Within the Brain Awareness Week prof. Gal Richter-Levin (University of Haifa) gave a wonderful lecture about how stress influence on brain.

1. Stress and trauma

3. A survival response -

4. Freeze!
Fight!
Or flight

5. Good stress, bad stress and very bad stress

6. The
Response to
Stress -

7. The
Response to
Stress -

8. But it is first and outmost – the brain who respond to stress!

9. How can we study the brain?

11. Computerized Tomography (CT)

12. MRI

14. Functional
MRI

23. Charles R. Darwin
12.2.1809-19.4.1882

35. But what about emotions?

36. Darwin, C. R. 1872. The expression of
the emotions in man and animals.
London: John Murray. 1st edition.

37. Darwin, C. R. 1872. The expression of the emotions in
man and animals. London: John Murray. 1st edition.

40. Translational animal models in brain research:

42. 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

43. 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

44. 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

45. Towards an effective animal model for PTSD

46. PTSD is triggered by the exposure to a traumatic event!?
Trauma Exposure

47. Daily Stress

48. Traumatic events

49. Neutral
Emotional
Stressful
Traumatic
PTSD

50. Neutral
Emotional
Stressful
Traumatic
PTSD

51. Behavioral testing
The Under Water Trauma (UWT) –
A model of a brief, intense traumatic experience
which is ecologically relevant to both humans and rats

52. PTSD – Long-term effects
Symptoms last at least one month

53. Behavioral testing
24 Hrs
PTSD – Long-term effects

54. Behavioral testing
PTSD – Long-term effects

55. One Month
Behavioral testing
PTSD – Long-term effects –
tested one months after the trauma

56. A hallmark of PTSD –
intense response to trauma reminder cues

57. One Month
Behavioral testing
A hallmark of PTSD –
intense response to trauma reminder cues

58. One Month
Behavioral testing
A hallmark of PTSD –
intense response to trauma reminder cues

59. One Month
Behavioral testing
A hallmark of PTSD –
intense response to trauma reminder cues

60. Exposed to a traumatic event
most people DO NOT develop
Post-traumatic stress disorder

61. 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.

63. Analysis
•Behavioral
•Electrophysiological
•Biochemical
Childhood
Exposure
Adulthood
Exposure
The Juvenile Stress model of risk factors in PTSD

64. One Month
One Month
Behavioral testing

65. 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)

66. 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-monthprevalence
Increased prevalence to PTSD
upon trauma later in life by
Childhood adversity

67. • 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

68. Group BGroup A

69. PTSD scale 6 month later
0
10
20
30
40
50
Group A Group B
PTSD symptoms
0
10
20
30
40
50
60
70
80
90
100
0.5 1 1.5 2 2.5
Group A Group B
** Pychiatric criteria

71. Can we Increase translational power of the animal
model by addressing individual differences

72. PND 64
±
±
1 month
Underwater trauma
(UWT) ± odor
ControlUWT(-)UWT(+)
“affected” = - 1 SD / + 1
SD from mean of
Control in
5 of 6 measurements
Behavioral Profiling

73. PND 64
±
±
1 month
Underwater trauma
(UWT) ± odor
ControlUWT(-)UWT(+)
19%
81%
UWT(-)
24%
76
%
UWT(+)
Unaffecte
dAffected
Behavioral Profiling

74. PND 64
±
±
1 month
Underwater trauma
(UWT) ± odor
ControlUWT(-)UWT(+)
Unaffecte
dAffected
Behavioral Profiling
Resilient Vulnerable
19%
81%
UWT(-)
24%
76%
UWT(+)
Risk Factors
T = 30 min
T = 15
min
T = 2 h
PND 27-29
Juvenile Stress (JS)

75. Unaffecte
dAffected
ControlUWT(-)UWT(+)J+UWT(-)J+UWT(+)
PND 64
±
±
1 month
T = 30 min
T = 15
min
T = 2 h
PND 27-29
Juvenile Stress (JS) Underwater trauma
(UWT) ± odor
Behavioral Profiling
Resilient Vulnerable
19%
81%
UWT(-)
24%
76%
UWT(+)
38%
62%
61%
39%
*** ***
$
J+U(-) J+U(+)

76. The proof is in the brain

79. Potential gender differences?

80. 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?

81. 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
Avoidance
Escape
Escape Failure

82. 0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10
*
avoidance
shuttles
Blocks of trials
*
* * *
Tsoory and Richter-Levin, 2006

83. 0
2
4
6
8
10
1 2 3 4 5 6 7 8 9 10
*
avoidance
shuttles
Blocks of trials
*
* * *

84. Two way Shuttle Avoidance
=
=
Juvenile stressed
Female rats
do not exhibit
Significant impairment
in the Two way Shuttle
Avoidance task!
Horovitz et al, 2014

85. 'Pre-Sac'
Juvenile stressed Female rats
do exhibit significant anhedonia -
Horovitz et al, 2014

86. Both Male and Female Juvenile stressed rats
do exhibit significantly reduced exploration -
Horovitz et al, 2014

87. Female rats
(n=17)
Male rats
(n=18)
<49.88<49.31Sac-Pre: below the 25th percentile
<6<7Exploration: below the 25th
percentile
<28.57<58.92Avoidance responses: below the
25th percentile
>66.42>37.14Escape responses: above the 75th
percentile
>4.28>3.57Escape failure: above the 75th
percentile
<63.56<41.82Sac-Post: below the 25th percentile
Differential classifications of 'Affected' rats
Horovitz et al, 2014

88. =
Horovitz et al, 2014

89. Horovitz et al, 2014

90. 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.

91. The sex differences in symptoms and in neural mechanisms
require separate diagnosis criteria -
Gender difference:

92. Detecting Individual differences will enable
more effective personalized treatment
to patients.
Individual difference:

93. Integrative Brain Research:

94. Behavioral models
Brain imaging
Sophisticated analysis tools
Genetic and molecular tools
Electrophysiological tools

95. Dr Ziv ArdiDr Gilad RitovDr Anne Albrecht
Dr. Shlomit Jacobson-Pick
Dr Michael Tsoory Dr Omer Horovitz
Dr. Femke Zitman

96. The Brain and behavior lab 2016/17

97. Thank You
University of Haifa
Prof. Mouna Maroun
Prof. Irit Akirav
Dr. Hanoch Kaphzan
Tel Aviv University
Dr. Segev Barak
The Weizmann Institute , Israel
Prof. Menahem Segal
Institute of Biology, Magdeburg, Germany
Iris Müller
Prof. Oliver Stork
Natural and Medical Sciences Institute (NMI),
Universität Tübingen
Dr. 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 Science
Prof. Lin Xu
East China Normal University (ECNU)
Prof. Xiahoua Cau

98. And thank you…
for listening.. …