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Quantifying Cardiovascular and
Behavioral Correlates of Fear in Mice:
Implications for PTSD and Cardiovascular
Disease Risk
Paul J. Marvar, PhD
Associate Professor
Department of Pharmacology & Physiology
George Washington University
Benjamin Turley
Master's Student
Systems Medicine
Georgetown University
Quantifying Cardiovascular and
Behavioral Correlates of Fear in Mice:
Implications for PTSD and Cardiovascular
Disease Risk
Dr. Paul Marvar and Benjamin Turley present
research pairing behavioral and cardiovascular
responses to cued fear learning and demonstrate
how fear-based disorders (such as PTSD) can
contribute to cardiovascular disease risk.
Quantifying Cardiovascular and
Behavioral Correlates of Fear in Mice:
Implications for PTSD and Cardiovascular
Disease Risk
Paul J. Marvar, PhD
Associate Professor
Department of Pharmacology & Physiology
George Washington University
Benjamin Turley
Master's Student
Systems Medicine
Georgetown University
V
Copyright 2021 P. Marvar, B. Turley and InsideScientific.
All rights reserved.
Key learning objectives:
• To understand the physiological impact
of PTSD on cardiovascular and
autonomic homeostasis, CVD risk
• Demonstrate utility of rodent models
in assessing real-time cardiovascular
and autonomic fear or defensive
emotional states
• Discuss benefits and translational
implications for using integrated
behavioral and cardiovascular multi-
modal methodologies
Key learning objectives:
• To understand the physiological impact
of PTSD on cardiovascular and
autonomic homeostasis, CVD risk
• Demonstrate utility of rodent models
in assessing real-time cardiovascular
and autonomic fear or defensive
emotional states
• Discuss benefits and translational
implications for using integrated
behavioral and cardiovascular multi-
modal methodologies
Why study behavioral and cardiovascular
correlates of learned fear in mice?
PTSD characterized by a persistent maladaptive reaction to exposure
to severe psychological trauma. (i.e., violent personal assaults, natural
or human made disasters, serious traffic collisions, or military combat)
o Psychological and Behavioral Symptoms:
o Symptoms (>3month) occurring after a traumatic event
• Intrusive recollection, avoidance
• Negative mood alterations
o Physiological Symptoms:
o Hypervigilance / physiological hyperarousual, increased
blood pressure, heart rate, sympathetic outflow,
respiratory distress, shortness of breath, sleep disturbances.
o Limited effective treatment options
o Highly co-morbid with poor overall physical health outcomes
and increased other diseases (ie., CVD, metabolic,
autoimmune)
Post Traumatic Stress Disorder (PTSD)
https://www.cdc.gov/heartdisease/mentalhealth.htm
Pain, fear, cardiac
reactivity, reduced blood
flow to heart, increased
cortisol
Smoking, physical
inactivity, medication
non-adherence……
Trauma, PTSD and Cardiovascular Disease (CVD) Risk
Adopted and modified from
O’Donnell et al., JAMA Cardiol. Published online July 14, 2021. doi:10.1001/jamacardio.2021.2530
PTSD as a CVD Risk Factor
Physiological and Behavioral Evidence from Epidemiological Studies
Edmonson et al., 2017 4:320-29
High Blood Pressure
1. Elevated blood pressure and
hypertension in trauma-
exposed populations,
including military veteran and
community-based samples.
2. Greater resting blood
pressure (BP) as well as
greater BP response to
trauma-related cues.
(Buckley and Kaloupek, 2001;
Pole, 2007)
PTSD as a CVD Risk Factor
Physiological and Behavioral Evidence from Epidemiological Studies
Edmonson et al., 2017 4:320-29
PTSD = impaired ability to process fear and perceived threats
Hippocampus
PTSD = exaggerated behavioral physiological responses
Threat Detection and Fear Circuitry
impacted by PTSD
Blood Pressure
Heart Rate
• PTSD = impaired ability to process fear and perceived threats
– Over-generalization of trauma-related stimuli and a reduced ability to suppress emotional
(stress) and physiological (ie., increase in blood pressure, heart rate, sympathetic nervous
system) responses to threat-associated stimuli.
The effects of PTSD are not limited to psychological symptoms.
Meakins and Wilson, 1918
Early observations of abnormal cardiovascular responses associated with trauma describe a
condition called “irritable heart syndrome”, and veterans with this condition exhibited greater
heart rate (HR) and respiratory responses to presentations of bright flames and pistol shots
2. Park, J. et al. Baroreflex dysfunction and augmented
sympathetic nerve responses during mental stress in veterans
with post-traumatic stress disorder. The Journal of Physiology
595, 4893–4908 (2017).
Jeanie Park, MD, MS
Emory University
3. Fonkoue I et al., Sympathoexcitation and impaired arterial
baroreflex sensitivity are linked to vascular inflammation in
individuals with elevated resting blood pressure. Physiol Rep.
