Michael H. Chase

Afferent vagal stimulation: Neurographic correlates of induced eeg synchronization and desynchronization

Summary o 1. Cortical synchronization and desynchronization were induced by afferent cervical vagal stimulation in the cat. 2. By simultaneously recording the vagal neurogram and the induced EEG responses, it was determined that rapidly conducted vagal potentials were associated with EEG synchronization, while potentials conducted at approximately 15 m/sec were correlated with EEG desynchronization. 3. The specific factor which determined the nature of the EEG response was whether synchronogenic or desynchronogenic vagal afferent fibers were stimulated and not the frequency of stimulation. 4. Following supranodose transection of the vagus nerve, the sensory elements remaining in the vagus could be stimulated to induce a vagal neurogram which contained the potential complexes seen in the intact nerve and which had been correlated with the induced EEG responses. A histologic analysis of intact and transected vagi confirmed the neurographic findings. 5. The patterns of the induced synchronization which occur as a result of afferent vagal stimulation are similar to those which occur spontaneously or during quiet sleep in the unrestrained cat. It was concluded that the vagal afferent system is comprised of fiber groups which are able to initiate and maintain either synchronization or desynchronization of the EEG and that these fiber groups are both functionally and structurally discrete.

Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat

Anatomical data demonstrate a dense projection, in the cat, from hypocretin (orexin) neurons in the hypothalamus to the laterodorsal tegmental nucleus (LDT), which is a critical pontine site that is involved in the regulation of the behavioral states of sleep and wakefulness. The present study was therefore undertaken to explore the hypocretinergic control of neurons in the LDT vis-à-vis these behavioral states. Accordingly, hypocretin-1 was microinjected into the LDT of chronic, unanesthetized cats and its effects on the percentage, latency, frequency and duration of wakefulness, quiet (non-REM) sleep and active (REM) sleep were determined. There was a significant increase in the time spent in wakefulness following the microinjection of hypocretin-1 into the LDT and a significant decrease in the time spent in active sleep. The increase in the percentage of wakefulness was due to an increase in the duration of episodes of wakefulness; the reduction in active sleep was due to a decrease in the frequency of active sleep episodes, but not in their duration. These data indicate that hypocretinergic processes in the LDT play an important role in both of the promotion of wakefulness and the suppression of active sleep.

Hypoglossal motoneurons are postsynaptically inhibited during carbachol-induced rapid eye movement sleep.

The obstructive sleep apnea syndrome is characterized by the occurrence of cyclic snoring and frequent apneic episodes during sleep, with consequent hypoxia and hypercapnia. Obstructive sleep apnea syndrome is associated with excess daytime sleepiness, depression, and an increased incidence of ischemic cardiopathy, cardiac arrhythmias, systemic hypertension and brain infarction. Hypoglossal motoneurons, which innervate extrinsic and intrinsic muscles of the tongue, play a key role in maintaining the patency of the upper airway and in the pathophysiology of obstructive sleep apnea syndrome. Based on data obtained by using extracellular recording techniques, there is a consensus that hypoglossal motoneurons cease to discharge during rapid eye movement sleep, because they are disfacilitated. Since other somatic motoneurons are known to be postsynaptically inhibited during rapid eye movement sleep, we sought to determine, by the use of intracellular recording techniques during cholinergically induced rapid eye movement sleep, whether postsynaptic inhibitory mechanisms act on hypoglossal motoneurons. We found that, during this state, a powerful glycinergic premotor inhibitory system acts to suppress hypoglossal motoneurons. This finding opens new avenues for the treatment of obstructive sleep apnea syndrome, and provides a foundation to explore the neural and pharmacological control of respiration-related motoneurons during rapid eye movement sleep.

Somatomotor and visceromotor correlates of operantly conditioned 12–14 c/sec sensorimotor cortical activity ☆

Abstract 1. 1. Adult cats were trained in a free operant paradigm to produce a synchronized pattern (12–14 c/sec) of sensorimotor or cortical activity in order to obtain a milk reward. 2. 2. Somatic and visceral motor functions were monitored before and during episodes of conditioned sensorimotor activity. 3. 3. During conditioned 12–14 c/sec activity, consistent patterns of motor phenomena were observed which included a cessation of movement and a depression of somatic motor activity. 4. 4. A shift in visceral motor processes toward levels of activity which were parasympathetic in nature occurred during 12–14 c/sec activity. Heart rate decreased, and the pattern of respiration became more regular than during control periods. The onset of a conditioned EEG episode was correlated with inspiration and its termination with expiration. 5. 5. The following hypotheses were suggested based upon the results presented in this paper: (a) the specific EEG patterns of sensory and motor cortical gyri are correlated with uniform and functionally adaptive variations in somatic and visceral motor activity; (b) patterns of synchronized activity may reflect localized sites of “idling” within cortical areas devoted to primary sensory functions; and (c) the processes or conditions underlying 12–14 c/sec activity of the sensorimotor cortex are analogous to those responsible for the alpha activity of the visual cortex.

