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The Journal of Neuroscience, January 1, 1999, 19(1):248-257
Neuronal Degeneration in Canine Narcolepsy
J. M.
Siegel1,
R.
Nienhuis1,
S.
Gulyani1,
S.
Ouyang1,
M. F.
Wu1,
E.
Mignot2,
R. C.
Switzer3,
G.
McMurry1, and
M.
Cornford4
1 Veterans Administration Medical Center Sepulveda
and Department of Psychiatry and Brain Research Institute, University
of California Los Angeles School of Medicine, Neurobiology Research
151A3, Sepulveda, California 91343, 2 Department of
Psychiatry and Behavioral Sciences, Sleep Research Center, Richard
Lucas/Lab Surge Building, Palo Alto, California 94304, 3 NeuroScience Associates, Knoxville, Tennessee 37922, and
4 Department of Pathology, Harbor University of California
Los Angeles Medical Center, Torrance, California 90509
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ABSTRACT |
Narcolepsy is a lifelong illness characterized by persistent
sleepiness, hypnagogic hallucinations, and episodes of motor paralysis
called cataplexy. We have tested the hypothesis that a transient
neurodegenerative process is linked to symptom onset. Using the
amino-cupric silver stain on brain sections from canine narcoleptics,
we found elevated levels of axonal degeneration in the amygdala, basal
forebrain (including the nucleus of the diagonal band, substantia
innominata, and preoptic region), entopeduncular nucleus, and
medial septal region. Reactive neuronal somata, an indicator of
neuronal pathology, were found in the ventral amygdala. Axonal
degeneration was maximal at 2-4 months of age. The number of reactive
cells was maximal at 1 month of age. These degenerative changes precede
or coincide with symptom onset. The forebrain degeneration that we have
observed can explain the major symptoms of narcolepsy.
Key words:
narcolepsy; REM sleep; amygdala; basal forebrain; canine; amino-cupric silver; degeneration; cataplexy
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INTRODUCTION |
Narcolepsy, which occurs at a rate
of 0.2-1.6 per thousand (Aldrich, 1990 ; Hublin et al., 1994), was
first recognized 118 years ago by Gélineau (Passouant, 1976). Its
symptoms include excessive daytime sleepiness, hypnagogic
hallucinations (dream-like mentation in waking), REM sleep at sleep
onset, cataplexy (a loss of muscle tone in waking, usually triggered by
sudden, strong emotions), and sleep paralysis (an inability to move at
sleep onset or awakening) (Guilleminault, 1994). Narcolepsy has been reported in horses, cattle, and dogs (Mitler et al., 1976; Strain et
al., 1984). Canine narcoleptics have been intensively studied. Like
human narcoleptics, they are excessively sleepy and have cataplexy.
Symptoms in canine and human narcoleptics display a similar response to
pharmacological agents (Guilleminault, 1994; Nishino and Mignot, 1997).
The cause of narcolepsy is unknown.
Narcolepsy is not a progressive disease, in that once symptoms have
become fully established, in both human and canine narcoleptics, they
do not become worse (or markedly better) with age. This suggests that
narcolepsy may be caused by a transient degenerative process. Examinations of postmortem tissue in human narcoleptics have not produced consistent evidence for degenerative changes. However, symptom
onset is typically 50 or more years before autopsy, a sufficient
interval for the removal of any debris resulting from degeneration at
the time of disease onset. The age of onset of canine narcolepsy is
between 1 and 4 months. In the current study, we have used the
amino-cupric stain (de Olmos et al., 1994), an extremely sensitive
indicator of degenerating neurons and axons (Switzer, 1991; Fix et al.,
1996), to test the hypothesis that narcolepsy onset is linked to
neuronal degeneration.
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MATERIALS AND METHODS |
Eighteen Doberman pinscher dogs, nine narcoleptic and nine age-
and breed-matched controls (four male narcoleptics and seven male
controls), from six narcoleptic and five normal litters ranging from 1 to 8 months of age were used (Table 1).
Control and narcoleptic dogs were reared under similar conditions and
never given any pharmacological agents before killing. They were
anesthetized with sodium pentobarbital (50 mg/kg) and perfused with a
rinsing solution of 0.8% sucrose, 0.4% glucose, and 0.8% NaCl in
0.067 M cacodylate buffer, pH 7.3. Fixation was with 4%
formaldehyde in 0.067 M cacodylate buffer containing 4%
sucrose. After the brains were allowed to harden in situ for
24 hr, they were removed from the skull and placed in fixative for
7 d.
