Abnormal neuronal excitability in hippocampal slices from kindled rats

To determine if electrophysiological properties of hippocampal pathways are altered in kindled rats, extracellular recordings were made from hippocampal slices of rats kindled in the lateral entorhinal cortex and compared with those from implanted but unstimulated controls. Studies were made either 24 h or 28 days after the last kindled seizure and done in normal (3.5 mM) or elevated (7 mM) K+. The preparation of slices, data accumulation, and data analyses were done blind. One day or 28 days after the last kindled seizure, the proportion of slices with spontaneous epileptiform bursts recorded from the CA2/3 region in elevated K+ was significantly (P less than 0.001) increased in the kindled animals. The frequency of spontaneous burst firing was also increased and reached significance (P less than 0.02) at 28 days following the last kindling stimulus. One day after the last kindling stimulus, paired-pulse (GABAergic) inhibition in the CA1 region was decreased (P less than 0.001). Several measures suggested an increased synaptic inhibition in the dentate gyrus of slices from the kindled groups 1 day after kindling. Paired-pulse inhibition was increased (P less than 0.01), the current required to evoke a near-threshold population spike was increased (P less than 0.05), and the population spike amplitude was reduced for a given field excitatory postsynaptic potential (EPSP) (P less than 0.01). Twenty-eight days after the last kindling stimulus, however, paired-pulse inhibition in the dentate was slightly less in slices from kindled rats (P less than 0.005). In other respects the CA1 and dentate regions did not differ between kindled and control groups within 24 h of the last stage V seizure. Thus the maximum amplitudes of presynaptic fiber volley, population spike, and field-excitatory postsynaptic potential (EPSP) slope, and the number of population spikes evoked by a near-maximally effective afferent stimulus, were unchanged. In the CA1 region the input-output curve of field EPSP versus population spike, and the current intensity required to evoke a near-threshold population spike were also unchanged. In addition, no spontaneous bursts were recorded from CA1 in 3.5 mM K+. We conclude that either synapses or neurons intrinsic to the hippocampus are altered by kindling stimuli applied outside this brain area. The transient increase in inhibition in the dentate gyrus suggests that it may reflect a compensatory reaction to kindled seizures. In contrast, the long-lasting (at least 28 days) increase in burst firing in CA2/3 may represent a mechanism for the initiation or propagation of kindled seizures.(ABSTRACT TRUNCATED AT 400 WORDS)     

Firing relations of medial septal neurons to the hippocampal theta rhythm in urethane anesthetized rats

Summary On the basis of spontaneous firing patterns and relations to the hippocampal theta rhythm, three cell types were identified within the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca (MSN-NDB). In addition to the well known rhythmically bursting cells that fired in bursts on each cycle of the hippocampal theta rhythm, two other cell types are distinguished. Clock cells fired at high rates with a very regular, periodic firing pattern that was unrelated to the theta rhythm. Irregular cells fired at much lower rates, especially during theta rhythm, and had a pseudo-random firing pattern. The firing of irregular cells was often significantly phase-locked to the hippocampal theta rhythm. Crude estimates of the relative proportions of these cell types suggest that the rhythmically bursting cells comprise about 75% of the cells of the MSN-NDB. These three cell types bear a remarkable resemblance, in firing patterns and relative proportions, to the three principal cell types of the medial septal nuclei described in the freely moving rat (Ranck 1976). Measurements of the preferred phases of firing of 128 rhythmically bursting septal neurons (including 22 atropine-resistant and 11 atropine-sensitive cells) indicate that there is no single preferred phase of firing for the population. Rather the distribution of phases over the theta cycle is statistically flat. Variations in recording locations cannot account for this distribution since large differences in preferred phase were found for pairs of cells at the same location. Similarly, plotting only the group of cells identified as projection cells by antidromic activation from the fimbria/fornix, failed to reveal a peak in the distribution. In contrast to the rhythmically bursting cells, the distribution of preferred firing phases for the irregular cells with a significant phase-locking to the theta rhythm did have a clear peak. The peak occurred near the dentate theta rhythm positivity, consistent with the hypothesis that they are driven by feedback from CA1 complex-spike cells.     

