Papers by Yoshimasa Koyama
Orexinergic neurones in the perifornical lateral hypothalamus project to structures of the midbra... more Orexinergic neurones in the perifornical lateral hypothalamus project to structures of the midbrain, including the substantia nigra and the mesopontine tegmentum. These areas contain the mesencephalic locomotor region (MLR), and the pedunculopontine and laterodorsal tegmental nuclei (PPN/LDT), which regulate atonia during rapid eye movement (REM) sleep. Deficiencies of the orexinergic system result in narcolepsy, suggesting that these projections are concerned with switching between locomotor movements and muscular atonia. The present study characterizes the role of these orexinergic projections to the midbrain. In decerebrate cats, injecting orexin-A (60 µM to 1.0 mM, 0.20-0.25 µl) into the MLR reduced the intensity of the electrical stimulation required to induce locomotion on a treadmill (4 cats) or even elicit locomotor movements without electrical stimulation (2 cats). On the other hand, when orexin was injected into either the PPN (8 cats) or the substantia nigra pars reticulata (SNr, 4 cats), an increased stimulus intensity at the PPN was required to induce muscle atonia. The effects of orexin on the PPN and the SNr were reversed by subsequently injecting bicuculline (5 mM, 0.20-0.25 µl), a GABA A receptor antagonist, into the PPN. These findings indicate that excitatory orexinergic drive could maintain a higher level of locomotor activity by increasing the excitability of neurones in the MLR, while enhancing GABAergic effects on presumably cholinergic PPN neurones, to suppress muscle atonia. We conclude that orexinergic projections from the hypothalamus to the midbrain play an important role in regulating motor behaviour and controlling postural muscle tone and locomotor movements when awake and during sleep. Furthermore, as the excitability is attenuated in the absence of orexin, signals to the midbrain may induce locomotor behaviour when the orexinergic system functions normally but elicit atonia or narcolepsy when the orexinergic function is disturbed.
Neurosurgical Re-Engineering of the Damaged Brain and Spinal Cord, 2003
Noradrenergic projection originating in the locus coeruleus, serotonergic projection from the dor... more Noradrenergic projection originating in the locus coeruleus, serotonergic projection from the dorsal raphe nucleus, and cholinergic projection from neurons gathering in the laterodorsal tegmental nucleus and scattering in the pedunculopontine tegmental nucleus constitute three diffuse projection systems arising from the brainstem and innervating wide areas of the brain. They may function as controllers of sleep and wakefulness. We have investigated functional roles of the projections by recording neuronal activity in these brainstem nuclei, and by observing effects of stimulation of the brainstem nuclei. The projection from the locus coeruleus is an arousal system, since the noradrenergic neurons are active specifically during waking, and activation of the noradrenergic projection excites upper brain structures. Functions of the serotonergic projection are still mysterious, since its action on upper brain is inhibitory in spite of waking-specific activity of the neurons. A group of cholinergic neurons constitute a system to induce and maintain paradoxical sleep. The cholinergic projection may have another role, i.e. to induce a rapid, transient elevation of vigilance level by their phasic response to novel, unfamiliar stimuli.
Neuroscience Research Supplements, 1992
Urology, 2004
To examine the effect of desmopressin (DDAVP) on bladder contraction and on the neurons that fire... more To examine the effect of desmopressin (DDAVP) on bladder contraction and on the neurons that fire in relation to spontaneous bladder contraction (bladder-related neurons) in and around Barrington's nucleus, the micturition center. DDAVP is used for the treatment of nocturnal enuresis because of its antidiuretic action, but the mechanism of this action has not been proved. Urethane-anesthetized Sprague-Dawley male rats (n = 20) were used. DDAVP was infused intravenously or as an intracerebroventricular infusion into the lateral ventricle. We encountered three types of bladder-related neurons: those that fired before the start of the contraction (type E1), those that fired synchronous with the bladder contraction (type E2), and those that fired during bladder relaxation (type I). Intravenous infusion caused inhibition in three of five type E1 neurons, excitation in two of five type E2 neurons, and excitation (one neuron) and inhibition (one neuron) of four type I neurons. With int...
