Neurobiology of the stress response

Eberhard Fuchs
Clinical Neurobiology Laboratory, German Primate Center, Gttingen
d and
Department of Neurology, Medical School, University of Gttingen
efuchs@gwdg.de
Stress Research
The science of our flexible responses
to an unpredictable world
Fight or flight Fight or flight
Stimuli
Central nervous i nterpretati on
resul ting in
activati on/ i nhi biti on
1
2
1
2
which influence
of CNS structures (1)
3 7 7
3 7 7
Behavior
secretion sf ACTH from the pituitary (2)
5 5
4 4
5 5
of
heart rate (3)
bl ood pressure (4)
6 6
rel ease of corti sol/ epi nephrine
from the adrenals (5)
formation of sex hormones (6)
i t (7) immune system (7)
Overall organization of the mammalian nervous system
A schematic rendering of the architecture g
The mammalian brain is composed of p
evolutionary old and young systems
Reptilian brain
- find food find food
- find a mate
- reflexes
- sleep-wake behavior - sleep-wake behavior...
Limbic system
(Paleomammalian) (Paleomammalian)
- affective behavior
Neocortex
(Neomammalian)
- cognitive capabilities
- conscious actions
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
Brain noradrenaline regulates mood / emotions g
through modulation of neuronal activity
Locus coeruleus = A6
- wide projections: p j
modulation of emotions,
attention...
A5 and A7
- in the pons:
autonomic functions, pain
A1 and A2
- in the medulla oblongata:
cardiovascular and
neuroendocrine functions
Serotonin (5-HT) neurons innervate ( )
almost all brain regions
Stress increases 5-HT
release in the forebrain
Kirby &Lucki, 1997 Kirby & Lucki, 1997
Dopaminergic neurons regulate motivation p g g
Ventral tegmental area (VTA)
Mesocortical / mesolimbic
pathway
striatum
frontal
cortex
SN
pathway
- to frontal and temporal cortex
- to limbic system
(emotions thoughts (emotions, thoughts,
memory)
Deficit: Schizophrenia
Substantia nigra (SN)
Nigro-striatal pathway
VTA
- to striatum
(initiation of motor
response)
The mesocortical / mesolimbic
pathway is important for
reinforcement / reward
p )
Deficit: Parkinsons disease
reinforcement / reward
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
Schematic view of the mammalian brain
Complex Complex
processing processing
Vision Vision
Auditory Auditory
Somato Somato- -
sensory sensory sensory sensory
The thalamus: gateway to the cerebral cortex
Functions:
- Processes all sensory information
(except olfaction) prior to relaying to
cerebral cortex
- Regulates excecution of motor programs
- Controls the level of cortical excitability
- Influences motivational & emotional
Th th f th d ki ll l i th th l
processes
The sensory pathways from the eye, ear and skin all relay in the thalamus
before terminating in the cerebral cortex.
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
Sensorystimuli
F i l i
Monoaminergicsystems
C l
Inputs and outputs of neuronal stress-processing systems
- schematic and not complete -
Se so y st u
(aversiv)
Facialexpression
(anxious,stressed)
Freezing,analgesia
(noradrenaline,dopamine,
serotonin)
Centralgrey
Spinalcord
Motoricnucleiofthe
trigeminal&fascialnerves
Sensorystimuli
(neutral,conditioned)
Subjectivefeeling
(nausea,anxiety)
( , )
Nucleus
parabrachialis
g
Insular&prefrontal
cortex
Sensory&
Cortex
( i )
Startlereaction
Nucleusreticularis
pontiscaudalis
polymodal
thalamicnuclei
Baso
lateral
Lateral
Central
(primarysensoryareas)
Cortex
(association areas)
Attention arousal
HPAaxis
(CRH,ACTH,cortisol)
Paraventricular
nucleusofthe
hypothalamus
BNST
Locus coeruleus ventral
(associationareas)
Perirhinar,insular
cortex
Miction,defecation,
gastric ulcer
Attention,arousal,
vigilance
Para
sympathicus
Locuscoeruleus,ventral
tegmentum,Raphenuclei
Dorsalnucleus
f th l
Hippocampus
Increasedrespiratory
rate
gastriculcer
Nucleusparabrachialis
sympathicus
ofthevagalnerve
Lateral
hyperthalamus
Rostroventrolateral
medulla
Sympathicus
Increasedbloodpressure,tachycardia,