2019 Apr;7(7):e14057.
1. Fonkoue, I., et al., Elevated resting blood pressure augments autonomic balance in posttraumatic stress
disorder. Am J Physiol Regul Integr Comp Physiol. 2018 Dec 1;315(6):R1272-R1280
Mechanistic studies using animal
models are required for a more comprehensive understanding, including
neurocircuits, autonomic dysregulation,
neurotransmitter abnormalities, and increased inflammation
Autonomic and Cardiovascular Dysfunction in PTSD
Conditioned Stimulus (CS)
(light or tone)
Unconditioned Stimulus (US)
(footshock or airblast)
Threat Stimuli
Conditioned
Stimulus (CS)
Fear Responses
Defensive Behavior
Autonomic Arousal
Reflex potentiation
Stress hormones
Respiratory distress
LeDoux, J. E. (2000) Annual Review of Neuroscience, 23(1), 155-184.
Modeling fear responses in rodents and humans
Pavlovian Fear Conditioning
Day 1:
Creating a fearful
association
Day 2:
Weakening the
association via
repeated
presentations
Day 3:
Testing recall of the
weakened association
Modeling fear responses in rodents and humans
Pavlovian Fear Conditioning
PTSD
%
Freezing
Modeling fear responses in rodents and humans
Pavlovian Fear Conditioning
Freezing behavior
Integrated behavioral and cardiovascular measures
of learned threat / fear
Cardiovascular activity
Data Exchange Matrix
Ponemah
Workstation
Computer interface with Ponemah software DSI
Cardiovascular and Autonomic Assessments
in Rodents
Surgical implant Recovery Home cage monitoring
Heart rate variability (HRV)
is a measure of autonomic
nervous system function
Automatic R-R
detection
Blood Pressure ECG
Systolic Diastolic
Mean Arterial
Pressure
Rejection of R-R not
within ± 2 s.d. of mean
Heart Rate
Variability
Time Domain
Analysis
Frequency Domain
Analysis
Channel 1 Channel 2
Mean Heart Rate
Data Signal Processing and Analysis
24hr baseline
recording
Post-FC
recording
Post-Ext
recording
Swiercz et al., Front Behav Neurosci 2018
We hypothesized that a fear conditioned cardiovascular response could be detected
in a novel context and attenuated by extinction training.
To evaluate the effects of extinction learning on the
conditioned cardio-autonomic response
Experimental Design
2 weeks
Fear Conditioning Extinction Training
Implant transmitter
Ext Day 1
recording
Ext Day 2
recording
Behavioral and Cardiovascular Changes During
Extinction Training
Swiercz et al., Front Behav Neurosci 2018
2 weeks
Fear Conditioning Extinction Training
Implant transmitter
Effects of Fear Conditioning and Extinction on
Resting Blood Pressure and Heart Rate
Swiercz et al., Front Behav Neurosci 2018
Swiercz et al., Front Behav Neurosci 2018
Behavioral and cardiovascular changes during extinction training
Novel Context
Swiercz et al., Front Behav Neurosci 2018
Context-Dependent Cardiovascular and Activity Measures
Elevated baseline cardiovascular measures
mask conditioned stimulus (CS) dependent
cardiovascular reactivity to the tone (CS).
Study 2:
To examine the effects of extinction training
on cardiovascular reactivity in a home cage
environment.
Novel Context
Swiercz et al., Front Behav Neurosci 2018
Home Cage Context
Context-Dependent Cardiovascular and Activity Measures
P
r
e
-
C
S
0
3
0
6
0
9
0
1
2
0
1
5
0
1
8
0
2
1
0
90
100
110
120
130
140
Mean
Arterial
Pressure
(mmHg)
Time (s)
Ext
No Ext
CS1 CS2 CS3 CS4
P
r
e
-
C
S
0
3
0
6
0
9
0
1
2
0
1
5
0
1
8
0
2
1
0
400
450
500
550
600
650
700
Heart
Rate
(BPM)
Time (s)
P
r
e
-
C
S
4
C
S
(
a
v
g
)
P
r
e
-
C
S
4
C
S
(
a
v
g
)
90
100
110
120
130
140
Mean
Arterial
Pressure
(mmHg)
* *
No Ext
Ext
P
r
e
-
C
S
4
C
S
(
a
v
g
)
P
r
e
-
C
S
4
C
S
(
a
v
g
)
400
500
600
700
Heart
Rate
(BPM)
* *
Day 1
Day 2
Day 3
80
100
120
140
Mean
Arterial
Pressure
(mmHg)
*
Pre Post
Sal
Los
(MAP mean)
15 30 45 60 75 90
105
60
80
100
120
140
160
Mean
Arterial
Pressure
(mmHg)
Pre
(30min)
(Minutes)
Post Injection
Sal
Los
15 30 45 60 75 90
105
200
400
600
800
Heart
Rate
(BPM)
Pre
(30min)
(Minutes)
Post Injection
C.
B.
D. E.
200
400
600
800
Heart
Rate
(BPM)
Pre Post
(MAP mean)
80
100
120
140
Mean
Arterial
Pressure
(mmHg)
*
Pre Post
Sal
Los
(MAP mean)
1
5
3
0
4
5
6
0
7
5
9
0
1
0
5
60
80
100
120
140
160
Mean
Arterial
Pressure
(mmHg)
Pre
(30min)
(Minutes)
Post Injection
Sal
Los
1
5
3
0
4
5
6
0
7
5
9
0
1
0
5
200
400
600
800
Heart
Rate
(BPM)
Pre
(30min)
(Minutes)
Post Injection
C.
B.
