developing brain as an endocrine organ : a paradoxiСal reality m.v. ugrumov institute of...
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DEVELOPING BRAIN AS AN ENDOCRINE ORGAN : A PARADOXIСAL REALITY
M.V. Ugrumov
Institute of Developmental Biology RAS, Moscow
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
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
Developing brain as an endocrine organ: a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Endocrine functions of the brain in adulthood
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 regulationDirect regulation
Brain
Endocrine glands
Pituitary
Target organs
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
Developing brain as an endocrine organ: a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Direct regulationFeedback regulationBrain
Endocrineglands Pituitary
II. Postnatal close-looped neuroendocrine system
Brain
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 and the 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.
Development of the neuroendocrine regulations in ontogenesis. Current concept
I. Prenatal and neonatal open-looped neuroendocrine system
Placenta
Pituitary
Endocrine gland
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
Neuronogenesis
Expression of specificphenotype
Development of neuronal networks, synaptogenesis
Brain blood barrier
Adult (rat)P15
Birth
Age
P1E20E15 ‗‗
Period of the neuron functioning as a secretory cell
and the brain operation as an endocrine organ
Embryonic day Postnatal day
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
Developing brain as an endocrine organ: a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
Generalcirculation
3 ventricleV
Dopamine
GnRH
Portal circulation
IIIventricle
Pituitary
Serotonin
GnRH system
Opticchiasma
Median eminence
Olfactorybulbs
Median eminence
Dopaminergic system
A10
A8A9
A12
А11А13
A14Opticchiasma
Olfactorybulbs
Dopaminergic system
A10A8A9
A12
А11А13
A14
Serotoninergic system
Rahenuclei
GnRH, dopamine and serotonin as markers of brain endocrine activity in ontogenesis
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
sma
(p
g /
ml)
0
2
4
6
8
10
12
14
E18 E21 P3 P30
0.5
1.5
3.5
2.0
1.0
2.5
3.0 **
*
Co
nce
ntr
atio
n in
pla
sma
(n
g /
ml)
Age (days)
0
Dopamine
Blood brainbarrier
E18 P36P3E21
**
*
GnRH
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.
Concentrationin portal bloodof adult rats
Blood brainbarrier
Age (days)
Whether the developing brain is a principal source of circulating neurohormones
?
I. Dopamine in plasma of encephalectomized rat fetuses
Medianeminence
PituitaryRetinaA17
Olfactorybulb
NucleusaccumbensEntorhinal
cortexAmigdalaPyriform
cortex
Prefrontal cortex
Anteriorcongulate
cortex
Lateralseptum
Caudate,putamen
Corpuscollosum
FemalesMales
0.5
3.0
2.5
2.0
1.5
1.0
Do
pa
mi n
e in
pl a
sma
(n
g /
ml)
*
0
3.5
ControlEncephalectomyEncephalectomy
E18 E21
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
Do
pa
min
e c
on
cen
tra
tion
( %
)
0
20
40
60
80
100
Brain Plasma
α-МPТ
*
*
Delivery of brain-derived dopamine into the general circulation in rats in ontogenesis
Ugrumov (2010) Neurochem. Res., 35, 837-850;Ugrumov et al. (2012). Mol. Cell. Endocrinol. 348, 78-86.
Control
Ugrumov et al. (2005) Comp. Biochem.Physiol. A 141, 271-279; Ugrumov (2010) Neurochem. Res., 35, 837-850.
