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CURE:Digestive Diseases Research Center, West Los Angeles VA Medical Center, Department of Medicine and Brain Research Institute, UCLA, Los Angeles, California 90073
Address all correspondence and requests for reprints to: Hong Yang, M.D., Ph.D., CURE:DDRC, West Los Angeles VA Medical Center, Building 115, Room 203, 11301, Wilshire Boulevard, Los Angeles, California 90073. E-mail: hoyang{at}ucla.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thyroid hormones have profound effects on the synthesis and turnover of neuropeptides and neurotransmitters through modulation of nuclear gene expression (10, 11). However, little attention has been paid to the influence of thyroid status on the gene expression of neuropeptides that are involved in the brain regulation of the autonomic nervous system. Convergent evidence has established that medullary TRH synthesized in the caudal raphe nuclei plays a physiological role in autonomic regulation (12). Motoneurons regulating vagal efferent activities are located in the dorsal motor nucleus of the vagus (DMN) and the nucleus ambiguus (Amb), which mainly project to the gastrointestinal tract and thoracic organs respectively (13). TRH receptors are expressed in the DMN and Amb neurons (14). Also, both nuclei are densely innervated by TRH containing nerve terminals that, at least for those in the DMN, originate solely from TRH synthesizing neurons in the raphe obscurus (Rob), raphe pallidus (Rpa) and the parapyramidal regions (15). Microinjection of TRH or the stable TRH analog into the DMN or Amb induces vagal-dependent cardiac and gastrointestinal responses, including bradycardia (16) and stimulation of gastrointestinal secretion and motility (12). Activation of raphe cell bodies by microinjection of kainic acid (16, 17) or glutamate (18, 19) into the Rpa or Rob induces similar vagal-mediated cardiovascular and gastrointestinal responses (12). Cold exposure, which increases pro-TRH messenger RNA (mRNA) in the Rpa and Rob (20), also results in vagal dependent stimulation of gastric acid secretion and motility (21). The autonomic responses to cold stress or to chemical stimulation of the caudal raphe nuclei can be prevented by blockade of endogenous TRH action using TRH antibody injected into the cisterna magna (21), or microinjected into the DMN (17) or Amb (16), or using TRH receptor antisense oligodeoxynucleotides injected into the cisterna magna (19). Tracing studies showed that TRH synthesizing neurons in the caudal raphe nuclei also contribute dense projections to the sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord (22), where TRH acts as an excitatory neurotransmitter (23). Taken together, these findings provide strong evidence that TRH-containing projections from caudal raphe nuclei to the vagal and sympathetic preganglionic motoneurons play an important role in brain stem regulation of the peripheral autonomic nervous system.
The negative feedback regulation of TRH gene expression by thyroid hormones has been well documented in neurons of the medial paraventricular nucleus (PVN) of the hypothalamus (24, 25, 26). The simultaneous occurrence of increased pro-TRH mRNA and TRH prohormone in these neurons following thyroidectomy indicate that hypothyroidism may enhance both transcription and translation of the TRH prohormone (25, 26). In contrast, TRH gene expression in other hypothalamic nuclei or thalamic sites containing TRH synthesizing neurons is not altered by hypothyroidism or hyperthyroidism (24, 25, 27). Although the medullary caudal raphe nuclei contain the most abundant group of TRH synthesizing neurons outside of the hypothalamus (20, 25), the influence of thyroid hormones on TRH gene expression in the medullary Rpa and Rob is still unknown. The aim of the present study was to determine whether alterations of circulating thyroid hormone levels induced by surgical thyroidectomy with or without T4 replacement influence TRH gene expression in the medullary caudal raphe nuclei in rats. Also, because hypothalamic TRH gene expression is suppressed by fasting (28) and medullary TRH is known to be involved in the regulation of feeding related gastric secretion and motility (29), the influence of hypothyroidism on medullary TRH gene expression was compared in both 24 h fasted and normally fed rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thyroidectomy
Rats were anesthetized with an ip injection of a 3:1 volume
mixture of ketamine (75 mg/kg; Fort Dodge Laboratories, Fort Dodge, IA)
and xylazine (5 mg/kg; Mobay Corporation, Shawnee, KS). Before
extirpating the thyroid gland, the anterior and posterior thyroid
arteries were ligated, and the external parathyroid glands were
carefully isolated from the thyroid gland with a fine glass needle and
kept intact during extirpation of the thyroid gland. Sham operations
were performed under the same conditions except that the thyroid and
parathyroid glands as well as the blood supply to the glands were kept
intact. Rats were awake within 15 min after the surgery and kept in
individual cages for at least one week. Drinking water for
thyroidectomized rats was supplemented with 2% calcium gluconate to
maintain calcium homeostasis.
Experimental protocols
Rats were either sham-operated and ip injected with saline or
T4 (10 or 100 µg/100 g for in situ
hybridization or Northern blot analysis, respectively) (Sigma Chemical Co., St. Louis, MO) or surgically thyroidectomized and
injected with saline or T4 (2 or 4 µg/100 g for in
situ hybridization or Northern blot analysis, respectively).
Saline or T4 was injected daily from days 2 to 30 after
surgery. The T4 replacement doses were selected based on
previous reports showing that administration of pharmacological doses
of thyroid hormones inhibited the hypothyroidism-induced rise in
hypothalamic pro-TRH mRNA (24, 25, 26, 31, 32). Body weights were monitored
every 3 days. At the end of the treatments, rats were deprived of food
but not water for 24 h and then killed. Five additional paired
groups of sham-operated and thyroidectomized rats receiving daily
saline injections and fasted for 24 h were killed respectively at
1, 2, 3, 4, and 5 weeks after surgery. Two groups of sham-operated and
thyroidectomized rats receiving daily saline injections were kept
normally fed without fasting before they were killed. In all
experiments, animals were decapitated in a "one in each
group-alternative" order. Trunk blood was collected for measuring
T4 levels by RIA and brainstems were collected for
measuring pro-TRH mRNA levels by Northern blot analysis and for
locating the mRNA by in situ hybridization.
T4 RIA
Blood samples were immediately put on ice and centrifuged. The
serum was kept at -80 C until assayed. Serum aliquots (10 µl) were
used to measure total T4 levels with a commercial RIA kit
(Amerlite Diagnostics Limited, Rochester, NY). The sensitivity of the
assay ranged from 0 to 500 nmol/liter. All samples were measured in
duplicate.
Pro-TRH hybridization probe
The hybridization probe was prepared as described in our
previous studies (20). All reagents were purchased from Promega Corp. (Madison, WI). The 1322 bp EcoRI pro-TRH DNA
fragment cloned in plasmid pUC12 (kindly provided by Dr. R. Goodman,
Vollum Institute, Portland, OR) was subcloned into pGEM-3. The
antisense cRNA probe was synthesized using 1 µg of
SmaI-linearized plasmid DNA in transcription buffer
containing DTT, each of ATP, GTP, and CTP, and 50 µCi
[
-32P]UTP (for Northern blot analysis) or 100 µCi
[-35S]UTP (for in situ hybridization). The
reaction was initiated by adding T7 RNA polymerase and incubated at 37
C for 60 min. The plasmid DNA was removed by ribonuclease-free
deoxyribonuclease I. Radio-labeled RNA was purified by
phenol/chloroform extraction and alcohol precipitation. For in
situ hybridization, the probe was hydrolyzed by incubation with
0.2 M Na2CO3 and 0.2 M
NaHCO3 at 60 C for 15 min to obtain fragments about 150
nucleotides in length.
The specificity of the pro-TRH probe has been validated in our previous studies (20). The addition of a 50-fold excess of cold probe simultaneously with the radiolabeled probe into the hybridization mix solution almost completely abolished the pro-TRH mRNA signal. Pro-TRH mRNA signal was also observed in the PVN using the same probe (20).