Cortical and subcortical patterns of response to afferent vagal stimulation

Cortical and subcortical patterns of activity were studied upon electrical stimulation of the cut central end of the cervical vagus nerve in acutely prepared adult cats. The effects of different frequencies and voltages of afferent vagal stimulation were studied while the duration of the stimulus pulses was kept constant (0.75 msec). High-frequency (> 70/sec) low voltage (< 3v) stimulation resulted in the induction of cortical EEG synchronization, while all other combinations of frequency and voltage gave rise to cortical activation. Subcortical structures responded in a manner consistent with the cortical observations. The cerebral cortex and thalamic nuclei responded to synchronogenic vagal afferent stimulus parameters only after an initial latent period, while the hippocampus responded immediately. All responses were bilaterally equivalent and could be induced by either vagus nerve. Severance of both sympathetic trunks and vagi and transection of the neuraxis at the spinomedullary junction indicated that the central responses were neurogenic in origin. These and other studies presently in progress offer convincing evidence that the different cortical responses (synchronization or desynchronization) observed by various investigators from stimulation of the central end of the cervical vagus nerve result from the differential stimulation of specific afferent fiber systems within that nerve.

Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: a double-labeling immunohistochemical study

In trigeminal and hypoglossal motor nuclei of adult cats, hypocretin immunoreactive fiber varicosities were observed in apposition to retrogradely labeled motoneuron somata and dendrites. Among those lateral hypothalamus neurons that project to the hypoglossal nucleus some were determined to be hypocretin immunoreactive and were located amongst the single-labeled hypocretinergic neurons. These data suggest that hypocretin may play a role in the synaptic control of these motoneurons.

Intracellular potential of medullary reticular neurons during sleep and wakefulness.

Abstract Intracellular records were obtained in the chronic cat from neurons of the nucleus reticularis gigantocellularis (NGC) during naturally occurring sleep and wakefulness. When wakefulness and quiet sleep was compared with active sleep, the membrane potential level of NGC neurons gradually decreased; a depolarized membrane potential was maintained tonically and selectively throughout active sleep. These data support the concept that NGC neurons assist in the generation of somatic atonia during active sleep and suggest that this state-dependent inhibitory function may be controlled by the nucleus pontis oralis as part of the general phenomenon of reticular response reversal.

Hyperpolarizing membrane responses induced in lumbar motoneurons by stimulation of the nucleus reticularis pontis oralis during active sleep

Intracellular recordings were obtained from lumbar motoneurons in unanesthetized, undrugged, normally respiring cats during the states of wakefulness, quiet sleep and active sleep. The objective was to examine the state-dependent control of spinal cord motoneurons exerted by the pontomesencephalic reticular formation. Accordingly, electrical stimulation was applied to the nucleus reticularis pontis oralis while the membrane potential of lumbar motoneurons was recorded. Short latency depolarizing and/or hyperpolarizing potentials were observed throughout sleep and wakefulness; no state-dependent pattern was found in the direction of polarization or amplitude for these early potentials. However, a long latency hyperpolarizing potential emerged exclusively during active sleep; it was characterized by a peak latency of 45 +/- 1 (S.E.M.) ms, a duration of 40 +/- 2 ms, and an amplitude of 3 +/- 0.5 mV. This active sleep-selective potential was capable of inhibiting spontaneous motoneuron activity. These and previously obtained data support the notion that excitation of the nucleus reticularis pontis oralis results in somatomotor inhibition at the level of the spinal cord and brainstem selectively during the state of active sleep.

Postsynaptic control of lumbar motoneuron excitability during active sleep in the chronic cat

A correlated intracellular and extracellular study of lumbar motoneuron excitability during sleep and wakefulness was performed in the chronic, unanesthetized, undrugged, normally respiring cat. Experiments were designed to reveal the extent to which hypotonia during active sleep in mammals is dependent on postsynaptic inhibition of somatic motoneurons. Variations in the antidromic field potential, antidromic and orthodromic spike, EPSP, membrane input resistance and rheobasic current were studied. No change in motoneuron excitability occurred when quiet wakefulness was compared to quiet sleep. A decrease in excitability was present, due to postsynaptic inhibition, during active sleep. Further phasic decreases in excitability, also due to postsynaptic inhibition, occurred during active sleep in conjunction with clusters of rapid eye movements.

Effects on sleep of melanin-concentrating hormone (MCH) microinjections into the dorsal raphe nucleus.

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area, and project diffusely throughout the central nervous system, including areas that participate in the generation and maintenance of the states of sleep and wakefulness. Recent studies have shown that the hypothalamic MCHergic neurons are active during rapid eye movements (REM) sleep, and that intraventricular microinjections of MCH induce slow wave sleep (SWS) and REM sleep. There are particular dense MCHergic projections to the dorsal raphe nucleus (DR), a neuroanatomical structure involved in several functions during wakefulness, and in the regulation of sleep variables. Because of this fact, we analyzed the effect of microinjections of MCH into this nucleus on sleep and waking states in the rat. Compared to control microinjections, MCH (100 ng) produced a moderate increase in SWS (243.7+/-6.0 vs. 223.2+/-8.8 min, p<0.05) and an important increment in REM sleep (35.5+/-2.5 vs. 20.8+/-3.4 min, p<0.01) due to an increase in the number of REM sleep episodes. The increase of REM sleep was accompanied by a reduction in the time spent in light sleep and wakefulness. We therefore conclude that the hypothalamic MCHergic system, via its action in the DR, plays an important role in the generation and/or maintenance of the states of sleep.