developing brain as an endocrine organ : a paradoxi al … · 2015. 11. 10. · endocrine functions...

DEVELOPING BRAIN AS AN ENDOCRINE ORGAN :

A PARADOXIСAL REALITY

2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA

M.V. Ugrumov

Institute of Developmental Biology RAS, Moscow

Endocrine functions of the brain in adulthood

Developing brain as an endocrine organ:

a paradoxical reality


Current concept of neuroendocrine regulations in ontogenesis and contradictions.

Revised concept of neuroendocrine regulations in ontogenesis.

Summary and prospect


Brain

Endocrine glands

Pituitary

Target organs

General circulation

Portal circulation

Adenohypophysis

Posterior hypophysis

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.

Magnocellular nuclei(vasopressin, oxytocin)

Blood vessels

Parvocellular nuclei(releasing- / inhibiting-hormones)

Extrahypothalamic centers

Hypothalamus

Feedback regulation

Direct regulation

Target organs





Current concept of neuroendocrine regulations in ontogenesis and contradictions

Revised concept of neuroendocrine regulations in ontogenesis


Brain

Development of the neuroendocrine regulations in ontogenesis. Current concept

I. Prenatal and neonatal open-looped neuroendocrine system

Placenta

Pituitary

Endocrine gland

Direct regulation

Feedback regulationBrain

Endocrineglands Pituitary

II. Postnatal close-looped neuroendocrine system

Dörner (1981); Daikoku et al. (1981); Gorski (1988); Jacobson (1991); Ugrumov (1991), Int. Rev. Cytol. 129, 207-267;

Ugrumov (2002) Microsc Res Tech 56, 164-171.

Milestones of the concept:

� The development of peripheral endocrine glands precedes that of the “endocrine” hypothalamus andthe brain as a whole;

� The hypothalamic neurons begin to secrete the adenohypophysiotropic neurohormones after the axon

sprouting to the hypophysial portal circulation;

� Neurohormones secreted by the differentiating neurons contribute, first, to the autocrine and paracrine

regulation of the neuron development and, significantly later, to the endocrine control

of the adenohypophysial functions.

2010. 35, 837-850.Neurochem. Res. 2010. 35, 837-850.

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)

E12 Adult (rat)P15

Birth

Age

P1E20E15

Embryonic day Postnatal day

Neuronogenesis

Expression of specificphenotype

Development of neuronal networks, synaptogenesis

Brain blood barrier

Age

Period of the neuron functioning as a secretory cell

and the brain operation as an endocrine organ






Revised concept of neuroendocrine regulations

in ontogenesis


3 ventricle

Dopamine

GnRH

Serotonin

GnRH system

Opticchiasma

Median eminence

Olfactorybulbs

Dopaminergic system

Dopaminergic system

GnRH, dopamine and serotonin as markers of brain endocrine activity in ontogenesis

Generalcirculation

3 ventricle

V

Portal circulation

IIIventricle

Pituitary

Median eminence

A10

A8A9

A12

А11А13

A14Opticchiasma

Olfactorybulbs

A10A8A9

A12

А11А13

A14

Serotoninergic system

Rahenuclei

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

?

Concentration of neurohormones in general circulation in rats in ontogenesis

Co

nce

ntr

atio

n in

pla

sm

a (

pg /

ml)

8

10

12

14

3.5

2.0

2.5

3.0 **

*

Co

nce

ntr

atio

n in

pla

sm

a(n

g /

ml)

Dopamine

**

*

GnRH

Concentration

in portal blood

of adult rats

Co

nce

ntr

atio

n in

pla

sm

a (

pg /

ml)

0

2

4

6

8

E18 E21 P3 P30

0.5

1.5

1.0

Co

nce

ntr

atio

n in

pla

sm

a

Age (days)

0

Blood brainbarrier

E18 P36P3E21

Male & female; Female; Male; E, embryonic day; P, postnatal day

Ugrumov et al. (2005) Comp. Biochem. Physiol. A 141, 271-279; Ugrumov (2010) Neurochem. Res. 35, 837-850;

Ugrumov et al. (2012) Mol. Cell. Endocrinol. 348, 78-86.

