Modulation of the reaction of hippocampal neurons to sensory stimuli by cholinergic substances.

The influences of increasing endogenous acetylcholine (eserine) and its blockade (scopolamine) on the effects of sensory stimuli were analyzed through the extracellular recording of the activity of individual hippocampal neurons of awake rabbits. An increase in the level of acetylcholine, accompanied by the appearance of stable theta rhythm, leads to a substantial decrease in the reactivity of neurons, the suppression, attenuation, and inversion of the majority of inhibitory reactions and of a substantial proportion of activational reactions including on-responses of a specific type. At the same time, a limited group of activational reactions is intensified and extended against the background of eserine. Scopolamine, which blocks theta rhythm, does not change or intensifies inhibitory and some activational reactions, including on-responses. Tonic reactions are shortened; however, their gradual extinction disappears. The effects described are preserved in the hippocampus in the presence of basal undercutting of the septum which eliminates ascending brainstem pathways. These data make it possible to draw the conclusion that, under normal conditions, a new (significant) sensory stimulus elicits in the hippocampus an initial stoppage (reset) of activity with the coordinated triggering of theta rhythm and the passage against this background of signals along the cortical input in a specific phase relationship to it. The period of theta modulation switched on by the signal fosters its recording and the limitation of the passage of subsequent, interfering signals. The septohippocampal influences may thus support the mechanism of selective attention, as a necessary precondition for memory.

Modulation of the influences of cortical input on hippocampal neurons by cholinergic substances.

The cholinergic modulation of responses of individual neurons and of the focal potentials of the hippocampus, induced by electrical stimulation of the perforant path or mossy fibers were studied in two groups of unanesthetized rabbits, one with an intact septal region (IS), and one with its basal undercutting (BU). In all of the animals the responses to stimulation were blocked or markedly suppressed in a substantial portion of the neurons (50% in IS, 69% in BU) against the background of the administration of eserine. Facilitation of the responses was observed in 10 and 8% of cases, respectively. Scopolamine restored the initial reactivity of hippocampal neurons and intensified responses to stimulation of the perforant path. The effect of eserine was reproduced by stimulation of the medial septal region (MS-DB). The depressive effect of stimulation of the MS-DB was intensified by the administration of eserine and blocked by scopolamine. Brief conditioning stimulation of the MS-DB which imitates a theta salvo facilitated responses to test stimulation of the MS-DB with delays of 70-150 msec, but suppressed them at smaller and greater intervals. Focal potentials in response to stimulation of the perforant path in CA1 were suppressed to an equal extent (by 43%) during sensory stimulation inducing natural theta rhythm, during the action of eserine, and with stimulation of the MS-DB In the BU group, these effects led to the complete suppression of focal potentials; scopolamine restored them. It is hypothesized that the principal function of the septohippocampal cholinergic input resided in the negative filtration of signals arriving against the background of theta rhythm that has been turned on by another, preceding influence, as a result of which their interference with the processing and recording of received information is prevented.

Modulation of septal influences on hippocampal neurons by cholinergic substances.

The effects of electrical stimulation of the medial septal area (MS-DB) for the purpose of distinguishing and assessing the cholinergic component of the septohippocampal input were investigated in awake rabbits in chronic experiments. Initial inhibitory effects of a standard duration of 40-140 msec (54%) predominated in the intact rabbits. In animals with chronic basal undercutting of the MS-DB, initial inhibitory reactions predominated absolutely (90%). An increase in the level of endogenous acetylcholine by administration of eserine led to a partial or complete suppression of all effects of stimulation in 78% of the hippocampal neurons of the intact rabbits against the background of intensification of the theta modulation of the activity of hippocampal neurons. Scopolamine removed theta modulation and restored the reactivity of neurons to stimulation of the MS-DB. These influences of cholinergic substances were maintained in the animals with basal undercutting of the MS-DB. It is inferred that the general initial influence of septal input on neurons of the hippocampus is expressed in the suppression of their activity ("reset"), which depends on the noncholinergic (GABAergic) component of the septohippocampal connections. The cholinergic component limits the effectiveness of both extraseptal (brainstem) and primary inhibitory septal influences on hippocampal neurons.

Integration of hippocampal suspension grafts with host neocortex.

