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Endocrinology, doi:10.1210/en.2003-0414
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Endocrinology Vol. 144, No. 9 4117-4122
Copyright © 2003 by The Endocrine Society

Functional Activation of Cerebral Metabolism in Mice with Mutated Thyroid Hormone Nuclear Receptors

Takanori Esaki, Hideyo Suzuki, Michelle Cook, Kazuaki Shimoji, Sheue-Yann Cheng, Louis Sokoloff and Jacques Nunez

Laboratory of Cerebral Metabolism, National Institute of Mental Health (T.E., M.C., L.S., J.N.); Positron Emission Department, Clinical Center (K.S.); and Laboratory of Molecular Biology, National Cancer Institute (H.S., S.-Y.C.), National Institutes of Health, Bethesda, Maryland 20892

Address requests for reprints to: Dr. Louis Sokoloff, Laboratory of Cerebral Metabolism, National Institute of Mental Health, Building 36, Room 1A-07, 36 Convent Drive, MSC 4030, Bethesda, Maryland 20892. E-mail: louis{at}shiloh.nimh.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neonatal hypothyroidism impairs structural maturation in the brain and results in diminished electrical activities and energy metabolism. We recently found that glucose utilization (CMRglc) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor {alpha}1 (TR{alpha}1), but not TRß. Previous studies had shown that CMRglc increases linearly with spike frequency in the afferent pathways to synapse-rich regions in neuropil, but not in neuronal cell bodies. To determine whether the decreased CMRglc in mutant TR{alpha}1PV/+ mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMRglc bilaterally in four stations of the whisker-to-barrel cortex pathway. Baseline CMRglc (unstimulated side) was markedly lower in all four stations in the TR{alpha}1PV/+ mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na+,K+-adenosine triphosphatase expression and neuronal differentiation. Despite the lower baseline CMRglc, however, vibrissal stimulation evoked percent increases in CMRglc in the TR{alpha}1PV/+ mutants that were as great as those in wild-type mice. These results indicate that in the TR{alpha}1PV/+ mutants there it is a reduction in synaptic density that is responsible for the decrease in CMRglc, but functionality of existing synapses is retained.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE MOST prominent effects of neonatal hypothyroidism in brain are retarded outgrowth of neuronal processes, reduced neuropil, and impaired development of electrical activities (1, 2, 3). This leads in adulthood to impaired learning, memorization, and understanding capabilities, i.e. a type of mental retardation characteristic of cretinism. Animals made hypothyroid from birth have about half the number of synapses as euthyroid animals (1), and the size and packing density of dendritic spines (4, 5, 6) are reduced throughout the brain. Structural maturation of mammalian brain is normally accompanied by profound increases in local rates of glucose utilization (CMRglc) (7), but in adult rats made cretinous by radiothyroidectomy soon after birth CMRglc is markedly depressed throughout the brain (8). The effects of thyroid hormone (TH) are mediated by nuclear receptors that are transcription factors regulating gene expression (9).

Experiments have been carried out in mice with knockout and knock-in mutations to identify which of the two major TH receptors, TR{alpha}1 and TRß, mediates the expression of TH-regulated genes in the brain. Both knock-in mutant receptors are unable to bind TH (10, 11). The {alpha} receptor mutant mouse (TR{alpha}1PV/+) exhibits increased mortality, infertility, and dwarfism (10), and the knock-in ß gene mutant (TRßPV/PV) leads to severe dysfunction of the pituitary-thyroid axis, delayed growth and bone maturation (11), and impaired hearing (12). Recent studies of cerebral energy metabolism have shown that local CMRglc is decreased by 57–72% throughout the brain in TR{alpha}1PV/+ mutant, but not in TRßPV/PV, mice (13). Inasmuch as local CMRglc has been shown to be linearly related to the frequency of action potentials in the afferent inputs to synapses in neuropil and, therefore, to reflect the degree of synaptic activity (14), the lower rates of local CMRglc suggested that either the density of synapses or the functional activity in existing synapses was reduced in the TR{alpha}1PV/+ mutants.

