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Animal modal of PTSD

In this animal model, populations of exposed rats are classified according to the degree of their individual behavioral response using standardized "cut-off behavioral criteria" (CBC), creating three distinct groups entitled "extreme behavioral response" (EBR) and "minimal behavioral response" (MBR) at the extremes, and a middle group of "partial responders" (PBR).


Effect of PSS (predator scent stress) exposure on body temperature

37.2

BL

Tim e (h our s)

EBR

2 1 BL

SS tP

3

Da ys

1

4 12:00 PM 09:00 AM 06:00 AM 03:00 AM 12:00 AM 09:00 PM 06:00 PM 03:00 PM

pos

Da ys pos tP SS

2

5

5

4

4 12:00 PM 09:00 AM 06:00 AM 03:00 AM 12:00 AM 09:00 PM 06:00 PM 03:00 PM

Tim e

(ho urs

3 2 1 BL

)

EBR

38.2 38.0 37.8 37.6 37.4 37.2 37.0

re

38.4

Body Tempera tu

Tim e (h our s)

6

6

5

3

37.0

37.0

6

12:00 PM 09:00 AM 06:00 AM 03:00 AM 12:00 AM 09:00 PM 06:00 PM 03:00 PM

37.4 37.2

PS S

37.6 37.4

37.8 37.6

pos t

37.2 37.0

37.8

38.2 38.0

Da ys

37.4

38.0

Body Tempera ture

Body Tempera ture

38.2

38.0

37.6

38.4

38.4

38.2

re

38.4

37.8

PBR

MBR PBR

Body Tempera tu

Naive MBR

6 5

Tim e (h our s)

3 2 1 BL

Da ys p

12:00 PM 09:00 AM 06:00 AM 03:00 AM 12:00 AM 09:00 PM 06:00 PM 03:00 PM

ost PS S

4

During PSS-exposure, all groups demonstrated a significant increase in body temperature, as compared to both controls and baseline values.


Effect of PSS exposure on locomotor activity (LMA) p<0.004

p<0.03

p<0.007

Inactive Phase

PSS- 1d

Active Phase

PSS- 1d

12000

Locomotor Activity

Locomotor Activity

28000

24000

20000

16000

12000

8000

10000

8000

6000

4000

4000

Naive

MBR

PBR

Naive

EBR

PBR

EBR

Inactive Phase

PSS- 6d

Active Phase

PSS- 6d

MBR

20000

p<0.0001 p<0.0008

28000

Locomotor Activity

Locomotor Activity

p<0.007 24000

p<0.015 20000

p<0.0015 p<0.02

16000

12000

16000

12000

8000

8000

4000

4000

Naive

MBR

PBR

EBR

Naive

MBR

PBR

EBR

MBR individuals showed significantly increased LMA during the nocturnal (active) phase, compared to the unexposed, EBR and PBR groups. The EBR group showed decreased. During the diurnal (inactive) phase the EBR animals showed significantly increased LMA.


400 380 360 6

6

PS SE xpo sur DA e

10 5 0 -5 -10

3

2 1

12 : 10 00 P :0 M 08 0 A :0 M 06 0 A M :0 04 0 A M :0 02 0 AM :0 12 0 AM :00 AM 10 :0 08 0 PM :0 06 0 PM :0 04 0 PM :0 02 0 PM :00 PM

BL

BL

-25

500

Naive

MBR

PBR

480

EBR

460

-40

440

xpo sur

5

e

420 400 380 360 6

The EBR group displayed only minimal HR recovery.

ATE (bp m)

520

-20

-35

2 1

EBR

-15

-30

4

3

HEART R

Heart Rate Recovery (Baseline nimus 7d post PSS)

15

YS

12 : 10 00 P :0 M 08 0 A :00 M 06 :00 AM 04 :0 AM 02 0 AM :00 12 :0 AM 10 0 AM :00 08 PM :0 06 0 PM :00 PM 04 :0 02 0 PM :00 PM

4

PS SE xpo sur DA e

5

5

20

RATE (b pm

440 420

HEART

420 400 380 360

480 460

HEART

460 440

500

YS

500 480

520

RATE (b pm)

520

)

Effect of PSS exposure on circadian rhythm of Heart PBR Rate (HR) Naive

1

DA YS

3 2

PS SE

12 : 10 00 P :0 M 08 0 A M :0 06 0 A M :0 04 0 A :00 M 02 :0 AM 12 0 AM :00 AM 10 :0 08 0 PM :00 PM 06 :0 04 0 PM :00 P 02 :00 M PM

4

BL

The EBR and PBR groups displayed a robust increase in HR as compared to both controls and baseline values. The EBR animals displayed an elevated HR in both active and inactive phases.