The possibility of histological and functional integration of nervous tissue heterotopically grafted into the adult host brain was investigated. Suspensions of embryonic (E17-18) rat hippocampus with dentate fascia were placed into acute cavities in the barrel field of young adult rats (n = 25). Golgi-Cox silver impregnation and Cresyl Violet stain were used for histological analysis 3-4 months postgrafting. The surviving grafts were present in 80% of the grafted animals. Only three out of 20 surviving grafts were completely isolated from the surrounding host brain; other grafts had areas of direct confluence with the host neuropil. Extracellular recording of neuronal activity revealed normal spontaneous activity typical of the hippocampus in the majority of the grafts. Electrical stimulation of the posterior nucleus of the thalamus, homolateral motor neocortex, contralateral barrel field, and sensory stimulation of the host evoked responses in 50-60% of the grafted neurons. This did not differ significantly from the responsiveness of the similarly tested neurons of homotopic neocortical suspension grafts. The latencies of the responses in the hippocampal grafts were consistently longer (by about 10 ms) than in the neocortical ones. Comparison of the hippocampal suspension grafts with other types of hippocampal and neocortical grafts suggests that under certain conditions heterotopic tissue can be successfully integrated into the host brain. Development of the host-graft interconnections depends on topical proximity, the presence of denervated synaptic loci in both tissues, elimination of the intragraft neuronal targets and disruption of the intrinsic connections between them.

[The modulation by cholinergic substances of the neuronal reaction of the hippocampus to sensory stimuli]. / Moduliatsiia kholinergicheskimi veshchestvami reaktsii neironov gippokampa na sensornye razdrazhiteli.

Neuronal activity was recorded extracellularly in the hippocampus of waking rabbits. Modifications of the effects of sensory stimulation were analysed on the background of increased level of endogenous acetylcholine (injection of physostigmine) and during its blocking by scopolamine. Significant decrease of responsiveness (about 40%) of the hippocampal neurons to sensory stimuli occurred after physostigmine injection. Suppression, decrease and reversal of the inhibitory responses (including initial reset phase) and of some excitatory reactions, including on-effects was observed on the background of stable theta-rhythm. However, a limited group of excitatory responses was augmented and prolonged by physostigmine. Under scopolamine action the responsiveness of the neurons was not changed. Some of the inhibitory and excitatory effects, especially on-responses were augmented. Tonic responses became shorter, but they were stably reproduced without the typical gradual habituation. All the effects were also present in the hippocampus after the basal septal undercutting eliminating ascending brainstem input. It is suggested that under the normal conditions a new or significant sensory stimulus evokes in the hippocampus initial inhibitory reset of neuronal activity with the following coordinated triggering of theta-rhythm and arrival of the cortical input signal phase-locked to it. During the period of theta triggered by a stimulus its processing and fixation in the memory occurs, while the other, interfering stimuli are actively filtered out. Thus, the septo-hippocampal interactions provide for mechanisms of selective attention as a necessary condition of memory trace formation.

[The modulation by cholinergic substances of the influences of cortical input on hippocampal neurons]. / Moduliatsiia kholinergicheskimi veshchestvami vliianii kortikal'nogo vkhoda na neirony gippokampa.

Cholinergic modulation of the single-cell responses and field potentials evoked in the hippocampus by electrical stimulation of its cortical input was investigated in two groups of chronic anaesthetized rabbits--with the intact septum (IS) and basally undercut (BS). In both groups of animals responses to stimulation of the perforant path (PP) or mossy fibers were blocked or significantly suppressed in substantial proportion of the neurons (50% in IS, 69% in BS) by i.v. physostigmine injection; facilitation of responses was observed in minor groups of the neurons (10% and 8%). Scopolamine restored initial responsiveness of the hippocampal neurons and augmented responses to stimulation in some of them (37.5% in IS, 65% in BS). Effect of physostigmine was reproduced by single stimuli applied to the MS--DB. Field potentials evoked by PP stimulation in CA of IS group were equally suppressed (by 43%) by the sensory stimulation evoking natural theta, by physostigmine and MS--DB stimulation. In BS group of animals these influences completely suppressed the focal potentials to PP stimulation. Scopolamine restored the focal potentials. It is concluded that the main function of the septo-hippocampal cholinergic input consists in filtering out the signals appearing at the background of the theta-rhythm triggered by a previous signal thus preventing their interference with its processing and recording.

[The modulation of septal influences on the hippocampal neurons by cholinergic substances]. / Moduliatsiia septal'nykh vliianii na neirony gippokampa kholinergicheskimi veshchestvami.