To ascertain which or both of these possibilities might be true, we measured CMRglc by the quantitative autoradiographic 2-[14C]deoxyglucose (2-[14C]DG) method (15) in four stations of the whisker-to-barrel cortex sensory pathway of unanesthetized TR{alpha}1PV/+ and TRßPV/PV mutant mice and wild-type controls during unilateral vibrissal stimulation as previously described (16). The four stations were the spinal and principal trigeminal nuclei in the brainstem, the ventral posteromedial (VPM) nucleus of the thalamus, and the barrel cortex (the terminal zone of this pathway is easily identified by its barrel-like structures within the sensory cortex) (17).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
2-[1-14C]DG (specific activity, 53 mCi/mmol) was obtained from PerkinElmer Life Sciences (Boston, MA). Antibody specific for the MAP2 protein (microtubule-associated protein) was obtained from Chemicon International (Temecula, CA).

Generation and characterization of mutant mice
The mutant mice with the targeted TRß and TR{alpha} gene mutations were generated by knock-in mutations in the carboxyl-terminal 14-amino-acid sequence that contains the TH-binding site and has been shown to produce defective TR{alpha}1PV (10) and TRßPV (11) proteins that are unable to bind thyroid hormone.

Animal preparation
All procedures performed on animals were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local animal care and use committee. Local CMRglc was determined in 4-wk-old wild-type mice (n = 7), mice with the TR{alpha}PV/+ (n = 5) mutation, and mice with the TRßPV/PV mutation (n = 5). All mice had been maintained on a 12-h light, 12-h dark cycle with humidity and temperature controlled at normal levels and were allowed food and water ad libitum. On the day of the experiment the mice were anesthetized with halothane (5% for induction, 1.0–1.5% for maintenance) in 100% O2, and 13-cm polyethylene catheters (PE10, Clay-Adams, Parsippany, NJ) were inserted into the left femoral artery and vein. The skin incision was then sutured and treated with 5% lidocaine ointment, and a loose-fitting plaster cast was applied to the lower torso and pelvis and taped to a plastic box to prevent locomotion. At least 3 h were allowed for recovery from the anesthesia and surgery before initiation of the measurement of CMRglc. Body temperature was maintained throughout all procedures by warming of the environment with a heating lamp and a hand warmer.

Physiological variables
Mean arterial blood pressure (MABP) was measured with a Digi-Med Blood Pressure Analyzer (Micro-Med, Louisville, KY). Hematocrit was determined in arterial blood samples centrifuged in a Microfuge B (Beckman Instruments, Fullerton, CA). Arterial plasma glucose concentration was measured in a Glucose Analyzer 2 (Beckman Instruments).

Determination of local cerebral glucose utilization
CMRglc was determined by the quantitative 2-[14C]DG method (14) modified slightly for use with small animals. The measurement was initiated by the iv injection of a pulse of 2-[14C]DG (120 µCi/kg), followed immediately by the drawing of 10–12 timed arterial blood samples of 15–30 µl each over the 45-min experimental period. At the end of the experimental period the mice were injected with a lethal dose of pentobarbital, and the brains were removed and frozen in isopentane maintained at -40 to -50 C with dry ice. The frozen brains were stored at -70 C until cut into 20-µm-thick coronal sections in a cryostat maintained at -22 C. The sections were thaw-mounted on glass coverslips, immediately dried on a hot plate at about 60 C, and autoradiographed together with calibrated [14C]methylmethacrylate standards on Kodak EMC-1 x-ray film (Kodak, Rochester, NY). The autoradiograms were digitized in a Howtek MultiRAD 850 scanner (Howtek, Hudson, NH) and displayed on a computer monitor for densitometric analysis. Local tissue 14C concentrations were determined from the local tissue ODs in the autoradiograms, and a calibration curve derived from the relationship between the calibrated 14C concentrations and the measured OD of the autoradiographic representations of the standards. Local CMRglc was computed from the local tissue 14C concentrations and the time courses of the arterial plasma glucose and 2-[14C]DG concentrations by the operational equation of the method (15) and the computerized image-processing system developed by G. Mies (Max Planck Institut für Neurologische Forschung, Koln, Germany) for use the NIH Image program (W. Rasband, NIMH, Bethesda, MD). Rate constants and lumped constants used in the computation were those previously determined in the rat (15).

