DEVELOPING BRAIN AS AN ENDOCRINE ORGAN : A PARADOXIСAL REALITY

Transcription

1 2nd International Conference on Endocrinology October 2-22, 214, Chicago, USA DEVELOPING BRAIN AS AN ENDOCRINE ORGAN : A PARADOXIСAL REALITY M.V. Ugrumov Institute of Developmental Biology RAS, Moscow

2 2nd International Conference on Endocrinology October 2-22, 214, Chicago, USA Developing brain as an endocrine organ: a paradoxical reality Endocrine functions of the brain in adulthood Current concept of neuroendocrine regulations in ontogenesis and contradictions. Revised concept of neuroendocrine regulations in ontogenesis. Summary and prospect

3 Endocrine functions of the brain in adulthood Pituitary Endocrine glands Target organs Direct regulation Feedback regulation Hypothalamus Criteria of the brain functioning as an endocrine organ : Existence of the neurons, secreting neurohormones; Delivery of neurohormones into the blood vessels; Maintaining of the physiologically active concentration of neurohormones in blood; Delivery of neurohormones from secretory neurons to the distant target cells via circulation. Portal circulation Adenohypophysis Magnocellular nuclei (vasopressin, oxytocin) Blood vessels Posterior hypophysis General circulation Parvocellular nuclei (releasing- / inhibiting-hormones) Extrahypothalamic centers

4 2nd International Conference on Endocrinology October 2-22, 214, Chicago, USA Developing brain as an endocrine organ: a paradoxical reality Endocrine functions of the brain in adulthood Current concept of neuroendocrine regulations in ontogenesis and contradictions Revised concept of neuroendocrine regulations in ontogenesis Summary and prospect

5 Development of the neuroendocrine regulations in ontogenesis. Current concept I. Prenatal and neonatal open-looped neuroendocrine system Placenta Pituitary Endocrine gland II. Postnatal close-looped neuroendocrine system Milestones of the concept: The development of peripheral endocrine glands precedes that of the endocrine Direct hypothalamus regulationand the brain as a whole; Feedback The hypothalamic neurons begin to secrete the adenohypophysiotropic neurohormones after the axon sprouting to the hypophysial portal circulation; Neurohormones secreted Endocrine by the differentiating neurons contribute, first, to the autocrine and paracrine regulation of the neuron glands development and, significantly later, to Pituitary the endocrine control of the adenohypophysial functions. Dörner (1981); Daikoku et al. (1981); Gorski (1988); Jacobson (1991); Ugrumov (1991), Int. Rev. Cytol. 129, ; Ugrumov (22) Microsc Res Tech 56,

6 21. 35, Neurochem. Res , If the hypothesis is valid: The concentration of the brain-derived neurohormones in general circulation before the closing of the blood brain barrier in ontogenesis should be as large as that in the hypophysial portal circulation in adulthood; The concentration of the brain-derived neurohormones in peripheral blood should drop under inhibition of their synthesis in the brain; Circulating brain-derived neurohormones should contribute to the endocrine regulation of the developing peripheral target organs and the brain itself (autoregulation) Embryonic day Birth Postnatal day E12 E15 E2 P1 P15 Adult (rat) Neuronogenesis Age Expression of specific phenotype Development of neuronal networks, synaptogenesis blood barrier Period of the neuron functioning as a secretory cell and the brain operation as an endocrine organ

7 2nd International Conference on Endocrinology October 2-22, 214, Chicago, USA Developing brain as an endocrine organ: a paradoxical reality Endocrine functions of the brain in adulthood Current concept of neuroendocrine regulations in ontogenesis and contradictions Revised concept of neuroendocrine regulations in ontogenesis Summary and prospect

8 GnRH, dopamine and serotonin as markers of brain endocrine activity in ontogenesis GnRH system Serotonin Olfactory bulbs 3 ventricle III ventricle V Dopamine GnRH Portal circulation General circulation Optic chiasma Dopaminergic system system Olfactory bulbs A14 Optic chiasma А13 Serotoninergic system Median eminence А11 A9 Median A12 eminence 2 A8 A1 Pituitary Rahe nuclei

9 Whether the concentration of neurohormones in peripheral blood in ontogenesis before the blood brain barrier closing is sufficient to provide an endocrine control of the target organs?