D. E.
200
400
600
800
Heart
Rate
(BPM)
Pre Post
(MAP mean)
4
Swiercz et al., Front Behav Neurosci 2018
Conditioned Cardiovascular Responses in the Home Cage
Conditioned CV Test #3
Fear Conditioning
Test #1
Extinction
x 35
x 4
Extinction
x 35
5 x
Test #2
x 4
Test #3
x 4
Conditioned CV Test #2
Day
1
Day
2
Day
3
Swiercz et al., Front Behav Neurosci 2018
The Effects of Extinction learning on the Conditioned
Cardiovascular (CV) Response
 Resting blood pressure, heart rate, heart rate variability, or
activity levels were unaltered by fear conditioning and
extinction training.
 Recall of consolidated extinction memories modulate the
conditioned cardiovascular response, which is influenced by
context-dependent differences in blood pressure and HR
sensitivity.
*Conditioned blood pressure responses may serve as a novel
index in the evaluation of extinction efficiency and may aid
in further understanding mechanisms driving exaggerated
physiological responses in PTSD
Take Home Points and Conclusion
Take Home Points and Conclusion
● Conditioned cardiovascular responses can be confounded by
environmental and physiological factors that affect physiological state
○ Environmental factors (ie., foreign scents, noise)
○ Cage setup and proximity to other animals
○ Physiological – circadian rhythms and routine (e.g. nest building)
● Blood pressure response to acute stress is differentially affected by
circadian rhythms (Bernatova I et al., Hypertension. 2002 Nov;40(5):768-73).
These factors contribute to the variability in recording
cardiovascular measures of learned or conditioned fear as well as
comparing those responses across time.
Challenges with Assessing Integrated Conditioned Cardiovascular,
Autonomic and Behavioral Measures in Mice
Triggered audible tone (CS) from customized scheduling program
Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
Software solution for multi-modal cardiovascular and autonomic data
collection of cardiovascular consistent physiological data
o The telemetry system and
data acquisition software
used was Ponemah (version
6.3), which has the ability to
send telemetry information
over Transmission Control
Protocol (TCP)
o The CS delivery program communicates with Ponemah via TCP sockets
o Sent in real-time data packets from Ponemah containing live
physiological information on blood pressure, heart rate, and oxygen
saturation among others.
1) A HDX-11 transmitter was subcutaneously implanted
2) Speakers were wired into home cages
3) Animals were fear conditioned - 5CS/US pairings
4) The software was scheduled to give 6 conditioned stimuli (audible tones) over a
24-hour period only when the mouse’s Mean Arterial Pressure (MAP) was within
85 and 100 mmHg for at least 10 seconds
5) Time MAP must be in parameter range before a CS can be presented.
Methods
1) For multiple speakers, whether
the CS schedule is shared or
randomized.
2) Shifting the parameter range
up for the nighttime to account
for diurnal mouse behavior.
3) Time MAP must be in
parameter range before a CS
can be presented.
4) Enables state-dependent CS
presentation.
Customized software with modifiable physiological, time
and interval dependent parameters
Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
Remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the
animals instantaneous cardiovascular state while in its home-cage environment
Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
Remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the
animals instantaneous cardiovascular state while in its home-cage environment
1) CS dependent variation
in MAP response
across day / night.
2) CS presented during
the animal’s active
period (CS 2,3,4), the
response was
immediate.
3) Potential need for a
dynamic baseline
response.
Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
Remotely scheduled (diurnal) conditioned cue delivery
and cardiovascular response
o Remote Scheduling and Usage Functionality
 Because the schedule is automatic, it removes the need for the experimenter to be
present (day/night) and performed in the animal’s natural (home cage) environment.
 Defined set parameter ranges before CS presentation eliminates the possibility
external factors that could confound collected data
o Customizable to multiple behavioral or physiological parameters
 The software is open source and can be customized to perform many behavioral and
physiological functions and conditioned triggers beyond the delivery of audible tones.
 Ponemah has the capability to send other physiological parameters (e.g. HR, SpO2,
Sys/Dia, EEG)
 Defined dynamic baseline can be used for when the animal outside of normal ranges
(ie., day/night)
*Software tool extends the ability to quantify integrated physiological
correlates of learned fear
*May aid in further understanding mechanisms related to enhanced
cardiovascular and autonomic arousal in fear and anxiety based disorders.
Functionality and utility of software TCP application
Berntson & Khalsa, (2021) Trends in Neurosciences
Threat dependent
cardiovascular signals and
influence on PTSD risk and
CVD development
Maddox et. al., 2019 Neuron. 2019 Apr 3;102(1):60-74
Interoceptive processes and disease
Cardiovascular
Signals
(ie., baroreceptor
sensitivity,
HR contractility)
 Psychopharmacological experimental applications
(Swiercz et al., Transl Psychiatry. 2020 Oct 27;10(1):363.