Nihon rinsho. Japanese journal of clinical medicine, 1998
The mesopontine tegmentum has a pivotal role for regulation of paradoxical sleep. Noradrenergic n... more The mesopontine tegmentum has a pivotal role for regulation of paradoxical sleep. Noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe have similar firing properties during sleep-waking cycles (active in waking and silent during paradoxical sleep). However, several findings suggest that these two populations of neurons have different influences on sleep-waking regulation. A population of cholinergic neurons in the brainstem which are most active during paradoxical sleep (PS-on neuron) are inhibited by carbachol and excited by bicuculline, while those of another population, active both during waking and paradoxical sleep, are inhibited by carbachol and excited by noradrenaline and histamine. Non-cholinergic PS-on neurons are excited by carbachol and inhibited by noradrenaline. Slow wave sleep is thought to be generated by a neural mechanism in the preoptic area, but neurons in the preoptic area display several kinds of firing patterns in relation ...
Sleep and Biological Rhythms, 2006
We note the importance of an appropriate combination of excitability for the higher (neocortex, b... more We note the importance of an appropriate combination of excitability for the higher (neocortex, basal ganglia, and limbic system) and lower (brainstem-spinal cord) motor systems could be necessary for normal behavior during wakefulness and REM sleep. Neurotransmitters such as acetylcholine, the monoamines, GABA, and the orexins, would regulate the background excitability of the higher and lower motor systems so that an interaction of these systems could be appropriately maintained. Pathophysiological mechanisms of sleep deficiency may be induced by not only an organic disturbance of brain structures (hardware) but also by dysfunction of the neurotransmitter systems (software). From these considerations, we provide a hypothetical model for "state-dependent interaction of the higher and lower motor systems" for understanding normal behavior and pathophysiological mechanisms of sleep-related disorders such as narcolepsy and the REM-sleep behavioral syndrome.
Sleep and Biological Rhythms, 2003
ABSTRACT In head-restrained rats, spontaneous neuronal activities in the ventroposterior thalamic... more ABSTRACT In head-restrained rats, spontaneous neuronal activities in the ventroposterior thalamic nuclei were recorded during slow wave sleep (SWS) and paradoxical sleep (PS). The slow dynamics of neuronal activity, represented by a power spectra in the range of 0.04–1.0 Hz, were white noise-like during SWS and 1/f noise-like during PS. The result was similar to that observed previously in other various brain areas in the cat. It supports our hypothesis that the state-dependent alternation of slow dynamics in the activity of the central processor neurons during sleep is common in different species.
Sleep and Biological Rhythms, 2003
ABSTRACT Abstract This study investigated the correlation of firing pattern of the cholinergic ne... more ABSTRACT Abstract This study investigated the correlation of firing pattern of the cholinergic neurons in the brainstem and the fluctuation of blood pressure during paradoxical sleep (PS) in unanesthesized, head-restrained rats. Of 13 cholinergic neurons recorded from the laterodorsal tegmental nucleus, five showed phasic firing, which was in close correlation with the fluctuation of the blood pressure during PS. The increase in firing was observed 1–3 s prior to the increase of blood pressure. The results suggest that a population of cholinergic neurons in the brainstem are closely involved in the fluctuation of blood pressure during PS.
