Cortisol and nightmares: the role of neuroendocrine stress ......Cortisol: asteroid hormone...
Transcript of Cortisol and nightmares: the role of neuroendocrine stress ......Cortisol: asteroid hormone...
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Cortisol and nightmares: the role of neuroendocrine stress response
Maria R. D’Orsogna (CSUN), Tom Chou (UCLA), Lae Kim (UCLA), Apeshka Singh (UCLA)
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Cortisol/neuroendocrine axis disorders also appear in PTSD patients
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Memories of trauma accompanied by intense emotional and physical reactions:
flashbacks, nightmares, and anxiety,irritability, trembling, nausea, chronic pain
PTSD: a mental health condition triggered by experiencing or seeing a terrifying event
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Low cortisol levels and nightmareshallmark of PTSD
How do PTSD patients develop low cortisol levels and nightmares
after exposure to stress?
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Death of a loved one, Car accidents, Natural disasters
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Diagnosis of PTSD
Diagnostic and Statistical Manual of Mental Health Disorders – 5 APA
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Treatment
EMDR - Eye Movement Desensitization and Reprocessing
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Biological markers?
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Major player in PTSD: cortisol
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Major player in PTSD: cortisolCortisol: a steroid hormone (glucocorticoid)
Released in response to stress and low blood glucose concentrations
Facilitates fear extinction, increases blood sugar, suppresses the immune system, wound healing,
regulates metabolism, influences memory
Hypo vs. hypercortisolism
Basal (un-stimulated) cortisol: LOWER in PTSD patients
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Cortisol
PTSD
Control
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Cortisol
Cortisol oscillates with hourly and diurnal cycles
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How does external input – stresslead to lower cortisol?
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External input and the brain
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External input and the brain
Input to the PVN in the hypothalamus
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External input and the brain
Input to the PVN in the hypothalamus
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Hypothalamus (PVN) (nervous system control)
Pituitary & Adrenal(hormonal glands)
HPA axis
The HPA axisHypothalamus Pituitary Adrenal Axis
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The HPA axis
I(t) = input(basal and/or external)
Central Nervous System sends a “signal” to the
PVN in the hypothalamus
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The HPA axis
The PVN in the Hypothalamus
releases CRH into the hypo-physeal portal vein
to the pituitary gland
CRH = corticotropin releasing hormone
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The HPA axis
The pituitary glandreleases ACTH into the
bloodstream
ACTH = adreno-corticotropin hormone
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The HPA axis
The adrenal cortexsynthesizes and secretes
CORT into the bloodstream
CORT = cortisol hormone
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The HPA axis
Cortisol imparts a negative feedback on the
pituitary and on the hypothalamus
Cortisol binds to the glucocorticoid receptor
GR, and stimulates further GR production in
the pituitary through homodimerization
CORT = cortisol hormone
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GR Homodimerization
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How can we model the HPA axis?
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What do we want from this model?
1. Steady states with “low” cortisol (diseased state) and “high” cortisol (normal state)
hypocortisolismnightmares
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What do we want from this model?
1. Steady states with “low” cortisol (diseased state) and “high” cortisol (normal state)
Bistability – hypocortisolism/nightmares
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Bistability:May explain how PTSD arises without physical trauma
We don’t need changes in parameters (physical trauma)just external input (psychological trauma)
Normalcortisol
dreaming
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Bistability:May explain how PTSD arises without physical trauma
We don’t need changes in parameters (physical trauma)just external input (psychological trauma)
Abnormalcortisol
nightmares
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What do we want from this model?
1. Steady states with “low” cortisol (diseased state) and “high” cortisol (normal state)
Hhypocortisolismnightmares
2. Reproduce realistic features such as oscillations in cortisol (and ACTH – no oscillations in CRH)
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So let’s build our model
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From experiments on sheep:
Oscillations in CORT and ACTH persist even aftersurgically removing the
hypothalamus
The PA system (without H)
should still support oscillations
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From experiments on sheep:
D Engler, Endocrinology (1990)
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From experiments on rats:
E Papaikonomou, J Physiology (1977) adrenal gland: inherent delay in ACTH to CORT
production
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The PA subsystem:Fix C (CRH) as input
dAdT
= pACfA(OR)−dAA
dOdT
= pOA(T −Td )−dOO
dRdT
= pRgR(OR)−dRR
C = CRH, A = ACTH, O = CORT, R= GR receptor
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The PA subsystem:Fix C (CRH) as input
fA, gR= functions of cortisol and GR receptor concentrations OR
dAdT
= pACfA(OR)−dAA
dOdT
= pOA(T −Td )−dOO
dRdT
= pRgR(OR)−dRR
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The PA subsystem:Fix C (CRH) as input
dAdT
= pACfA(OR)−dAA
dOdT
= pOA(T −Td )−dOO
dRdT
= pRgR(OR)−dRR
stimulate/decay/delay/feedback
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Forms for gA, fA
fA negative effect of cortisol-GR complex on ACTH production, positive and decreasing
gR self-upregulation of cortisol-GR complex on GR production in pituitary, positive and increasing
fA(OR) gR(OR)
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Parameters
“Free parameters” – variability in individual patientsHPA - highly conserved
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Simulate – c constantUse relevant parameters, fix undetermined ones,
non-dimensionalize and change c
Mean and amplitude of cortisol o change with c
o
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Simulate
o(T)
c=20, c=30, c=40
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Simulate
c=20, c=30, c=40
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What do we want from this model?