 Animal models of cardiovascular disease
 Chemogenetic and Optogenetic integration /
applications
Neuroscience and Cardiovascular Applications
Collaborators
Jeanie Park, MD – Emory University
Peter Nemes, PhD – University of Maryland
Robert C. Speth, Phd - Nova Southeastern University
Nikki Posnack, PhD, Childrens National Medical
Antonia Seligowski, PhD Harvard / McLean
Kerry Ressler, MD/Phd – Harvard / McLean Hospital
Murray Stein, MD - UCSD
Anastas Popratiloff MD PhD - Director GWU
Nanofabrication and Imaging Center
University of Florida – Eric Krause / Annete DeKloet labs
Lab Members
Elizabeth Paronett, MS – Research Lab Manager
Zhe Yu, PhD – Post Doctoral Fellow
Laxmi Iyer, PhD – Post Doctoral Fellow
Shara Grant, PhD – Post Doctoral Fellow
Hannah Smith – Grad Stud. IBS 3rd year
Adam P. Swiercz, PhD
(NIMH Postdoc)
Funding
Acknowledgements – Thank You
Thanks for participating!
• Want to learn more and watch the webinar on demand?
Visit: www.insidescientific.com
• Want to learn more about DSI’s implantable telemetry
techology? Visit: www.datasci.com
• Want to learn more about Coulbourn Instruments’ behavioral
research instrumentation? Visit: www.coulbourn.com

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Quantifying Cardiovascular and Behavioral Correlates of Fear in Mice: Implications for PTSD and Cardiovascular Disease Risk

  • 1. Quantifying Cardiovascular and Behavioral Correlates of Fear in Mice: Implications for PTSD and Cardiovascular Disease Risk Paul J. Marvar, PhD Associate Professor Department of Pharmacology & Physiology George Washington University Benjamin Turley Master's Student Systems Medicine Georgetown University
  • 2. Quantifying Cardiovascular and Behavioral Correlates of Fear in Mice: Implications for PTSD and Cardiovascular Disease Risk Dr. Paul Marvar and Benjamin Turley present research pairing behavioral and cardiovascular responses to cued fear learning and demonstrate how fear-based disorders (such as PTSD) can contribute to cardiovascular disease risk.
  • 3. Quantifying Cardiovascular and Behavioral Correlates of Fear in Mice: Implications for PTSD and Cardiovascular Disease Risk Paul J. Marvar, PhD Associate Professor Department of Pharmacology & Physiology George Washington University Benjamin Turley Master's Student Systems Medicine Georgetown University V Copyright 2021 P. Marvar, B. Turley and InsideScientific. All rights reserved.
  • 4. Key learning objectives: • To understand the physiological impact of PTSD on cardiovascular and autonomic homeostasis, CVD risk • Demonstrate utility of rodent models in assessing real-time cardiovascular and autonomic fear or defensive emotional states • Discuss benefits and translational implications for using integrated behavioral and cardiovascular multi- modal methodologies
  • 5. Key learning objectives: • To understand the physiological impact of PTSD on cardiovascular and autonomic homeostasis, CVD risk • Demonstrate utility of rodent models in assessing real-time cardiovascular and autonomic fear or defensive emotional states • Discuss benefits and translational implications for using integrated behavioral and cardiovascular multi- modal methodologies Why study behavioral and cardiovascular correlates of learned fear in mice?
  • 6. PTSD characterized by a persistent maladaptive reaction to exposure to severe psychological trauma. (i.e., violent personal assaults, natural or human made disasters, serious traffic collisions, or military combat) o Psychological and Behavioral Symptoms: o Symptoms (>3month) occurring after a traumatic event • Intrusive recollection, avoidance • Negative mood alterations o Physiological Symptoms: o Hypervigilance / physiological hyperarousual, increased blood pressure, heart rate, sympathetic outflow, respiratory distress, shortness of breath, sleep disturbances. o Limited effective treatment options o Highly co-morbid with poor overall physical health outcomes and increased other diseases (ie., CVD, metabolic, autoimmune) Post Traumatic Stress Disorder (PTSD)
  • 7. https://www.cdc.gov/heartdisease/mentalhealth.htm Pain, fear, cardiac reactivity, reduced blood flow to heart, increased cortisol Smoking, physical inactivity, medication non-adherence…… Trauma, PTSD and Cardiovascular Disease (CVD) Risk
  • 8. Adopted and modified from O’Donnell et al., JAMA Cardiol. Published online July 14, 2021. doi:10.1001/jamacardio.2021.2530
  • 9. PTSD as a CVD Risk Factor Physiological and Behavioral Evidence from Epidemiological Studies Edmonson et al., 2017 4:320-29
  • 10. High Blood Pressure 1. Elevated blood pressure and hypertension in trauma- exposed populations, including military veteran and community-based samples. 2. Greater resting blood pressure (BP) as well as greater BP response to trauma-related cues. (Buckley and Kaloupek, 2001; Pole, 2007) PTSD as a CVD Risk Factor Physiological and Behavioral Evidence from Epidemiological Studies Edmonson et al., 2017 4:320-29
  • 11. PTSD = impaired ability to process fear and perceived threats Hippocampus PTSD = exaggerated behavioral physiological responses Threat Detection and Fear Circuitry impacted by PTSD Blood Pressure Heart Rate