To evaluate the functional significance of the cholinergic component of the septo-hippocampal input the effects of electrical stimulation of the medial septal area (MS--DB) on the hippocampal neurons were studied in chronic waking rabbits. Initial inhibitory effects 40-140 msec long were observed in 54% of neurons in intact rabbits. Other neurons usually responded by a diffuse excitation. Initial inhibitory effects absolutely dominated (90%) in the animals with the septum basally undercut. Increase of the endogenous acetylcholine level by physostigmine completely or partially blocked the effects of the stimulation in 78% of the hippocampal neurons at the background of increased theta-modulation. Scopolamine restored responsiveness of the neurons to the MS--DB stimulation. These effects were preserved in the animals with the septal undercutting. It is concluded that the general effect of the MS--DB on the hippocampal neurons consists in a non--cholinergic (GABA-ergic) primary suppression (reset) of their activity. The cholinergic component limits the efficacy of both extraseptal (brainstem) and septal inhibitory influences.

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 high-frequency (> 25 spikes/sec) and an increase in the low-frequency (< 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.

Neuronal activity in suspension transplants of the neocortex.

The characteristics of suspension (ST) and tissue (TT) transplants of the embryonal neocortex, transplanted into adult rats into the neocortical region of the representation of the vibrissae, were compared. The degree of taking of the ST and the TT did not differ significantly (89.5 and 95%, respectively). Transplants completely isolated from the brain were not found in the ST on the basis of histological and electrophysiological indices. The reactivity of ST neurons during electrical stimulation of the brain structures of the recipient and sensory stimulation, like the latent periods of the on-responses, did not differ significantly in the ST and the TT; however, the per cent of neurons responding with on-responses, was nearly twice as low in the ST as in the TT. At the same time, there were substantially more neurons in the ST responding to tactile stimulation with inhibition of discharges. It is hypothesized that the disruption in the primary cytoarchitectonics of the ST which takes place inevitably in the preparation of the suspensions is a cause of the differences indicated between the ST and the TT.

Theta modulation of neurons of the hippocampus of the rabbit and its interrelationship with other parameters of spontaneous and evoked activity.

The reliability of the existing functional criteria of the differentiation of pyramidal ("neurons with complex spikes") and inhibitory ("theta neurons") cells of the hippocampus is examined on the basis of a statistical analysis of the spontaneous and evoked activity of neurons of the hippocampus of the awake rabbit. The analysis shows that the parameters of average frequency, the presence of theta modulation of activity, the behavior of the neurons in situations evoking theta rhythm in the EEG of the hippocampus (inhibition or activation during the effect of sensory stimuli), and the character of the influences of stimulation of the medial septal region of the internal connections of the hippocampus do not permit the reliable identification of different types of neurons of the hippocampus in the awake rabbit. The available data on the functional classification of neurons of the hippocampus are discussed in connection with notions regarding their state in situations associated with the generation of theta rhythm.

Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit--I. Spontaneous activity.

The background activity of hippocampal neurons was recorded extracellularly in waking rabbits in the control state and after systemic injections of physostigmine and scopolamine. Similar analysis was done in the hippocampus chronically deprived of ascending brainstem afferents. Cholinergic drugs control the number of hippocampal neurons with theta modulation and stability, but not the frequency of theta modulation. Increase of endogenous acetylcholine also resulted in regularization of the activity with suppression of delta modulation and complex spike discharges; its blockade produced the opposite changes. Both drugs changed the level of background activity in the majority of the neurons, but the overall mean frequency did not vary between the states. Regression analysis demonstrated significant negative correlations with dominating decrease in the level of discharges in high-frequency neurons (> 25 spikes/s) and its increase in low-frequency ones (< 25 spikes/s) after injection of both drugs. Stability of the overall mean frequency and uniformity of its shifts during both stimulation and suppression of the cholinergic component of theta-rhythm presumably indicate that the frequency of background activity, unlike its pattern, is not directly controlled by the cholinergic septal input.

Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit--II. Septal input.

