AGN as potential factories for eccentric black hole mergers.

There is some weak evidence that the black hole merger named GW190521 had a non-zero eccentricity1,2. In addition, the masses of the component black holes exceeded the limit predicted by stellar evolution3. The large masses can be explained by successive mergers4,5, which may be efficient in gas disks surrounding active galactic nuclei, but it is difficult to maintain an eccentric orbit all the way to the merger, as basic physics would argue for circularization6. Here we show that active galactic nuclei disk environments can lead to an excess of eccentric mergers, if the interactions between single and binary black holes are frequent5 and occur with mutual inclinations of less than a few degrees. We further illustrate that this eccentric population has a different distribution of the inclination between the spin vectors of the black holes and their orbital angular momentum at merger7, referred to as the spin-orbit tilt, compared with the remaining circular mergers.

Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus.

Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism.

Hierarchical Black Hole Mergers in Active Galactic Nuclei.

The origins of the stellar-mass black hole mergers discovered by LIGO/Virgo are still unknown. Here we show that if migration traps develop in the accretion disks of active galactic nuclei (AGNs) and promote the mergers of their captive black holes, the majority of black holes within disks will undergo hierarchical mergers-with one of the black holes being the remnant of a previous merger. 40% of AGN-assisted mergers detected by LIGO/Virgo will include a black hole with mass ≳50M_{⊙}, the mass limit from stellar core collapse. Hierarchical mergers at traps in AGNs will exhibit black hole spins (anti)aligned with the binary's orbital axis, a distinct property from other hierarchical channels. Our results suggest, although not definitively (with odds ratio of ∼1), that LIGO's heaviest merger so far, GW170729, could have originated from this channel.

Theta-rhythmic drive between medial septum and hippocampus in slow-wave sleep and microarousal: a Granger causality analysis.

Medial septum (MS) plays a critical role in controlling the electrical activity of the hippocampus (HIPP). In particular, theta-rhythmic burst firing of MS neurons is thought to drive lasting HIPP theta oscillations in rats during waking motor activity and REM sleep. Less is known about MS-HIPP interactions in nontheta states such as non-REM sleep, in which HIPP theta oscillations are absent but theta-rhythmic burst firing in subsets of MS neurons is preserved. The present study used Granger causality (GC) to examine the interaction patterns between MS and HIPP in slow-wave sleep (SWS, a nontheta state) and during its short interruptions called microarousals (a transient theta state). We found that during SWS, while GC revealed a unidirectional MS→HIPP influence over a wide frequency band (2-12 Hz, maximum: ∼8 Hz), there was no theta peak in the hippocampal power spectra, indicating a lack of theta activity in HIPP. In contrast, during microarousals, theta peaks were seen in both MS and HIPP power spectra and were accompanied by bidirectional GC with MS→HIPP and HIPP→MS theta drives being of equal magnitude. Thus GC in a nontheta state (SWS) vs. a theta state (microarousal) primarily differed in the level of HIPP→MS. The present findings suggest a modification of our understanding of the role of MS as the theta generator in two regards. First, a MS→HIPP theta drive does not necessarily induce theta field oscillations in the hippocampus, as found in SWS. Second, HIPP theta oscillations entail bidirectional theta-rhythmic interactions between MS and HIPP.

Fitness cost associated with resistance to fluoroquinolones is diverse across clones of Klebsiella pneumoniae and may select for CTX-M-15 type extended-spectrum ß-lactamase.