Amino-cupric protocol
Embedding and sectioning
Brains were treated with 20% glycerol and American Optical
dimethylsulfoxide to prevent freeze artifacts. Two half brains (a
narcoleptic and control) were embedded side by side, with their medial
surfaces aligned using the anterior commissure as a landmark. The block
of embedded brains was allowed to cure and then rapidly frozen by
immersion in isopentane chilled to  70°C with crushed dry ice.
Blocks were mounted on a freezing stage of an American Optical sliding
microtome and sectioned coronally at 40 µm beginning at the olfactory
bulb and proceeding to the spinal medullary junction (i.e., decussation
of the pyramids). All sections cut (none were discarded) were collected
sequentially into a 4 × 6 array of containers. These containers
were filled with either standard 10% commercial, phosphate-buffered
formaldehyde or 3.7-4% formaldehyde buffered with 4.2% sodium
cacodylate, pH 7.2, for sections to be stained with the amino-cupric
silver method. At the completion of sectioning, each container held a
serial set of one of every 24th section (or, one section every 960 µm). Each of the large sections cut from the block was a composite
section holding sections from both of the half brains.
Staining
Selection of sections for staining. A serial set of
every sixth section (a 240 µm interval) was selected for staining
with the amino-cupric-silver stain of de Olmos (1994) to reveal
disintegrative degeneration. The free-floating sections were taken
through the following major steps: preimpregnation, impregnation,
reduction, bleaching, and fixing.
The preimpregnation solution contained cupric nitrate, silver nitrate,
cadmium nitrate, lanthanum nitrate, neutral red,  -amino butyric
acid, alanine, pyridine, triethanolamine, isopropanol, and deionized
water. After the components were well mixed, the solution was
microwaved until it reached 45-50°C. The solution was left to cool
to room temperature, then filtered. The sections were removed from the
cacodylate-buffered formaldehyde and rinsed with deionized water. They
were then placed into dishes containing the preimpregnation solution
and heated in the microwave to 45-50°C. To allow for cooling, the
sections remained in this solution overnight.
The impregnation solution contained silver nitrate, 100% ethanol,
acetone, lithium hydroxide, ammonium hydroxide, and deionized water.
The sections were rinsed first in deionized water, second in acetone,
and then placed into the impregnation solution. They incubated in this
solution for 50 min.
The reducer solution contained 100% ethanol, formalin, citric acid,
and deionized water. The sections were transferred from the
impregnation solution into the reducer solution and placed in a water
bath with a maintained temperature between 32 and 35°C. After 25 min
in the reducer solution, the sections were transferred into deionized
water rinses, then an acetic acid rinse and back into deionized water.
The bleaching solutions were potassium ferricyanide in potassium
chlorate with lactic acid, potassium permanganate with sulfuric acid,
and sodium thiosulfate. The sections were rapidly transferred through
these bleaching solutions, then fixed in rapid fixer solution for 1 min
30 sec. The sections were then rinsed in deionized water, mounted on
subbed glass slides, and counterstained with neutral red to reveal
normal cell bodies.
Using a Neurolucida microscope-computer interface, with bright-field
and dark-field illumination, we mapped the entire brain for evidence of
axonal debris and reactive neuronal somata. A preliminary analysis was
done by J.M.S., who had hemisected and labeled the tissue. When it
became apparent that there were consistent differences between the
narcoleptic and control data, all the data were systematically
analyzed. The data presented herein were all scored by R.N. or by G.M.,
who were blind to the condition of the animals. Under 2000× or 4000×
magnification, axonal fragments and reactive neuronal somata were
visually identified. An interrupted "string of pearls appearance"
characterized axon fragments. These could be followed for considerable
differences within sections (Fig. 1).
Reactive cells were characterized by a darkened, labeled cytoplasm and
often by a shrunken appearance, as illustrated in Figure 1. Axons and
cells were counted and mapped onto computer reconstructions of each
section.
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Figure 1.
Examples of degenerative changes seen in canine
narcolepsy. a, b, Low-power dark-field
view of amygdala of narcoleptic (a) and control
(b) half brains of 4-month-old dogs. Increased
numbers of labeled axons in the narcoleptic dog are visible as brightly
illuminated foci in amygdala and pyriform cortex (bottom
arrow) and central nucleus of the amygdala [top
arrow compared with the same areas in the control half brain
(arrows)]. Optic tract is visible in top
right of a and top left of
b. c, Higher magnification of
amino-cupric silver-stained sections counterstained with neutral red
Nissl showing axonal degeneration (black interrupted
lines) in pyriform cortex nucleus of 3-month-old narcoleptic.