enlargementofthepupils,reduced
resistanceoftheskin
The amygdala transforms sensory stimuli
into an emotional reaction into an emotional reaction
The limbic system the emotional brain
Paul Broca, 1878 Paul Broca, 1878
The Papez circuit
links the cortex to the hypothalamus
Emotional
coloring
Emotional Emotional
experience
James Papez (1930):
Emotional centers are
interconnected by fiber tracts.
Emotional
expression p
Lateral view of the cerebral cortex in three mammalian species
Notice:
Th i f th h t i ith t i tl i t i tl t The expansion of the human cortex is neither strictly primary sensory nor strictly motor
A cortical neuron type unique to humans and great apes
Spindle cells in layer Vb of the anterior cingulate cortex
Bonobo Chimpanzee Chimpanzee Gorilla Gorilla
Orangutan Orangutan Human Gibbon Gibbon Patas Patas Lemur Lemur Orangutan Orangutan Human Gibbon Gibbon Patas Patas Lemur Lemur
Nimchinsky et al., PNAS, 1999
Evolution of specialized pyramidal neurons Evolution of specialized pyramidal neurons
in primate visual and motor cortex
C.C. Sherwood et al., Brain Behav Evol 61:28-44, 2003
Types of glia cells
d th i i t ti ith and their interactions with neurons
Evolution of cortical astrocytes and neurons
(a) Graphical representation and GFAP
immunostaining of mouse (i) and human (ii)
cortical astrocytes cortical astrocytes.
(b) Graphical representation and MAP2
immunostaining of mouse (i) and human (ii)
cortical neurons.
(c) Bars illustrating the sizes of human
astrocytes (left) and neurons (right) relative astrocytes (left) and neurons (right) relative
to the sizes of these cells in mice.
Human cortical astrocytes are almost
threefold larger, have approximately tenfold
more GFAP-positive processes, and are
more symmetrical than mouse astrocytes.
The increase in complexity and size of The increase in complexity and size of
astrocytes from mouse to man is
proportionate to the evolution of neuronal
structure, possibly reflecting the increasing
importance of astrocytes in the brain
function of higher organisms.
Evolution of increased glia-neuron ratios
in the human frontal cortex in the human frontal cortex
C.C. Sherwood, PNAS, 103:13606-13611, 2006
Glianeuron ratios in layer II / III of different areas in frontal cortex
Species n Area 4 Area 9L Area 32 Area 44 Species n Area 4 Area 9L Area 32 Area 44
Homo sapiens 6 2.19 (0.06) 1.65 (0.09) 1.63 (0.09) 1.55 (0.18)
Pan troglodytes 6 1.54 (0.05) 1.20 (0.06) 0.91 (0.09) 1.24 (0.13)
Macaca maura 6 1.29 (0.09) 0.84 (0.03) 0.68 (0.05) 0.95 (0.06) ( ) ( ) ( ) ( )
Data are presented as mean (standard error).
Results suggest that greater metabolic consumption of human neocortical Results suggest that greater metabolic consumption of human neocortical
neurons relates to the energetic costs of maintaining expansive dendritic arbors
and long-range projecting axons in the context of an enlarged brain and long range projecting axons in the context of an enlarged brain.
The human brain comprises about 2% of body mass
but captures about 20% of the bodys total glucose utilization.
Our findings suggest significant modifications of dopamines role in the cortical .Our findings suggest significant modifications of dopamines role in the cortical
organization occurred in the evolution of apes, with further changes in the descent of
humans.
Cerebral Cortex, 2008
Differences in cortical serotonergic innervation among humans, chimpanzees,
and macaque monkeys: a comparative study
Raghanti MA StimpsonCD Marcinkiewicz J L Erwin J M Hof PR SherwoodCC Raghanti MA, Stimpson CD, Marcinkiewicz J L, Erwin J M, Hof PR, Sherwood CC
these results indicate a significant reorganization of cortical serotonergic
transmission in humans and chimpanzees.
The hippocampus The hippocampus
1564: First description by the Italian anatomist Giulio Cesare Aranzi (1530-1589)
similarities with seahorse
Anterior
View
from
below