Lowered fitness cost associated with resistance to fluoroquinolones was recently demonstrated to influence the clonal dynamics of methicillin-resistant Staphylococcus aureus (MRSA) in the health care setting. We investigated whether or not a similar mechanism impacts Klebsiella pneumoniae. The fitness of K. pneumoniae isolates from major international hospital clones (ST11, ST15, ST147) already showing high-level resistance to fluoroquinolones and of strains from three minor clones (ST25, ST274, ST1028) in which fluoroquinolone resistance was induced in vitro was tested in a propagation assay. Strains from major clones showed significantly less fitness cost than three of four fluoroquinolone-resistant derivatives of minor clone isolates. In addition, plasmids with CTX-M-15 type extended-spectrum ß-lactamase (ESBL) genes were all retained in both major and minor clone isolates, irrespective of the strains' level of fluoroquinolone resistance, while each plasmid harboring SHV-type ESBLs had been lost during the induction of resistance. Major clone K. pneumoniae strains harbored more amino acid substitutions in the quinolone resistance determining regions (QRDRs) of the gyrA and parC genes than minor clone isolates. The presence of an active efflux system could be demonstrated in all fluoroquinolone-resistant derivatives of originally SHV-producing minor clone isolates but not in any CTX-M-15-producing strain. Further investigations are needed to expand and confirm our findings on a larger sample. In addition, a long-term observation of our ciprofloxacin-resistant minor clone isolates is required in order to elucidate whether or not they are capable of restoring their fitness while concomitantly retaining high minimum inhibitory concentration (MIC) values.

Modulation of hippocampal theta oscillation by histamine H3 receptors.

Preclinical findings demonstrate procognitive actions of histamine 3 (H3) receptor antagonists/inverse agonists. Since a prominent role of neuronal network oscillations of the hippocampus, such as theta band oscillation, has been recognized in numerous cognitive functions, in the present study, the potential involvement of H3 receptors in modulation of hippocampal theta activity has been investigated using various recording paradigms. Systemic administration of the selective H3 receptor antagonists/inverse agonists, thioperamide and ciproxifan (0.1 mg/kg to 1 mg/kg i.v.), dose dependently increased hippocampal theta power, similarly to methylphenidate (0.1-1 mg/kg i.v.), in chloral hydrate anesthetized rats. When hippocampal theta oscillation was elicited by electrical brainstem (nucleus pontis oralis) stimulation, ciproxifan (1 mg/kg i.v.) augmented the power of stimulation-induced theta. In contrast, systemic administration of methylphenidate (1 mg/kg i.v.) did not modify elicited theta. To analyze the role of H3 receptors on stage- and behavior-dependent hippocampal theta activity, polysomnographic recordings were carried out together with field potential recordings at the hippocampal fissure in freely moving rats for 8 h during the light phase of the circadian cycle. Systemic administration of ciproxifan (3.0 mg/kg, i.p.) promoted wakefulness with a concomitant reduction in cortical delta power and augmented novelty-induced hippocampal theta activity. These findings provide evidence that H3 receptors play an important role in regulation of hippocampal theta oscillation, representing one of the probable mechanisms involved in histamine-induced modulation of higher brain functions, such as attention and learning.

Zabofloxacin for chronic bronchitis.

Treatment of lower respiratory tract infection poses as an ongoing challenge among respiratory tract diseases. Bacterial infections are causes of acute exacerbations in chronic bronchitis and indications for antibacterial therapy. Several antibiotics were applied to treat bacterial infections in chronic bronchitis, among them fluoroquinolones are considered potent, broad-spectrum agents with excellent tissue penetration. This monograph focuses on zabofloxacin, a novel fluoroquinolone agent recently approved and launched in South Korea, and summarizes the drug's antibacterial efficacy, pharmacokinetic properties and toxicity. Recent advances concerning fluoroquinolones in chronic bronchitis will be discussed, along with a comparison between zabofloxacin and moxifloxacin. Zabofloxacin has proved to be noninferior to moxifloxacin against major community-acquired Gram-positive and Gram-negative respiratory tract pathogens and found to be well tolerated in both oral and parenteral administrations. These features can make it a potential antimicrobial agent in therapy of chronic bronchitis and other lower respiratory tract infections.

Interdependence of multiple theta generators in the hippocampus: a partial coherence analysis.

