DEVELOPING BRAIN AS AN ENDOCRINE ORGAN : A PARADOXI AL … · 2015. 11. 10. · Endocrine functions...
Transcript of 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
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Current concept of neuroendocrine regulations in ontogenesis and contradictions.
Revised concept of neuroendocrine regulations in ontogenesis.
Summary and prospect
Endocrine functions of the brain in adulthood
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
Endocrine functions of the brain in adulthood
Developing brain as an endocrine organ:
a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Current concept of neuroendocrine regulations in ontogenesis and contradictions
Revised concept of neuroendocrine regulations in ontogenesis
Summary and prospect
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
Endocrine functions of the brain in adulthood
Developing brain as an endocrine organ:
a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Current concept of neuroendocrine regulations in ontogenesis and contradictions
Revised concept of neuroendocrine regulations
in ontogenesis
Summary and prospect
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
.
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.
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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
Endocrine functions of the brain in adulthood
Developing brain as an endocrine organ:
a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Current concept of neuroendocrine regulations in ontogenesis and contradictions
Revised concept of neuroendocrine regulations in ontogenesis
Summary and prospect
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