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SUMMARY
The metabolism of [14C]testosterone in vitro by various areas of the human foetal brain has been studied and compared with that of adult brain. The predominant metabolites were 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol, and also androstenedione, and all areas of the foetal brain showed similar activity. In the foetal pituitary gland, the activity of 5α-reductase was less prominent than that of 17β-hydroxysteroid-dehydrogenase. Small quantities of oestradiol-17β were produced from testosterone by the hypothalamus, temporal lobe and amygdala only, and no aromatization could be detected in the pituitary gland. 5α-Reductase activity was much lower in adult brain tissues and no oestradiol was identified in adult temporal lobe tissue.
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ABSTRACT
The rat brain is sexually dimorphic with respect to structure and function, and there is evidence that these differences are effected in the fetus through changes in protein synthesis, some of which may result from the intervention of gonadal steroids. To investigate this, messenger RNA (mRNA) from the limbic system and cerebellum of neonatal rats was prepared, translated in a rabbit reticulocyte system in vitro and the products were analysed by two-dimensional electrophoresis and fluorography. Some of the results were further analysed using image analysis. There was a striking sexual dimorphism in the patterns of incorporation of [35S]methionine into proteins using mRNA from the limbic system, in that groups of proteins were apparently present in male-but not in female-derived fluorograms and vice versa. One protein, tentatively identified from its coordinates as α-tubulin, was more abundant in male-derived fluorograms. Although there were no clear-cut qualitative sex differences using mRNA derived from the cerebellum, that derived from the male cerebellum appeared to be consistently more active. These results provide direct evidence for a sexual dimorphism at the transcriptional level in the neonatal limbic system of the rat.
J. Endocr. (1986) 109, 23–28
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A sensitive, reliable assay of activity of RNA polymerase in purified nuclei from the rat brain is described. The assay measured the incorporation of [3H]guanosine triphosphate into RNA by nuclei. Little incorporation occurred in the presence of α-amanitin (400 ng) suggesting that RNA polymerase B activity was being measured. Preliminary evidence showed that after administration of oestradiol benzoate to 18-day-old female rats RNA polymerase activity was raised in areas of brain known to contain oestrogen receptors.
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Search for other papers by Arthur JR in
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Adequate dietary iodine supplies and thyroid hormones are needed for the development of the central nervous system (CNS) and brown adipose tissue (BAT) function. Decreases in plasma thyroxine (T4) concentrations may increase the requirement for the selenoenzymes types I and II iodothyronine deiodinase (ID-I and ID-II) in the brain and ID-II in BAT to protect against any fall in intracellular 3,3',5 tri-iodothyronine (T3) concentrations in these organs. We have therefore investigated selenoenzyme activity and expression and some developmental markers in brain and BAT of second generation selenium- and iodine-deficient rats. Despite substantial alterations in plasma thyroid hormone concentrations and thyroidal and hepatic selenoprotein expression in selenium and iodine deficiencies, ID-I, cytosolic glutathione peroxidase (cGSHPx) and phospholipid hydroperoxide glutathione peroxidase (phGSHPx) activities and expression remained relatively constant in most brain regions studied. Additionally, brain and pituitary ID-II activities were increased in iodine deficiency regardless of selenium status. This can help maintain tissue T3 concentrations in hypothyroidism. Consistent with this, no significant effects of iodine or selenium deficiency on the development of the brain were observed, as assessed by the activities of marker enzymes. In contrast, BAT from selenium- and iodine deficient rats had impaired thyroid hormone metabolism and less uncoupling protein than in tissue from selenium- and iodine-supplemented animals. Thus, the effects of selenium and iodine deficiency on the brain are limited due to the activation of the compensatory mechanisms but these mechanisms are less effective in BAT.
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The influence of maternal hypothyroxinemia on the expression of the glucose transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated. Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the onset of fetal thyroid hormone synthesis. Placental weights were normal, but placental total protein concentration was reduced at 19 days gestation (dg). Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at 16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16 dg. In fetal brain, the concentration of microsomal protein was deficient at 16 dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1 mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia results in fetal growth retardation and impaired brain development before the onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be compromised directly, due to deficient GLUT1 expression in this tissue, and indirectly, as a result of reduced placental GLUT1 expression. Though corrected by the onset of fetal thyroid hormone synthesis, these deficits are present during the critical period of neuroblast proliferation and may contribute to long term changes in brain development and function seen in this model and in the progeny of hypothyroxinemic women.
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ABSTRACT
The influence of hypothyroidism in the adult rat on brain biochemistry was investigated. Hypothyroidism was induced in 6-month-old male rats by partial thyroidectomy coupled with the administration of 6-n-propyl-2-thiouracil (0·005%, w/v) in the drinking water. Age-matched euthyroid males served as the controls.