Behavioral consequences of selective destruction of neuron perikarya in septal area of rats

Iontophoretic application of the neurotoxin kainic acid (KA) to the septal region resulted in significant depletion of neurons in medial septum. The lateral septum was entirely intact (n=7) or affected only unilaterally (n=7) by these injections. Selective destruction of neurons indigenous to the septal area reproduced some but not all of the behavioral effects of septal lesions we investigated. KA injections produced transient hyperdipsia and hyperphagia as well as marked disinhibitory effects on punished licking (passive avoidance) but failed to affect shuttle box avoidance, sucrose or saline preference, or locomotor activity in a novel environment.     

Effects of opioid microinjections into the medial septal area on spatial memory in rats

Recent work has demonstrated that posttraining systemic opioid antagonist administration facilitates the acquisition of a radial arm maze task in new spatial environments. In this study, we examined the effect of posttraining naloxone and beta-endorphin microinjections into the medial septal area on the acquisition of a radial maze task in new spatial environments. The results of these experiments demonstrated that posttraining intraseptal naloxone administration facilitated, whereas posttraining intraseptal beta-endorphin administration impaired, the acquisition of criterion performance on a maze task performed in new spatial environments. Further, intraventricular beta-endorphin administration did not produce effects that were comparable to those observed following intraseptal beta-endorphin administration, which indicates that the septal region is a brain site that is sensitive to the effects of opioids on spatial memory in new environments. Further, posttraining intraseptal beta-endorphin administration had no effect on working memory in a familiar spatial environment, whereas pretraining intraseptal beta-endorphin administration had no effect on the performance of a previously acquired spatial task.     

Sensory evoked neuronal activity in the hippocampus before and after lesions of the medial septal nuclei

The evoked activity of 142 single neurons in the hippocampus of 44 rats was recorded following presentation of one of several modalities of peripheral stimulation. In the intact rat, 41% of the neurons encountered showed some period of inhibition of neuronal firing following peripheral stimulation. In subjects that had received lesions of the medial septal nuclei, only 21% of the cells encountered showed such inhibition. Medial septal lesions were made in 23 animals while recording the activity of cells which exhibited inhibition following stimulation. Of these 23 cells, only 5 continued to exhibit response inhibition after the lesion, while 13 displayed only response excitation, and 5 showed a complete loss of responsiveness. These findings suggest that the integrity of the medial septal nucleus is necessary for the inhibition of neuronal firing observed in many hippocampal neurons following peripheral stimulation.     

Distinct neuronal excitability alterations of medial prefrontal cortex in early‐life neglect model of rats

ObjectEarly‐life neglect has irreversible emotional effects on the central nervous system. In this work, we aimed to elucidate distinct functional neural changes in medial prefrontal cortex (mPFC) of model rats.MethodsMaternal separation with early weaning was used as a rat model of early‐life neglect. The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole‐cell patch clamp.ResultsGlutamatergic and GABAergic neurons of mPFC were distinguished by typical electrophysiological properties. The excitation of mPFC glutamatergic neurons was significantly increased in male groups, while the excitation of mPFC GABAergic neurons was significant in both female and male groups, but mainly in terms of rest membrane potential and amplitude, respectively.ConclusionsGlutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early‐life neglect, which can contribute to distinct mechanisms for emotional and cognitive manifestations.     

Vasoactive intestinal polypeptide modulates neuronal excitability in hippocampal slices of the rat.

Vasoactive intestinal polypeptide added at submicromolar concentrations to the perfusion fluid of rat hippocampal slices and slice cultures enhanced the excitability of CA1 and CA3 pyramidal cells in several ways. Specifically, cells were depolarized and the Ca(2+)- and cyclic AMP-dependent potassium conductance was blocked as demonstrated by reduction of the long-lasting afterhyperpolarization and the accommodation of firing. This was also found in tetrodotoxin-containing medium. In low Ca(2+)-high Mg2+ medium (in synaptic isolation) the firing rate was increased. Synaptic transmission was potentiated: extracellularly registered excitatory postsynaptic potentials and population spikes in response to stratum radiatum stimulation and intracellularly recorded excitatory postsynaptic potential-inhibitory postsynaptic potential sequences were enhanced. These results are in keeping with the known stimulation of adenylate cyclase by vasoactive intestinal polypeptide.     