The extracellularly recorded theta oscillation reflects a dynamic interaction of various synaptic and cellular mechanisms. Because the spatially overlapping dipoles responsible for the generation of theta field oscillation may represent different mechanisms, their separation might provide clues with regard to their origin and significance. We used a novel approach, partial coherence analysis, to reveal the various components of the theta rhythm and the relationship among its generators. Hippocampal field activity was recorded by a 16-site silicon probe in the CA1-dentate gyrus axis of the awake rat. Field patterns, recorded from various intrahippocampal or entorhinal cortex sites, were used to remove activity caused by a common source by the partialization procedure. The findings revealed highly coherent coupling between theta signals recorded (1) from the hippocampal fissure and stratum (str.) oriens of the CA1 region and (2) between CA1 stratum radiatum and the dentate molecular layer. The results of partial coherence analysis indicated that rhythmic input from the entorhinal cortex explained theta coherence between signals recorded from the hippocampal fissure and str. oriens but not the coherence between signals derived from str. radiatum and the dentate molecular layer. After bilateral lesions of the entorhinal cortex, all signals recorded from both below and above the CA1 hippocampal pyramidal cell layer became highly coherent. These observations indicate the presence of two, relatively independent, theta generators in the hippocampus, which are mediated by the entorhinal cortex and the CA3-mossy cell recurrent circuitry, respectively. The CA3-mossy cell theta generator is partially suppressed by the dentate gyrus interneuronal output in the intact brain. We suggest that timing of the action potentials of pyramidal cells during the theta cycle is determined by the cooperation between the active CA3 neurons and the entorhinal input.

Projections of the dorsal raphe nucleus to the brainstem: PHA-L analysis in the rat.

Early studies that used older tracing techniques reported exceedingly few projections from the dorsal raphe nucleus (DR) to the brainstem. The present report examined DR projections to the brainstem by use of the anterograde anatomical tracer Phaseolus vulgaris leucoagglutinin (PHA-L). DR fibers were found to terminate relatively substantially in several structures of the midbrain, pons, and medulla. The following pontine and midbrain nuclei receive moderate to dense projections from the DR: pontomesencephalic central gray, mesencephalic reticular formation, pedunculopontine tegmental nucleus, medial and lateral parabrachial nuclei, nucleus pontis oralis, nucleus pontis caudalis, locus coeruleus, laterodorsal tegmental nucleus, and raphe nuclei, including the central linear nucleus, median raphe nucleus, and raphe pontis. The following nuclei of the medulla receive moderately dense projections from the DR: nucleus gigantocellularis, nucleus raphe magnus, nucleus raphe obscurus, facial nucleus, nucleus gigantocellularis-pars alpha, and the rostral ventrolateral medullary area. DR fibers project lightly to nucleus cuneiformis, nucleus prepositus hypoglossi, nucleus paragigantocellularis, nucleus reticularis ventralis, and hypoglossal nucleus. Some differences were observed in projections from rostral and caudal parts of the DR. The major difference was that fibers from the rostral DR distribute more widely and heavily than do those from the caudal DR to structures of the medulla, including raphe magnus and obscurus, nucleus gigantocellularis-pars alpha, nucleus paragigantocellularis, facial nucleus, and the rostral ventrolateral medullary area. A role for the dorsal raphe nucleus in several brainstem controlled functions is discussed, including REM sleep and its events, nociception, and sensory motor control.

Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus.