Hypothyroidism resulted in brain region-specific changes in certain catabolic enzyme activities. Acid phosphatase activity was reduced in the cerebellum (by 34%) and the medulla (by 38%), whereas alkaline phosphatase activity was decreased in the mid-brain (by 37%) and the subcortex (by 49%). A differential response was also observed in the case of aryl sulphatase activity: aryl sulphatase A (myelin-degradative activity) was diminished in the cerebellum (by 56%), whereas aryl sulphatase B remained unchanged in all regions. Acetylcholine esterase activity was reduced in the cerebellum (by 45%), the medulla (by 34%) and the subcortex (by 45%), whereas monoamine oxidase activity was affected in only one region, the cerebellum, where it was increased by (61%).
The compromise of myelin and neurotransmitter degradative enzyme activities may place severe restrictions on normal brain function. The vulnerability of the adult rat cerebellum to the effects of thyroidectomy is commensurate with the known clinical signs of cerebellar dysfunction in adult hypothyroid man. These findings raise the possibility of an important role for the thyroid hormones in the mature brain.
Journal of Endocrinology (1993) 138, 299–305
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SUMMARY
The afferent path of the milk-ejection reflex has been studied in the brain of the anaesthetized lactating rabbit. Electrical stimulation was applied between a monopolar electrode in the brain and an indifferent electrode in the scalp. The brain was transected at the mid-cerebellar level to eliminate sympathetico-adrenal activation, and intramammary pressure and arterial blood pressure were monitored to detect release of neurohypophysial hormones.
In the mid-brain, the afferent path of the reflex is compact, lying in the lateral tegmentum of each side and passing forwards to lie medio-ventral to the medial geniculate body. On entering the diencephalon, the pathway on each side bifurcates: a dorsal path passing forwards in association with the extreme rostral central grey and periventricular region, and a ventral path ascending through the subthalamus. The dorsal and ventral paths reunite in the posterior hypothalamus. Delineating the pathway further forward in the hypothalamus, using a simple stimulation technique, was not possible because at this level it intermingles with efferent fibres descending from the paraventricular nucleus to the pituitary stalk. The afferent path of the reflex is concerned with the preferential release of oxytocin from the neurohypophysis, is not a major pathway for the release of vasopressin and its neural substrate in the mid-brain is believed to be the spinothalamic system of fibres.
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Although brain amines have been suggested as neurotransmitters regulating the release of hypothalamic hormones, some conflicting evidence has still to be explained. Scapagnini, Van Loon, Moberg & Ganong (1970) have implicated brain noradrenaline in the inhibitory control of adrenocorticotrophin (ACTH) secretion, based on the results of intraperitoneal injection of α-methyl-p-tyrosine. However, we found no increase in corticosterone after oral administration of α-methyl-p-tyrosine to rats (Uchimura, Kumeda, Kawabata, Maeda, Tada, Okamoto, Ogawa & Inamori, 1972).
In this study we have examined the effects of intraventricular administration of 6-hydroxydopamine (6-OHDA), a specific and long-lasting catecholamine depletor which does not cross the blood-brain barrier thus excluding the effects of serotonin, peripheral noradrenaline or peritoneal irritation. We performed the experiments 2 weeks after intraventricular administration of 6-OHDA to avoid the stress effects of the administration of 6-OHDA itself.
Male Wistar rats (125–250 g), caged singly, were used. Each rat was
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Search for other papers by A. S. McNEILLY in
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Search for other papers by J. S. TINDAL in
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SUMMARY
The position of the pathway for the release of oxytocin in the mid-brain was ascertained by exploration of a transverse stereotaxic plane (A4) in 23 anaesthetized goats. Electrical stimulation was applied between a monopolar electrode and an indifferent electrode in the scalp. Oxytocin release was monitored by simultaneous collection of blood samples during stimulation from a catheter in a jugular vein. The blood samples were extracted by the Sephadex G-25 or fuller's earth method and assayed for oxytocin content on the lactating guinea-pig preparation.
Oxytocin release occurred occasionally after stimulation of certain sites in the tectum, central grey and reticular formation. Regular releases of oxytocin, however, were only obtained after stimulation of a pathway which was compact and lay in the lateral tegmentum of the mid-brain in association with the spinothalamic tract. The position of this pathway corresponds to that described previously for the afferent pathway of the milk-ejection reflex in the mid-brain of the guinea-pig and rabbit. In these three species therefore, the impulses concerned in oxytocin release appear to ascend through the mid-brain in the spinothalamic tract.
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In the present study, we have investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in hampering the access of the synthetic glucocorticoid, prednisolone. In vivo, a tracer dose of [(3)H]prednisolone poorly penetrated the brain of adrenalectomised wild-type mice, but the uptake was more than threefold enhanced in the absence of Pgp expression in mdr1a (-/-) mice. In vitro, in stably transfected LLC-PK1 monolayers the human MDR1 P-glycoprotein was able to transport prednisolone present at a micromolar concentration. A specific Pgp blocker, LY 335979, could block this polar transport of [(3)H]prednisolone. Human Pgp does not transport all steroids, as cortexolone was not transported at all and aldosterone was only weakly transported. The ability of Pgp to export the synthetic glucocorticoid, prednisolone, suggests that uptake of prednisolone in the human brain is impaired, leading to a discrepancy between central and peripheral actions. Furthermore, the ensuing imbalance in activation of the two types of brain corticosteroid receptors may have consequences for cognitive performance and mood.