1. Steady states with “low” cortisol (diseased state) and “high” cortisol (normal state)
“hypocortisolism”
Reproduce realistic features such as oscillations in cortisol (and ACTH – no oscillations in CRH)
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Let’s add CRH dynamics
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Stored and released CRH
CRH is stored within neurons
in the PVNCs(T)
CRH is releasedupon stimulation
C(T)
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Neuronal activity
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Stored CRH Cs
CRH is stored within neurons
in the PVNCs(T)
CRH is releasedupon stimulation
The amount of stored CRH depends on cortisol
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Cortisol: negative feedback on CRH synthesis
Cortisol injected into adrenalectomized rats for 5-7 days
C∞(O)=C∞ + e−bO
dCs
dT=C∞(O)−Cs
TC
C∞(O)
Tc = 12 hours time for stored CRH to relax to Cs = C∞O
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Released CRH CReleased CRH depends on
1. Input from CNS I(T)
2. Available stored CRH h(Cs)
3. Already present CRH gc(C)
self - upregulation
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Self upregulation of CRH
Positive feedback
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Released CRH C
dCdT
= pCI(T )h(Cs )gc(C)−dcC
h(Cs )=1− e−kCs
gc(C)=1−µcKc
n
Kcn +Cn
low Cs à h(Cs) = 0 high Cs à h(Cs) = 1low Cà gc(C) = 1-µc high Cà gc(C) = 1
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Full problem – non dimensional
SLOW
FAST
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Determine behavior (c,cs,a,o,r) at “steady state”
given a fixed input I=I0
Once c is known, a,o,r are also known
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Determine behavior (c,cs,a,o,r) at “steady state”
given a fixed input I=I0
Once c is known, a,o,r are also known
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Bistability in CRH release
“q”
dcdt= pCI(t)h(cs )gc(c)−q2c
Since cs is slow, if we look at the “fast dynamics”with cs fixed – q can be seen as a bifurcation parameter
For fixed q we can find the nullclines of c
0 = qgc(c) – q2c
fixed input I(t) = I0
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Bistability in CRH release
0 = qgc(c) – q2c One (stable) or three (two stable, one unstable)
intersections depending on q
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Bistability in CRH release
0 = qgc(c) – q2c q bifurcation parameter controlling fast flow at short
time
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Bistability in CRH release
Once c is determined we can use the PA subsystem to determine the rest of the a-gr-o variables
as shown above
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What do we want from this model?
Reproduce realistic features such as oscillations in cortisol and ACTH
Steady states with “low” cortisol (diseased state) and “high” cortisol
(normal state)
Mission accomplished!
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What about cs?
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Include slow dynamics
dcsdt
=c∞(o)− cs
tc= 0
csà c∞(o) becomes cs(c)I(t) =I0
q(cs) = pc I(t) h(cs) à q(c) = pc I0 h(c)
cs ≈ c∞(o(c)) ≈ c∞(c) ≈ 0
2π∫ c∞(o(θ ,c))
dθ2π
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Nullclines in (q,c)
FAST: qgc(c) – q2 c =0
SLOW: q = pc I0 h(c)
Intersections yield (q,c)
From c find (a,o,r)From q find h(cs) and cs
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Full Dynamics?
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q changes slowlyc changes fast
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Full Dynamics
Two equilibrium states
Normal with higher c,o
Diseased with lower c,o
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Initial State 1Quickly find the
nearest “fast nullcline” with
flow xf
Slowly move along the “fast nullcline” with
flow xs
Reach normalstate
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Initial State 2Quickly find the
nearest “fast nullcline” with
flow xf
Slowly move along the “fast nullcline” with
flow xs
Reach diseasedstate
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Normal to Diseased?