The aim of this paper was to evaluate the cholinergic component of the septohippocampal input signals in neuronal activity of the hippocampal fields CA1 and CA3 recorded extracellularly in chronic alert rabbits. Effects of electrical stimulation of the medial septal area were analysed in the control state, on the background of an increased level of endogenous acetylcholine (by physostigmine injection) and during its blockade by antimuscarinic drugs (scopolamine, atropine). Two groups of animals were used in the experiments: intact rabbits and rabbits with complete chronic undercutting of the septum, depriving the septohippocampal system of ascending medial forebrain bundle afferents. Primary inhibitory effects of standard duration (40-140 ms) evoked by medial septal area stimulation dominated in the hippocampus of intact rabbits (54%), though some neurons responded by initial diffuse excitation (37.5%); responses by single-spike on-effects were observed in a minority of neurons (8.5%). The primary suppression of activity prevailed (90%) in animals with basal undercutting of the septum. In intact rabbits under physostigmine action, the effects of medial septal area stimulation were depressed or completely blocked in 78% of hippocampal neurons on the background of increased theta modulation of activity. Neuronal responses to medial septal area stimulation recovered at the background of muscarinic antagonists. These effects of cholinergic drugs were reproduced in animals without medial forebrain bundle. It is concluded that the initial effect of the septal input upon the hippocampal neurons consists of a general suppression of their activity (reset), depending upon a non-cholinergic (presumably GABAergic) component of the septohippocampal connections.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit--III. Cortical input.

Cholinergic modulation of single cell responses and field potentials evoked in the hippocampus by electrical stimulation of the perforant path and mossy fibres was investigated in two groups of chronic unanesthetized rabbits--with intact hippocampus and with basally undercut septum (without ascending medial forebrain bundle afferents). In both groups of animals responses to stimulation were blocked or significantly depressed by i.v. physostigmine injection in many neurons (50% in the intact hippocampus and 69% in the hippocampus without medial forebrain bundle). In minor groups of neurons (10 and 8%, respectively), facilitation of responses was observed. Scopolamine restored initial responsiveness of hippocampal neurons and augmented effects of stimulation in some of them. The effect of physostigmine was reproduced by stimulation of the medial septum. Depressive influence of medial septal area stimulation was increased by physostigmine and blocked by scopolamine. Population spikes evoked by stimulation of the perforant path of the intact group were equally suppressed (by 43%) during sensory stimulation evoking natural theta, after physostigmine and after medial septal area stimulation. In the group of animals without medial forebrain bundle these influences resulted in a complete suppression of field potentials; scopolamine restored them. It is concluded that the main function of the septohippocampal cholinergic input consists of filtering out the signals appearing at the background of theta-rhythm triggered by a previous signal, thus preventing their interference with its processing and registration.

Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit--IV. Sensory stimulation.

Modifications of responses of hippocampal neurons to sensory stimuli at the background of increased endogenous acetylcholine level (injection of physostigmine) and during blocking by scopolamine were analysed in the chronic alert rabbit. A significant decrease of reactivity (about 40%) of hippocampal neurons to sensory stimuli occurred after physostigmine injection, inducing stable theta modulation. Suppression and decrease of inhibitory responses (including initial reset phase) and of some excitatory reactions (including on-effects) were observed. However, a limited group of excitatory responses was augmented and prolonged under physostigmine action. Scopolamine, which blocked electroencephalogram theta-rhythm, did not change the responsiveness of hippocampal neurons. Some of the inhibitory and excitatory effects of sensory stimuli, especially on-responses, were strongly facilitated. Tonic responses were shorter, but they were stably reproduced without typical gradual habituation. All these effects were also present in the hippocampus after basal undercutting of the septum, which eliminates ascending brainstem input. It is suggested that under normal conditions a new or significant sensory stimulus evokes, in the hippocampus, an initial inhibitory reset of neuronal activity with subsequent coordinated triggering of rhythmic theta modulation by the septal input and arrival of the cortical input signal phase-locked to it. During the period of theta triggered by the stimulus, its processing and fixation in memory occurs, while the other, interfering stimuli, which are not phase-locked to the ongoing theta activity, are actively filtered out. Thus, septohippocampal interactions may participate in the organization of selective attention as a necessary condition for memory trace formation.

[The spontaneous neuronal activity of the hippocampus during the modulation of the theta rhythm by cholinergic substances]. / Spontannaia aktivnost' neironov gippokampa pri moduliatsii teta-ritma kholinergicheskimi veshchestvami.