  • 12. • PTSD = impaired ability to process fear and perceived threats – Over-generalization of trauma-related stimuli and a reduced ability to suppress emotional (stress) and physiological (ie., increase in blood pressure, heart rate, sympathetic nervous system) responses to threat-associated stimuli. The effects of PTSD are not limited to psychological symptoms. Meakins and Wilson, 1918 Early observations of abnormal cardiovascular responses associated with trauma describe a condition called “irritable heart syndrome”, and veterans with this condition exhibited greater heart rate (HR) and respiratory responses to presentations of bright flames and pistol shots 2. Park, J. et al. Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder. The Journal of Physiology 595, 4893–4908 (2017). Jeanie Park, MD, MS Emory University 3. Fonkoue I et al., Sympathoexcitation and impaired arterial baroreflex sensitivity are linked to vascular inflammation in individuals with elevated resting blood pressure. Physiol Rep. 2019 Apr;7(7):e14057. 1. Fonkoue, I., et al., Elevated resting blood pressure augments autonomic balance in posttraumatic stress disorder. Am J Physiol Regul Integr Comp Physiol. 2018 Dec 1;315(6):R1272-R1280 Mechanistic studies using animal models are required for a more comprehensive understanding, including neurocircuits, autonomic dysregulation, neurotransmitter abnormalities, and increased inflammation Autonomic and Cardiovascular Dysfunction in PTSD
  • 13. Conditioned Stimulus (CS) (light or tone) Unconditioned Stimulus (US) (footshock or airblast) Threat Stimuli Conditioned Stimulus (CS) Fear Responses Defensive Behavior Autonomic Arousal Reflex potentiation Stress hormones Respiratory distress LeDoux, J. E. (2000) Annual Review of Neuroscience, 23(1), 155-184. Modeling fear responses in rodents and humans Pavlovian Fear Conditioning
  • 14. Day 1: Creating a fearful association Day 2: Weakening the association via repeated presentations Day 3: Testing recall of the weakened association Modeling fear responses in rodents and humans Pavlovian Fear Conditioning
  • 15. PTSD % Freezing Modeling fear responses in rodents and humans Pavlovian Fear Conditioning
  • 16. Freezing behavior Integrated behavioral and cardiovascular measures of learned threat / fear Cardiovascular activity
  • 17. Data Exchange Matrix Ponemah Workstation Computer interface with Ponemah software DSI Cardiovascular and Autonomic Assessments in Rodents Surgical implant Recovery Home cage monitoring
  • 18. Heart rate variability (HRV) is a measure of autonomic nervous system function Automatic R-R detection Blood Pressure ECG Systolic Diastolic Mean Arterial Pressure Rejection of R-R not within ± 2 s.d. of mean Heart Rate Variability Time Domain Analysis Frequency Domain Analysis Channel 1 Channel 2 Mean Heart Rate Data Signal Processing and Analysis
  • 19. 24hr baseline recording Post-FC recording Post-Ext recording Swiercz et al., Front Behav Neurosci 2018 We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. To evaluate the effects of extinction learning on the conditioned cardio-autonomic response Experimental Design 2 weeks Fear Conditioning Extinction Training Implant transmitter
  • 20. Ext Day 1 recording Ext Day 2 recording Behavioral and Cardiovascular Changes During Extinction Training Swiercz et al., Front Behav Neurosci 2018 2 weeks Fear Conditioning Extinction Training Implant transmitter
  • 21. Effects of Fear Conditioning and Extinction on Resting Blood Pressure and Heart Rate Swiercz et al., Front Behav Neurosci 2018
  • 22. Swiercz et al., Front Behav Neurosci 2018 Behavioral and cardiovascular changes during extinction training
  • 23. Novel Context Swiercz et al., Front Behav Neurosci 2018 Context-Dependent Cardiovascular and Activity Measures Elevated baseline cardiovascular measures mask conditioned stimulus (CS) dependent cardiovascular reactivity to the tone (CS). Study 2: To examine the effects of extinction training on cardiovascular reactivity in a home cage environment.
  • 24. Novel Context Swiercz et al., Front Behav Neurosci 2018 Home Cage Context Context-Dependent Cardiovascular and Activity Measures
  • 25. P r e - C S 0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0 90 100 110 120 130 140 Mean Arterial Pressure (mmHg) Time (s) Ext No Ext CS1 CS2 CS3 CS4 P r e - C S 0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0 400 450 500 550 600 650 700 Heart Rate (BPM) Time (s) P r e - C S 4 C S ( a v g ) P r e - C S 4 C S ( a v g ) 90 100 110 120 130 140 Mean Arterial Pressure (mmHg) * * No Ext Ext P r e - C S 4 C S ( a v g ) P r e - C S 4 C S ( a v g ) 400 500 600 700 Heart Rate (BPM) * * Day 1 Day 2 Day 3 80 100 120 140 Mean Arterial Pressure (mmHg) * Pre Post Sal Los (MAP mean) 15 30 45 60 75 90 105 60 80 100 120 140 160 Mean Arterial Pressure (mmHg) Pre (30min) (Minutes) Post Injection Sal Los 15 30 45 60 75 90 105 200 400 600 800 Heart Rate (BPM) Pre (30min) (Minutes) Post Injection C. B. D. E. 200 400 600 800 Heart Rate (BPM) Pre Post (MAP mean) 80 100 120 140 Mean Arterial Pressure (mmHg) * Pre Post Sal Los (MAP mean) 1 5 3 0 4 5 6 0 7 5 9 0 1 0 5 60 80 100 120 140 160 Mean Arterial Pressure (mmHg) Pre (30min) (Minutes) Post Injection Sal Los 1 5 3 0 4 5 6 0 7 5 9 0 1 0 5 200 400 600 800 Heart Rate (BPM) Pre (30min) (Minutes) Post Injection C. B. D. E. 200 400 600 800 Heart Rate (BPM) Pre Post (MAP mean) 4 Swiercz et al., Front Behav Neurosci 2018 Conditioned Cardiovascular Responses in the Home Cage
  • 26. Conditioned CV Test #3 Fear Conditioning Test #1 Extinction x 35 x 4 Extinction x 35 5 x Test #2 x 4 Test #3 x 4 Conditioned CV Test #2 Day 1 Day 2 Day 3 Swiercz et al., Front Behav Neurosci 2018 The Effects of Extinction learning on the Conditioned Cardiovascular (CV) Response
  • 27.  Resting blood pressure, heart rate, heart rate variability, or activity levels were unaltered by fear conditioning and extinction training.  Recall of consolidated extinction memories modulate the conditioned cardiovascular response, which is influenced by context-dependent differences in blood pressure and HR sensitivity. *Conditioned blood pressure responses may serve as a novel index in the evaluation of extinction efficiency and may aid in further understanding mechanisms driving exaggerated physiological responses in PTSD Take Home Points and Conclusion
  • 28. Take Home Points and Conclusion