Paradoxical state-dependent excitability of the medial septal neurons in brain slices of ground squirrel, Citellus undulatus

Spontaneous and evoked neuronal activity of the medial septum-diagonal band complex was investigated extracellularly in slices, taken from the brain of the three groups of animals: hibernating ground squirrels, waking ground squirrels, and guinea-pigs. All slices were incubated at 31-32 degrees C. The slices of the ground squirrels' brain were retested after keeping them for 15-36 h in the refrigerator at 2-4 degrees C. In all experimental groups the majority of the medial septum-diagonal band complex neurons had high regular or rhythmic burst spontaneous activity, which in half of the neuronal population persisted in conditions of synaptic blockade. The low-frequency irregular activity of the surrounding structures (lateral septum, caudate, accumbens, medial preoptic area) was completely suppressed in these conditions. The density of the spontaneously active neurons in the slices, as well as the mean frequency of discharges in the medial septum-diagonal band complex of hibernating ground squirrels, was significantly higher than that in waking ground squirrels and guinea-pigs. Stimulation of the medial forebrain bundle evoked initial suppression of activity in majority of the medial septum-diagonal band complex units; in many of them the suppression was followed by a burst discharge. The neurons with background rhythmic burst activity always responded by resetting the spontaneous bursts. In total, about 50-60% of the medial septum-diagonal band complex neurons of waking ground squirrels and guinea-pigs responded by post inhibitory bursts to the stimulation of medial forebrain bundle, while in hibernating ground squirrels such responses were observed in nearly all neurons. The threshold values of the stimulating current were significantly lower in the hibernating ground squirrels' group, the mean duration of the initial suppression was shorter, the intraburst density of spikes and/or duration of the bursts was increased. Thus, evaluation of spontaneous and evoked activity on the basis of various criteria revealed surprising similarity between the two groups of active animals, while the activity and excitability of the medial septum-diagonal band complex neurons was approximately doubled in the hibernating animals. This difference between active and hibernating ground squirrels was preserved during retesting after deep and prolonged cooling of the slices. The experiments demonstrate paradoxical stable increase of activity and excitability of the medial septum-diagonal band complex neurons in the hibernating ground squirrels.(ABSTRACT TRUNCATED AT 250 WORDS)     

The nicotinic receptor blocker hexamethonium alters neuronal responses to glutamate in the medial septal area of the brain of the ground squirrel in vitro

Despite extensive interest in studies of the medial septal area, the nature of the interactions of its various neurochemical systems remains largely unclear. The aim of the present work was to clarify the role of nicotinic receptors in mediating the interaction of the glutamatergic and cholinergic systems in this structure. Extracellular recording of neuron activity in living slices of ground squirrel brain was used to study the influences of L-glutamate (1 μM) during application of the nicotinic receptor blocker hexamethonium (1 mM). The responses of septal neurons to glutamate depended on the type of their initial activity and the presence of pacemaker properties. This study is the first to show that glutamate increases the frequency of volleys in rhythmic neurons in the septum. Hexamethonium induced changes in neuron activity similar to the influences of glutamate. After prior application of hexamethonium, the responses of neurons to glutamate changed: activatory responses were masked and inhibitory responses were enhanced. Cholinergic modulation of the responses of septal neurons to glutamate were shown to occur, as did modulation of the strength of the oscillatory properties of the septal network by nicotinic receptors. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 57, No. 2, pp. 191–204, March–April, 2007.     

Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning

Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging.     

Assessment of the septal area neuronal activity during penile erections in rapid eye movement sleep and waking in the rats

To understand the central mechanism of penile erections during rapid eye movement (REM) sleep and waking, single units were recorded from the septal area in un-anesthetized head-restrained rats simultaneous with erections. Erectile events were assessed by pressure in the bulb of the corpus spongiosum of the penis and bulbospongiosus-muscle activity. Of 143 recorded neurons, 36% showed increased activity (E-type) and 24% decreased activity (I-type) during different phases of erection in REM sleep, while 10% were E-type and 35% were I-type during erections in waking. Most E-type neurons were recorded from the dorsal and intermediate part of lateral septum, whereas I-type neurons were from the medial septum. The findings illustrate the extensive network of various types of neurons in the septal area that fire in concert in relation to erection during REM sleep and waking. This study provides a unique prospective of the septal area for perpetuation of erectile circuitry during sleep.     