Functional activation of the whisker-to-barrel cortex pathway
Local CMRglc was determined bilaterally in four structures of the whisker-to-barrel cortex sensory pathway (i.e. spinal and principal trigeminal nuclei, ventral posteromedial nucleus of the thalamus, and barrel region of the sensory cortex) in wild-type and both types of the mutant mice during unilateral stimulation of the whisker-to-barrel cortex pathway. Whiskers on the unstimulated right side of the face were clipped close to the skin to minimize spurious stimulation, and the vibrissae on the left side of the face were stroked with a soft paintbrush at a frequency of two or three per second beginning with the injection of the pulse of 2-[14C]DG and continuing throughout the 45 min of the procedure.

Northern blot analysis
Total RNA was prepared from cerebella with TRIzol (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. Ten micrograms of total RNA were used for Northern blot analysis. After electrophoresis, RNA was transferred onto membranes (Hybond-N+, Amersham Pharmacia Biotech, Boston, MA), which were hybridized with appropriate probes. cDNA probes for the various Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) isoforms (18) were labeled with [{alpha}-32P]deoxy-CTP in accordance with a random primer hexamer protocol. For quantification, the intensities of the mRNA bands were normalized against the intensities of GAPDH mRNA. Thus, the blots were stripped and rehybridized with 32P-labeled cDNA for GAPDH. Quantification of the bands was done with a PhosphorImager (Molecular Dynamics, Sunnyvale, CA).

Immunohistochemical studies
Brains of wild-type and TR{alpha}1 and TRß mutant mice were removed on postnatal d 15, fixed overnight in 4% formaldehyde and 0.1% glutaraldehyde in 0.1 M phosphate buffer (pH 7.6), and, after washing in phosphate buffer, cut into 30-µm-thick sagittal sections in a Vibratome (Series 1000, Technical Products International, St. Louis, MO). The sections were treated to inhibit endogenous peroxidase activity and then labeled by the peroxidase-antiperoxidase method as previously described (19) with antibody raised against the dendrite-specific MAP2 protein (Chemicon International).

Statistical analyses
The significance of differences in physiological variables between wild-type control and mutant mice was evaluated by unpaired t tests. Side to side differences in structures of the whisker-to-barrel cortex pathway on the stimulated and unstimulated sides of brain were statistically compared by paired t tests. Differences in absolute rates of local CMRglc and of the logarithms of the percent changes in local CMRglc due to vibrissal stimulation between wild-type mice and mutant mice were statistically analyzed by ANOVA, followed by unpaired t tests.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Physiological variables
TR{alpha}1PV/+ mutant mice exhibited significantly retarded body and brain growth, whereas in the TRßPV/PV mice total body weight was normal, although brain weight was comparably reduced (Table 1Go). MABP was significantly lower in the TR{alpha}1 mutants than in the wild-type mice, but was essentially normal in the TRß mutants. All of the other physiological variables examined were the same in both types of mutant mice as in the wild-type mice.