  • 29. ● Conditioned cardiovascular responses can be confounded by environmental and physiological factors that affect physiological state ○ Environmental factors (ie., foreign scents, noise) ○ Cage setup and proximity to other animals ○ Physiological – circadian rhythms and routine (e.g. nest building) ● Blood pressure response to acute stress is differentially affected by circadian rhythms (Bernatova I et al., Hypertension. 2002 Nov;40(5):768-73). These factors contribute to the variability in recording cardiovascular measures of learned or conditioned fear as well as comparing those responses across time. Challenges with Assessing Integrated Conditioned Cardiovascular, Autonomic and Behavioral Measures in Mice
  • 30. Triggered audible tone (CS) from customized scheduling program Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414 Software solution for multi-modal cardiovascular and autonomic data collection of cardiovascular consistent physiological data o The telemetry system and data acquisition software used was Ponemah (version 6.3), which has the ability to send telemetry information over Transmission Control Protocol (TCP) o The CS delivery program communicates with Ponemah via TCP sockets o Sent in real-time data packets from Ponemah containing live physiological information on blood pressure, heart rate, and oxygen saturation among others.
  • 31. 1) A HDX-11 transmitter was subcutaneously implanted 2) Speakers were wired into home cages 3) Animals were fear conditioned - 5CS/US pairings 4) The software was scheduled to give 6 conditioned stimuli (audible tones) over a 24-hour period only when the mouse’s Mean Arterial Pressure (MAP) was within 85 and 100 mmHg for at least 10 seconds 5) Time MAP must be in parameter range before a CS can be presented. Methods
  • 32. 1) For multiple speakers, whether the CS schedule is shared or randomized. 2) Shifting the parameter range up for the nighttime to account for diurnal mouse behavior. 3) Time MAP must be in parameter range before a CS can be presented. 4) Enables state-dependent CS presentation. Customized software with modifiable physiological, time and interval dependent parameters Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
  • 33. Remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the animals instantaneous cardiovascular state while in its home-cage environment Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414
  • 34. Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414 Remotely trigger a conditioned stimulus (CS) (i.e., audible tone) based on the animals instantaneous cardiovascular state while in its home-cage environment
  • 35. 1) CS dependent variation in MAP response across day / night. 2) CS presented during the animal’s active period (CS 2,3,4), the response was immediate. 3) Potential need for a dynamic baseline response. Turley et al., Physiology & Behavior, 2021-07-01, Volume 236, Article 113414 Remotely scheduled (diurnal) conditioned cue delivery and cardiovascular response
  • 36. o Remote Scheduling and Usage Functionality  Because the schedule is automatic, it removes the need for the experimenter to be present (day/night) and performed in the animal’s natural (home cage) environment.  Defined set parameter ranges before CS presentation eliminates the possibility external factors that could confound collected data o Customizable to multiple behavioral or physiological parameters  The software is open source and can be customized to perform many behavioral and physiological functions and conditioned triggers beyond the delivery of audible tones.  Ponemah has the capability to send other physiological parameters (e.g. HR, SpO2, Sys/Dia, EEG)  Defined dynamic baseline can be used for when the animal outside of normal ranges (ie., day/night) *Software tool extends the ability to quantify integrated physiological correlates of learned fear *May aid in further understanding mechanisms related to enhanced cardiovascular and autonomic arousal in fear and anxiety based disorders. Functionality and utility of software TCP application
  • 37. Berntson & Khalsa, (2021) Trends in Neurosciences Threat dependent cardiovascular signals and influence on PTSD risk and CVD development Maddox et. al., 2019 Neuron. 2019 Apr 3;102(1):60-74 Interoceptive processes and disease Cardiovascular Signals (ie., baroreceptor sensitivity, HR contractility)  Psychopharmacological experimental applications (Swiercz et al., Transl Psychiatry. 2020 Oct 27;10(1):363.  Animal models of cardiovascular disease  Chemogenetic and Optogenetic integration / applications Neuroscience and Cardiovascular Applications
  • 38. Collaborators Jeanie Park, MD – Emory University Peter Nemes, PhD – University of Maryland Robert C. Speth, Phd - Nova Southeastern University Nikki Posnack, PhD, Childrens National Medical Antonia Seligowski, PhD Harvard / McLean Kerry Ressler, MD/Phd – Harvard / McLean Hospital Murray Stein, MD - UCSD Anastas Popratiloff MD PhD - Director GWU Nanofabrication and Imaging Center University of Florida – Eric Krause / Annete DeKloet labs Lab Members Elizabeth Paronett, MS – Research Lab Manager Zhe Yu, PhD – Post Doctoral Fellow Laxmi Iyer, PhD – Post Doctoral Fellow Shara Grant, PhD – Post Doctoral Fellow Hannah Smith – Grad Stud. IBS 3rd year Adam P. Swiercz, PhD (NIMH Postdoc) Funding Acknowledgements – Thank You
  • 39. Thanks for participating! • Want to learn more and watch the webinar on demand? Visit: www.insidescientific.com • Want to learn more about DSI’s implantable telemetry techology? Visit: www.datasci.com • Want to learn more about Coulbourn Instruments’ behavioral research instrumentation? Visit: www.coulbourn.com

Notes de l'éditeur

  1. Why Study… Ans: There is increasing attention to the brain-heart-body relationship to psychological (and physical) health; In this context, my research is focused on understanding the link between anxiety disorders such as PTSD and CVD risk.