Similarities with seahorse similarities with seahorse Similarities with seahorse
Hippocampus
Posterior
Fromthe Greek language:
hippos - horse
kampos seamonster From the Greek language: kampos - seamonster
Hippocampus is the Latin name for seahorse
Rhesus monkey
Hippocampal anatomy Hippocampal anatomy
Overview Overview
Keuker J IH Michaelis T De BiurrunG LuitenPGM Witter MP Fuchs E : Keuker J IH, Michaelis T, De Biurrun G, Luiten PGM, Witter MP, Fuchs E.:
Methodological considerations when studying the aging process in the nonhuman primate brain. In: Aging in
Nonhuman Primates, Erwin J M, Hof PR (eds). Interdisciplinary Topics in Gerontology. Basel, Karger 2002,
31:76101.
Hippocampal subfields Hippocampal subfields
CA1
CA2 C
CA3
S bi l Subiculum
Dentate gyrus Hilus
Hippocampal circuitry Hippocampal circuitry
Perforant Perforant
pathway pathway
Entorhinal Entorhinal
Entorhinal Entorhinal
cortex cortex
layer IV layer IV
Mossy Mossy
fibers fibers
cortex cortex
layer II layer II
Schaffer Schaffer
collaterals collaterals collaterals collaterals
CA1 CA1 - - subicular subicular
pathway pathway pathway pathway
Within the brain, the hippocampus has the highest density
of glucocorticoid receptors
Glucocorticoid receptor
GR
Mineralocorticoid receptor
MR
GR is downregulated
by stress
U. Meyer et al., 2001
The stress cascade:
The hippocampal hypothalamic pituitray adrenal axis The hippocampal-hypothalamic-pituitray-adrenal axis
The pituitary and its hormones
Releasing hormones
MSH
Corticosterone
ACTH
End
MSH
GH
- End
LH
FSH
Estrogens
Progesterone
Testosterone
Vasopressin Vasopressin
Oxytocin Oxytocin
TSH Thyroxin
PRL
Oxytocin Oxytocin
TSH Thyroxin
Hippocampal damage associated
with prolonged and fatal stress in primates
Uno H Tarara R Else JG Suleman MA Sapolsky RM Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM,
J. Neuroscience 9: 1705- 1711, 1989
Bob Sapolsky and one
St
Bob Sapolsky and one
of his friends
Control
Stress
Cascade model of glucocorticoid hypersecretion,
t i d hi l d ti (S l k ) stress, aging and hippocampal degeneration (Sapolsky)
Hippocampal
pyramidal neurons
Stress
Endangerment
and loss (?)
Gl ti id
Adrenal glands
Glucocorticoid
hypersecretion
Conseq ences of h percortisolism Consequences of hypercortisolism
........
Depressive disorders
Impaired cognitive functions
Phylogenetic position of the tree shrews Phylogenetic position of the tree shrews y g p y g p
140 120 100 80 60 40 20 0
Million years
Cenozoic Mesozoic
Monotremata
Masurpialia
Lagomorpha
Rodentia
Primates Primates
Dermoptera
Tree shrews
Chiroptera
Insectivora
Carnivora
Cetacea
Perissodactyla
Proboscidea Proboscidea
The chronic social stress paradigm in tree shrews
Dominant Subordinate
~ 1hour / day
Rest of the day
Lack of
outlets
predictibility
sense of control sense of control
Perception that things
are getting worse
A. Raab (1971); D. v. Holst (1977); E. Fuchs & G. Flgge (2002)
The chronic social stress paradigm in tree shrews
Hyperactivity of HPA axis - no suppression by DEX
Reduced hippocampal glucocorticoid & CRH receptors
Subordinates are characterized by
Dominant Subdominant
Reduced hippocampal glucocorticoid & CRH receptors
Reduced hippocampal volume
Weight loss
R d d d l f ti Reduced gonadal function
Reduced motor activity
Disturbances in circadian rhythms
Di t b i l i b h i
Dominant
Subordinate
Disturbances in sleeping behavior
Face validity
Symptoms of major depression (DSM IV) Symptoms of major depression (DSM-IV)
Predictive validity
Several antidepressants counteract stress effects;
the prototypic anxiolytic diazepam is ineffective
Molecular validity
Homology of receptors and similar drug metabolism
Fuchs & Flgge, Pharmacol. Biochem. Behav., 2002
A suitable animal model of major depression
Homology of receptors and similar drug metabolism
Chronic social stress
does not affect the number of hippocampal pyramidal neurons does not affect the number of hippocampal pyramidal neurons
CA3 CA1
0
0
0
)
500
b
e
r