Northern blot analysis of pro-TRH mRNA
Rat brains were rapidly removed after decapitation, and the
brainstems were dissected, put on dry ice immediately, and kept at -80
C until RNA extraction. The landmarks for dissection of the brain stem
and the performance of Northern blot analyzes were as previously
described (20). Briefly, denatured total RNA samples (20 µg)
extracted (33) from control and experimental groups were separated on
the same 1.2% formaldehyde-agarose gel and then were transferred to
the same nylon membrane (Hybridization, 0.45 micron, 10 x 15 cm,
Amersham Corp., Arlington, Heights, IL). RNA blots were prehybridized
for 6–10 h and then incubated with fresh hybridization buffer in the
presence of radiolabeled probe for 24–48 h at 55 C. The blots were
exposed to x-ray films (XAR-5, Eastman Kodak Co.,
Rochester, NY) for 1–3 days at -80 C. The relative densities of the
mRNA signals were measured quantitatively by using a Bio-Rad Laboratories, Inc. densitometer (model 620, Hercules, CA) and
control levels were expressed as 100%. The consistency of RNA loading
and transferring were assessed by rehybridizing the membrane with an
18S ribosomal RNA oligodeoxynucleotide probe (5'CGG CAT GTA TTA GCT CTA
GAA TTA CCA CAG 3') labeled with 32P-ATP by standard 5'
end-labeling techniques (34).
In situ hybridization of pro-TRH mRNA
Brains were removed after decapitation and immediately frozen
with dry ice. Cryostat-cut brain stem sections (10 µm) were collected
at the levels from interaural -2.80 to -4.30 mm according to the
atlas of Paxinos and Watson (35). Sections were fixed in 4%
paraformaldehyde (Sigma Chemical Co., St. Louis, MO)/PBS
for 15 min and rinsed twice in PBS. Then the sections were transferred
to a solution containing 0.25% acetic anhydride in 0.1 M
triethanolamine (pH 8.0) for 10 min at room temperature followed by
dehydrating through graded ethanol, delipidating in chloroform, rinsing
in ethanol and air-drying. In situ hybridization was based
on the procedures of Fremeau et al. (36). In brief, labeled
cRNA probe (1 x 106 cpm/slide) was added to a
hybridization cocktail (90 µl/slide), which consisted of 50%
formamide, 600 mM NaCl, 80 mM Tris-HCl (pH
7.5), 4 mM EDTA, 0.1% sodium pyrophosphate, 0.2% SDS,
10% dextran sulfate, 100 mM dithiothreitol, 1 x
Denhardt’s solution and 0.5 mg yeast transfer RNA per milliliter.
Final hybridization was carried out for 24 h at 50 C. Then, slides
were washed in 2 x SSC, treated with ribonuclease A to digest the
unhybridized RNA, desalted in 1 x and 0.5 x SSC at 55 C and
in 0.1 x SSC at room temperature. Slides were then washed in
demineralized water followed by 95% ethanol and air-dried. Labeled
sections were coated with liquid emulsion (Kodak NTB-2
diluted 1:1 with water), exposed for 7 weeks at 4 C, developed in D-19
developer and fixed in Kodak fixer. Sections were
subsequently stained with Cresyl Violet and photographed under the
microscope with light and dark fields. Silver grains were counted under
the light microscope with oil immersion lens only on neurons cut across
the nuclei as previously described (37). The numbers of neurons cut
across the nuclei in each nucleus (Rpa or Rob) were 6–15 neurons per
section and various in different caudal to rostral levels. For each
rat, the number of silver grains per neuron in each nucleus represents
the mean ± SE of five random selected neurons (cut
across the cell nucleus) per section and five sections in different
caudal-rostral levels.
Statistics
Results are expressed as means ± SE.
Comparisons between two groups were analyzed by Student’s t
test, and multiple groups were compared by one-way ANOVA followed by
Duncan’s contrast. P values of < 0.05 were considered
statistically significant.
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Results |
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Serum T4 levels in thyroidectomized rats decreased by
75–87% compared with sham-operated controls throughout the 5-week
period (Table 1
). Thirty days after
surgery, thyroidectomized rats injected daily with saline had a 2- to
3-fold decrease in T4 levels; T4 replacement (2
or 4 µg/100 g·day) reversed the hypothyroidism in thyroidectomized
rats. Injection with T4 at 10
or 100 µg/100 g in the sham-operated rats resulted in 8- or >10-fold
increases in serum T4 levels, respectively, compared with
sham-operated rats injected daily with saline (Tables 2 and 3).
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illustrates
medullary pro-TRH mRNA and 18S ribosomal RNA signals in 24 h
fasted rats with different thyroid statuses after 30 days of treatment.
Quantitative analysis of the signals showed that thyroidectomized rats
injected with saline had a 120% increase in medullary pro-TRH mRNA
levels compared with sham-operated rats (Fig. 2). T4
replacement (4 µg/100 g·day for 30 days) completely inhibited the
increase in medullary pro-TRH mRNA levels induced by thyroidectomy
(Fig. 2). Sham-operated rats injected with T4 (100 µg/100
g·day for 30 days) showed no change in the pro-TRH mRNA levels
compared with saline injected rats (Fig. 2). Time course studies
indicated that medullary pro-TRH mRNA levels were significantly
enhanced by 72.5% one week after thyroidectomy and reached a plateau
at the third week after surgery (133% increase) that was maintained
throughout the 5-week experimental period (Fig. 3).
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). The pro-TRH mRNA signals in the Rpa and Rob were
about 2-fold more dense in thyroidectomized rats compared with
sham-operated rats 30 days after surgery (Fig. 1, A and B). In
addition, the number of silver grains per neuron was increased more
than 3-fold in thyroidectomized rats compared with control (Table 4). T4
replacement (2 µg/100 g·day for 30 days) reversed the increase of
pro-TRH mRNA signal in thyroidectomized rats (Fig. 1C, Table 4). A
tendency to decrease pro-TRH mRNA signals was observed in hyperthyroid
rats compared with euthyroid rats, however, the difference did not
reach statistical significance (Fig. 1D, Table 4).
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shows the pro-TRH mRNA signal
levels in sham-operated and thyroidectomized rats 30 days after surgery
in both 24 h fasted or normally fed conditions. A 24 h
fasting did not change pro-TRH mRNA levels in euthyroid rats but
reduced significantly the magnitude of the medullary pro-TRH mRNA
response to thyroidectomy. While the pro-TRH mRNA levels in 24 h
fasted/thyroidectomized rats were 180% of the 24 h
fasted/sham-operated controls (P < 0.02), the TRH mRNA
levels of normally fed/thyroidectomized rats were 500% of the normally
fed/sham-operated rats (P < 0.001) (Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The difference in medullary pro-TRH mRNA levels between the
sham-operated and thyroidectomized rats does not result from circadian
variations (30) or cold exposure (20, 30) because rats in all groups
were kept under same conditions of illumination and temperature, and
were killed in a "one in each group-alternative" order. Data from
the present study indicates that the stimulation of medullary TRH gene
expression in thyroidectomized rats is related to the removal of the
negative feedback signal exerted by thyroid hormones. First, elevated
levels of medullary pro-TRH mRNA were maintained after thyroidectomy,
which correlated with the sustained decrease in serum T4
levels throughout the experimental period. Second, T4
replacement inhibited the hypothyroidism-induced rise in medullary TRH
gene expression. In support of this concept, we recently found
immunoreactivities of thyroid hormone receptor isoforms and
colocalization of prepro-TRH immunoreactivity with TR1 mRNA or
TRß2 immunoreactivity in the neurons of the Rpa and Rob (40, 41, 42).
Although the hormone replacement with ip injection of T4 at
4 µg/100 g·day in thyroidectomized rats brought serum
T4 levels into the superphysiological range, there was no
functional manifestation of hyperthyroidism, as shown by the constant
body weight gain in the last two weeks of the treatment. Previous
studies have documented that the suppression of the rise in
hypothalamic TRH gene expression in hypothyroid rats to euthyroid
levels required peripheral infusion of T3 doses inducing
supraphysiological and hyperthyroid circulating range (at least 1.7
times of normal) (31, 43). High doses of T3 administration
were also required to reverse changes in heart rate (9) and nuclear
thyroid hormone receptor levels in the anterior pituitary (43) of
hypothyroid animals. It was proposed that both T4 and
T3 contribute to the feedback regulation of TRH
biosynthesis in hypophysiotropic neurons of the PVN and T4
monodeiodination exists within the central nervous system (31, 43).
Although many studies used T3 (9, 31, 43), T4
was also used to replace thyroid hormone in hypothyroid rats in
previous studies (26, 32). The threshold dose at which exogenous
thyroid hormone reverses the increase in medullary pro-TRH mRNA after
thyroidectomy needs to be further assessed. However, in the present
study, T4 replacement at the dose of 2 µg/100 g·day,
which resulted in a 2-fold high serum T4 levels
vs. the control, also reversed the increase in medullary
pro-TRH mRNA in thyroidectomized rats as assessed by in situ
hybridization.
Although most investigations on the feedback regulation of TRH gene expression in the PVN by thyroid hormones were studied using only hypothyroid animal models (24, 26, 31, 43), there are reports that hyperthyroidism further suppressed the pro-TRH mRNA levels in the PVN (25, 27). In the present study, however, medullary pro-TRH mRNA levels in hyperthyroid rats did not appear to have a significant change when assayed by Northern blot analysis, and only slightly decreased when assayed by in situ hybridization compared with euthyroid rats. The lack of a significant decrease may result from relatively low basal levels and/or insufficient sensitivity to measure changes in the present condition. Alternatively, it is also possible that medullary TRH gene expression is not sensitive to supraphysiological levels of circulating thyroid hormone. Future study is needed to assess whether medullary pro-TRH mRNA levels is influenced by hyperthyroidism under stimulated conditions that increase medullary pro-TRH mRNA levels, such as cold stress (20).
It is interesting to note that the increase in medullary pro-TRH mRNA levels in hypothyroid rats (30 days after thyroidectomy) was more remarkable in normally fed rats than in 24 h fasted rats. A 24 h fasting did not influence basal medullary pro-TRH mRNA levels in euthyroid rats. By contrast, the increase in pro-TRH mRNA levels induced by hypothyroidism was three times higher in normally fed rats compared with 24 h fasted rats. These results indicate that feeding and/or the fed state enhanced the stimulation of medullary TRH gene expression-induced by hypothyroidism. Alternatively, the regulation of medullary TRH gene expression is more sensitive to the stimulation of feeding and/or fed state in hypothyroid rats than in euthyroid rats. Recent studies have revealed that fasting induces suppression of TRH gene expression in the PVN (28). This may be due to a resetting of the set point for thyroid hormone dependent inhibition of pro-TRH biosynthesis by a fall in circulating leptin levels during fasting (28). Whether leptin is also involved in the regulation of medullary TRH gene expression needs further investigation. Another explanation for the difference of medullary pro-TRH mRNA levels between fasted and normally fed thyroidectomized rats may relate to the specific function of medullary caudal raphe nuclei. Previous observations have established that the activation of the medullary raphe-DMN TRH system is one of the important steps in central vagal activation mediating the cephalic and gastric phases of gastric acid secretion and motility during digestion (12). Enhanced TRH gene expression in the caudal raphe nuclei in response to feeding and digestion in thyroidectomized rats may provide further evidence that medullary TRH gene expression relates with gastrointestinal regulation, and that increases in TRH gene expression may have pathophysiological consequences related to gastrointestinal disorders accompanying hypothyroidism. Although the detailed mechanisms still need to be investigated, we recently obtained supportive evidence of such a relationship. Hypothyroidism induced a significant increase in the activity of gastric corpus histidine decarboxylase, the key enzyme in the synthesis of histamine. This increase was more remarkable (three times higher) in normally fed rats than in 24 h fasted rats (44). In addition, increased histidine decarboxylase activity could be induced by central injection of a TRH analog in fasted euthyroid rats (45).
In summary, pro-TRH mRNA levels are significantly elevated in the medulla from 1 to 5 weeks after surgical thyroidectomy in association with low circulating levels of T4 in rats. Conversely, the peripheral injection of T4 inhibited this response. These data, together with the main location of pro-TRH mRNA changes in the Rpa and Rob neurons, clearly support the view that in addition to the medial PVN, caudal medullary raphe nuclei are important sites where TRH gene expression is negatively regulated by thyroid hormones. Because TRH synthesizing neurons in the caudal raphe nuclei project directly to the medullary vagal motoneurons (15) and play an important role in central autonomic regulation (12, 29), the enhanced TRH gene expression in these caudal raphe nuclei may have important functional relevance to the understanding of autonomic-related visceral alterations induced by abnormal thyroid statuses.
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Acknowledgments |
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Footnotes |
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Received May 6, 1998.
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1 mRNA in TRH immunoreactive neurons in the rat caudal
raphe nuclei. Soc Neurosci 23:430 (Abstract)
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