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  		TABLE 1. Physiological variables

 
Effects of neuronal functional activation on local cerebral glucose utilization
By stimulating vibrissae unilaterally and measuring local CMRglc bilaterally in the stimulated and unstimulated sides of the brain, it was possible to determine in the same animal CMRglc during baseline conditions and during neuronal functional activation in the sensory pathway. Baseline (unstimulated side) CMRglc was markedly and statistically significantly lower (-34% to -53%) in all four stations of the pathway in the TR{alpha}1PV/+ mutant mice than in the wild-type mice, but was essentially the same in the TRßPV/PV as in the wild-type mice (Figs. 1Go and 2Go). Vibrissal stimulation evoked large increases in CMRglc in all four stations of the pathway in every one of the mice, and the percent increases (i.e. percent differences between unstimulated and stimulated sides) were the same in all the groups, even in the TR{alpha}1PV/+ mice in which the baseline levels had been reduced (Figs. 1Go and 2Go).



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  		FIG. 1. Quantitative color-coded autoradiograms showing local rates of CMRglc in representative regions and in four stations of the whisker-to-barrel cortex sensory pathway during unilateral vibrissal stimulation in the brains of wild-type and TR{alpha}PV/+ and TRßPV/PV mutant mice. Stimulation of the vibrissae on the left side of the face markedly increased CMRglc in the ipsilateral spinal and principal trigeminal nuclei and the contralateral VPM thalamic nucleus and barrel region of the sensory cortex in all the mice. Baseline (unstimulated side) CMRglc is markedly and statistically significantly lower (-34% to -53%) in all four stations of the whisker-to-barrel pathway in the TR{alpha}1PV/+ mutant mice than in the wild-type mice, whereas the values in TRßPV/PV mice are essentially the same as those in wild-type mice.

 


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  		FIG. 2. Local CMRglc in four structures of the whisker-to-barrel cortex sensory pathway. Bar heights and error bars represent the mean ± SEM obtained in the number of mice indicated in parentheses. Unilateral vibrissal stimulation evoked statistically significant side to side differences in all four structures in all groups of mice (by paired t tests, P < 0.006). Baseline CMRglc (unstimulated side) was statistically significantly lower by 34–53% in all four stations of the whisker-to-barrel cortex pathway in the TR{alpha}1V/+ mice than in the wild-type mice (by ANOVA, followed by unpaired t tests: **, P < 0.01; ***, P < 0.001). The percent values above the bars are the mean ± SEM of the individual percent increases in CMRglc in each animal evoked by vibrissal stimulation. Statistical significance of the differences in the percent increases due to stimulation between wild-type and mutant mice was determined by comparisons of the logarithms of the percent increases (by ANOVA, followed by unpaired t test: {dagger}{dagger}, P < 0.01).

 
Expression of the Na+,K+-ATPase isoenzymes
The expression of {alpha}1, {alpha}2, {alpha}3, and ß1 Na+,K+-ATPase isoenzymes, which are known to be under TH control, was also examined. Although Na+,K+-ATPase activity has been shown to be a major mediator of the coupling of energy metabolism to synaptic activity (14), the expression of these isoenzymes was not altered in the brain of the TR{alpha}1 mutant (Fig. 3Go). In contrast, a small, but statistically significant, increase in expression of the {alpha}3 Na+,K+-ATPase isozyme was found in the brain of the TRß mutant.



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  		FIG. 3. Na+,K+-ATPase isoform gene expression in cerebellum of mutant TR mice. Total RNA was prepared from the cerebella of 4-wk-old male TR{alpha}1PV/+, TRßPV/PV mutant mice and their wild-type siblings for Northern blot analysis. cDNA probes for the various Na+,K+-ATPase isoforms (26 ) were used. The mean fold of changes is indicated compared with wild-type (+/+) mice (n = 3–4 for each genotype). **, P < 0.01 (by t test).

 
Immunohistochemical labeling of the cerebellum with anti-MAP2 antibodies
The effects of the TR{alpha}1 and TRß mutations on the morphological development of the cerebellum were examined by immunohistochemistry with a polyclonal antibody specific for the dendritic protein MAP2. As apparent in Fig. 4Go (A and B), the development of the dendritic tree of Purkinje cells in the cerebellum is essentially the same in the TR{alpha}1 mutant as in the wild-type mouse. At the same postnatal age, i.e. 15 d after birth, the development of the dendritic tree is severely impaired in the cerebellum of hypothyroid rats (2). The cerebellum of the TRß mutant mouse, however, showed some impairment in the development of the cerebellum, i.e. shorter Purkinje cell dendrites (Fig. 4CGo).