(
x

1
0
400
300
o
n

n
u
m
b
200
N
e
u
r
o
100
Control Stress Control Stress
Vollmann-Honsdorf et al., Neurosci Lett, 1997
Chronic social stress induces
shrinkage of apical dendrites shrinkage of apical dendrites
of CA3 pyramidal neurons
Magarios et al., 1996
Control Stress
Chronic stress affects morphology of
CA3 hippocampal pyramidal neurons
Stress experience
Gl ti id
Severe,
l d
Glucocorticoids
Glutamate
Biogenic amines
prolonged
exposure
X
Reversible
shrinking
Neuronal death
?
X
g
?
Shrinkage prevented by
blockade of glucocorticoid receptors g
NMDA receptor antagonists
antidepressant (Tianeptine)
benzodiazepines benzodiazepines
blockade of Na
+
- and T-type Ca
++
-channels
testosterone, estrogens
The paradigm shift:
Neurogenesis in the adult brain Neurogenesis in the adult brain
- Dentate gyrus of the hippocampal formation -
1965 Altman &Das: Autoradiographic
and histological evidence of postnatal
neurogenesis in rats.
J Comp Neurol
1985 Rakic: Limits of adult 1985 Rakic: Limits of adult
neurogenesis in primates.
Science
1998 Eriksson et al: Neurogenesis in
humans.
Nature Medicine a u e ed c e
1999 Gould et al: Neurogenesis in
adult Old World primates adult Old World primates.
PNAS
Ch i h i l t i hibit Chronic psychosocial stress inhibits
adult dentate neurogenesis in tree shrews
m
m
3
8
c
e
l
l
s

/

m
6
f

B
r
d
U
+

4
e
n
s
i
t
y

o
f
*
2
D
e
Control Stress
0
Gould et al., J Neurosci, 1997
Adult dentate cell proliferation is age dependent: Adult dentate cell proliferation is age dependent:
Decrease with increasing age
CA1
CA3
14 000
c
e
l
l
s
Dentate gyrus
6000
10 000
r

o
f

B
r
d
U
+

2000
6000
N
u
m
b
e
r
< 10 11 - 20 21 - 30
0
Age (months) g ( )
Simon et al., Brain Res, 2005
Age-dependent susceptibility
f d lt d t t ll lif ti of adult dentate cell proliferation
to chronic psychosocial stress
CA1
CA3
14 000
No stress
Stress
- 41%
c
e
l
l
s
Dentate gyrus
6000
10 000
- 48%
*
r