Heart Rate Variability (HRV)

0 .0 0 .0 0.0

3d

2d 1d BL

y Da

6d

5d

4d

sp

t os

0 .0

PS

08

06

04

02

00

S

0. 0 0 .0 0 .0 0. 0 0. 0 0 .0

2d

3d

1d BL

Da

ys

0 .0 1

0

5d

10

08

06

04

02 0 . 0 6d 00

s po

t

S PS

0 .0

7 0

0

6 0

10

08

06

0

4

1

3 2 1

PBR EBR

04 02

00

5

1

1

y Da

sp

o

P st

SS

14

12

12

0 .0

1

N aive MBR

4d

0 .0

1

0 .0

00 0 .5 .4 1 7 0 333 0 . 2 50 0. 167 0. 083 0. 000 1. 917 0. 33 0 .8 5 0 0 .7 67 0 .6 83 0 .5

0 .0

1

Heart Ra te Variab ility

00 0 . 5 .4 1 7 0 .3 3 3 0 50 0.2 167 0. 083 0 . 000 1. 17 0 .9 8 3 3 0. 50 0.7 67 0.6 83 0.5

10

0 .0

14

0.0 0 .0 0 .0 0 .0 0.0

2d

3d

4d

1d BL

y Da

5d

sp

PS

12

08

06 04

0.0 02 0 6d . 0 0 0

t os

14

10

0 .0

00 0 . 5 .4 1 7 0 33 3 0 . 25 0 0 . 16 7 0 . 08 3 0 . 00 0 1. 9 17 0. 33 0 .8 5 0 0 .7 67 0 .6 83 0. 5

Variabilit y

0 .0

12

0. 0

Heart Ra te

0 .0

0. 0

Heart Ra te Variab ility

0.0

14

Heart Ra te Variab ility

0 .0

S

After PSS-exposure, the EBR group displayed a significantly decreased in HRV as compared to all other groups and baseline values.


Effect of PSS exposure on circadian rhythm genes

p<0.0001

p<0.0001

p<0.0001

1.00 0.75 0.50 0.25

DG Clock mRNA/ β actin

1.25

p<0.015

EBR

PBR

MBR p<0.025

3.0

2

1

p<0.03 2.5 2.0 1.5 1.0 0.5

EBR

PBR

MBR

PBR

MBR

Naive p<0.04

1.50

p<0.02

p<0.025

1.25 1.00 0.75 0.50 0.25 0.00

0.0

EBR

p<0.03

p<0.0008

p<0.02

3

Naive

p<0.001

p<0.03

4

0

0.00

DG AANAT mRNA/ β actin

5

1.50

DG Bmall mRNA/ β actin

DG Period 2 mRNA/ β actin

Dentate Gyrus - (Hippocampus)

EBR

PBR

MBR

Naive

Naive

In the hippocampal DG subregion, PSS-exposure significantly increased Period 1 and Clock mRNA levels in EBR individuals as compared to controls, MBR and PBR groups. Moreover, PSS-exposure significantly increased Aanat and Bmall mRNA levels in both EBR and PBR individuals as compared to controls and as compared to MBR.


6

p<0.045

FC Period 2 mRNA/ β actin

FC Period 1 mRNA levels/ β actin

Frontal Cortex p<0.004 p<0.002

5 4 3 2 1 0

EBR

PBR

MBR

p<0.0035

p<0.0035

p<0.035

3

2

1

EBR

PBR

MBR

Naive

0.5

FC Bmall mRNA/ β actin

FC Clock mRNA/ β actin

4

0

Naive

2.0

1.5

1.0

0.5

0.0

5

EBR

PBR

MBR

Naive

0.4

p<0.015 p<0.004

0.3

p<0.0015

0.2

0.1

0.0

EBR

PBR

MBR

In the frontal cortex, PSS-exposure significantly decreased Period 1, Clock, Aanat and Bmall mRNA levels in EBR and PBR individuals as compared to controls and MBR individuals.

Naive


4