State-dependent effects of some neuropeptides and neurotransmitters on neuronal activity of the medial septal area in brain slices of the ground squirrel, Citellus undulatus

Neuronal activity of the medial septal area was recorded extracellularly in brain slices taken from hibernating (winter) and waking (summer) ground squirrels. The effects of neuropeptides identified in the brain tissue of hibernators (Thr-Ser-Lys-Tyr, Thr-Ser-Lys-Tyr-Arg and Asp-Tyr) on the background activity and responses to electrical stimulation of the median forebrain bundle were analysed. For comparison, the effects of bath application of noradrenaline and serotonin were also tested. Spontaneous activity in half of all neurons (47-56%) was changed under the influence of neuropeptides in hibernating ground squirrels, while in waking ground squirrels the proportion of responsive neurons was significantly lower (25-30%). The tendency for higher efficacy in hibernating ground squirrels was observed for serotonin; only noradrenaline was equally effective in both groups of animals. Electrically evoked responses of the medial septal nucleus-nucleus of the diagonal band neurons were also strongly modulated by neuropeptides; their changes could occur in the absence of shifts in the level and pattern of spontaneous activity. All three neuropeptides had differential action on the level of spontaneous activity, as well as on inhibitory and excitatory components of electrically evoked responses. Thus, the character and distribution of the effects were state dependent and differed greatly in hibernating and waking ground squirrels. The experiments confirmed that medial septal nucleus-nucleus of the diagonal band neurons have higher excitability and responsiveness to some neuropeptides and neurotransmitters in hibernating ground squirrels.The data obtained suggest an increased latent excitability and responsiveness of septal neurons during hibernation and their possible active participation in urgent arousal under the influence of sensory signals.     

Effect of physiologically active substances isolated from the thymus on wound healing after cryosurgical destruction in rats

Experiments were carried out on 40 male albino rats after whole-body irradiation in a dose of 200 R to study the effect of thymarin, a preparation obtained from bovine thymus and consisting of a combination of three fractions of physiologically active polypeptides with a mean molecular weight of about 10,000 on the course of local wound healing after cryosurgical destruction of the mucous membrane of the hard palate. Thymarin was injected subcutaneously daily for 10 days after cryosurgical destruction. The experimental results reveal a beneficial effect of thymarin on the course of regeneration and, in particular, more rapid sloughing of necrotic tissues, a shortening of the period of epithelization of the wound surface, and prevention of the development of secondary infection.Department of Surgical Stomatology, I. P. Pavlov First Leningrad Medical Institute, S. I. Vavilov State Optical Institute, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR A. I. Rybakov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 9, pp. 355–358, September, 1977.     

Interaction between the lateral hypothalamic area (LHA) and the medial septal area (MSA) in the control of sodium and potassium excretion in rats

In studies of the role of the hypothalamus in regulating body ionic balances it was found that carbachol injected into the lateral hypothalamic area (LHA) and medial septal area (MSA) elicited an increase in natriuresis and kaliuresis. This efflux reached its peak between 40 and 60 minutes after such injections. A blockage of this response was observed when LHA stimulation by carbachol was performed in animals whose MSA had been blocked previously by atropine or destroyed by electrolytic lesion. Similarly, stimulation of the MSA after pharmacological blockade or destruction of the LHA elicited a response of greatly decreased intensity. On the basis of these results it was concluded that the natriuretic-kaliuretic response elicited by cholinergic stimulation of the LHA depends in part on synapses located in MSA; the response elicited by cholinergic stimulation of the MSA utilized also synapses located in the LHA, unilaterally and bilaterally.     

A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations

The medial septum-vertical limb of the diagonal band of Broca (MSvDB) is important for normal hippocampal functions and theta oscillations. Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing <4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15～30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these "pro-arousal" neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation.     