o
f

B
r
d
U
+

2000
6000
- 76%
***
**
N
u
m
b
e
r
< 10 11 - 20 21 - 30
0
Age (months)
**
g ( )
Simon et al., Brain Res, 2005
Older animals are more vulnerable
to the adverse effects of stress to the adverse effects of stress
on dentate cell proliferation
10.0
No stress Stress
9.0
7 0
8.0
r = 0.62
p < 0.001
2
6.0
7.0
r = 0.81
2
0 4 8 12 16 20 24 28 32
r 0.81
p < 0.001
Age (months) Age (months)
Simon et al., Brain Res, 2005
Acute psychosocial stress inhibits neurogenesis Acute psychosocial stress inhibits neurogenesis
in the dentate gyrus of adult marmoset monkeys
Control Stress
Gould et al., PNAS, 1998
Neurogenesis in the adult brain g
All vertebrates including nonhuman primates and humans
Dentate gyrus
Positive modulation: Negative modulation:
Gould, Nature Reviews Neuroscience, 2007
Positive modulation:
- Enriched environment
- Exercise (running)
Negative modulation:
- Aging
- NMDA receptor activation
- Learning
- Estrogen
- Glucocorticoids
- Acute and chronic stressors
Prenatal stress in rhesus monkeys Prenatal stress in rhesus monkeys
P t ti l l l ti ff t Potential long-lasting effects on -
Behavior
Endocrine system
Central nervous system:
Hippocampus / dentate gyrus Hippocampus / dentate gyrus
Neurogenesis
Hippocampal volume
Prenatal stress procedure (PNS)
C ti Bi th
Prenatal stress procedure (PNS)
in rhesus monkeys
n=4 Control
Conception

Birth

n=4
n=4
Control
Early PNS
n=4
Late PNS
Week
0 6 12 14 20 26

D il d i 10 i Daily, during 10 min
3 unexpected noise bursts (1 sec)
Postnatal procedure Postnatal procedure
Birth

Control n=4

Early PNS
L t PNS
n=4
4
Late PNS
n=4
Pair-
housed
Group-housed;
control,

Months 0 6 20 24 26 28
with
mother
early PNS,
late PNS
were mixed
Behavioral
and
endocrine
BrdU injections
(3 consecutive days)
3 weeks survival
f assessments after injection
Prenatal stress has long-lasting effects
on behavior and the endocrine system y
Disturbed behavior Disturbed HPA-axis
Locomotor activity Basal cortisol Locomotor activity
200
300
Basal cortisol
40
60
100
0
20
Control Early PNS Late PNS
0
Exploration
40
Control Early PNS Late PNS
0
Dexamethasone test
20
30
40
20
Control Early PNS Late PNS
0
10
Control Early PNS Late PNS
0
10
y y
Coe et al.: Biol Psychiat. 54: 2003
Prenatal stress has long-lasting effects Prenatal stress has long lasting effects
on neurogenesis in the dentate gyrus
800
Number of BrdU-labeled cells/mm
3
600
BrdU
CA 1
400
CA3
200
NeuN
Dentate gyrus
Control Early PNS Late PNS
0
BrdU +NeuN
Coe et al.: Biol Psychiat. 54: 2003
Prenatal stress has long-lasting effects g g
on hippocampal volume
)
*
*
225
e

(

m
m
3
125
175
V
o
l
u
m
e
75
125
0
25
0
Control Early PNS Late PNS
Coe et al.: Biol Psychiat. 54: 2003
Stress, glucocorticoids and
d hi l l and hippocampal volume
Depression Depression
e
pp
v
o
l
u
m
e
Cushings Cushings
Duration (days)
1000
4000
c
a
m
p
a
l

