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Departments of Physiology (D.F.B., F.J.K.) and Biology (L.A.T.), Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109-0404
Address all correspondence and requests for reprints to: Dr. F. J. Karsch, Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Room 1101 SW, Ann Arbor, Michigan 48109-0404. E-mail: fjkarsch{at}umich.edu
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Abstract |
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Introduction |
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Thyroid hormones are obligatory for expression of the seasonal reproductive cycle of sheep and other seasonal breeders such as deer, mink, and certain birds (7, 8, 9, 10, 11, 12, 13). In the ewe, thyroid hormones, but not their seasonal changes, are required for progression of one stage of the rhythm, the neuroendocrine processes that lead to seasonal suppression of pulsatile GnRH secretion (14, 15). Although thyroid hormones ultimately influence central mechanisms involved in the regulation of pulsatile GnRH secretion, it is not known whether their primary site of action is central or peripheral. On the one hand, central sites of action of thyroid hormones appear to be critical for the development and maintenance of normal brain functions (16, 17). On the other hand, thyroid hormones act peripherally to regulate many metabolic and physiological functions (18), which themselves could potentially alter GnRH secretion.
The goal of this study was to test the hypothesis that thyroid hormones act directly within the brain to promote the seasonal inhibition of reproductive neuroendocrine function. To test this hypothesis, we studied the effect of small doses of T4, delivered centrally or peripherally, on seasonal suppression of LH secretion in thyroidectomized (THX) ewes. If thyroid hormones indeed act centrally, replacement of a low dose of T4 directly to the brain should restore seasonal LH inhibition in THX animals. In contrast, the same low dose administered peripherally should not be effective due to dilution of the hormone.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Procedure for chronic central infusion of
T4
Previous studies demonstrated that thyroid hormones must be
present for 60–90 days late in the breeding season (January-March) for
anestrus to develop at the usual time (21). Therefore, a cannulation
system was devised to infuse T4 centrally for this duration
in unrestrained and normally behaving sheep. The cannula itself did not
protrude externally, thus minimizing risks of bacterial contamination
and mechanical damage. To insert the cannula, a 5-cm midline skin
incision was made posterior to a line joining the caudal poles of the
two orbits. The skin and periosteum were retracted to visualize bregma.
A 1-cm hole was drilled through the frontal bone 7 mm rostral to bregma
and 5 mm lateral to the medial frontal bone suture. Cannulation of a
lateral ventricle was achieved with a 22-gauge stainless steel cannula
equipped with a right angle side arm (Plastic One, Roanake, VA; length,
27 mm). The side arm was connected to microbore tubing (Tygon, Norton
Performance Plastics Corp., Akron, OH; id, 0.51 mm; od, 1.52
mm). Using a stereotaxic apparatus adapted for sheep (David Kopf,
Tujunga, CA), the cannula was lowered vertically until isotonic saline
flowed by gravity through the tube connected to the cannula (usually
about 19 mm from the meningeal surface). The cannula was then
progressively lowered until flow stopped, indicating that the tip
contacted the bottom of the ventricle. The final position was set 1–2
mm above this point. The cannula was permanently fixed in place with
dental cement anchored to the skull through approximately 2-mm diameter
tunnels drilled through the bone. The skin was then sutured, completely
covering the surgical site, so that none of the apparatus was exposed.
The Tygon tubing attached to the side arm was plugged and tunneled sc
to the back of the neck. The tubing and cannula were flushed and filled
with 500 µl bacteriostatic saline solution and hermetically
closed.
This study included two runs of intracerebroventricular (icv) T4 replacement performed during 2 consecutive years. In run 1, the Tygon tubing was left completely internalized, and T4 solution was administered by sc osmotic pumps. In run 2, the end of the tubing was exteriorized at the back of the neck, coated with antibiotic spray, and wrapped in a protective bandage, and T4 was delivered by an externalized pump placed in a back pack.