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  		FIG. 4. Vibratome sections from the cerebellum of 2-wk-old male TR{alpha}1PV/+ and TRßPV/PV mice and their wild-type siblings. Anti-MAP2 polyclonal antibodies revealed the dendritic tree of the Purkinje cells. Intense labeling of the packed Purkinje cell bodies is also seen at this developmental stage.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present studies confirm previous findings (13) that it is the TR{alpha}1 and not the TRß receptor that is required for the thyroid hormone-mediated maturation of cerebral energy metabolism. Furthermore, the findings of lower baseline CMRglc and yet normal percent increases in CMRglc evoked by neuronal functional activation indicate that although the density of functional synapses may be reduced in TR{alpha}1PV/+ mice, those that are present can be normally activated. A decreased density of functional synapses is consistent with the diminished neuropil and decreased electrical activity described by Eayrs and colleagues (1, 3) in animals deprived of thyroid hormone from birth as well as with the marked decreases in CMRglc found in cretinous rats (8) and in mice with the mutated TR{alpha}1 receptor (13). It is also noteworthy that the changes in baseline and functionally activated CMRglc found in the TR{alpha}1 mutants were essentially the same in the spinal and principal trigeminal nuclei, the structures containing the primary synapses, as in the VPM thalamic nucleus and barrel cortex, which contain the higher level synapses of the pathway. This suggests that relatively simple and more complex synaptic functions were equally affected, but all of the structures retained a residue of normal functionally active synapses despite the dysfunctional thyroid hormone receptor. It is conceivable that the residue of functional synapses in the structures had already been formed before the onset of thyroid hormone production and that the loss of synapses occurred in those that are normally formed later, are thyroid hormone dependent, and represent more complex synaptic connections.

Reduced rates of glucose utilization may not reflect deficits in total synaptic density in the brain tissues. Local CMRglc is known to correlate with functional activity in the synapses (14), and it is possible that in the brains of hypothyroid and TR{alpha}1 mutant animals some synapses may be formed that are functionally inactive because of impaired expression of one or more components known to be under thyroid hormone control. Deficiencies in synapse formation could result from impaired neuronal differentiation, as seen in the rat forebrain (1, 3) and cerebellum (2), and from the delayed expression of several axonal and dendritic markers observed in the hypothyroid brain (20, 21, 22, 23), and formed synapses might not become functional because of failure to establish functional connections. Immunohistochemical staining with specific antibodies directed against some of these markers failed to reveal in the cerebellum of the TR{alpha}1 mutant mice the major morphological abnormalities found in the brains of animals with thyroid hormone deficiency (1, 2, 24). It was recently reported (25) that a knockout TR{alpha}1 mutant mouse also failed to reveal the same morphological abnormalities that are seen in the cerebellum of hypothyroid wild-type rodents. The density and branching of the Purkinje cell dendrites in the cerebellum of the TRß mutant appeared to be decreased compared with those in the wild type and the TR{alpha} mutant. Only some of the dendritic trees appeared to be sufficiently developed to reach the surface of the cerebellum of the TRß mutant, whereas all the Purkinje cells have a reduced and poorly branched dendritic tree in the cerebellum of the hypothyroid rats (2, 26). Reduced growth of Purkinje cell dendrites observed in the cerebellum of the TRß mutant, but not the TR{alpha} mutant, mice probably reflects the difference in the expressions of each receptor; TRß is expressed predominantly in Purkinje cells (27), whereas TR{alpha} is expressed in the granular cells (28). The number of Purkinje cells in the cerebellum of the mice is several orders of magnitude lower than that of granule cells, and their contribution to overall glucose utilization is, therefore, likely to be only a small fraction of the total glucose metabolism in the cerebellum. This may explain why glucose utilization is normal in the cerebellum of the TRß mutant despite the lesser Purkinje cell outgrowth shown in Fig. 4Go.