H
i
p
p
o
c
18 24 30 36
Plasma Cortisol (mg/dl)
Combat stress Combat stress
PTSD PTSD
No PTSD
10 20 30 40
Months
C l i Conclusions:
In rhesus monkeys, prenatal stress
has long-lasting effects on
the central nervous system
the endocrine system
the behavior
well beyond the infant stage of the
animals.
Exogenous / endogenous glucocorticoids
The casacade of prenatal programming
Fetal-placental barrier (11-HSD2)
Exogenous / endogenous glucocorticoids
Stress
Fetal placental barrier (11 HSD2)
11-HSD2 inhibition
Fetal glucocorticoid
overexposure
Genetic factors
Maternal factors
Fetal adaptation
- Organ development
- Hormonal activity
V l
Genetic factors
Environment
- Vascular responses
- Metabolic function
Ad lt i t
Adult disorders
- Hypertension
- Type 2 diabetes
Adult environment
- Lack of exercise
- Alcohol excess
- Excess salt
- Metabolic syndrome
- Atheromatous disorders
- Neuro-psychiatric disorders
- Smoking
- Obesity
- Stress
Gl ti id h i Glucocorticoid hormone programming
in early life and its impact on adult health
Th th ti l ti id h d th (DEX) The synthetic glucocorticoid hormone dexamethasone (DEX)
is used in the clinic in preterm-risk pregnancies.
The foetus widely expresses the DEX-binding glucocorticoid
receptor (transcripton factor).
In rat and sheep experimental evidence for long-term psycho-neuro-
endocrine effects of prenatal DEX.
Investigate in a nonhuman primate the long-term
psycho-neuro-endocrine effects of prenatal exposure to DEX.
Glucocorticoid hormone programming
in early life and its impact on adult health
Experimental design p g
p
t
i
o
n
i
n
f
a
n
t
l
e
s
c
e
n
t
C
o
n
c
e
B
i
r
t
h
,

J
u
v
e
n
i
A
d
o
l
e
s
A
d
u
l
t
142-148
days
Months
0-6
Months
7-12
Months
13-18

4
0
-
4
6
9
0
-
9
6
S i l b h i S i l b h i
Endocrinology Endocrinology
S i l b h i
Endocrinology
Cardiophysiology
-
m
o
r
t
e
m
Physical growth Physical growth Physical growth
E

E

DEX Treatment *
5mg/kg/day per os
Social behavior Social behavior
Emotionality
Motor dexterity
Cognition
Social behavior
Emotionality
Cognition
P
o
s
t
-
Intrauterine dexamethasone hyperexposure
reduces the number of Ki 67 positive cells reduces the number of Ki-67 positive cells
in the dentate gyrus of newborn marmoset monkeys
L t D
Tauber et al., Brain Pathol, 2006
Control
Early Dex Late Dex
: p <0.02
No differences in the number of Ki-67 positive cells
in the dentate gyrus of marmoset monkeys in the dentate gyrus of marmoset monkeys
2 years after intrauterine dexamethasone hyperexposure
Tauber et al., Brain Pathol, 2008
... It is for this reason that once the ... It is for this reason that, once the
development was ended, the founts of
growth and regeneration of
th d d d it d i d the axons and dendrites dried up
irrevocably. In adult centres the nerve
paths are something fixed, ended,
immutable. Everything may die,
nothing may regenerate.
S R C j l (1928) D ti d ti f S.R. Cajal (1928) Degeneration and regeneration of
the nervous system. Oxford University Press,
London, p.750.
Santiago Ramn y Cajal
1852 -1934
The adult brain: a plastic organ The adult brain: a plastic organ
Structural and functional adaptations following external and / or Structural and functional adaptations following external and / or
internal stimuli (stressors).
Dynamic processes.
Absolutely necessary for adequate functioning of an individual Absolutely necessary for adequate functioning of an individual
in the continuously changing environment (learning).
But: not all neuroplastic processes are beneficial -
e.g. altered structures and functions in the brains of patients
with mood disorders.