  2. Why Study… Ans: There is increasing attention to the brain-heart-body relationship to psychological (and physical) health; In this context, my research is focused on understanding the link between anxiety disorders such as PTSD and CVD risk.
  3. 1. Understanding PTSD related physical health (ie., CVD risk) co-morbidities and their underlying mechanisms has become a major public health concern. This was recently recognized and highlighted by the CDC! 2. As shown here is this schemaitic there is a bi-directional relationship – as population and clinical based studies demonstrate both causal and consequential evidence for the link between PTSD – CVD Likely contributors stems from both…. Physiological and Behavioral (modifiable) pathways… The physiological and behavioral mechanisms linking PTSD with CVD risk are yet to be confirmed, and there are many potential confounding and mediating factors that could contribute to this association. There is currently a great need for further understanding underlying causal and/or consequential of PTSD / CVD risk In 2018 the NHLBI assembled a working group of scientists and clinicians (of which I was proud to contribute) who were tasked with identifying the state of this research including, gaps current understanding and opportunities for future research. PTSD is associated with both an increased prevalence of major CVD risk factors, such as hypertension and diabetes, as well as an increased risk of CVD events, such as myocardial infarction and stroke, increased progression of CVD to heart failure, and premature mortality.
  4. In 2018 the NHLBI assembled a working group of scientists and clinicians (of which I was proud to contribute) who were tasked with identifying the state of this research including, gaps current understanding and future opportunities for research. It was concluded that the research to date has been largely descriptive, with very little known regarding the underlying biological and behavioral mechanisms or insights into the causal nature and reversibility linking PTSD and CVD. Despite these observations, prospective data from well designed studies that fully account for confounding factors and assess possible pathways in ways that permit causal inference are limited. Multi-disciplinary approach needed to establish causal inference; Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. (Figure) These factors include a wide spectrum of health risk behaviors that characterize PTSD (eg, disturbed sleep physiology, maladaptive dietary changes, tobacco use, substance use, physical inactivity, and noncompliance with medical therapy) and other associated psychological states (eg, depression or hostility).
  5. Review article by Donald Edmondson – Lancet Psychiatry --- provides a nice illustration that highlights the state of the epidemiological and clinical evidence, (BLUE-strong) vs orange (emerging)… High blood pressure may be one mechanism by which PTSD contributes to heightened CVD risk. (Meta101 analytic evidence suggests that…) PTSD was an independent risk factor for incident coronary heart disease and cardiac-specific mortality8. More recent reports show that the problem is even greater in Veteran populations as those Veterans diagnosed with PTSD are at approximately 45% greater risk of myocardial infarction and roughly 30% greater risk of developing congestive heart failure and peripheral vascular disease later in life compared to veterans without PTSD9,10 . A comprehensive understanding of ANS / CV dysfunction, including neurocircuits, autonomic dysregulation, neurotransmitter abnormalities, and increased inflammation, requires mechanistic studies using animal models…..as much of the experimental work is not feasible in humans (Pitman et al., 2012).
  6. Review article by Donald Edmondson – Lancet Psychiatry --- provides a nice illustration that highlights the state of the epidemiological and clinical evidence, (BLUE-strong) vs orange (emerging)… High blood pressure may be one mechanism by which PTSD contributes to heightened CVD risk. (Meta101 analytic evidence suggests that…) PTSD was an independent risk factor for incident coronary heart disease and cardiac-specific mortality8. More recent reports show that the problem is even greater in Veteran populations as those Veterans diagnosed with PTSD are at approximately 45% greater risk of myocardial infarction and roughly 30% greater risk of developing congestive heart failure and peripheral vascular disease later in life compared to veterans without PTSD9,10 . A comprehensive understanding of ANS / CV dysfunction, including neurocircuits, autonomic dysregulation, neurotransmitter abnormalities, and increased inflammation, requires mechanistic studies using animal models…..as much of the experimental work is not feasible in humans (Pitman et al., 2012).