We present a new model for the generation of theta rhythm of the hippocampus. We propose that theta at CA1 involves extracellular current fluxes produced by alternating depolarizing and hyperpolarizing membrane potential fluctuations of large populations of hippocampal pyramidal cells. Pyramidal cells are, in turn, controlled by rhythmically bursting cholinergic and GABAergic cells of the medial septum/vertical limb of the diagonal band. We postulate that septal cholinergic and GABAergic rhythmically bursting cells fire in relative synchrony; their coordinated burst discharge (burst mode) drives the positive-going phase of intracellular theta and associated firing of pyramidal cells; their synchronized pauses (interburst mode) give rise to the negative-going phase of intracellular theta and an inhibition of pyramidal cells. We further demonstrate that the theta rhythm is controlled by a network of cells extending from the brainstem to the septum/hippocampus. During theta, tonically discharging cells of the nucleus reticularis pontis oralis activate neurons of the supramammillary nucleus; the supramammillary nucleus, in turn, converts this steady barrage into a rhythmical pattern of discharge which is relayed to GABAergic/ cholinergic rhythmically bursting cells of the medial septum. The septal rhythmically bursting cells modulate subsets of hippocampal interneurons and principal cells in the generation of the theta rhythm. We review evidence showing that the serotonin-containing neurons of the median raphe nucleus desynchronize the hippocampal electroencephalogram, presumably by disrupting the rhythmical discharge of septal cholinergic and GABAergic neurons. Finally, we summarize recent work indicating that the theta rhythm is critically involved in memory functions of the hippocampus and that its disruption (electroencephalographic desynchronization) may block or temporarily suspend mnemonic processes of the hippocampus.

Reduction of the extracellular level of glutamate in the median raphe nucleus associated with hippocampal theta activity in the anaesthetized rat.

The relationship between hippocampal activity and the extracellular level of excitatory amino acids in the median raphe nucleus has been studied in urethane anaesthetized rats, using the in vivo microdialysis technique. Dialysates were collected from the median raphe nucleus during two to eight sampling periods of equal length (20 min) and hippocampal electroencephalogram was continuously monitored. For each observation period, the average glutamate level in the median raphe nucleus was determined and the percentage of theta and non-theta segments in the hippocampal recordings was calculated. Theta synchronization, in these experiments, either developed spontaneously or it was elicited by injection of anticholinesterase (Physostigmine or Sintostigmine, i.p.) or by a series of short tail pinches. The relationship between hippocampal activity and glutamate release in the median raphe nucleus was characterized by comparison of the direction of changes in these two parameters in consecutive sampling periods. We found that as long as theta/non-theta ratio changed spontaneously or under the effect of anticholinesterase (n = 7), the extracellular level of glutamate in the median raphe nucleus was elevated during periods dominated by desynchronized hippocampal activity as compared with those mostly containing long and/or frequently occurring theta segments. Such relationship was not observed in the adjacent reticular formation (n = 4) and in the median raphe nucleus during sensory stimulation (n = 2). The present data complete those found earlier indicating that the desynchronizing serotonergic influence originating from the brainstem is maintained by a tonic excitatory input to the median raphe nucleus. Since the majority of glutamatergic afferents to the median raphe nucleus originates from the lateral habenula and the interpeduncular nucleus, known to connect limbic forebrain to the brainstem, theta associated changes in median raphe nucleus glutamate levels might reflect descending forebrain influences, suggesting therefore a feedback regulation of the hippocampal activity involving brainstem structures.

The supramammillary nucleus: is it necessary for the mediation of hippocampal theta rhythm?

Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.

Pharmacological suppression of the median raphe nucleus with serotonin1A agonists, 8-OH-DPAT and buspirone, produces hippocampal theta rhythm in the rat.