Background activity of the hippocampal neurons, extracellularly recorded in waking chronic rabbits, was analysed in control state and after systemic injection of physostigmine and scopolamine. Similar analysis was done in the hippocampus chronically deprived of ascending brain stem afferents. Cholinergic drugs controlled the number of hippocampal neurons with theta-modulation and the degree of its stability but not the frequency. Activation of cholinergic theta-rhythm resulted also in regularization of activity with suppression of delta-modulation and complex spike discharges; its blockade was accompanied by the opposite changes. Both drugs shifted the level of background activity in the majority of neurons, but the overall mean frequency did not vary between the states. Regression analysis demonstrated significant negative correlations with dominating decrease in the level of activity in high-frequency neurons ( > 25 sp/s) and its increase in low-frequency ones ( < 25 sp/s) after injection of both drugs. Stability of the overall mean frequency and uniformity of its shifts presumably indicate that the frequency, unlike the pattern of the background activity, is not directly controlled by the cholinergic septal input.

[The neuronal activity of suspension grafts of the neocortex]. / Neironnaia aktivnost' v suspenzionnykh transplantatakh neokorteksa.

Were compared electrophysiological characteristics of suspension (SUS) and solid (SOL) tissue grafts of embryonic neocortex transplanted into the barrel field of adult rats. The level of survival of SUS and SOL grafts did not differ significantly (89% and 95% correspondingly). All SUS grafts were integrated with the host brain judging by histological and electrophysiological criteria. Reactivity of neurons to electrical stimulation of the recipient's brain and to sensory (tactile) stimulation, as well as the latencies of on-responses were similar in both types of the grafts. However, proportion of neurons with on-responses was nearly twice lower in SUS grafts, while the number of neurons responding to tactile stimulation by primary suppression of activity was significantly higher than in SOL ones. It is suggested that the derangement of primary architectonics unavoidable during preparation of suspensions is responsible for the described differences between SUS and SOL grafts.

[The theta modulation of rabbit hippocampal neurons and its correlation with other indices of spontaneous and evoked activity]. / Teta-moduliatsiia neironov gippokampa krolika i ee sootnoshenie s drugimi pokazateliami spontannoi i vyzvannoi aktivnosti.

Reliability of the existing functional criteria for differentiation of pyramidal ("complex spike neurones") and inhibitory ("theta neurones") cells in the hippocampus of waking rabbit is evaluated on the basis of statistical analysis of neuronal spontaneous and evoked activity. The analysis shows, that the criteria of mean frequency, presence of theta modulation, neuronal behaviour in situations provoking EEG theta rhythm (e.g., excitation or inhibition during presentation of sensory stimuli), effects of medial septum and intrahippocampal stimulation do not permit reliable identification of the hippocampal neuronal types in the waking rabbit. The data on functional classification of the hippocampal neurones are discussed in connection with existing suggestions about their state in situations inducing theta rhythm generation.

Sensory deprivation prevents integration of neocortical grafts with the host brain.

The histological and electrophysiological properties of embryonic neocortical grafts transplanted into the barrel field of adult rats were compared between the side receiving normal vibrissae input vs. chronic deprivation of input produced by clipping of the recipients vibrissae. Each animal received ablation of the neocortex and transplantation of neocortical tissue bilaterally. Vibrissae were clipped unilaterally immediately after surgery and were trimmed for up to 4 months. Significant differences were found between volume of the grafts as well as the number of grafts showing contact with the wall of the lesion cavity, indicating that the tissue growth was directly influenced by sensory deprivation. Decrements in functional integration with the host brain measured electrophysiologically were also observed.

[Effect of electric stimulation of the septum of the rabbit brain on subiculum cells with different types of spontaneous activity]. / Vliianie élektricheskoi stimuliatsii septuma mozga krolika na kletki subikuluma s razlichnymi vidami fonovoi aktivnosti.

Neuronal activity was recorded extracellularly in subiculum of unanaesthetized rabbits during stimulation of the medial septal nucleus and hippocampal field CA1. According to the pattern of the background activity subicular cells were divided into three groups: cells with theta-modulation, cells with delta-modulation and complex spikes, cells with irregular single-spike activity. The theta-cells were specifically related to the septal input: their reactivity to septal stimulation was higher and the latencies of their responses significantly shorter than those of the other groups of cells. Stability of the theta-modulation was increased during and after septal stimulation. Reactivity to CA1 stimulation, as well as latencies of responses were identical for all groups of subicular cells. Rhythmic theta-modulation was damped after CA1 stimulation. The data indicate specific properties of the septal input to the subicular cells with theta-modulation.