GABA release in the medial preoptic area of cyclic female rats

GABA is a potent regulator of gonadotropin-releasing hormone neurons in the hypothalamus. To determine the profile of GABA release in the medial preoptic area where the gonadotropin surge generator resides, an in vivo microdialysis study was performed in cyclic female rats. The microdialysis samples were collected and sequential blood samples (150 microl each) were also obtained, at 1-h intervals. During estrus and diestrus 1, GABA release in the medial preoptic area was relatively low. A small increase in the GABA release began in the afternoon of diestrus 1 and attained its peak in the morning of diestrus 2, but declined in the afternoon of that day. The GABA release markedly increased from late in the night of diestrus 2 through the morning of proestrus, when it attained its peak, and thereafter it declined sharply until the critical period of proestrus. A distinct preovulatory luteinizing hormone surge was observed in the afternoon of proestrus in all proestrous rats. From these results we suggest that the preovulatory elevation of the GABA release from the night through to the morning of proestrus, followed by a sharp decline, is closely associated with the onset of the preovulatory luteinizing hormone surge in cyclic female rats. The present study is the first to report the 4-day profile of GABA release in the medial preoptic area during the estrous cycle.     

Open-field social behavior of rats following lateral or medial septal lesions

Long-Evans hooded rats were selected at random and assigned to one of six groups. Animals in each group were rated on an emotionality scale and observed in pairs on 10 successive preoperative days and 14 successive postoperative days in an open field. Total number of contacts, length of contact time, and number of aggressive or submissive behaviors which occurred in a 15 min observation period were recorded daily. Following surgery animals with lateral septal lesions displayed hyperemotionality which decreased after handling. The emotionality of the animals with medial septal or cingulate cortex lesions did not change postoperatively. Medial septal lesions resulted in a postoperative increase in contact time, a decrease in number of discrete contacts, and a higher frequency of submissive behaviors. Lateral septal lesions had little effect upon contact time or number of contacts but increased aggressive encounters slightly. Cingulate cortex lesions did not affect open-field social behavior. Changes observed in social behavior were related to changes in both an animal's tendency to emit behaviors and its tendency to react to behavior emitted by its partner.     

Influence of medial preoptic-anterior hypothalamic area stimulation of the excitability of mediobasal hypothalamic neurones in the rat.

1. Extracellular action potentials recorded from 798 neurones in the mediobasal hypothalamus (MBH) of pentobarbitone anaesthetized male rats were analysed for a change in excitability following stimulation in the medial preoptic and anterior hypothalamic areas. 2. An increase in excitability characteristic of orthodromic excitation was observed from 11-5% (n=92) of MBH neurones. Latencies for excitation were shorter for cells tested with anterior hypothalamic area stimulation (n=42; mean 5-4 +/- 2-6 msec S.D.) than for cells tested with medial preoptic stimulation (n=50; mean 15-2 +/- 7-2 msec S.D.). With spontaneously active neurones, excitation was followed by a decrease in excitability lasting 150-250 msec. An initial decrease in excitability, suggestive of post-synaptic inhibition, over a wide latency range (4-30 msec) and with duration of 100-400 msec was observed from 3-6% of MBH neurones. 3. Features of antidromic invasion were observed from 149 MBH neurones. From the medial preoptic area, the latency range was 0-5-38 msec (mean 7-8 +/- 5-5); from the anterior hypothalamic area the latency range was 0-4-9-5 msec (mean 3-1 +/- 2-3). Occasionally an abrupt decrease in latency followed an increase in stimulus intensity. Most cells followed paired stimuli at frequencies up to 500 Hz. Axon conduction velocities were estimated to be under 2-0 m/sec. Antidromic invasion was usually followed by a decrease in excitability lasting approximately 100-150 msec. 4. Twenty MBH neurons displayed antidromic invasion from both the medial preoptic or anterio hypothalamic areas and one other stimulation site: the median eminence (five cells); the amygdala (six cells); the region of thalamic nucleus medialis dorsalis (three cells) and the midbrain periaqueductal gray (six cells). Interaction studies indicated that the axons of these cells branched close to the origin of the axon itself. 5. Antidromic invasion from the surface of the median eminence identified thirty-nine tuberoinfundibular neurones. Stimulation in the medial preoptic and anterior hypothalamic area produced orthodromic excitatory (n = 5) and inhibitory (n = 4) actions on HVM neurones, but was without an action on most other neurones (n = 30). Tuberoinfundibular neurones in the ventromedial nucleus also responded to stimulation in the amygdala, but usually at latencies greater than that for medial preoptic area evoked responses. 6. These observations indicate a close relationship between MBH neurones and cells located in both the amygdala and the medial preoptic-anterior hypothalamic area. The data for tuberoinfundibular neurones indicates that several extrahypothalamic areas may send fibres to these cells. These pathways may be important for the adaptive neuroendocrine responses reported in the literature.