The effects on the hippocampal electroencephalogram of microinjections of procaine hydrochloride and the serotonin1A agonists, 8-OH-DPAT and buspirone, into the median raphe nucleus were examined in the urethane anesthetized rat. Injections of procaine, 8-OH-DPAT or buspirone into the median raphe nucleus produced a change in the hippocampal electroencephalogram from a spontaneous desynchronized pattern to a synchronized pattern (theta rhythm) within short latencies and for long durations post-injection. Procaine was shown to elicit theta at a mean latency of 52 s and for a mean duration of 21.75 min; buspirone at a mean latency of 2 min and for a mean duration of 34.5 min. A dose dependent relationship was observed between 8-OH-DPAT injections and latencies but not durations. Small doses (0.5 micrograms) of 8-OH-DPAT produced theta at a mean latency of 1.33 min and large doses (3.0 micrograms) at a mean latency of 1.17 min. 8-OH-DPAT injections generated theta for a mean duration of 62 min. Injections of each of these substances into structures dorsal, lateral or rostrocaudal to the median raphe (dorsal raphe nucleus, pontine reticular formation, caudal linear nucleus or raphe pontis, respectively) failed to generate theta or in a few cases produced theta at very long latencies (> 24 min). Saline injections in the median raphe nucleus or control structures were without effect. The demonstration that agents injected into the median raphe nucleus that inhibit its activity (procaine and serotonin1A agonists) produce theta indicate that serotonin-containing median raphe neurons normally suppress theta or are involved in the control of hippocampal desynchronization. The present findings are consistent with previous work showing that median raphe nucleus stimulation desynchronizes the hippocampal electroencephalogram and that median raphe nucleus lesions produce constant theta, but are at odds with the proposal that serotonergic mechanisms may play a role in the generation of the theta rhythm.

GABA(B) receptors in the median raphe nucleus: distribution and role in the serotonergic control of hippocampal activity.

Previous studies have shown that serotonergic neurons of the median raphe nucleus have a suppressive effect on theta synchronization in the hippocampus. Median raphe lesion, suppression of 5-HT neuronal activity by administration of GABA(A) receptor antagonist or by glutamate blockade or depletion produced long-lasting non-interrupted hippocampal theta in freely behaving rats independent of behavior and in rats anesthetized with urethane. Serotonergic neurons show a characteristic sleep-wake pattern of activity and there is evidence that GABAergic mechanisms play an important role in their regulation. In this study we analyzed the distribution and subcellular localization of GABA(B) receptors in the midbrain raphe complex using combined 5-HT/GABA(B) receptor immunohistochemistry at the light and electron microscopic levels and studied the effects of their pharmacological manipulation on hippocampal electroencephalographic activity in urethane-anesthetized rats. We found that sustained infusion of the GABA(B) receptor agonist baclofen into the median raphe nucleus, using the microdialysis technique, elicited lasting theta activity in the hippocampus. The effect was antagonized by selective GABA(B) receptor antagonists. The predominant localization of GABA(B) receptors in the median, as well as in dorsal raphe was found on serotonergic neurons which strongly indicates that the increase in theta occurrence after baclofen injection resulted from suppression of the serotonergic output originating from the median raphe. On the electron microscopic level, we found GABA(B) receptors located extrasynaptically indicating that these receptors are preferentially activated by strong inputs, i.e. when GABA released from the synaptic terminals is sufficient to spill over from the synaptic cleft. Such conditions might be satisfied during rapid eye movement sleep when GABAergic neurons in the raphe are firing at their highest rate and in rhythmic synchronized bursts. Our data indicate that midbrain raphe GABA(B) mechanisms play an important role in behavioral state control and in hippocampal activity, in particular.

Possible glutamatergic/aspartatergic projections to the supramammillary nucleus and their origins in the rat studied by selective [(3)H]D-aspartate labelling and immunocytochemistry.

The supramammillary neurons projecting directly to the hippocampus or indirectly via the septum participate in the regulation of hippocampal theta activity. Inputs to the supramammillary nucleus are only partly specified neurochemically. Glutamate appears to be an excitatory transmitter in this cell group, however, the origin of the glutamatergic afferents is unknown. The present investigations were devoted to study this question. The transmitter-selective [(3)H]D-aspartate retrograde transport method was used injecting the tracer into the lateral subregion of the nucleus. The radioactive tracer was visualized by autoradiography. Non-selective retrograde tracing experiments were also performed for reference injecting wheat germ agglutinin-conjugated colloidal gold into the same supramammillary region. Retrogradely radiolabelled neurons in various numbers were detected in several brain regions including medial septum-diagonal band complex, lateral septum, rostral part of medial and lateral preoptic areas, lateral habenula, ventral premammillary nucleus, apical subregion of interpeduncular nucleus, laterodorsal tegmental nucleus, and dorsal and median raphe nuclei. Radiolabelled neurons in the mentioned raphe nuclei were serotonin-immunonegative. In the non-selective retrograde tracing experiments combined with immunocytochemistry, about 50% of the retrogradely labelled neurons in the raphe nuclei was serotonin-immunonegative, showing that not only serotonergic raphe neurons project to the supramammillary nucleus. The findings indicate that a significant part of the afferents from telencephalic, diencephalic and brainstem regions to the supramammillary nucleus may contain glutamate/aspartate as neurotransmitter. The most important functional implications of these observations concern the role of the supramammillary nucleus in controlling the electrical activity of the hippocampus, and in particular the generation and maintenance of the theta rhythm.