Inasmuch as glucose is normally the almost sole substrate for the brain’s energy metabolism, its metabolism is essential for normal cerebral functional activity. It provides the ATP required by processes associated with synaptic transmission and for the ion transport needed to restore membrane potentials degraded by neuronal firing. Restoration of the ion gradients is catalyzed by different isoforms of Na+,K+- ATPase that consume large amounts of ATP, which is replenished by glucose consumption. Glucose metabolism (8) and both the mRNA expression and catalytic activities of various Na+,K+-ATPase isoforms increase during development and are TH-dependent (29). We could not, however, detect changes in the expression of the Na+,K+-ATPase isoforms in the brain of the TR{alpha}1 mutant mice to parallel those in glucose utilization.

It appears, then, that the effects of THs on energy metabolism, neuronal morphology, and the expression of some TH-dependent genes may be independent, additive, or mediated by different nuclear (9) and/or nonnuclear mechanisms (30).


   Footnotes
 
Abbreviations: CMRglc, Cerebral glucose utilization; 2-[14C]DG, 2-deoxy-D-[1-14C]glucose; MABP, mean arterial blood pressure; MAP, microtubule-associated protein; Na+,K+-ATPase, Na+,K+-adenosine triphosphatase; TH, thyroid hormone; TR, thyroid hormone receptor; VPM, ventral posteromedial.

Received April 3, 2003.