Regulatory Peptides, 2005
The serotonergic dorsal raphe (DR) neurons play an important role in sleep-wakefulness regulation... more The serotonergic dorsal raphe (DR) neurons play an important role in sleep-wakefulness regulation. Orexinergic neurons in the lateral hypothalamus densely project to the brainstem sites including the DR. To test the effects of orexins on the serotonergic DR neurons, we applied orexin A (0.1 mM) by pressure to these neurons in unanesthetized and urethane anesthetized rats. Orexin A caused excitation in 10 of 15 neurons under unanesthetized condition. The excitation was characterized by slow onset (0-18 s), long lasting duration (15-150 s) and state-dependency. Orexin A applied during REM sleep or slow wave sleep induced significant excitation while during wakefulness, the similar amount of orexin A did not increase the firing rate any more. In the anesthetized animals, orexin A induced excitation in four of eight neurons. The excitation had slow onset and was long lasting. These results suggest that orexinergic neurons exert excitatory influence on the serotonergic DR neurons to maintain tonic activity of them, thereby participating in regulation of sleep-wakefulness cycles and other functions.
Psychiatry and Clinical Neurosciences, 2000
To clarify a relation between contractile condition of the urinary bladder and vigilance conditio... more To clarify a relation between contractile condition of the urinary bladder and vigilance condition, bladder pressure was monitored simultaneously with cortical electroencephalogram (EEG) in urethane‐anesthetized rats. Slow waves of large amplitude and those of lower amplitude appeared in EEG alternately. The bladder showed no contractile activity in the former EEG condition, while it contracted intermittently or continuously to urinate in the latter EEG condition. The relative power of EEG delta waves was significantly different in these two conditions. These results suggest that activity of the micturition system changes according to vigilance conditions, which may serve to prevent enuresis during sleep.
Psychiatry and Clinical Neurosciences, 2002
In undrugged, head-restrained rats, neuronal activity was recorded in and around the laterodorsal... more In undrugged, head-restrained rats, neuronal activity was recorded in and around the laterodorsal hypothalamic area where orexin neurones are distributed. Among 22 neurones observed across whole sleep-waking states, half (n = 11) were most active during paradoxical sleep and least active during waking. Others were equally more active during paradoxical sleep and waking than during slow-wave sleep (n = 6), or were most active during waking and least active during paradoxical sleep (n = 3). The majority of neurones started to increase firing activity prior to the transition of sleep-waking states. These results suggest that the area of the hypothalamus containing orexin neurones plays a role in sleep-waking regulation.
Neuroscience Research, 2011
Neuroscience Research, 2009
Emotion is an essentical property for humans. However, the brain mechanisms of emotion are not fu... more Emotion is an essentical property for humans. However, the brain mechanisms of emotion are not fully understood. Especially, negative emotion-related motor phenomenon, such as freezing or startle, has received little attention in humans. We investigated whether the negatively emotional visual stimuli can modulate the human primary motor cortex (M1) activation by using the International Affection Picture System (IAPS) and the transcranial magnetic stimulation (TMS). In addition to the conventional single pulse TMS, we also utilized the paired TMS to evaluate the intracortical inhibitory circuit within M1 (short-latency intracortical inhibition: SICI). We found the increase of cortico-spinal excitability measured by motor evoked potential amplitude and the enhanced SICI associated with negatively emotional stimuli but not with neutral ones. We, for the first time, reported the enhancement of intracortical inhibition by negative emotion, which may be the physiologic correlate of motor deactivation induced by negative emotion.
Neuroscience, 2000
The mesopontine tegmentum, which contains both cholinergic and non-cholinergic neurons, plays a c... more The mesopontine tegmentum, which contains both cholinergic and non-cholinergic neurons, plays a crucial role in behavioral state control. Using microiontophoresis in unanesthetized cats, we have examined the effect of cholinergic and monoaminergic drugs on two putative cholinergic neurons located mostly in the laterodorsal tegmental nucleus and X area (or the cholinergic part of the nucleus tegmenti pedunculopontinus, pars compacta): one (type I-S) exhibiting slow tonic discharge during both waking and paradoxical sleep, and the other (PGO-on) displaying single spike activity during waking and burst discharges in association with ponto-geniculo-occipital (PGO) waves during paradoxical sleep. We found that: (i) application of carbachol, a potent cholinergic agonist, inhibited single spike activity in both PGO-on and type I-S neurons, but had no effect on the burst activity of PGO-on neurons during paradoxical sleep; the inhibition was associated with either blockade or increased latency of antidromic responses, suggesting membrane hyperpolarization; (ii) application of glutamate, norepinephrine, epinephrine, or histamine resulted in increased tonic discharge in both PGO-on and type I-S neurons; this was state-independent and resulted in a change in the firing mode of PGO-on neurons from phasic to tonic; (iii) application of serotonin had only a weak state-dependent inhibitory effect on a few type I-S neurons; and (iv) application of dopamine had no effect on either type of neuron. The present findings suggest that cholinergic, glutamatergic and monoaminergic (especially noradrenergic, adrenergic and histaminergic) inputs have the capacity to strongly modulate the cholinergic neurons, altering both their rate and mode of discharge, such as to shape their state specific activity, and thereby contribute greatly to their role in behavioral state control.
Neuroscience, 1993
In urethane-anesthetized rats, single neuronal activity was recorded in or around the central gra... more In urethane-anesthetized rats, single neuronal activity was recorded in or around the central gray of the caudal mesencephalon to rostral pons with multibarrel microelectrodes for ionophoretic application of acetylcholine, noradrenaline and serotonin. Neurons were classified by spike shape into broad-spike and brief-spike neurons. In the laterodorsal tegmental nucleus, locus coeruleus or dorsal raphe, broad-spike neurons, marked by Pontamine Sky Blue and discriminated in sections processed for histochemistry of reduced nicotinamide adenine dinucleotide phosphate diaphorase or Nissl staining, were presumed to be cholinergic, noradrenergic or serotonergic, respectively. The majority of these neurons were inhibited through autoreceptors, except some laterodorsal tegmental neurons which might not be furnished by autoreceptors. Noradrenaline and serotonin inhibited more than two-thirds of the laterodorsal tegmental neurons tested, while a few neurons were excited by noradrenaline. Though effects of noradrenaline on dorsal raphe neurons and those of serotonin on locus coeruleus neurons were not clear in many neurons tested, neurons affected in these examinations (30%) were all inhibited clearly and no excitatory effect was observed. Acetylcholine exerted inhibition on about one-half of dorsal raphe neurons, while effects of acetylcholine on locus coeruleus neurons were the only case in the present study in which excitation was the major effect, though more than a half of locus coeruleus neurons were not sensitive to this drug. Thus, in this study some new data on the pharmacological properties of the cholinergic laterodorsal tegmental neurons were obtained. In addition, mutual interactions between brainstem cholinergic, noradrenergic and serotonergic neurons were assayed by comparing the pharmacological properties of these neurons tested with a uniform procedure. The interactions between these diffuse projection neurons may be involved in neural mechanisms controlling vigilance, wakefulness and/or sleep.
Neuron, 2005
sights into the neural pathways that regulate sleep/ wakefulness states.
European Urology, 1998
The three diffuse projection systems arising in the brainstem, that is, noradrenergic projection ... more The three diffuse projection systems arising in the brainstem, that is, noradrenergic projection originating in the locus coeruleus, serotonergic projection from the dorsal raphe nucleus, and cholinergic projection from neurons gathering in the laterodorsal tegmental nucleus and scattering in the pedunculopontine tegmental nucleus, may function as controllers of sleep and wakefulness. We have investigated the functional roles of these projections by recording neuronal activity in these brainstem nuclei and by stimulating the brainstem nuclei. It is suggested that the projection from the locus coeruleus is an arousal system; the function of the serotonergic projection is still mysterious, since these neurons are active specifically during waking; activation of the noradrenergic projection excites the upper brain sites whereas activation of the serotonergic projection depressed them. It is clear that a group of cholinergic neurons constitute a system to induce and maintain paradoxical sleep. The cholinergic projection may also have the role to induce a rapid, transient elevation of the vigilance level by its phasic response to novel, unfamiliar stimuli.
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Papers by Yoshimasa Koyama