Narcolepsy patients often suffer from insomnia in addition to excessive daytime sleepiness. Narcoleptic animals also show behavioral instability characterized by frequent transitions between all vigilance states, exhibiting very short bouts of NREM sleep as well as wakefulness. The instability of wakefulness states in narcolepsy is thought to be due to deficiency of orexins, neuropeptides produced in the lateral hypothalamic neurons, which play a highly important role in maintaining wakefulness. However, the mechanism responsible for sleep instability in this disorder remains to be elucidated. Because firing of orexin neurons ceases during sleep in healthy animals, deficiency of orexins does not explain the abnormality of sleep. We hypothesized that chronic compensatory changes in the neurophysiologica activity of the locus coeruleus (LC) and dorsal raphe (DR) nucleus in response to the progressive loss of endogenous orexin tone underlie the pathological regulation of sleep/wake states. To evaluate this hypothesis, we examined firing patterns of serotonergic (5-HT) neurons and noradrenergic (NA) neurons in the brain stem, two important neuronal populations in the regulation of sleep/wakefulness states. We recorded single-unit activities of 5-HT neurons and NA neurons in the DR nucleus and LC of orexin neuron-ablated narcoleptic mice. We found that while the firing pattern of 5-HT neurons in narcoleptic mice was similar to that in wildtype mice, that of NA neurons was significantly different from that in wildtype mice. In narcoleptic mice, NA neurons showed a higher firing frequency during both wakefulness and NREM sleep as compared with wildtype mice. In vitro patch-clamp study of NA neurons of narcoleptic mice suggested a functional decrease of GABAergic input to these neurons. These alterations might play roles in the sleep abnormality in narcolepsy.
Acupuncture of the sacral vertebrae has therapeutic effects in patients with overactive bladders. The mechanism of these effects, however, remains unclear. The present study, using urethane-anesthetized rats, investigated the effects of acupuncture stimulation of the sacral vertebrae on bladder activity and bladder activity-related neurons in and around Barringtons nucleus. In 95 of 147 trials (64.6%), acupuncture stimulation of the sacral vertebrae for 1 min suppressed bladder contraction for 27-2347s. Acupuncture-induced suppression of bladder contraction was blocked by intraperitoneal injection of bicuculline (Bic). Acupuncture stimulation strongly affected bladder activity-related neurons, including those which fired only prior to the start of contraction (Type E1), those whose firing was maintained during contraction (Type E2), and those whose firing was strongly suppressed during contraction (Type I). All Type E1 neurons and most (93.8%) Type E2 neurons decreased firing when bladder activity was suppressed by acupuncture stimulation. Four of 14 (28.6%) Type I neurons exhibited an excitatory response while 3 of 14 (21.4%) exhibited an inhibitory response. These findings suggest that acupuncture stimulation of the sacral vertebrae suppresses bladder contraction and changes the firing properties of bladder activity-related neurons in and around Barringtons nucleus, and that these changes are mediated by GABAergic systems.
To elucidate the role of the preoptic area (POA) in the regulation of penile erection, we examined the effects of electrical stimulation in and around the POA on penile erection in rats, which was assessed by changes in pressure in the corpus spongiosum of the penis (CSP) and electromyography (EMG) of the bulbospongiosus (BS) muscle. In unanesthetized and anesthetized rats, four types of responses were induced by stimulation in and around the POA; (1) normal type responses, which were similar to spontaneously occurring erections, characterized by slow increase in CSP pressure and sharp peaks concurrent with BS muscle bursting; (2) muscular type responses, which included sharp CSP pressure peaks (muscular component) with almost no vascular component; (3) mixed type responses, which included a sequence of high-frequency CSP peaks followed by low-frequency CSP peaks; and (4) micturition type responses, which had higher-frequency and lower-amplitude CSP peaks than other responses which were identical to those of normal micturition. In unanesthetized condition, erections were evoked by stimulation of the lateral preoptic area (LPOA), medial preoptic area (MPOA), bed nucleus of the stria terminalis (BST), paraventricular nucleus (PVN), reuniens thalamic nucleus (Re) and lateral septum (LS). Lower-intensity stimulation evoked erections from the LPOA, BST, PVN and RE, but not the MPOA. In anesthetized condition, stronger stimuli were required and effective sites were restricted to the LPOA, MPOA and BST. These findings suggest that the lateral and medial subdivisions of the preoptic area play different roles in mediating penile erection.
Sleep and wakefulness are regulated in the brainstem and hypothalamus. Classical brain dissecting or stimulating studies have proposed the concept of an ascending reticular activating system, presently known as the wakefulness center, located in the caudal midbrain/rostral pontine (mesopontine) areas, comprising the serotonergic, noradrenergic and cholinergic neural populations. These neural groups, in association with the histaminergic and orexinergic neurons in the hypothalamus, activate the cerebral the cortex through the thalamus or basal forebrain. This activating (waking) system is controlled by the slow wave sleep (SWS) generating system in the preoptic area, which receives inhibitory signals from the waking center. The mesopontine area is also involved in the regulation of rapid eye movement (REM) sleep. Reciprocal interactions between the cholinergic/glutamatergic excitatory systems and the aminergic/GABAergic inhibitory systems are crucial for the regulation of REM sleep. In the REM activating system, mutual excitatory interactions between cholinergic and glutamatergic neurons serve to maintain the state of REM sleep. The REM activating system in the mesopontine area receives GABAergic inhibitory signals from several neural groups in the periaqueductal gray and the medulla. Thus, sleep and wakefulness are controlled by the interplay of various neural populations located in several areas in the central nervous system.
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