10 Concentration of neurohormones in general circulation in rats in ontogenesis Concentration in plasma (ng / ml) Dopamine Concentration in portal blood of adult rats GnRH Concentration in plasma (pg / ml) E18 E21 P3 P3 Age (days) Blood brain barrier E18 E21 P3 Age (days) P36 Blood brain barrier Male & female; Male; Female; E, embryonic day; P, postnatal day Ugrumov et al. (25) Comp. Biochem. Physiol. A 141, ; Ugrumov (21) Neurochem. Res. 35, ; Ugrumov et al. (212) Mol. Cell. Endocrinol. 348,

11 Whether the developing brain is a principal source of circulating neurohormones?

12 Delivery of brain-derived dopamine into the general circulation in rats in ontogenesis Anterior congulate cortex Prefrontal Olfactory cortex bulb Lateral septum Retina A17 Pyriform Amigdala cortex I. Dopamine in plasma of encephalectomized rat fetuses Caudate, putamen Corpus collosum Nucleus Pituitary Entorhinal accumbens cortex Median eminence Encephalectomy E18 E21 Males Control Encephalectomy Females II. Dopamine in the brain and plasma following an inhibition of its synthesis in the brain Control α-мpт Animals: rats at the 3rd postnatal day; Inhibitor: α-methyl-p-tyrosine (α-мpт) Administration: lateral ventricle 4 2 Plasma Ugrumov (21) Neurochem. Res., 35, ; Ugrumov et al. (212). Mol. Cell. Endocrinol. 348,

13 Delivery of brain-derived GnRH into the general circulation in rats in ontogenesis Microsurgical lesion of GnRH neurons in fetal brain Fetus Control Encephalectomy Encephalectomy at E18; GnRH assay at E Inhibition of GnRH synthesis in the brain 4 2 Neonates: intracerebral administration of GnRH si-rna (in progress) Males Females Ugrumov et al. (25) Comp. Biochem.Physiol. A 141, ; Ugrumov (21) Neurochem. Res., 35,

14 Delivery of brain-derived serotonin into the general circulation in rats in ontogenesis 5-HT concentration in plasma, ng / ml I. Serotonin (5-HT) in blood of perinatal rats E21 P4 P16 P3 Rate of increase of 5-HT content in plasma, ng / day E21-P4 P4-P16 P16-P3 Blood brain barrier II. Serotonin in the brain and blood following inhibition of its synthesis in the brain Control 1 µg p-chlorophenylalanine Blood brain barrier HT Duodenum E, embryonic day P, postnatal day 1 5 Plasma Platelets General circulation Zubova et al. (214) Molecular and Cellular Endocrinol. 393,

15 Whether the brain-derived neurohormones provide a direct endocrine action on peripheral targets and the brain itself?

16 Potential targets for circulating brain-derived GnRH and monoamines in the developing organism GnRH Dopamine Serotonin : hippocampus, septum, amigdala GnRH-R (type II) (Badr et al., 1989) Pituitary: gonadotropes GnRH-R (type I) Testis: Leydig cells - GnRH-R (type II) (Raeside et al., 1984; Hbert et al., 1991; Botte et al., 1998) : suprachiasmatic nucleus D1 (Weaver et al., 1992; Strother et al., 1998) Pituitary: lactotropes D2 (Felder eta l., 1989) Kidney: proximal tubule cells, cortical collecting duct, blood vessels D1, D2 (Felder et al., 1989;Carey, 21) : GnRH neurons (Pronina Ugrumov, 23a,b) Heart: cardiomyocytes (Etienne et al., 24) Blood vessels (Etienne et al., 24) Ovaries: interstitial, granulosa, and luteal cells - GnRH-R (type II) (Botte et al., 1998; Kogo et sl., 1999) Immunocompetent cells: liver lymphocytes and thymocytes (Zakharova Ugrumov, 2)

