagnosis predicted M50 gating independent of hippocampal volume. These results are consistent with the finding that hippocampus is a critical part of a fronto-temporal circuit involved in auditory gating.     

The entorhino-septo-supramammillary nucleus connection in the rat: morphological basis of a feedback mechanism regulating hippocampal theta rhythm.

Recent electrophysiological observations suggest that, in addition to the medial septal area pacemaker system, several alternative or additional mechanisms are involved in the generation/regulation of hippocampal theta activity. Discharging neurons phase-locked to hippocampal theta waves have been observed in the dorsal raphe, nucleus reticularis pontis oralis and especially in the supramammillary region of rats. Since these areas are reciprocally interconnected with the hippocampal formation, including the entorhinal cortex, it would aid our understanding of limbic function to elucidate the location and neurochemical content of the entorhino-septal and septo-supramammillary projection neurons, as well as that of their postsynaptic targets. Light and electron microscopic immunostaining for calretinin, in combination with antero- and retrograde tracer techniques, postembedding immunostaining for GABA and the transmitter specific [3H]D-aspartate retrograde radiolabeling, as well as a co-localization experiment for calretinin and glutamate decarboxylase in rat supramammillary and septal neurons, demonstrated that: (i) a large population of entorhinal cells that forms asymmetric synaptic contacts on calretinin-containing neurons located at the border between the medial and lateral septal areas contains calretinin and are aspartate/glutamatergic; (ii) the overwhelming majority of calretinin-immunoreactive cells located at the border between the lateral and medial septal area are GABAergic; (iii) these neurons can be retrogradely labeled from the supramammillary area; (iv) anterogradely labeled axons originating in the border between the medial and lateral septum are GABAergic and (v) terminate on supramammillary area non-GABAergic, calretinin-containing neurons, which are known to project to the septal complex and hippocampus. These observations indicate that a large population of cells participating in the hippocampal feedback regulation of theta regulation/generation contain the same calcium-binding protein. Furthermore, entorhinal excitatory transmitter-containing neurons can depress the activity of supramammillary theta generating/regulating cells via septal inhibitory neurons.     

Brainstem sites for the carbachol elicitation of the hippocampal theta rhythm in the rat

The effects of brainstem microinjections of carbachol on the hippocampal theta rhythm were examined in urethane anesthetized rats. The two most effective theta-eliciting sites with carbachol were the nucleus pontis oralis (RPO) and the acetylcholine-containing pedunculopontine tegmental nucleus (PPT) of the dorsolateral pontine tegmentum. RPO injections generated theta at mean latencies of 38.5±70.8 s and for mean durations of 12.9±5.1 min. Five of seven RPO injections gave rise to theta virtually instantaneously, i.e., before the completion of the injection. PPT injections generated theta at mean latencies of 1.7±1.1 min and for mean durations of 11.9±6.0 min. Injections rostral or caudal to RPO in the caudal midbrain reticular formation (RF) or the caudal pontine RF (nucleus pontis caudalis) generated theta at considerably longer latencies (generally greater than 5 min) or were without effect. Medullary RF injections essentially failed to alter the hippocampal EEG. The finding that theta was produced at very short latencies at RPO suggests that RPO, the putative brainstem source for the generation of theta, is modulated by a cholinergic input. The further demonstration that theta was also very effectively elicited with PPT injections suggests this acetylcholine-containing nucleus of the dorsolateral pons may be a primary source of cholinergic input to RPO in the generation of theta. The hippocampal theta rhythm is a major event of REM sleep. The present results are consistent with earlier work showing that each of the other major events of REM sleep, as well as the REM state, are cholinergically activated at the level of the pontine tegmentum.     

The spontaneous activity of hippocampal neurons during the modulation of theta rhythm by cholinergic substances

A statistical analysis of the baseline activity of neurons, recorded intracellularly in the hippocampus of awake, nonimmobilized rabbits in three states, control and during the systemic administration of eserine and scopolamine, was carried out. Neurons of the hippocampus were additionally tested in a similar manner following the chronic basal undercutting of the septum, removing stem influences. The cholinergic substances regulate the number of neurons of the hippocampus having theta modulation and the degree of its stability, but do not influence its frequency. When the cholinergic theta rhythm is activated, regularization of the activity takes place with the suppression of delta modulation and of complex spikes; its blockade is accompanied by the opposite changes. Both substances stably alter the level of the baseline frequency of discharges of the majority of neurons, although the total average frequency remains constant. Regression analysis shows the predominance of a decrease in the activity in highfrequency (> 25 spikes/sec) and an increase in the lowf-requency (< 25 spikes/sec) neurons during the effect of both substances. The constancy of the total average frequency and the unidirectionality of the shifts in the level of discharges of the neurons during the intensification (eserine) and blockade (scopolamine) of the cholinergic component of the theta rhythm points to the fact that the cholinergic septal input directly influences mainly the structure but not the level of the activity of the hippocampal neurons.Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 42, No. 5, pp. 944–954, September–October, 1992.     