Blood brainbarrier

Age (days)

Whether the developing brain

is a principal source of circulating neurohormones

??

I. Dopamine in plasma of encephalectomized rat fetuses

Median

PituitaryRetinaA17

Olfactorybulb

NucleusaccumbensEntorhinal

cortexAmigdalaPyriform

cortex

Prefrontal cortex

Anteriorcongulate

cortex

Lateralseptum

Caudate,putamen

Corpuscollosum

0.5

3.0

2.5

2.0

1.5

1.0

*

3.5

Control

EncephalectomyEncephalectomy

E18 E21

Delivery of brain-derived dopamine into the general circulation in rats in ontogenesis

Medianeminence

A17 accumbenscortexcortex

FemalesMales0

II. Dopamine in the brain and plasma following an inhibition of its synthesis in the brain

Animals: rats at the 3rd postnatal day;

Inhibitor: α-methyl-p-tyrosine (α-МPТ)Administration: lateral ventricle

0

20

40

60

80

100

Brain Plasma

α-МPТ

*

*

Ugrumov (2010) Neurochem. Res., 35, 837-850;

Ugrumov et al. (2012). Mol. Cell. Endocrinol. 348, 78-86.

Control

Fetus

Delivery of brain-derived GnRH into the general circulation in rats in ontogenesis

Microsurgical lesion of GnRH neurons

in fetal brain

12

14

Control

Encephalectomy

Ugrumov et al. (2005) Comp. Biochem.Physiol. A 141, 271-279; Ugrumov (2010) Neurochem. Res., 35, 837-850.

Encephalectomy at E18;GnRH assay at E21

Inhibition of GnRH synthesis

in the brain

Neonates: intracerebral administration

of GnRH si-RNA (in progress)

2

4

6

8

10

FemalesMales

* *

0

I. Serotonin (5-HT) in blood of perinatal rats

Delivery of brain-derived serotonin into the general circulation in rats in ontogenesis

100

120

140

*

0

20

40

60

80

E21 P4 P16 P30

5-H

T c

on

ce

ntr

atio

n

in p

lasm

a, n

g /

ml

**

E21-P4 P4-P16 P16-P30Ra

te o

f in

cre

ase

of

5-H

T c

on

ten

t in

pla

sm

a,

ng

/d

ay

0

10

15

20

25

5

II. Serotonin in the brain and blood following inhibition of its synthesis in the brain

0

50

100

150

200

250

Brain

*

300

250

Platelets

*

Plasma

*

0

25

50

300

400

500

600

700

800Control

100 µg p-chloro-

phenylalanine

Blood brain barrier

Blood brain barrier

E21-P4 P4-P16 P16-P30

5-HTBrain Duodenum

General circulation

E, embryonic day

P, postnatal day

Zubova et al. (2014) Molecular and Cellular Endocrinol.

393, 92-98.

Whether the brain-derived neurohormones provide a direct endocrine action

on peripheral targets and the brain itself

?

Potential targets for circulating brain-derived GnRH and monoamines in the developing organism

GnRH Dopamine Serotonin

Brain: hippocampus, septum, amigdala – GnRH-R (type II) (Badr et al., 1989)

Brain: suprachiasmatic nucleus – D1 (Weaver et al., 1992; Strother et al., 1998)

Brain: GnRH neurons (Pronina…Ugrumov, 2003a,b)

Pituitary: gonadotropes –GnRH-R (type I)

Pituitary: lactotropes – D2 (Felder eta l., 1989)

Heart: cardiomyocytes (Etienne et al., 2004)

Testis: Leydig cells - GnRH-R (type II) (Raeside et al., 1984;

Kidney: proximal tubule cells, cortical collecting duct, blood

Blood vessels (Etienne et al., 2004)(type II) (Raeside et al., 1984;

Hbert et al., 1991; Botte et al., 1998)

cortical collecting duct, blood vessels – D1, D2 (Felder et al., 1989;Carey, 2001)

2004)

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, 2000)