17 Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats In vivo study x 1 2 Dopamine Dopamine concentration, ng / g tissue Hypothalamus Dopamine 12 Portal circulation Pituitary Prolactin General circulation Hypothalamus Whole brain NaCl 6-OHDA Plasma 2,5 2, 1,5 1,,5 Prolactin concentration, ng / ml Zubova et al, in preparation

18 Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats In vitro study Krebs-Ringer buffer Dopamine Lactotropes, prolactin D2 Pituitary D2 Haloperidol D2, dopamine receptors Zubova et al, in preparation Plasma D2 Dopamine Prolactin, ng / mg pituitary / 3 µl med dium Incubation of the pituitaries of 3-day-old rats Krebs-Ringer buffer Plasma of rats Control (pure medium) Control (plasma) Dopamine (1.5 ng/ml) Plasma &.9 Dopamine (1.5 ng/ml) haloperidol & haloperidol Prolactin, ng / mg pituitary / 3 µl plas sma

19 Krebs-Ringer buffer Endocrine regulation of testosterone secretion by brain-derived GnRH in neonatal rats Plasma In vitro study Incubation of the testes of 3-day-old rats Testis Krebs-Ringer buffer Plasma GnRH Leydig cells, testosterone Cetrorelix GnRH Bondarenko et al., in preparation medium Testosterone, ng / mg testis / 3 µl 2,5 2 1,5 1,5 Control (medium) GnRH (3 pg / ml) GnRH (3 pg / ml) & cetrorelix Control (plasma) Plasma & cetrorelix Testosterone, ng / mg testis / 3 µl medium

20 Developing brain as a multipotent endocrine Neurons Cranium Congenital diseases Norm Fetus Adult Neurons Blood brain General barrier circulation Kallmann syndrome : Inability of GnRH neurons for migration Neuron Cranium Target organs Periphery Infertility Pronina T., Ugrumov M. et al. (23a,b) J. Neuroendocrinol. 15, ; J. Neuroendocrinol. 15, ; Fechner A. et al. (28) Obstet. Gynecol. Surv. 63,

21 Neuroendocrine regulations in ontogenesis: current and revised concepts I. Prenatal open-looped regulatory system Placenta Pituitary Endocrine glands III. Reciprocal II. Postnatal regulatory close-looped system regulatory in ontogenesis, system before the blood brain barrier closure (Ugrumov, 21) Placenta Pituitary Endocrine glands Endocrine glands Pituitary Direct regulation Feedback regulation

22 2nd International Conference on Endocrinology October 2-22, 214, Chicago, USA Developing brain as an endocrine organ: a paradoxical reality Endocrine functions of the brain in adulthood Current concept of neuroendocrine regulations in ontogenesis and contradictions Revised concept of neuroendocrine regulations in ontogenesis Summary and prospect

23 The concept on the role of the brain in neuroendocrine regulations in ontogenesis: in the past, at present and in the future In the past. The brain does not participate in neuroendocrine regulations up to its complete maturation, in rodents at prepuberty. At present. The developing brain provides the paraadenohypophysial endocrine regulations of peripheral target organs and the brain itself in ontogenesis, over a period from the neuron origin till the establishment of synaptic interneuronal relations and the blood brain barrier closing. In the future. It should be ascertain: Whether the brain-derived neurohormones contribute to the paradenohypophysial endocrine regulation either of functioning or morphogenesis of the target organs; What is the functional significance of a temporal combination of paracrine and endocrine regulations of the target cells by the same neurohormones; What is a role of impairing metabolism of the brain-derived neurohormones in the development of congenital diseases

24 Laboratory of Hormonal Regulations Yu. Saifityarova (PhD student) A. Sapronova (PhD) A. Sapronova (PhD), E. Volina (PhD) Thanks for your attention T. Pronina (PhD) L. Dilmuchametova (PhD student) V. Khaindrava (PhD) E. Kozina (PhD student) E. Degtyareva (PhD student) Michael V. UGRUMOV G. Chakimova (PhD499 student) Tel V. Kirillova (technician)