Frontal-midline theta from the perspective of hippocampal "theta"

Electrical recordings from the surface of the skull have a wide range of rhythmic components. A major task of analysis of this EEG is to determine their source and functional significance. The hippocampal "theta rhythm" has been extensively studied in rats and its rhythmicity has recently been shown to be functionally significant, per se. Here, we use relevant aspects of the hippocampal literature to provide perspective on one of the most studied human EEG rhythms: frontal-midline theta. We review its electrographic features, localization, prevalence, age distribution, behavioural modulation (particularly in relation to working memory, spatial navigation, episodic memory, internalised attention and meditation), relationship to personality, drug interactions, neurochemical relationships, and coherence with rhythmic activity at other sites. We conclude that FM-theta, like hippocampal theta, appears to play a role in (or at least occur during) processing of memory and emotion. It is correlated with working memory and/or sustained attention; but this does not entail a role in function since clear behavioural correlates of hippocampal theta have been demonstrated that are not sensitive to hippocampal damage. FM-theta is increased by anxiolytic drug action and personality-related reductions in anxiety, whereas hippocampal theta is decreased by anxiolytic drugs. In animals, frontal theta and hippocampal theta can be phase-locked or independent, depending on behavioural state. So, the cognitive functions of FM-theta, and their relationship to hippocampal theta, are unclear and definitive evidence for functional involvement in cognitive or emotional processing is lacking. One possible solution to this problem is analysis of FM-theta in animals-provided homology can be determined. The issues of sporadicity and low incidence of FM-theta also need to be addressed in the future. Changes in functional connectivity, indicated by changes in coherence, are also a largely untapped resource. We suggest that the most hopeful path to assessing the functions of FM-theta will be through the use of drugs, and the variation of their effects depending on baseline levels of FM-theta. Finally, we review some theories of theta function. Despite the apparent richness of the current data, we conclude that it is difficult (and may ultimately be impossible) to formulate a theory that attributes a specific cognitive function to FM-theta. However, the theories share some general computational assumptions and these should be a useful guide to future work and, ultimately, a definite theory of the function or functions of FM-theta.     

Frequency analysis of rat hippocampal electrical activity.

Hippocampal electrical activity was recorded in free-moving rats and behavioral observations carried out simultaneously. The hippocampal EEG was analysed by an EEG spectrograph giving the amplitudes of 20 frequencies in the 2–30 Hz band in the form of spectrograms. Twenty spectrograms per sec were generated, often showing considerable fluctuations even during any one behavioral pattern. Therefore mean spectrograms of several behavioral patterns were constructed by averaging 256 spectrograms, which corresponds to an analysis time of 12.8 sec per behavioral pattern. This was also performed, in modified form, for the hippocampal EEG accompanying sleep. Spectrograms could be classified into three groups. The first group includes the spectrograms, composed of a theta EEG, made during patterns of voluntary behavior (walking, rearing, sniffing objects) and paradoxical sleep. The spectrograms accompanying patterns of automatic behavior (grooming head and body, eating, sniffing air) belong to the second group whereas those made during immobile behavior (sitting, lying, slow wave sleep) form the third group. In using this method the results of Vanderwolf and Whishaw were generally confirmed in that there exists a strong temporal relationship between hippocampal electrical activity and behavior.     

Simultaneous activation of gamma and theta network oscillations in rat hippocampal slice cultures

Hippocampal activity in vivo is characterized by concurrent oscillations at theta (4–15 Hz) and gamma (20–80 Hz) frequencies. Here we show that cholinergic receptor activation (methacholine 10–20 nm) in hippocampal slice cultures induces an oscillatory mode of activity, in which the intrinsic network oscillator (located in the CA3 area) expresses simultaneous theta and gamma network oscillations. Pyramidal cells display synaptic theta oscillations, characterized by cycles consisting of population EPSP-IPSP sequences that are dominated by population IPSPs. These rhythmic IPSPs most probably result from theta-modulated spiking activity of several interneurons. At the same time, the majority of interneurons consistently display synaptic gamma oscillations. These oscillatory cycles consist of fast depolarizing rhythmic events that are likely to reflect excitatory input from CA3 pyramidal cells. Interneurons comprising this functional group were identified morphologically. They include four known types of interneurons (basket, O-LM, bistratified and str. lucidum-specific cells) and one new type of CA3 interneuron (multi-subfield cell). The oscillatory activity of these interneurons is only weakly correlated between neighbouring cells, and in about half of these (44 %) is modulated by depolarizing theta rhythmicity. The overall characteristics of acetylcholine-induced oscillations in slice cultures closely resemble the rhythmicity observed in hippocampal field and single cell recordings in vivo . Both rhythmicities depend on intrinsic synaptic interactions, and are expressed by different cell types. The fact that these oscillations persist in a network lacking extra-hippocampal connections emphasizes the importance of intrinsic mechanisms in determining this form of hippocampal activity.     

Discharge properties of neurons of the median raphe nucleus during hippocampal theta rhythm in the rat

The serotonin (5-HT)-containing median raphe nucleus has been shown to be critically involved in the control of desynchronized (non theta) states of the hippocampal electroencephalogram (EEG). We examined the activity of 181 cells of the median raphe nucleus in the urethane-anesthetized rat and found that approximately 80% (145/181) of them showed changes in activity associated with changes in the hippocampal EEG. These cells were subdivided into theta-on (68%) and theta-off (32%) based on increased or decreased rates of activity with theta, respectively. They were further classified as slow-firing (~1 Hz), moderate-firing (5-11 Hz), or fast-firing (>12 Hz) theta-on or theta-off cells. The slow-firing cells as well as a subset of moderate-firing theta-off cells displayed characteristics of "classic" serotonin-containing raphe neurons. All fast-firing neurons were theta-on cells and showed either tonic or phasic (rhythmical) increases in activity with theta. We propose that: (1) the slow-firing cells (on and off) as well as a subset of moderate-firing theta-off cells are serotonergic neurons; (2) the phasic and tonic fast-firing theta-on cells are GABAergic cells; and (3) these populations of cells mutually interact in the modulation of the hippocampal EEG. An activation of local serotonergic and GABAergic theta-on cells would inhibit 5-HT slow- or moderate-firing theta-off projection cells to release or generate theta, whereas the suppression of serotonergic- or GABAergic theta-on cells would disinhibit 5-HT theta-off cells, resulting in a blockade of theta or a desynchronization of the hippocampal EEG. A role for the median raphe nucleus in memory-associated functions of the hippocampus is discussed.