Note several counterstained nonreactive neuronal soma in this and other
sections (arrows). d is detail from area
indicated in c. e, Axonal degeneration in
basalis magnocellularis nucleus of 3-month-old narcoleptic.
f, Detail (1000×) of axonal degeneration in
medial nucleus of the amygdala of 2-month-old narcoleptic.
g-i, Reactive neuronal somata in the
amygdala and subjacent pyriform cortex of narcoleptic dogs.
g, A pair of darkly stained cells are visible in the
center of a 2-month-old. h, i, Labeled
cells in the basalis parvicellularis amygdala of a 3-month-old. Scale
bars: a, b, 1 mm; c,
e, 50 µm; d,
g-i, 25 µm; f, 10 µm.
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RESULTS |
Axonal degeneration was elevated in the amygdala, septal nucleus,
diagonal band of Broca, and adjacent basal forebrain regions of
narcoleptics (Fig. 1a-f). Narcoleptics
had significantly higher levels of degeneration across the entire age
spectrum than age-matched controls (F = 15.6, 8, and
124 df; p < .0001). There was no significant difference between amounts of degeneration in male and female dogs
within either group, or in the ratio of numbers of degenerating axons
or reactive cells in male-female or same sex pairs of narcoleptics and controls. At all ages, and in every pair of narcoleptic-control brains examined, the narcoleptic half had higher levels of degeneration than the control (Wilcoxon test, t = 8.4;
p < .01).
Certain structures contained degenerating axons at 1 month of age (Fig.
2) but not at later ages. At 1 month of
age, intense labeling was seen in the medial septal nucleus, diagonal
band, fornix, magnocellular preoptic region, substantia innominata, entopeduncular nucleus, and pyriform cortex. Within the amygdala, the
basalis magnocellularis, central, lateral, and anterior nuclei were
most heavily labeled. Figure 3 shows the
distribution of degenerating axons at 6 months of age. At 2-6 months
of age, degeneration was seen in medial septal nucleus, diagonal band,
amygdala, and pyriform cortex, but not in the fornix, substantia
innominata, magnocellular preoptic, or entopeduncular nucleus.
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Figure 2.
Anatomical distribution of
degenerating axons in a pair of half brains from 1-month-old
narcoleptic and control dogs processed together. Each
dot indicates a degenerating axon fragment. The
numbers below each section give the total count of
degenerating axons. Sections go from anterior (top) to
posterior (bottom). AAA, Anterior
amygdala area; ACOA, anterior cortical area;
AC, anterior commissure; ACC, nucleus
accumbens; CC, corpus callosum; DBB,
diagonal band of Broca; DBB-H,
horizontal limb of the diagonal band of Broca; EC,
external capsule; EN, entopeduncular nucleus;
F, column of the fornix; GP, globus
pallidus; IC, internal capsule, LOT,
lateral olfactory tract: MCPO, magnocellular preoptic
nucleus; NB, nucleus basalis;
NBM, nucleus basalis magnocellularis;
NBP, nucleus basalis parvicellularis;
NCE, nucleus centralis; NCO, cortical
nucleus; NL, lateral nucleus; NM, medial
nucleus; PAM, periamygdaloid area; PIR,
pyriform cortex; PU, putamen; SI,
substantia innominata; SFN, septofimbrial nucleus;
SMT, stria medullaris; SNL, lateral
septal nucleus; SNM, medial septal nucleus (nomenclature
from Lim et al., 1960). Definitions also apply to Figures 3 and
6.
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Figure 3.
Anatomical distribution of degenerating
axons in a pair of half brains from 6-month-old narcoleptic and control
dogs processed together.
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Axonal degeneration was maximal at 1-3 months of age, with the level
of degeneration greatly decreased by 8 months of age (Fig.
4). Increased levels of degeneration were
present in the septal nucleus, but not in the amygdala, between 6 and 8 months of age (Fig. 4). Despite the role of the brainstem in REM sleep generation (Siegel, 1994) and the involvement of brainstem efferent mechanisms in cataplexy (Siegel et al., 1991), we saw no evidence for
elevated levels of degeneration in the brainstem of the narcoleptic dogs at any age.
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Figure 4.
Time course of levels of axonal degeneration with
age in narcoleptic and control dogs. All data are from the same group
of 18 canines. There was one narcoleptic and one control at each data
point except for two of each at 2 months of age.