Preliminary experiments: determination of dose
The desired dose of T4 for icv infusion
was selected to be that which restored the approximate euthyroid
concentration of total T4 in the cerebrospinal
fluid (CSF) of THX ewes. To determine this concentration, CSF was
sampled by puncture of the cisterna magna of three thyroid-intact ewes
and four thyroidectomized ewes injected sc with
T4 (THX+T4) to restore the
euthyroid state (L-T4; Sigma Chemical Co., St. Louis, MO; 3 µg/kg·day; 
210 µg/sheep, for 5
days; T4 blood concentration, 48.3 ± 5.7
ng/ml). Total T4 concentrations in CSF were
similar between groups (1.9 ± 0.5 vs. 2.8 ± 0.5
ng/ml in thyroid-intact and THX+T4 animals,
respectively).
The T4 dose needed to restore a CSF total
T4 concentration of about 2 ng/ml was estimated
based upon the reported CSF production rate and total volume in the
goat and sheep (120–160 µl/min and 14 ml, respectively) (22, 23).
Assuming that at equilibrium the amount of T4
entering the CSF is the same as that leaving the CSF, we calculated
that the infusion rate should be about 0.4 µg/day. However,
continuous icv infusion of 0.5 µg/day [5 µl/h of a
T4 solution containing 4 µg/ml, using Alzet
Corp. (Palo Alto, CA) osmotic minipumps] did not induce any detectable
T4 in the CSF of one THX ewe. We therefore
increased the dose and infused either 4 or 40 µg/day, icv, in two THX
ewes (2% and 20% of the sc dose that renders THX ewes euthyroid).
The CSF total T4 concentrations after 6 and 15
days of treatment averaged 2.0 and 20.3 ng/ml for the 4 and 40 µg/day
doses, respectively. The 4 µg/day dose thus restored a physiological
T4 CSF concentration and was chosen as one dose
for run 1 of the main experiment. However, as thyroid hormones can
reach brain sites via routes other than transport through CSF (24),
restoration of a physiological CSF concentration in the THX ewe may not
achieve a physiological concentration at the target sites. Therefore, a
second, 10-fold higher, dose was also administered in run 1.
Main experiment: run 1
To test the hypothesis that thyroid hormones act centrally,
OVX+E ewes were THX between December 4 and December 8, 1995, and
allocated to five groups balanced for body weight and treated as
follows: 1) euthyroid controls (n = 4) received daily peripheral
T4 injections to restore the euthyroid state (3
µg/kg day, sc; ~210 µg/day·sheep); 2) vehicle controls (n
= 8) received icv infusion of the vehicle used to deliver
T4; 3) low dose central ewes (n = 8) received
continuous icv infusion of a dose of T4 (4.8 µg/day)
calculated to restore a physiological CSF T4 concentration;
4) high dose central ewes (n = 8) received continuous icv infusion
of a 10-fold greater dose (48 µg/day); and 5) low dose peripheral
ewes (n = 6) received continuous sc infusion of T4 at
twice the low icv dose (9.6 µg/day). One lateral ventricle was
cannulated between December 15 and December 29, and T4 or
vehicle was infused between January 25 and April 24. The neuroendocrine
reproductive state was monitored by assaying LH in blood sampled twice
a week from November 2 to May 6.
Continuous infusion was achieved by 2-week sc osmotic pumps delivering
5 µl/h. Pumps were filled under sterile conditions, implanted sc on
the side of the neck, and replaced every 2 weeks under local
anesthesia. Concentrated stock solutions (0, 1.2, 2.4, and 12 mg/ml)
were prepared at the start by diluting T4 in 0.4
N sodium hydroxide in 60% ethanol. One milliliter of stock
was diluted just before use in 29 ml sodium PBS (0.01 M; pH
7.3) containing 0.1% sterile BSA (Sigma Chemical Co.;
final pH 12).
Several ewes receiving icv infusion developed health problems (see Results). To discriminate the physiological seasonal LH inhibition from a health-related decrease in LH secretion, the functionality of the GnRH/LH secretory system was tested in icv T4- and vehicle-treated ewes exhibiting low LH at the end of run 1 by N-methyl-D,L-aspartate (NMDA) challenge (5 mg/kg, iv). This treatment markedly stimulates LH secretion in healthy anestrous ewes (25).
Main experiment: run 2
The results of run 1 were not definitive, as group sizes were
reduced due to health problems arising from icv infusion. Five
modifications were made for run 2. First, each animal was fitted with
an icv cannula at the time of thyroidectomy to avoid repeated general
anesthesia and brain surgery on severely hypothyroid animals. Second,
continuous infusions were achieved using externalized back-pack pumps
instead of internalized 2-week osmotic pumps. Thus, the infusion
solution could be renewed with minimal animal intervention, and
repeated skin trauma due to osmotic pump replacement could be avoided.
