brainy. stress and the brain
TRANSCRIPT
Stress and trauma
A survival response -
Freeze!
Fight!
Or flight
Good stress, bad stress and very bad stress
TheResponse to Stress -
TheResponse to Stress -
BLA
BLA
BLA
But it is first and outmost – the brain who respond to stress!
How can we study the brain?
Computerized Tomography (CT)
MRI
Functional MRI
Charles R. Darwin12.2.1809-19.4.1882
But what about emotions?
Darwin, C. R. 1872. The expression of the emotions in man and animals. London: John Murray. 1st edition.
Darwin, C. R. 1872. The expression of the emotions in man and animals. London: John Murray. 1st edition.
Translational animal models in brain research:
Construct Validity – Introducing a similar physiological / neural mechanism of inducing the disorder as in the human disorder.
Pharmacological Validity –Drugs that are effective in humans are effective in reducing symptoms in the model.
Face or Ecological Validity – The set of symptoms in the animal model holds great resemblance to the human disorder
Validating an animal model of a PTSD
Construct Validity –Introducing a similar physiological / neural mechanism
of inducing the disorder as in the human disorder.
Pharmacological Validity– Drugs that are effective in humans are effective in reducing
symptoms in the model.
Face or Ecological Validity – The set of symptoms in the animal model
holds great resemblance to the human disorder
Validating an animal model of a PTSD
Construct Validity –Introducing a similar physiological / neural mechanism
of inducing the disorder as in the human disorder.
Pharmacological Validity– Drugs that are effective in humans are effective in reducing
symptoms in the model.
Face or Ecological Validity – The set of symptoms in the animal model
holds great resemblance to the human disorder
Validating an animal model of a PTSD
PTSD is triggered by the exposure to a traumatic event!?
Trauma Exposure
Daily Stress
Traumatic events
Neutral
Emotional
Stressful
Traumatic
PTSD
Neutral
Emotional
Stressful
Traumatic
PTSD
Behavioral testing
The Under Water Trauma (UWT) – A model of a brief, intense traumatic experience which is ecologically relevant to both humans and rats
PTSD – Long-term effects
Symptoms last at least one month
Behavioral testing
24 Hrs
PTSD – Long-term effects
Behavioral testing
PTSD – Long-term effects
One Month
Behavioral testing
PTSD – Long-term effects – tested one months after the trauma
A hallmark of PTSD – intense response to trauma reminder cues
One Month
Behavioral testing
A hallmark of PTSD – intense response to trauma reminder cues
One Month
Behavioral testing
A hallmark of PTSD – intense response to trauma reminder cues
One Month
Behavioral testing
A hallmark of PTSD – intense response to trauma reminder cues
Exposed to a traumatic eventmost people DO NOT developPost-traumatic stress disorder
The exposure to the traumatic experience is necessary, but not a sufficient condition to induce the disorder. There must be additional factors that determine the outcome of the exposure to the trauma.
Analysis•Behavioral•Electrophysiological•Biochemical
Childhood Exposure
Adulthood Exposure
The Juvenile Stress model of risk factors in PTSD
One Month
One Month
Behavioral testing
Effects of the UWT one month after exposure
With or without a history of juvenile stress
cm *
*
Activity Anxiety Index
(Ardi et al. Neurobiol. Dis. 2016)
Effects of the UWT one month after exposure
With or without a history of juvenile stress
McLaughlin et al., Psychol. Med., 2010
PTSD
Number of past year major stressful events
12-m
onth
pre
vale
nce
Increased prevalence to PTSD upon trauma later in life by Childhood adversity
• A brief, acute and intense, ecologically relevant trauma
• Tested a long time (one month) after the exposure (PTSD)
• Effects intensified by presentation of a reminder of the original trauma!
• Risk factors that contribute to developing PTSD also promote symptoms in this model.
• Individual differences are taken into consideration.