BrainDopamine

HypothalamusDopamine 12

14

16

ng / g

tis

su

e

2,0

2,5

ng / m

l*

NaCl

6-OHDA

x 102

Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats

In vivo study

Portalcirculation

General

circulation

PituitaryProlactin

0

2

4

6

8

10

Hypothalamus Wholebrain

Do

pa

min

e c

on

ce

ntr

atio

n,

ng / g

tis

su

e

0

0,5

1,0

1,5

Plasma

Pro

lactin

co

nce

ntr

ation

, n

g / m

l

*

Zubova et al, in preparation

Krebs-Ringer buffer

Control (pure medium) Dopamine (1.5 ng/ml)

Dopamine (1.5 ng/ml)0.9

Plasma of rats

Control (plasma)

Plasma & haloperidol

Incubation of the pituitaries of 3-day-old rats

pla

sm

a

med

ium

Lactotropes,prolactin

D2

Plasma

DopamineD2 Dopamine

Pituitary

D2

Krebs-Ringer buffer

Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats

In vitro study

D2, dopamine receptors

*

*

Dopamine (1.5 ng/ml)& haloperidol

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9 haloperidol

*

0

0.5

1.0

1.5

2.0

2.5

3.0

Pro

lacti

n,

ng

/m

g p

itu

itary

/300 µ

lp

lasm

a

Pro

lacti

n,

ng

/m

g p

itu

itary

/300 µ

lm

ed

ium

Zubova et al, in preparation

D2 DopamineD2

Haloperidol

Leydig cells,

testosterone

Plasma

Testis

Endocrine regulation of testosterone secretion by brain-derived GnRH in neonatal rats

12

Control (medium)

GnRH (30 pg / ml)

GnRH (30 pg / ml) &

cetrorelix2,5

Control (plasma)

Plasma & cetrorelix

med

ium

300 µ

lm

ed

ium

*

Krebs-Ringer buffer Plasma

Incubation of the testes of 3-day-old rats

GnRH GnRH

Krebs-Ringer buffer

In vitro study

0

3

6

9

0

0,5

1

1,5

2

Testo

ste

ron

e,

ng

/m

gte

sti

s /

300 µ

l

Testo

ste

ron

e,

ng

/m

g t

esti

s

/300 µ

*

*

Bondarenko et al., in preparation

GnRH GnRH

Cetrorelix

Developing brain as a multipotent endocrine

Brain

.

.

.

.

.

.

.

.

.

.

.

.

.

. .

.

.

.

Congenital diseases

Kallmann syndrome :

Inability of GnRH neurons for migration

Norm

BrainNeuronsCranium

BrainNeurons

Fetus Adult

General circulation

Periphery

Target organs

Blood brain barrier

Pronina T., Ugrumov M. et al. (2003a,b) J. Neuroendocrinol. 15, 549-558; J. Neuroendocrinol. 15, 925-932;Fechner A. et al. (2008) Obstet. Gynecol. Surv. 63,189-194.

Inability of GnRH neurons for migration

Infertility

Brain

Brain

CraniumNeuron

Neuroendocrine regulations in ontogenesis:current and revised concepts

BrainEndocrine

glands

Pituitary

Placenta

I. Prenatal open-looped regulatory system

Direct regulation

Feedback regulationBrain

Endocrine glands Pituitary

II. Postnatal close-looped regulatory systemIII. Reciprocal regulatory system in ontogenesis, before the blood brain barrier closure (Ugrumov, 2010)

BrainEndocrineglands

Pituitary

Placenta






Revised concept of neuroendocrine regulations in ontogenesis


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

T. Pronina (PhD)

Laboratory of Hormonal Regulations

A. Sapronova (PhD),E. Volina (PhD)

Yu. Saifityarova(PhD student)

A. Sapronova (PhD)

Thanks for your attention

V. Khaindrava (PhD)

L. Dilmuchametova(PhD student)

E. Kozina(PhD student)

G. Chakimova(PhD student)

E. Degtyareva (PhD student) V. Kirillova

(technician)

Thanks for your attention

Michael V. UGRUMOV

e-mail: [email protected];

Tel. +7 499 135 88 42

developing brain as an endocrine organ : a paradoxi al … · 2015. 11. 10. · endocrine functions...

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