Third, a single T4 dose was used (twice the
lowest icv dose used in run 1). Fourth, sodium hydroxide and ethanol
concentrations in the stock solution were reduced to 0.3 N
and 50%, respectively, to lower the pH of the infused solutions by
approximately 2 U (modification possible as the
T4 concentration was 5 times lower than the
highest icv dose of run 1). Fifth, infusions were begun 1 month earlier
(December 23), which is closer to the onset of the seasonal period of
sensitivity to thyroid hormones in the ewe (21).
Thirty OVX+E ewes were thyroidectomized and equipped with an icv
cannula between November 14 and December 12, 1996. Ewes were allocated
to four groups balanced for body weight: 1) euthyroid controls (n
= 5) received daily peripheral injections of T4
(3 µg/kg·day, sc; 210 µg/day·sheep); 2) vehicle controls
(n = 10) received icv vehicle infusion; 3) central
T4 ewes (n = 9) received icv
T4 infusion (9.6 µg/day; 100 µg/ml solution);
and 4) low dose peripheral ewes (n = 6) received sc infusion of
the same low T4 dose (9.6 µg/day; 5% daily
dose in euthyroid controls). Treatments continued from December 23
(late breeding season) until LH was confirmed to have fallen below 1
ng/ml in all euthyroid controls (April 4). LH concentrations were
determined in blood sampled twice a week from November 14 to April
10.
T4 or vehicle solutions were infused using a
programmable pump (Autosyringe, model 6 MP) contained in a backpack
allowing unrestricted movement of the ewe. The Tygon tubing exiting the
skin on the side of the neck was connected to a 1-ml syringe attached
to the pump. Solutions were renewed weekly. Two stock solutions were
prepared, one containing 6 mg/ml L-T4 and the
other containing no T4. These two solutions were
diluted at 1:60 in PBS-0.1% BSA to obtain the final infusion solution
(pH 10).
The completeness of thyroidectomy was assessed by measuring the serum total T4 concentration weekly throughout the experiment (first month of treatment in vehicle controls). Adequacy of central T4 replacement was evaluated by assaying total T4 in CSF collected at the end of the experiment by puncture of the cisterna magna of icv T4-treated ewes, euthyroid controls, and five randomly selected thyroid-intact ewes.
The functionality of the GnRH/LH secretory system in all ewes in which LH fell was assessed in two ways. First, the LH response to NMDA challenge (2 mg/kg, iv) was determined; blood was sampled at 20-min intervals for 1 h before and at 10-min intervals for 2 h after injection. Second, the LH response to withdrawal of estradiol negative feedback was determined by measuring LH in four daily samples collected 44–48 days after removing the estradiol implant in icv T4-treated ewes.
Finally, to evaluate whether the differing effects of T4 treatments on the neuroendocrine gonadotropic axis were associated with different effects on the hypothalamo-pituitary thyroid axis, TSH was assayed in blood sampled twice before thyroidectomy, at the time of treatment onset, and then twice a month from 3–9 weeks of the treatment.
Hormone assays
Blood was collected by jugular venipuncture, and serum was
stored at -20 C until assay. LH was measured in duplicate 20- to
200-µl aliquots of serum by a modification (26) of a previously
reported RIA (27, 28). Concentrations are expressed in terms of
NIH-LH-S12. The mean sensitivities for 200 µl (95% confidence
interval of buffer control) were 0.68 and 0.83 ng/ml for run 1 (14
assays) and run 2 (13 assays), respectively. The mean intraassay
coefficients of variation for serum pools displacing radiolabeled LH to
approximately 30% and 60% of the buffer control were 8% and 6% (run
1), and 11% and 8% (run 2). Interassay coefficients of variation for
the same serum pools were 10% and 10% (run 1), and 10% and 15% (run
2).
Total T4 was assayed in 50-µl aliquots of serum using Coat-A-Count total T4 kits (Diagnostic Products Corp., Los Angeles, CA), as previously validated for use in sheep (29). Because the T4 level in CSF was close to the sensitivity of the assay, CSF was concentrated 5 times by drying in a vortex evaporator and reconstituting in distilled water to one fifth of its initial volume. T4 was assayed in 50-µl aliquots of this concentrated CSF. The sensitivities for serum averaged 2.3 ng/ml and 1.6 ng/ml in run 1 (seven assays) and run 2 (nine assays), respectively. The sensitivity for CSF (concentrated samples) was 0.29 ng/ml in CSF. The mean intraassay coefficients of variation for serum pools displacing radiolabeled T4 to 15% and 40% of the buffer control were 10% and 8% (run 1), and 7% and 6% (run 2). Interassay coefficients of variation for the same serum pools were 9% and 7% (run 1), and 13% and 6% (run 2).
TSH was measured in duplicate 20- to 200-µl aliquots of serum with a double antibody heterologous RIA previously validated in our laboratory (30), using an antiserum to ovine TSH generously provided by Dr. A. F. Parlow and the NIDDK. All values were determined in a single assay. The mean assay sensitivity was 0.33 ng/ml for 200 µl serum. The mean intraassay coefficient of variation for a serum pool displacing radiolabeled TSH to approximately 50% of buffer control was 18%.
Data analysis
The time of seasonal reproductive inhibition (onset of
neuroendocrine anestrus) was defined as the date of the first of three
consecutive samples in which serum LH concentration fell below 1 ng/ml.
The mean onset times of anestrus, the mean LH concentration after
estradiol removal, and the LH peak after NMDA challenge (mean value of
two highest points within 30 min after the injection) were analyzed by
a one-factor ANOVA (group) followed by Fisher’s test for
post-hoc comparisons. The time courses of TSH concentrations
were compared between groups using two-way ANOVA for repeated measures
(one factor between, groups; one factor within, time).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. All four euthyroid controls remained
healthy and exhibited a fall in LH below 1 ng/ml on March 25 ± 6
days, signifying the development of anestrus. This mean date of LH
seasonal inhibition is consistent with data accumulated in this
laboratory over several years in THX ewes treated with
T4 to restore the euthyroid state (15, 29, 31).
LH fell at the same time (March 21 ± 6 days) in seven of the nine
icv T4-treated ewes that remained healthy (two of
three low dose and five of six high dose) and displayed a robust
response to NMDA (LH peak, >10 ng/ml). In contrast, LH remained
elevated at a breeding season level through the end of the study (May
6) in five of six ewes treated peripherally with the low
T4 dose and in all three vehicle controls that
maintained good health.
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). Finally,
skin trauma and infections resulting from repeated osmotic minipump
changes suggested that this mode of infusion was not optimal for such
long term T4 replacement.
Run 2
The procedural modifications (see Materials and
Methods) eliminated the health problems encountered in run 1. The
completeness of thyroidectomy was confirmed by undetectable (<1.6
ng/ml) serum T4 levels in all but one THX ewe,
which was excluded from the study (T4 low dose sc
group). Serum T4 concentrations in euthyroid
controls averaged 52.3 ± 2.4 ng/ml and were similar to levels in
thyroid-intact ewes (31).
LH results (mean ± SEM) for all groups are
illustrated in Fig. 2. In the euthyroid
control (shading in each panel), LH fell to baseline (<1
ng/ml) on February 21 ± 4 days, signifying the beginning of
anestrus (1 month earlier than in run 1, probably due to the 1-month
earlier onset of T4 replacement). LH remained
high throughout the study in all 10 THX ewes receiving vehicle icv
(top panel), indicating failure to enter the anestrous
season. Of great interest, LH fell to baseline in 8 of 9 ewes receiving
T4 icv (middle panel; exception
plotted separately). The date LH fell below 1 ng/ml in the icv
T4-treated group (February 14 ± 9 days) was
not different from that in euthyroid controls. In striking contrast,
this low T4 dose failed to promote the seasonal
decline in LH when delivered sc (bottom panel).
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, top). Further, estradiol
implant removal after LH had fallen caused a dramatic increase in LH in
all eight icv T4-treated ewes that exhibited
seasonal LH inhibition. Mean LH concentrations 44–48 days after
estradiol removal were not different between these ewes and a separate
group of thyroid-intact OVX+E ewes in which estradiol replacement was
ended at the same time (n = 6; not included in the main study;
Fig. 3, bottom).
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. As expected, TSH was low in all
animals before thyroidectomy (November). TSH increased about 10-fold
during the month between thyroidectomy and the onset of T4
or vehicle treatment (December). T4 replacement
in euthyroid controls caused the mean TSH concentration to fall within
3 weeks to values approximating those before thyroidectomy. In
contrast, the TSH concentration remained high and unaffected by
treatment with the low dose of T4 (either icv or
sc) or with vehicle icv (i.e. ANOVA revealed no significant
interaction between time and group).
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2 µl) every 30 min. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Prior work in seasonal species in which the transition to the nonbreeding season is thyroid hormone dependent has shown that thyroid hormones ultimately impact the GnRH neurosecretory system. The earliest studies, performed in the male European starling, demonstrated that thyroid hormones are needed for seasonal changes in hypothalamic content of GnRH (32). Subsequent work in the ewe indicates that thyroid hormones must be present for the decrease in pulsatile GnRH secretion into the hypophyseal portal vasculature (14). Despite prior evidence that thyroid hormones ultimately impact central mechanisms of seasonal GnRH inhibition, the present study is the first to establish their primary target is located within the brain. One preliminary report has indicated that intracerebral administration of T4 can affect reproductive function in the hypothyroid Syrian hamster, a species in which seasonal reproductive suppression is driven by photoperiod (33). That study, however, failed to establish a link between this central action of thyroid hormone and photoperiod-induced gonadal regression. Further, that study even suggested central administration of T4 stimulated reproductive function. Because peripheral thyroid hormone action regulates a wide panel of endocrine and metabolic functions that could alter GnRH secretion, discrimination of a central vs. a peripheral primary site of action constitutes a critical step in understanding how thyroid hormones impact seasonal GnRH secretion. Moreover, our present finding implicating a central mechanism provides important direction, orienting future studies toward elucidating the central mechanisms of thyroid hormone action.
Several intriguing possibilities may be considered with respect to
where and how thyroid hormones act in the brain to promote seasonal
changes in GnRH secretion. Thyroid hormone receptors are widely
expressed throughout the adult brain. Of great interest, 40–60% of
GnRH neurons in the preoptic area/anterior hypothalamus of the sheep
express the 
-subtype of the T3 receptor (34). Thus, GnRH
neurons themselves might be the target. Of further interest, the
seasonal switch in GnRH secretion in the ewe is associated with changes
in the density of synaptic inputs onto cell bodies and dendrites of
GnRH neurons in the preoptic area (35). Thyroid hormones might,
therefore, act at the level of GnRH neurons to promote this type of
neuroplastic reorganization. Possibly related to this, GnRH cell bodies
and dendrites are heavily ensheated by glial cells and processes (36).
Thyroid hormone receptors have been identified in glia, and
differentiation and function of glia are thyroid hormone regulated
(37, 38, 39, 40). Thyroid hormones might therefore promote structural
reorganization of glia, influencing the ability of afferent neurons to
gain access to GnRH cells. In addition, GnRH secretion might be
regulated at the level of the median eminence, through structural
remodeling of the relationship between GnRH terminals and glial
processes (41, 42, 43). Such regulation could occur in a seasonal way under
the influence of thyroid hormones to alter either innervation of GnRH
neurons or their proximity to the portal vasculature, thereby
regulating GnRH secretion.
Beyond GnRH cells and glia, thyroid hormones may also act on other hypothalamic cells crucial to the regulation of seasonal reproduction. For example, they could act on inhibitory dopaminergic neurons or on cells that mediate estradiol negative feedback. In the ewe, hypothalamic dopaminergic pathways, including the A14 nuclei, play a critical role in seasonal and photoperiodically induced GnRH/LH inhibition (44, 45, 46, 47). Interestingly, tyrosine hydroxylase-immunoreactive neurons in the A14 nuclei express thyroid hormone receptor (34). Furthermore, thyroid hormones can regulate both differentiation and activity of dopaminergic neurons (48, 49). It could be hypothesized, therefore, that thyroid hormones act on dopaminergic neurons to regulate seasonal GnRH inhibition. With regard to cells that mediate estradiol negative feedback, it is interesting to note that thyroid hormones have been shown to enhance the number of estradiol receptor-immunoreactive neurons within the hypothalamus of the rat (50). Thus, it could be hypothesized that thyroid hormones somehow interact with the estradiol receptor to promote estradiol negative feedback on GnRH secretion.