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Stained neuronal somata were seen at increased levels in the amygdala
of narcoleptics from 1 to 4 months of age (Fig.
1g-i). Cell death preceded by reactivity to
cupric silver and followed by rapid lysis of the soma may be the
primary event, with axonal degeneration and relatively long-lasting
axonal debris fields as a consequence (Switzer, 1991; de Olmos, 1994;
Fix et al., 1996). Conversely, cells may become reactive to the cupric
silver stain during the chromatolytic reaction resulting from axonal
loss (Switzer, 1991; de Olmos et al., 1994). The highest levels of
reactive cells were at 1 month of age (Figs.
5, 6), with
a majority of the labeled cells in the ventral amygdala and pyriform
cortex. We stained adjacent sections of tissue from 2-month-old
narcoleptics with the TUNEL stain (Oncor), an indicator of apoptosis,
but did not see any labeling.
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Figure 6.
Distribution of reactive neuronal somata in 3- and
4-month-old narcoleptic and normal dogs. Number of reactive somata is
indicated below each series.
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DISCUSSION |
We found that degeneration was present in canine narcoleptics at
or shortly before the time of symptom onset. Degeneration was present
in areas that have been implicated in response to startle and in sleep control.
No consistent evidence for neuronal or axonal degeneration has been
reported in any brain region in human narcoleptics. However, a few
cases of "symptomatic" narcolepsy linked to tumors or other lesions
have been seen. Most patients with symptomatic narcolepsy have been
reported to have diencephalic-basal forebrain-septal nucleus damage,
whereas few had any brainstem pathology (Stahl et al., 1980; Erlich and
Itabashi, 1986; Aldrich and Naylor, 1989; Servan et al., 1995). A
recent report of brainstem lesions in narcolepsy (Plazzi et al., 1996)
has been disputed (Bassetti et al., 1997; Frey and Heiserman, 1997).
Gross anatomical lesions caused by neoplasms or strokes are absent in
the vast majority of human cases (Aldrich, 1990).
The time course of the degenerative process in the narcoleptic dogs
paralleled the lower levels of axonal and neuronal degeneration in each
brain region seen at the same stage of development in the control dogs,
with both peaking at 1-3 months. In the dogs, symptom onset occurs
relatively early in life, at 1-4 months of age (Mignot et al., 1993),
consistent with the observed neuronal degeneration. Human narcolepsy
has been seen in children as young as 3 years (Yoss and Daly, 1960;
Billiard, 1985; Kotagal et al., 1990; Challamel et al., 1994) but
typically starts in the second or third decade (Aldrich, 1990). Our
time course data suggest two possible scenarios for a comparable
degenerative process in humans. The first is that degeneration could
occur at the age of disease onset with no previous abnormality. The
second possibility is that degeneration could occur early in
development in narcoleptic humans, with some subsequent degenerative or
hormonal process triggering the disease at a later age.
The latter time course would resemble that of the degenerative process
thought to occur in schizophrenia. Schizophrenia, like narcolepsy, is
correlated with degeneration that includes portions of the amygdala and
other frontotemporal regions (Bogerts, 1993; Marsh et al., 1994;
Nasrallah et al., 1994). The best evidence is that the damage in
schizophrenics occurs prenatally or early in development (Bogerts,
1993), as we find in canine narcolepsy. Like narcolepsy, symptoms of
schizophrenia are usually not present in early childhood. Symptom onset
in schizophrenics is typically in the second or third decade and, as in
narcolepsy, damage does not appear to be progressive (Marsh et al.,
1994). Most narcoleptics have hypnagogic hallucinations, a symptom with
some resemblance to the hallucinatory mentation of certain
schizophrenics. Several cases of schizophrenia coexisting with or
misdiagnosed as narcolepsy have been reported (Cadieux et al., 1985;
Douglass et al., 1991).
The amygdala is one of the forebrain areas most strongly activated in
REM sleep (Maquet et al., 1996; Nofsinger et al., 1997). Amygdala
stimulation in normal cats potently increases REM sleep duration (Calvo
et al., 1996). The amygdala is also known to be involved in the
elaboration of emotional responses and has a powerful role in the
modulation of startle (Campeau and Davis, 1995). There are major
projections from the amygdala to the dorsolateral pontine cholinergic
and noradrenergic cell regions involved in the generation of REM sleep
phenomena (Wallace et al., 1992). We hypothesize that the loss of
neurons within the amygdala, basal forebrain, and septal region
disinhibits amygdala cells projecting to the brainstem. These
disinhibited cells are activated during sudden, strong emotions. This
triggers the brainstem motor inhibitory system and inactivates the
locus coeruleus (Wu et al., 1998), resulting in cataplexy. It has been
shown that activation of the amygdala produces EKG acceleration and
apnea (Frysinger et al., 1984), changes that also occur at the onset of
cataplexy (Siegel et al., 1989).