Contiguous pattern spreading in patients with Hodgkin's disease.

BACKGROUND: In 1966, Rosenberg and Kaplan hypothesized that Hodgkin's disease (HD) arises at a discrete primary site and subsequently spreads in a predictable manner via functionally contiguous lymph nodes. However, their results were not statistically evident. It was our aim to describe the spreading in the lymphatic system more precisely and to confirm their postulate. METHODS: Between 1971 and 1992, 297 patients underwent pathological staging for HD. Our subsequent evaluation was restricted to the 236 cases with cervical involvement (65 bilateral, 80 dextral and 91 sinistral), those with lymph nodes on the right side (65 + 80 = 145) being analyzed separately from those with tumours on the left (65 + 91 = 156). Spreading via the lymphatic system was assessed by scoring of the number of involved and uninvolved nodes in six regions, which are functionally contiguous in the lymph system but not necessarily anatomically neighboured. The number of 'gaps' (i.e. missed nodes) observed according to a systematic spreading model was compared with that expected (probability model) if a random course had been followed. RESULTS: Of the 156 patients with left cervical HD, 117 (75%) had para-aortic or spleen involvement, 90 (58%) had mediastinal involvement, 65 (42%) had right cervical involvement, 50 (32%) had axillary involvement and 23 (15%) had inguinal involvement. Of the 145 patients with right cervical HD, 112 (77%) had mediastinal involvement, 89 (61%) had para-aortic or spleen involvement, 65 (44%) had left cervical involvement, 44 (30%) had axillary involvement and 16 (11%) had inguinal involvement. In patients with left or right cervical lymph nodes, the proportions observed with gaps in the spreading were 37 and 27% (SE 7%), respectively, whereas the corresponding values of gaps expected in a probability model if a random course of spreading had been followed would have been 84 and 73% (P = 0.0001 and 0.0001, respectively). CONCLUSION: Our data support the concept that HD spreads in a predictable manner via functionally contiguous lymph nodes. In patients with right cervical lymph nodes, HD spreads via the upper mediastinum and pulmonary hila to the upper abdominal nodes and the spleen. In those with left cervical tumours, HD spreads directly to the abdomen (bypassing the mediastinum), then upward again via the pulmonary hila and upper mediastinum to the neck region (bilateral involvement) and from here it proceeds to the axillary nodes. Finally the inguinal nodes are involved.

Injections of muscimol into the median raphe nucleus produce hippocampal theta rhythm in the urethane anesthetized rat.

It has previously been shown that serotonergic [5-hydroxytryptamine (5-HT)] neurons of the median raphe nucleus (MR) are critically involved in the control of the hippocampal electroencephalogram (EEG). Activation of MR 5-HT neurons desynchronizes the hippocampal EEG, whereas inhibition of MR 5-HT activity produces hippocampal theta rhythm. The MR contains an intrinsic population of gamma-aminobutyric acid (GABA) containing neurons that synapse on 5-HT cells of the MR. The present study examined the effects on the hippocampal EEG of injections of the GABAA agonist muscimol hydrobromide into the MR. Low doses of muscimol (0.5 microgram) produced hippocampal theta rhythm at a mean latency of 6.81 min and for a mean duration of 23.6 min. Higher doses (1.0 microgram and 3.0 micrograms, respectively) produced theta at mean latencies of 2.24 min and 3.2 min and for mean durations of 31.84 min and 24.88 min. Injections of muscimol into regions adjacent to the MR generated theta at significantly longer latencies or were without effect. The present results indicate that MR injections of muscimol produce theta by inhibiting the activity of MR 5-HT neurons. It is concluded that MR GABAergic systems, via their influence on MR 5-HT cells, serve an important role in the control of the hippocampal EEG.