So farI(t) = I0 =1
What if we now change the stress level?I(t) = I0 + Iext (t)
Iext turned on for a finite amount of time
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Normal response
Normal state, START turn on Iext = 0.1 q = pc (I+Iext) h(cs(c))
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Turn off I0+ Iext à I0
The q nullclinewill shift back
towards its original location
The system will move vertically towards the original, normal state
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… returned the system back to its original state normal response – two hours of external stress
A temporary Iext ...
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The system returns back to its original state
Cortisol for Iext =0.1; stress for 2 hs
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Normal to Diseased?
Normal state, START turn on Iextq = pc (I+Iext) h(cs(c))
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Increase I0 à I0 + Iext
The system will find its
new equilibrium at
the new nullcline
intersection
Let’s now turn Iext off
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Turn off I0 + Iext à I0
The q nullclinewill shift back
towards its original location
The system will find the fast nullcline first and then move towards the diseased state
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A temporary but prolonged Iext ...
…led us from normal to diseased states30 hours of external stress
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Cortisol for Iext =0.2; stress for 30 hs
Normal (high cortisol) to diseased (low cortisol)
DISEASED
O(T)
NORMAL
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Resistant case
If there is only one intersection, the system eventuallyreturns to the normal state.
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Cortisol for Iext =0.2; stress for 30 hs
A resistant individual
NORMAL
O(T)
NORMAL
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Diseased to Normal?
Diseased state, START turn on Iextq = pc (I+Iext) h(cs(c))
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Diseased state, START turn on Iext
Increase I0 à I0 + Iext (short time)
q increases
We turn off stress before the
system can reach the new
equilibrium
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Turn off I0 + Iext à I0
The system will relax back to the fast nullcline first and finally to the
normal state
Short time stress can lead to a reverse transition!
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Diseased to Normal
Short time external stress can reverse transition!
o(T)
NORMALDISEASED
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Diseased to Normal?
Diseased state, START turn on Iextq = pc (I+Iext) h(cs)
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Diseased state, START turn on Iext
Increase I0 à I0 + Iext (long time)
q increases
We turn off stress almost at the
new equilibrium
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Turn off I0+ Iext à I0
q decreases
Not able to find the normal state
The fast nullclineis reached
Relax back to the diseased state
Long time external stress does not allow for a transition
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Diseased to Diseased
No permanent transition
DISEASEDDISEASED
O(T)
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Can induce transitionsbetween normal and diseased states and vice-versa depending on magnitude and
duration of stress
w/o changing physiological parameters
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Timing of stressor?
External stress: same 0.1 magnitude, 250 min duration, but different phases of cortisol oscillation
DISEASEDDISEASED
NADIR - DISEASED PEAK - NORMAL
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Higher intensity – Shorter durationPhase at onset dependenceAt peak transition more likely
Normal to diseased transition
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ConclusionsIntroduced a bistable dynamical model
Physiologically motivated feedbackNormal and diseased (oscillating) states
Stress-induced normal-diseased, reversible transitions
No physiological parameter changes
Transitions depend on magnitude, duration, timing of stress
Circadian Clock? Higher brain? I(t)? Experiments?
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Thanks:
L. Kim, T. Chou, A. Singh, Y. L. Chuang (UCLA)
T. Minor and M. Wechselberger (UCLA)
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Closing
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Recall
The separatrix lines determine basins of attractionL – lowerU - upper
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Non dimensionalization
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Changing k
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Include slow subsystemWe will only look at (q(cs), c)
all other variables can be determined via the PA subsystem for a given c
dcsdt
=c∞(o)− cs
tctc à ∞ cs à c∞(o) or c∞(o(c))
q(cs) = pc I(t) h(cs), use I(t) =I0
q(cs) à q(c∞(o)) or q(c∞(o(c)))
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Include slow subsystemWe will only look at (q(cs), c)
all other variables can be determined via the PA subsystem for a given c
dcsdt
=c∞(o)− cs
tctcà ∞ cs à c∞(o) or c∞(o(c))
q(cs) = pc I(t) h(cs), use I(t) =I0
q(cs) à q(c∞(o)) or q(c∞(o(c)))
Have a function q(c) as slow q nullcline ; use o
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Timing of stressor?
Timing of stress onset determines position of the staterelative to the separatrix at stress end
DISEASED NORMAL
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Timing of stressor?
Timing of stress onset determines position of the staterelative to the separatrix at stress end
DISEASED NORMAL