brainy. stress and the brain

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

Towards an effective animal model for 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… ..