The entopeduncular nucleus, like the amygdala, is important in the
elaboration of emotional responses and has a particularly important
role in the recognition of rewarding events (Hammer et al., 1993;
Breiter et al., 1997). Pleasurable stimuli, including food ingestion,
the most reliable trigger of canine cataplexy, activate the
entopeduncular nucleus (Lidsky, 1975; Schneider, 1987). As in the
amygdala, degenerative changes that alter circuitry or disinhibit cells
could be responsible for an abnormal output from this region to the
amygdala and brainstem regions (Schneider, 1987).
The septal nucleus is known to have important arousal and
startle-related functions. Electrolytic lesions of the septum produce a
dramatic exaggeration of the startle response (McCleary, 1961). Cholinergic and GABAergic neurons localized to the medial septal region
project to limbic structures and produce the theta rhythm in the
hippocampus (Vertes and Kocsis, 1997), a rhythm that is prominent in
both REM sleep and cataplexy (Wu et al., 1998).
The amygdala, diagonal band of Broca, and magnocellular preoptic region
are the major components of the basal forebrain hypnogenic region.
Sleep-active neurons, hypothesized to be involved in sleep induction,
are localized to this area (Szymusiak and McGinty, 1986b). Stimulation
of the ventral amygdala produces EEG synchrony (Kreindler and Steriade,
1964). Stimulation of the preoptic region also induces sleep
(Sterman and Clemente, 1962). Lesions of this area produce the most
profound insomnia seen after any brain lesion (Szymusiak and McGinty,
1986a). Narcoleptic canines have elevated levels of dopaminergic and
noradrenergic receptors in the amygdala, brainstem, and basal forebrain
(Mefford et al., 1983; Kilduff et al., 1986). Similar changes
are present in human narcoleptics (Aldrich et al., 1992, 1993, 1994).
Cholinergic stimulation of the basal forebrain triggers cataplexy in
narcoleptic, but not in control canines (Nishino et al., 1995).
Disinhibition of the basal forebrain region by loss of local
interneurons could produce the major non-REM sleep-related symptoms of
narcolepsy, disruption of nighttime sleep and excessive daytime
sleepiness (Aldrich, 1991), as well as the reported changes in receptor
levels. Thus, the degeneration we see in amygdala, basal forebrain, and
septum are consistent with the EEG, motor, and sleepiness symptoms of narcolepsy.
Human narcolepsy is correlated with the presence of the human leukocyte
antigen (HLA) DQB1*0602 genotype (Matsuki et al., 1992). The
association of narcolepsy with the major histocompatibility complex marker, HLA-DR2 and DQB1*0602, is one of the highest
disease-HLA linkages known (Behar et al., 1995). Most HLA-linked
disorders have been shown to be autoimmune in nature (Sinha et al.,
1990). Canine narcolepsy is linked to the presence of a marker
for an Ig switch-like sequence (Mignot et al., 1991) and
enhanced microglial expression (Tafti et al., 1996) at 1-3 months of
age. These findings all suggest that immune processes, perhaps related
to axonal pruning or cell necrosis, may be linked to narcolepsy onset.
Consistent evidence for immune abnormalities in human and canine
narcolepsy have not been found, indicating that narcolepsy probably
does not involve long-term generalized autoimmune activation
(Fredrikson et al., 1990; Mignot et al., 1995). However, autoimmune
processes linked to a localized, time-limited degenerative process,
preceding symptom onset would be missed by the techniques used to look
for autoimmune processes in previous studies. The degenerative changes we have observed could form the link between autoimmune activation and
the abnormalities of motor and sleep function that characterize narcolepsy.
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FOOTNOTES |
Received June 15, 1998; revised Oct. 2, 1998; accepted Oct. 12, 1998.
This work was supported by the Medical Research Service of the Veterans
Administration, United States Public Health Service Grants NS14610 and NS23724.
Correspondence should be addressed to Jerome Siegel, Department of
Psychiatry University of California Los Angeles, Neurobiology Research
151A3, Veterans Administration Medical Center, 16111 Plummer Street,
North Hills, CA 91343.
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Abstract
Introduction