Midbrain raphe cell firing and hippocampal theta rhythm in urethane-anaesthetized rats.

This study aimed to examine the functional coupling between midbrain raphe and the septohippocampal system at the level of neuronal firing. Raphe unit activity and hippocampal EEG were simultaneously recorded in urethane-anaesthetized rats and their relationship was examined in the frequency domain. Subsets of presumably non-serotonergic neurones in both the dorsal and median raphe nuclei fired rhythmically in synchrony with hippocampal theta activity. Theta cells in the median raphe showed higher coherence than those in dorsal raphe and formed a more homogeneous group of cells, according to their firing rates. Since the raphe-septal serotonergic system is known to desynchronize the hippocampal EEG, activation of a subset of nonserotonergic cells during theta in this nucleus indicates a feedback from the limbic circuitry on the ascending raphe control of forebrain activity.

Coordination between cardiovascular and respiratory control systems during and after cerebral ischemia.

The dissociation of cardiovascular (arterial hypertension) and respiratory (depression) reactions to severe cerebral ischemia seems to be inconsistent with the usual cooperative behavior of the two systems and their role in managing disturbances in the central chemical environment. In the present study the Cushing reaction was elicited by transient increase of the intracranial pressure 4-11 times in each experiment. The pressor response and changes in the vertebral sympathetic nerve discharge (SND) were compared with the respiratory reaction and with changes in the phrenic nerve activity. The reaction in both nerves developed in two phases. In the phrenic nerve, an initial hyperactivity (increased discharge amplitude and frequency) coincided with augmentation of the rhythmic SND (phase 1) and complete nerve depression developed when the SND was desynchronized (phase 2). The transition in both systems correlated in their latencies and the severity of the ischemia needed for their stimulation. Repetition of the ischemic stimuli increased the occurrence of the respiratory-related rhythmicity in the SND and later changed its character from rhythmic amplitude modulation to respiratory-related high-frequency bursting SND coinciding with the inspiration. It is concluded that, despite the apparent dissociation between the cardiovascular and respiratory reactions, there is a parallel response between the neurophysiological correlates of the two systems to increasing severity of cerebral ischemia.

Effect of preexisting brain ischemia on sympathetic nerve response to intracranial hypertension.

The performance of the sympathetic nervous system during sustained moderate cerebral ischemia (CI) was examined in the present study. For this purpose, a Cushing response was elicited repeatedly during incomplete global CI in anesthetized artificially ventilated cats after vagotomy and baroreceptor denervation. In control animals without CI, sympathetic activity in response to brief elevation of intracranial pressure (ICP) showed a well-repeatable two-phase reaction. During CI there was a progressive deterioration of background sympathetic nerve discharge (SND) over a period of 30 min. SND response to repeated elevation of ICP was initially similar to control response but later with progression of CI was seriously changed. 1) Instead of the usual hyperactivation, sympathetic nerve activity was depressed during intracranial hypertension. 2) The characteristic desynchronized activity either appeared later during the reperfusion period or remained absent. The progressive loss of SND response to raised ICP in developed CI was compared with the changes seen in experiments in which repeated ICP elevations were superimposed on asphyxia. These findings suggest that the sympathetic component of the Cushing reaction strongly depends on the actual state of brain stem autonomic circuits and may be seriously altered in pathological situations involving ischemic brain injury.