Accepted for publication May 23, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Eayrs JT 1966 Thyroid and central nervous development. In: The scientific basis of medicine annual reviews. London: Athlone; 317–339
  2. Legrand J 1986 Thyroid hormone effects on growth and development. In: Hennemann G, ed. Thyroid hormone metabolism. New York: Marcel Decker; 503–534
  3. Eayrs JT 1971 Thyroid and developing brain: anatomical and behavioral effects. In: Hamburgh M, Barrington EJW, eds. Hormone and development. New York: Appleton Century Crofts; 345–355
  4. Morreale de EG, Ruiz-Marcos A, Escobar del RF 1983 Thyroid hormone and the developing brain. In: Dassault JH, Walker P, eds. Congenital hypothyroidism. New York: Marcel Dekker; 85–126
  5. Rami A, Patel AJ, Rabie A 1986 Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217–1226[CrossRef][Medline]
  6. Gould E, Butcher LL 1989 Developing cholinergic basal forebrain neurons are sensitive to thyroid hormone. J Neurosci 9:3347–3358[Abstract]
  7. Duffy TE, Cavazzuti M, Cruz NF, Sokoloff L 1982 Local cerebral glucose metabolism in new born dogs: effects of hypoxia and halothane anesthesia. Ann Neurol 11:233–246[CrossRef][Medline]
  8. Dow-Edwards D, Crane AM, Rosloff B, Kennedy C, Sokoloff L 1986 Local cerebral glucose utilization in the adult cretinous rat. Brain Res 373:139–145[CrossRef][Medline]
  9. Zhang J, Lazar MA 2000 The mechanism of thyroid hormones. Annu Rev Physiol 62:439–466[CrossRef][Medline]
  10. Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, Barlow C, Willingham MC, Cheng S-Y 2001 A targeted dominant negative mutation of the thyroid hormone {alpha}1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci USA 98:15095–15100[Abstract/Free Full Text]
  11. Kaneshige M, Kaneshige K, Zhu X-G, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham MC, Barlow C, Cheng S-Y 2000 Mice with a targeted mutation in the thyroid hormone ß receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci USA 97:13209–13214[Abstract/Free Full Text]
  12. Griffith AJ, Szymko YM, Kaneshige M, Quinonez RE, Kaneshige K, Heintz KA, Mastroianni MA, Kelley MW, Cheng SY 2002 Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor ß gene disrupts cochlear morphogenesis. J Assoc Res Otolaryngol 3:279–88[CrossRef][Medline]
  13. Itoh Y, Esaki T, Kaneshige M, Suzuki H, Cook M, Sokoloff L, Cheng S-Y, Nunez J 2001 Brain glucose utilization in mice with a targeted mutation in the thyroid hormone {alpha} or ß receptor gene. Proc Natl Acad Sci USA 98:9913–9918[Abstract/Free Full Text]
  14. Sokoloff L 1999 Energetics of functional activation in neural tissues. Neurochem Res 24:321–329[CrossRef][Medline]
  15. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlack CS, Pettigrew KD, Sakurada O, Shinohara M 1977 The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916[Medline]
  16. Nakao Y, Itoh Y, Kuang T-Y, Cook M, Jehle J, Sokoloff L 2001 Effects of anesthesia on functional activation of cerebral blood flow and metabolism. Proc Natl Acad Sci USA 98:7593–7598[Abstract/Free Full Text]
  17. Woolsey TA, Van der Loos H 1970 The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17: 205–242
  18. Orlowski J, Lingrel JB 1988 Tissue specific and developmental regulation of rat Na,K-ATPase catalytic {alpha} isoforn and ß subunit mRNAs. J Biol Chem 263:10436–10442[Abstract/Free Full Text]
  19. Brion JP, Guilleminot J, Couchie D, Flament-Durand J, Nunez J 1988 Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum. Neuroscience 25:139–145[CrossRef][Medline]
  20. Aniello F, Couchie D, Gripois D, Nunez J 1991 Regulation of five tubulin isotypes by thyroid hormone during brain development. J Neurochem 57:1781–1786[CrossRef][Medline]
  21. Aniello F, Couchie D, Bridoux AM, Gripois D, Nunez J 1991 Splicing of juvenile and adult tau mRNA variants is regulated by thyroid hormone. Proc Natl Acad Sci USA 88:4035–4039[Abstract/Free Full Text]
  22. Poddar R, Paul S, Chaudhury S, Sarkar PK 1996 Regulation of actin and tubulin gene expression by thyroid hormone during rat brain development. Mol Brain Res 35:111–118[Medline]
  23. Silva JE, Rudas P 1990 Effects of congenital hypothyroidism on microtubule-associated protein-2 expression in the cerebellum of the rat. Endocrinology 126:1276–1282[Abstract/Free Full Text]
  24. Legrand J 1967 Variations en fonction de l’age de la reponse du cervelet a l’action morphogetique de la thyroide chez le rat. Arch Anat Microsc Morphol Exp 56:291–307[Medline]
  25. Morte B, Manzano J, Scanlan T, Vennstrom B, Bernal J 2002 Deletion of the thyroid hormone receptor {alpha}1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 99:3985–3989.[Abstract/Free Full Text]
  26. Nunez J, Couchie D, Brion JP 1988 Microtubule assembly: regulation by thyroid hormone. In: Delong GR, Robbins J, Condliffe P, eds. Iodine and the brain. New York: Plenum Press; 103–112
  27. Badley DJ, Young WS, Weinberger C 1989 Differential expression of {alpha} and ß thyroid hormone receptors genes in the brain and the pituitary. Proc Natl Acad Sci USA 86:7250–7254[Abstract/Free Full Text]
  28. Strait KA, Zou L, Oppenheimer JH 1992 ß1 Isoform-specific regulation of a triiodothyronine-induced gene during cerebellar development. Mol Endocrinol 6:1874–1880[Abstract/Free Full Text]
  29. Chaudbury S, Baipai M, Bhattacharya S 1996 Differential effects of hypothyroidism on Na+,K+-ATPase mRNA {alpha} isoforms in the developing rat brain. J Mol Neurosci 7:229–234[Medline]
  30. Davis PJ, Davis FB 1996 Nongenomic actions of thyroid hormone. Thyroid 6:497–504[Medline]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals