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J M Siegel

Publications and source records attributed to J M Siegel.

At least 19 recordsLinked to original sources
PubMed2005

Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy.

OBJECTIVE: To investigate whether neuronal activity-regulated pentraxin (Narp) colocalizes with hypocretin (Hcrt or orexin) in the normal human brain and to determine if Narp staining is lost in the narcoleptic human brain. BACKGROUND: Human narcolepsy is characterized by a loss of the peptide hypocretin in the hypothalamus. This loss could result from the degeneration of neurons containing hypocretin or from a more specific loss of the ability of these neurons to synthesize Hcrt. Narp has been found to colocalize with hypocretin in the rat hypothalamus. METHODS: We investigated the distribution of Narp in three normal and four narcoleptic human postmortem brains using immunohistochemistry with an antibody to Narp. Colocalization studies of Narp and hypocretin were also performed in two normal brains using immunohistochemistry with an antibody to Narp and an antibody to hypocretin. RESULTS: We found that Narp colocalizes with hypocretin in the lateral hypothalamic area (LHA), the dorsomedial hypothalamus (DMH), the dorsal hypothalamic area (DHA), and the posterior hypothalamic area (PHA) of the normal human. The number of Narp-positive neurons was reduced by 89% in these areas of the narcoleptic hypothalamus. In contrast, Narp staining in the paraventricular (Pa) and supraoptic nuclei (SO) of the human hypothalamus did not differ between normal and narcoleptic brains. CONCLUSIONS: This finding supports the hypothesis that narcolepsy results from the specific loss of hypocretin neurons. Loss of hypothalamic Narp may contribute to the symptoms of narcolepsy.

Brain Mapping↗
PubMed2004

Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs.

Cataplexy, a symptom associated with narcolepsy, represents a unique dissociation of behavioural states. During cataplectic attacks, awareness of the environment is maintained, as in waking, but muscle tone is lost, as in REM sleep. We have previously reported that, in the narcoleptic dog, noradrenergic cells of the locus coeruleus cease discharge during cataplexy. In the current study, we report on the activity of serotonergic cells of the dorsal raphe nucleus. The discharge patterns of serotonergic dorsal raphe cells across sleep-waking states did not differ from those of dorsal raphe and locus coeruleus cells recorded in normal rats, cats and monkeys, with tonic discharge in waking, reduced activity in non-REM sleep and cessation of activity in REM sleep. However, in contrast with locus coeruleus cells, dorsal raphe REM sleep-off neurones did not cease discharge during cataplexy. Instead, discharge continued at a level significantly higher than that seen in REM sleep and comparable to that seen in non-REM sleep. We also identified several cells in the dorsal raphe whose pattern of activity was the opposite of that of the presumed serotonergic cells. These cells were maximally active in REM sleep and minimally active in waking and increased activity during cataplexy. The difference between noradrenergic and serotonergic cell discharge profiles in cataplexy suggests different roles for these cell groups in the normal regulation of environmental awareness and muscle tone and in the pathophysiology of narcolepsy.

Action Potentials↗
PubMed2004

Treatment with immunosuppressive and anti-inflammatory agents delays onset of canine genetic narcolepsy and reduces symptom severity.

All Doberman pinschers and Labrador retrievers homozygous for a mutation of the hypocretin (orexin) receptor-2 (hcrtr2) gene develop narcolepsy under normal conditions. Degenerative changes and increased display of major histocompatibility complex class II antigens have been linked to symptom onset in genetically narcoleptic Doberman pinschers. This suggests that the immune system may contribute to neurodegenerative changes and narcoleptic symptomatology in these dogs. We therefore attempted to alter the course of canine genetic narcolepsy, as an initial test of principle, by administering a combination of three immunosuppressive and anti-inflammatory drugs chosen to suppress the immune response globally. Experimental dogs were treated with a combination of methylprednisolone, methotrexate and azathioprine orally starting within 3 weeks after birth, and raised in an environment that minimized pathogen exposure. Symptoms in treated and untreated animals were quantified using the food elicited cataplexy test (FECT), modified FECT and actigraphy. With drug treatment, time to cataplexy onset more than doubled, time spent in cataplexy during tests was reduced by more than 90% and nighttime sleep periods were consolidated. Short-term drug administration to control dogs did not reduce cataplexy symptoms, demonstrating that the drug regimen did not directly affect symptoms. Treatment was stopped at 6 months, after which experimental animals remained less symptomatic than controls until at least 2 years of age. This treatment is the first shown to affect symptom development in animal or human genetic narcolepsy. Our findings show that hcrtr2 mutation is not sufficient for the full symptomatic development of canine genetic narcolepsy and suggest that the immune system may play a role in the development of this disorder.

Age of Onset↗
PubMed2004

Relationship between sleep and eye state in Cetaceans and Pinnipeds.

We recorded EEG from both hemispheres and documented the state of the two eyes in two species of Cetaceans (one beluga and one bottlenose dolphin) and one species of Pinnipeds (two northern fur seals). In the dolphin and beluga we found that episodes of unihemispheric slow wave sleep (USWS) were associated with asymmetry in eye state. During USWS and asymmetrical SWS the eye contralateral to the sleeping hemisphere was mostly closed or in an intermediate state while the eye contralateral to the waking hemisphere was more often open or in an intermediate state. Bilateral eye opening indicated waking in about 80% cases and unilateral eye closure indicated USWS with an accuracy of about 75%. Bilateral eye closure was rare (< 2% of the observation time) and was not necessarily associated with high amplitude SWS. In fur seals, episodes of one eye briefly opening usually occurred in the beginning of sleep episodes and lasted several minutes. Those episodes were frequently associated with lower amplitude EEG slow waves in the contralateral brain hemisphere. During most of their sleep on land, fur seals had both eyes tightly closed. No EEG asymmetry was recorded at this time. Although eye state and EEG stage are correlated in the bottlenose dolphin, beluga and fur seals, short episodes of EEG synchrony (less then 1 min) occur contralateral to an open eye and waking (a more activated EEG) activity can be present contralateral to a closed eye. The available data suggest that two functions of USWS/EEG asymmetry during SWS in Cetaceans and fur seals are multisensory control of the environment and maintenance of motion and postures of sleep. The adaptive advantages of USWS throughout the evolution of Cetaceans and Pinnipeds from terrestrial mammals to present forms could include 1) the avoidance of predators and maintenance of contact with other animals of the same species; 2) continuance of regular breathing; 3) and effective thermoregulation in the water environment.

Adaptation, Physiological↗
PubMed2002

Unihemispheric slow wave sleep and the state of the eyes in a white whale.

We recorded electroencephalogram (EEG) and simultaneously documented the state of both eyelids during sleep and wakefulness in a sub-adult male white whale over a 4-day-period. We showed that the white whale was the fifth species of Cetaceans, which exhibits unihemispheric slow wave sleep. We found that the eye contralateral to the sleeping hemisphere in this whale was usually closed (right eye, 52% of the total sleep time in the contralateral hemisphere; left eye, 40%) or in an intermediate state (31 and 46%, respectively) while the ipsilateral eye was typically open (89 and 80%). Episodes of bilateral eye closure in this whale occupied less than 2% of the observation time and were usually recorded during waking (49% of the bilateral eye closure time) or low amplitude sleep (48%) and rarely in high amplitude sleep (3%). In spite of the evident overall relationship between the sleeping hemisphere and eye state, EEG and eye position in this whale could be independent over short time periods (less than 1 min). Therefore, eye state alone may not accurately reflect sleep state in Cetaceans. Our data support the idea that unihemispheric sleep allows Cetaceans to monitor the environment.

Animals↗
PubMed2002

Cataplexy-related neurons in the amygdala of the narcoleptic dog.

The amygdala plays an important role in the interpretation of emotionally significant stimuli and has strong projections to brainstem regions regulating muscle tone and sleep. Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, strong emotions. Extracellular single-unit recordings were carried out in the amygdala of narcoleptic dogs to test the hypothesis that abnormal activity of a subpopulation of amygdala neurons is linked to cataplexy. Of the 218 cells recorded, 31 were sleep active, 78 were active in both waking and rapid-eye-movement sleep, 88 were maximally active during waking, and 21 were state independent. Two populations of cells showed a significant change in activity with cataplexy. A population of sleep active cells localized to central and basal nucleus increased discharges prior to and during cataplexy. A population of wake active cells localized to the cortical nucleus decreased activity prior to and during cataplexy. We hypothesize that these cell populations have a role in mediation or modulation of cataplexy through interactions with meso-pontine regions controlling atonia. The anticholinesterase physostigmine, at doses which increased cataplexy, did not alter the activity of the cataplexy-related cells or of other amygdala cells, suggesting that its effect on cataplexy is mediated 'downstream' of the amygdala. The alpha-1 blocker prazosin, at doses which increased cataplexy, increased discharge in a subgroup of the cataplexy active cells and in a number of other amygdala cells, indicating that prazosin may modulate cataplexy by its action on amygdala cells or their afferents.

Action Potentials↗
PubMed2002

Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement.

Hypocretins (orexins) are recently discovered hypothalamic neuropeptides that have been implicated in the etiology of narcolepsy. The normal behavioral functions of these peptides are unclear, although a role in feeding has been suggested. We measured hypocretin-1 (Hcrt-1) in the cerebrospinal fluid of dogs during a variety of behaviors. We found that 48 h without food (24 h beyond normal 24-h fasting period) produced no significant change in Hcrt-1 levels nor did feeding after the deprivation. In contrast, 24 h of sleep deprivation produced on average a 70% increase in Hcrt-1 level compared with baseline levels. The amount of increase was correlated with the level of motor activity during the sleep-deprivation procedure. A 2-h period of exercise in the same dogs produced a 57% increase in Hcrt-1 levels relative to quiet waking levels, with the magnitude of the increase being highly correlated with the level of motor activity. The strong correlation between motor activity and Hcrt-1 release may explain some of the previously reported behavioral, physiological, and pathological phenomena ascribed to the Hcrt system.

Aging↗
PubMed2002

The distribution and morphological characteristics of catecholaminergic cells in the brain of monotremes as revealed by tyrosine hydroxylase immunohistochemistry.

The present study describes the distribution and cellular morphology of catecholaminergic neurons in the CNS of two species of monotreme, the platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus). Tyrosine hydroxylase immunohistochemistry was used to visualize these neurons. The standard A1-A17, C1-C3 nomenclature was used for expediency, but the neuroanatomical names of the various nuclei have also been given. Monotremes exhibit catecholaminergic neurons in the diencephalon (A11, A12, A13, A14, A15), midbrain (A8, A9, A10), rostral rhombencephalon (A5, A6, A7), and medulla (A1, A2, C1, C2). The subdivisions of these neurons are in general agreement with those of other mammals, and indeed other amniotes. Apart from minor differences, those being a lack of A4, A3, and C3 groups, the catecholaminergic system of monotremes is very similar to that of other mammals. Catecholaminergic neurons outside these nuclei, such as those reported for other mammals, were not numerous with occasional cells observed in the striatum. It seems unlikely that differences in the sleep phenomenology of monotremes, as compared to other mammals, can be explained by these differences. The similarity of this system across mammalian and amniote species underlines the evolutionary conservatism of the catecholaminergic system.

Animals↗
PubMed2002

The distribution and morphological characteristics of serotonergic cells in the brain of monotremes.

The distribution and cellular morphology of serotonergic neurons in the brain of two species of monotremes are described. Three clusters of serotonergic neurons were found: a hypothalamic cluster, a cluster in the rostral brainstem and a cluster in the caudal brainstem. Those in the hypothalamus consisted of two groups, the periventricular hypothalamic organ and the infundibular recess, that were intimately associated with the ependymal wall of the third ventricle. Within the rostral brainstem cluster, three distinct divisions were found: the dorsal raphe nucleus (with four subdivisions), the median raphe nucleus and the cells of the supralemniscal region. The dorsal raphe was within and adjacent to the periaqueductal gray matter, the median raphe was associated with the midline ventral to the dorsal raphe, and the cells of the supralemniscal region were in the tegmentum lateral to the median raphe and ventral to the dorsal raphe. The caudal cluster consisted of three divisions: the raphe obscurus nucleus, the raphe pallidus nucleus and the raphe magnus nucleus. The raphe obscurus nucleus was associated with the dorsal midline at the caudal-most part of the medulla oblongata. The raphe pallidus nucleus was found at the ventral midline of the medulla around the inferior olive. Raphe magnus was associated with the midline of the medulla and was found rostral to both the raphe obscurus and raphe pallidus. The results of our study are compared in an evolutionary context with those reported for other mammals and reptiles.

Animals↗
PubMed2002

The distribution and morphological characteristics of cholinergic cells in the brain of monotremes as revealed by ChAT immunohistochemistry.

The present study employs choline acetyltransferase (ChAT) immunohistochemistry to identify the cholinergic neuronal population in the central nervous system of the monotremes. Two of the three extant species of monotreme were studied: the platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus). The distribution of cholinergic cells in the brain of these two species was virtually identical. Distinct groups of cholinergic cells were observed in the striatum, basal forebrain, habenula, pontomesencephalon, cranial nerve motor nuclei, and spinal cord. In contrast to other tetrapods studied with this technique, we failed to find evidence for cholinergic cells in the hypothalamus, the parabigeminal nucleus (or nucleus isthmus), or the cerebral cortex. The lack of hypothalamic cholinergic neurons creates a hiatus in the continuous antero-posterior aggregation of cholinergic neurons seen in other tetrapods. This hiatus might be functionally related to the phenomenology of monotreme sleep and to the ontogeny of sleep in mammals, as juvenile placental mammals exhibit a similar combination of sleep elements to that found in adult monotremes.

Animals↗
PubMed2001

The REM sleep-memory consolidation hypothesis.

It has been hypothesized that REM (rapid eye movement) sleep has an important role in memory consolidation. The evidence for this hypothesis is reviewed and found to be weak and contradictory. Animal studies correlating changes in REM sleep parameters with learning have produced inconsistent results and are confounded by stress effects. Humans with pharmacological and brain lesion-induced suppression of REM sleep do not show memory deficits, and other human sleep-learning studies have not produced consistent results. The time spent in REM sleep is not correlated with learning ability across humans, nor is there a positive relation between REM sleep time or intensity and encephalization across species. Although sleep is clearly important for optimum acquisition and performance of learned tasks, a major role in memory consolidation is unproven.

Animals↗
PubMed2001

Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study.

A complete suppression of muscle tone in the postural muscles and a reduction of muscle tone in the respiratory related musculature occur in rapid eye movement (REM) sleep. Previous studies have emphasized the role of glycine in generating these changes. Because the activity of norepinephrine- and serotonin-containing neurons is known to decrease in REM sleep, we hypothesized that a decrease in release in one or both of these transmitters might be detected at the motoneuronal level during muscle tone suppression elicited by brainstem stimulation in the decerebrate animal. We compared release in the ventral horn with that in the hypoglossal nucleus to determine whether the mechanism of muscle tone suppression differs in these nuclei as has been hypothesized. Electrical stimulation and cholinergic agonist injection into the mesopontine reticular formation produced a suppression of tone in the postural and respiratory muscles and simultaneously caused a significant reduction of norepinephrine and serotonin release of similar magnitude in both hypoglossal nucleus and spinal cord. Norepinephrine and serotonin release in the motoneuron pools was unchanged when the stimulation was applied to brainstem areas that did not generate bilateral suppression. No change in dopamine release in the motoneuron pools was seen during mesopontine stimulation-induced atonia. We hypothesize that the reduction of monoamine release that we observe exerts a disfacilitatory effect on both ventral horn and hypoglossal motoneurons and that this disfacilitatory mechanism contributes to the muscle atonia elicited in the decerebrate animal and in the intact animal during REM sleep.

Animals↗
PubMed2001

A brief history of hypocretin/orexin and narcolepsy.

The hypothalamic peptides named the orexins, or hypocretins, were discovered in 1998. In 1999 it was established that genetic narcolepsy could be caused by mutations in the genes synthesizing these peptides or their receptors. In September of 2000 it was found that most human narcolepsy is caused by loss of hypocretin cells, most likely as a result of a degenerative process. This paper reviews these events and their implications for our understanding of brain arousal and motor control systems.

Animals↗
PubMed2001

Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area.

Orexin-A (OX-A) and orexin-B (OX-B) (hypocretin 1 and hypocretin 2) are synthesized in neurons of the perifornical, dorsomedial, lateral, and posterior hypothalamus. The locus coeruleus (LC) receives the densest extrahypothalamic projections of the orexin (OX) system. Recent evidence suggests that descending projections of the LC have a facilitatory role in the regulation of muscle tone. The pontine inhibitory area (PIA), located ventral to LC, receives a moderate OX projection and participates in the suppression of muscle tone in rapid-eye-movement sleep. We have examined the role of OX-A and -B in muscle-tone control using microinjections (0.1 microM to 1 mM, 0.2 microl) into the LC and PIA in decerebrate rats. OX-A and -B microinjections into the LC produced ipsi- or bilateral hindlimb muscle-tone facilitation. The activity of LC units was correlated with the extent of hindlimb muscle-tone facilitation after OX microinjections (100 microM, 1 microl) into fourth ventricle. Microinjections of OX-A and -B into the PIA produced muscle-tone inhibition. We did not observe any significant difference in the effect of OX-A and -B on muscle tone at either site. Our data suggest that OX release activates LC units and increases noradrenergic tonus in the CNS. Moreover, OX-A and -B may also regulate the activity of pontine cholinoceptive and cholinergic neurons participating in muscle-tone suppression. Loss of OX function may therefore disturb both facilitatory and inhibitory motor processes.

Animals↗
PubMed2001

State-related discharge of neurons in the brainstem of freely moving box turtles, Terrapene carolina major.

We have performed the first study of neuronal activity in freely-moving reptiles. 23 brainstem units were recorded from areas throughout the reticular formation, during wakefulness and quiescence in the box turtle. These units responded to various sensory stimuli and increased firing rates in relation to motor activity during wakefulness. All but one unit showed significant decreases in discharge during quiescence. Group I cells (32%) fired mostly during active movements and exhibited silent periods of 5 min or longer during quiescence while group II cells (68%) maintained slow tonic activity in quiescence. Polygraphic data showed no consistent, cyclically occurring phasic events during quiescence.

Action Potentials↗
PubMed2000

Activation of pontine and medullary motor inhibitory regions reduces discharge in neurons located in the locus coeruleus and the anatomical equivalent of the midbrain locomotor region.

Activation of the pontine inhibitory area (PIA) including the middle portion of the pontine reticular nucleus, oral part (PnO), or the gigantocellular reticular nucleus (Gi) suppresses muscle tone in decerebrate animals. The locus coeruleus (LC) and midbrain locomotor region (MLR) have been implicated in the facilitation of muscle tone. In the current study we investigated whether PIA and Gi stimulation causes changes in activity in these brainstem motor facilitatory systems. PIA stimulation evoked bilateral muscle tone suppression and inhibited 26 of 28 LC units and 33 of 36 tonically active units located in the anatomical equivalent of the MLR (caudal half of the cuneiform nucleus and the pedunculopontine tegmental nucleus). Gi stimulation evoked bilateral suppression of hindlimb muscle tone and inhibited 20 of 35 LC units and 24 of 24 neurons located in the MLR as well as facilitated 11 of 35 LC units. GABA and glycine release in the vicinity of LC was increased by 20-40% during ipsilateral PnO stimulation inducing hindlimb muscle tone suppression on the same side of the body. We conclude that activation of pontine and medullary inhibitory regions produces a coordinated reduction in the activity of the LC units and neurons located in the MLR related to muscle tone facilitation. The linkage between activation of brainstem motor inhibitory systems and inactivation of brainstem facilitatory systems may underlie the reduction in muscle tone in sleep as well as the modulation of muscle tone in the isolated brainstem.

Animals↗