Towards a relevant drug testing platform for PTSD
Group BGroup A
PTSD scale 6 month later
Group A Group B0
10
20
30
40
PTSD symptoms
0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 2.3 2.50
10
20
30
40
50
60
70
80
90
100
Group A Group B
** Pychiatric criteria
Can we Increase translational power of the animal model by addressing individual differences
PND 64
±
±
1 month
Underwater trauma (UWT) ± odor
Cont
rol
UW
T(-)
UW
T(+
)
“affected” = - 1 SD / + 1 SD from mean of
Control in 5 of 6 measurements
Behavioral Profiling
PND 64
±
±
1 month
Underwater trauma (UWT) ± odor
Cont
rol
UW
T(-)
UW
T(+
)
19%
81%
UWT(-)
24%
76%
UWT(+)
Unaffected Affected
Behavioral Profiling
PND 64
±
±
1 month
Underwater trauma (UWT) ± odor
Cont
rol
UW
T(-)
UW
T(+
)Unaffected Affected
Behavioral Profiling
Resilient Vulnerable
19%
81%
UWT(-) 24%
76%
UWT(+)
Risk Factors
T = 30 minT = 15 min
T = 2 h
PND 27-29Juvenile Stress (JS)
Unaffected Affected
Cont
rol
UW
T(-)
UW
T(+
)J+
UW
T(-)
J+U
WT(
+)
PND 64
±
±
1 month
T = 30 minT = 15 min
T = 2 h
PND 27-29Juvenile Stress (JS) Underwater trauma
(UWT) ± odor
Behavioral Profiling
Resilient Vulnerable
19%
81%
UWT(-) 24%
76%
UWT(+)
38%
62%
61%
39%
*** ***$
J+U(-) J+U(+)
The proof is in the brain
Potential gender differences?
Gender differences in the prevalence of ICD-10 PTSD
PETERS et al, Psychological Medicine (2006), 36:1:81-89
The pattern of gender difference at the diagnostic level was mirrored in the pattern of
gender differences at the criterion level for both DSM-IV and ICD-10.
Females only endorsed three symptoms at a significantly higher rate than
males. For all other symptoms, endorsement was equal.
This apparently small gender difference at the symptom level was sufficient to
cause the gender difference at the diagnostic level for ICD-10.
Potential gender differences?
Juvenile stress effects on learning under stress in adulthood
Age: 29 PND
Age: 60 PND
Age: 28 PNDAge: 27 PND
Forced swim stress : 10 minutes Elevated platform stress confinement: 2 hours
AvoidanceEscape
Escape Failure
0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10
*
avoi
danc
e sh
uttle
s
Blocks of trials
** * *
Tsoory and Richter-Levin, 2006
0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10
*
avoi
danc
e sh
uttle
s
Blocks of trials
** * *
Two way Shuttle Avoidance
=
=
Juvenile stressed Female rats do not exhibit Significant impairment in the Two way Shuttle Avoidance task!
Horovitz et al, 2014
'Pre-Sac'
Juvenile stressed Female rats do exhibit significant anhedonia -
Horovitz et al, 2014
Both Male and Female Juvenile stressed rats do exhibit significantly reduced exploration -
Horovitz et al, 2014
Female rats (n=17)
Male rats (n=18)
<49.88 <49.31 Sac-Pre: below the 25th percentile <6 <7 Exploration: below the 25th
percentile <28.57 <58.92 Avoidance responses: below the
25th percentile >66.42 >37.14 Escape responses: above the 75th
percentile >4.28 >3.57 Escape failure: above the 75th
percentile <63.56 <41.82 Sac-Post: below the 25th percentile
Differential classifications of 'Affected' rats
Horovitz et al, 2014
=
Horovitz et al, 2014
Horovitz et al, 2014
Summary and Conclusions:
• There is still no effective treatment to stress-related psychopathologies.
• Novel approaches developed in recent years bring hope that soon we will be able to develop better ways to treat stress and stress-related psychopathologies.
The sex differences in symptoms and in neural mechanisms require separate diagnosis criteria-
Gender difference:
Detecting Individual differences will enable
more effective personalized treatment to patients.
Individual difference:
Integrative Brain Research:
Behavioral models
Brain imaging
Sophisticated analysis tools
Genetic and molecular tools
Electrophysiological tools
Dr Ziv ArdiDr Gilad RitovDr Anne Albrecht
Dr. Shlomit Jacobson-Pick
Dr Michael Tsoory Dr Omer Horovitz
Dr. Femke Zitman
The Brain and behavior lab 2016/17
Thank You
University of HaifaProf. Mouna MarounProf. Irit AkiravDr. Hanoch Kaphzan
Tel Aviv UniversityDr. Segev Barak The Weizmann Institute , IsraelProf. Menahem Segal
Institute of Biology, Magdeburg, GermanyIris Müller
Prof. Oliver StorkNatural and Medical Sciences Institute (NMI),
Universität TübingenDr. Martin Kriebel ,
Prof. Hansjürgen Volkmer
Funding Agencies: Israel Science Foundation (ISF)Israel Ministry of Science and Technology (MOST)Programme of German-Israeli Project Cooperation (DIP)German Research Foundation (DFG) Department of Defense, USA (DoD)
Chinese Academy of ScienceProf. Lin Xu
East China Normal University (ECNU)Prof. Xiahoua Cau
And thank you…for listening… ..