Yet another possible pathway by which thyroid hormones might act centrally to influence GnRH seasonal secretion is the neuroendocrine-thyroid axis, specifically via alterations in TSH and TRH. The secretion of both of these hormones markedly increases in the ewe after thyroidectomy (30). Persistently elevated TRH/TSH might contribute to maintenance of the stimulated GnRH/LH secretion. However, neither TSH nor TRH has been functionally linked to stimulation of GnRH secretion. Further, our study uncoupled the effect of thyroid hormones on seasonal LH inhibition from their negative feedback on the neuroendocrine-thyroid axis. Indeed, icv T4 treatment in THX ewes restored seasonal LH inhibition without affecting the high serum TSH concentration. This result argues against a role for TSH/TRH and/or the hypothalamic mechanisms that regulate the hypothalamo-pituitary-thyroid axis in mediating the effect of thyroid hormones on seasonal GnRH/LH regulation.
Our conclusion that thyroid hormones act centrally must be qualified by considering three potential reservations. First, thyroid hormones delivered into the lateral ventricle might have targeted the pars distalis or pars tuberalis of the pituitary, sites that could affect gonadotrope responsiveness to GnRH or GnRH secretion itself. This possibility, however, seems unlikely for several reasons. The absence of obvious feedback of T4 delivered icv on TSH secretion suggests that centrally administered T4 in our study did not reach the pituitary in sufficient quantities to alter its function directly. In addition, all T4-treated ewes that exhibited LH seasonal suppression showed normal responses to NMDA (a potent GnRH secretagogue). Thus, pituitary responsiveness to GnRH was not seriously compromised by T4 delivered icv. Finally, the seasonal increase in response to estradiol negative feedback on LH secretion involves hypothalamic mechanisms (51) that inhibit pulsatile GnRH secretion (4). These mechanisms are not likely to be mediated by the pars tuberalis/distalis of the pituitary gland.
Second, it can be questioned whether our modalities of thyroid hormone treatment (specific hormone, dose, and route of administration) constituted a physiological replacement. T4 was administered rather than T3, the active hormone used by target cells, because T4 is the main form of thyroid hormone transported from blood into the CSF (52, 53) through a specific transport protein synthesized by the choroid plexus (52). Moreover, thyroid hormone action in the brain involves mainly in situ deiodination of T4 by the target cells themselves (54). Thus, we considered T4 to be more appropriate than T3 as the hormone for icv replacement. Further, the dose of T4 administered was chosen to be that which reproduced the CSF T4 concentration within the range observed in euthyroid animals. For these reasons, we consider the thyroid hormone replacement used in our study to have been physiological.
Third, this study does not exclude the possibility that a peripheral action of thyroid hormones contributes to seasonal LH inhibition in euthyroid animals. Although our findings demonstrate that a peripheral action of thyroid hormone is not required to promote seasonal LH inhibition, our study does not address whether peripheral actions play a role in thyroid-intact ewes. Despite this possibility, our results do suggest that the amount of T4 entering the CSF from the circulation of euthyroid sheep, mimicked in our study by low dose icv replacement, is sufficient to promote the end of the breeding season via an action within the brain.
In conclusion, our study supports the concept that thyroid hormones act centrally to promote seasonal inhibition of GnRH/LH secretion at the transition from the breeding season to anestrus. We suggest that this central action of thyroid hormones is needed for expression of the phase of the underlying circannual rhythm that leads to seasonal reproductive arrest. Our findings pave the way for future studies to address a question of fundamental importance: What are the central mechanisms by which thyroid hormones impact the circannual rhythm to regulate seasonal changes in reproductive neuroendocrine function?
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Acknowledgments |
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Footnotes |
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Received August 3, 1998.
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References |
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) distribution in hamster and
sheep brain: colocalization in gonadotropin-releasing hormone and other
identified neurons. Endocrinology 138:5039–5047 and ß thyroid receptors are expressed
by cultured ependymal cells. Correlation with the effect of
l-3,5,3'-triiodothyronine on glutamine synthetase mRNA. Neurosci Lett 150:174–178[CrossRef][Medline]
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