Fetus
Delivery of brain-derived GnRH into the general circulation in rats in ontogenesis
Microsurgical lesion of GnRH neurons in fetal brain
Encephalectomy at E18;GnRH assay at E21
Inhibition of GnRH synthesisin the brain
Neonates: intracerebral administration of GnRH si-RNA (in progress)
2
4
6
8
10
12
14
FemalesMales
* *
0
Gn
RH
co
nc e
nt r
ati o
n in
pl a
sma
(p
g /
ml)
Control
Encephalectomy
II. Serotonin in the brain and blood following inhibition of its synthesis in the brain
I. Serotonin (5-HT) in blood of perinatal rats
0
50
100
150
200
250
5-H
T c
on
t en
t p
er
br a
in,
ng
Brain
*
300
250
Platelets
*
5-H
T c
on
t en
t in
bl o
od
, n
g
Plasma
*
0
25
50
300
400
500
600
700
800
Delivery of brain-derived serotonin into the general circulation in rats in ontogenesis
Control
100 µg p-chloro-phenylalanine
100
120
140
*
0
20
40
60
80
E21 P4 P16 P30
5-H
T c
on
cen
tra
tion
in
pla
sma
, n
g /
ml
* *
Blood brain barrier
Blood brain barrier
E21-P4 P4-P16 P16-P30Ra
te o
f in
cre
ase
of
5-H
T c
on
ten
t in
pla
sma
, n
g /
da
y
0
10
15
20
25
5
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; Hbert et al., 1991; Botte et al., 1998)
Kidney: proximal tubule cells, cortical collecting duct, blood vessels – D1, D2 (Felder et al., 1989;Carey, 2001)
Blood vessels (Etienne et al., 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)
Brain
Portalcirculation
Generalcirculation
Pituitary
Dopamine
HypothalamusDopamine
Prolactin0
2
4
6
8
10
12
14
16
Hypothalamus Wholebrain
Do
pa
min
e c
on
cen
tra
tion
, n
g /
g t
issu
e
0
0,5
1,0
1,5
2,0
2,5
Plasma
Pro
lact
in c
on
cen
tra
tion
, n
g /
ml
*
*
NaCl
6-OHDA
x 102
Zubova et al, in preparation
Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats
In vivo study
D2, dopamine receptors
*
*
Krebs-Ringer buffer
Control (pure medium) Dopamine (1.5 ng/ml)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
Plasma of rats
Control (plasma)
Plasma & haloperidol
*
Incubation of the pituitaries of 3-day-old rats
0
0.5
1.0
1.5
2.0
2.5
3.0
Pro
lact
in,
ng
/ m
g p
itu
itar
y / 3
00 μ
l pla
sma
Pro
lact
in,
ng
/ m
g p
itu
itar
y / 3
00 μ
l med
ium
Zubova et al, in preparation
Lactotropes,prolactin
D2
Plasma
DopamineD2 Dopamine
Pituitary
D2
Haloperidol
Krebs-Ringer buffer
Endocrine regulation of prolactin secretion by brain-derived dopamine in neonatal rats
In vitro study
Leydig cells,testosterone
Plasma
Testis
Endocrine regulation of testosterone secretion by brain-derived GnRH in neonatal rats
0
3
6
9
12
Control (medium)GnRH (30 pg / ml)GnRH (30 pg / ml) & cetrorelix
0
0,5
1
1,5
2
2,5
Control (plasma)
Plasma & cetrorelix
Tes
tost
ero
ne,
ng
/ m
g t
esti
s / 3
00 µ
l med
ium
Tes
tost
ero
ne,
ng
/ m
g t
esti
s /
300
µl m
ediu
m
**
*
Krebs-Ringer buffer Plasma
Incubation of the testes of 3-day-old rats
Bondarenko et al., in preparation
GnRH GnRH
Cetrorelix
Krebs-Ringer buffer
In vitro study
General circulation
Periphery
Target organs
Developing brain as a multipotent endocrine
Brain
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.
Congenital diseases
Kallmann syndrome :Inability of GnRH neurons for migration
Infertility
Norm
BrainNeuronsCranium
BrainNeurons
Fetus Adult
BrainBrain
CraniumNeuron
Neuroendocrine regulations in ontogenesis:current and revised concepts
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
BrainEndocrine
glands
Pituitary
Placenta
I. Prenatal open-looped regulatory system
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
Developing brain as an endocrine organ: a paradoxical reality
2nd International Conference on EndocrinologyOctober 20-22, 2014, Chicago, USA
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)
V. Khaindrava (PhD)
L. Dilmuchametova(PhD student)
E. Kozina(PhD student)
G. Chakimova(PhD student)
E. Degtyareva (PhD student) V. Kirillova
(technician)
Laboratory of Hormonal Regulations
A. Sapronova (PhD),E. Volina (PhD)
Yu. Saifityarova(PhD student)
A. Sapronova (PhD)
Thanks for your attention
Michael V. UGRUMOV
e-mail: [email protected];
Tel. +7 499 135 88 42