  7. PTSD can be reflected by altered activity in multiple brain systems, including those that directly modify autonomic functions and behavioral and physiological responses.. Functional neuroimaging studies over the past two decades have implicated PTSD specific changes in regional activation and functional connectivity. More specifically, hyper-activation of amygdala, insula, dorsal anterior cingulate cortex (dACC), as well as hypo-activation in ventral medial prefrontal cortex (vmPFC) and impaired hippocampal function have been consistently detected (Lebois, Wolff, & Ressler, 2016; Liberzon & Abelson, 2016; Pitman et al., 2012; Stark et al., 2015). Autonomic neurophysiological states can be influenced by disruption in the hierarchically organized brain systems that comprise the central autonomic network (Williamson, Porges, Lamb, & Porges, 2014) Circuits of brain impacted by PTSD…….At the level of neural circuits, preclinical and human studies consistently support the concept of PTSD as a disorder of altered emotional memory formation and/or extinction33 and dysregulation of the response to environmental Threat and stress.34 ****The amygdala is part of the limbic system and is involved in processing positive and negative emotions by assigning valence to stimuli, is also involved in innate behaviors such as aggression, mating as well as fear Sokolowski K and Corbin JG, Frontiers in Molecular Neuroscience, 2012.
  8. (exaggerated physiological responses to threat related cues) A comprehensive understanding of ANS / CV dysfunction, including neurocircuits, autonomic dysregulation, neurotransmitter abnormalities, and increased inflammation, requires mechanistic studies using animal models…..as much of the experimental work is not feasible in humans (Pitman et al., 2012).
  9. A tool for investigating neural substrates of emotion. A previously neutral stimulus (tone or light) is paired with a noxious stimulus usually a mild electrical footshock so that the neutrail stimulus now becomes predictive of danger.
  10. Freezing is a universal fear response (evolutionarily conserved response across species), observed both in reaction to conditioned (learned) or unconditioned (acutely threatening) stimuli or situations [22]. It is a state of attentive immobility serving to avoid detection by predators and to enhance perception [9,10]
  11. Pavlovian fear conditioning ---The brain mechanisms of fear have been studied extensively using Pavlovian fear conditioning, a procedure that allows exploration of how the brain learns about and later detects and responds to threats. A tool for investigating neural substrates of emotional learning A typical rodent will show fear in the form of freezing behavior in a fear conditioning test.  Extinction ----- animals can also learn that stimuli previously associated with adverse outcomes no longer represent a threat. As noted above, the robust and rapidly learned nature of fear memory makes it an ideal model system for investigating memory processes such as learning (memory acquisition), storage (consolidation) and updating and persistence (reconsolidation). Indeed, the traction gained by research into memory recon-solidation, which had originally been described Pavlovian Fear Conditioning: A Technique and a Process Fear is the most extensively studied emotion, and the way it has most often been investigated is through Pavlovian fear conditioning. This procedure involves presenting a biologically neutral conditioned stimulus (CS), often a tone, with a noxious or harmful unconditioned stimulus (US), typically a mild electric shock. As a result, the CS comes to elicit species-typical (presumably innate) behavioral responses (e.g., freezing behavior) and supporting physiological adjustments controlled by the autonomic nervous system (e.g., changes in heart rate, blood pressure, respiration) or by endocrine systems (e.g., adrenocorticotropic hormone, cortisol, epinephrine) (7⇓⇓⇓⇓–12). Through fear conditioning, researchers thus have control of the antecedent conditions (the independent variables, namely the CS and US) and can measure the outcomes (dependent variables, such as freezing behavior or autonomic nervous system responses). The fear-conditioning procedure works because it taps into a process called associative learning that is a feature of circuits in the nervous systems of many if not all animals (4, 13⇓⇓–16) and may also exist in single-cell organisms (17, 18). When associative learning occurs in the circuit engaged by the fear conditioning procedure, the learning process itself is also called fear conditioning. The fear-conditioning process allows the US to alter the effectiveness of the CS in activating circuits that control defense responses in anticipation of harm.
  12. From the blood pressure channel, we can measure systolic, diastolic, and mean arterial pressure. The ECG channel monitors the electrical activity of the heart, which we analyze to detect R-waves. Ectopic beats and artifiacts are removed by excluding R-R intervals that do not lie within 2 standard deviations of the mean. If the rejected intervals make up more than five percent of the signal, that sample is removed from the study. We digitize our multilead ECG data, and compute physiologically meaningful parameters on a beat-to beat basis Heart rate variability is a measure of autonomic nervous system function, and can reflect the ability to adaptively cope with stress. It describes the variation in intervals between heart beats, and can be measured in both the time and frequency domain. Decreased HRV in humans is an independent predictor of cardiac morbidity and mortality in patients with heart disease. Heart rate in healthy individuals is not constant. Modulations of autonomic nervous system activity cause the heart rate to oscillate around a mean value. Autonomic control of the heart rate is carried out by the sympathetic and parasympathetic nervous systems. Time Domain Freq domain - High frequency considered to be a marker of vagal activity -LF power is a marker of both sympathetic, parasympathetic, and vagal activity The heart accelerates on inspiration and deccelerates on exhalation Time Domain: SDNN RMSSD pnnX Frequency Domain: Frequency Domain Analysis is a complex analysis technique that shows how much of a signal lies within one or more frequency bands (ranges). With regards to Heart Rate Variability, research has identified certain frequency bands that tend to correlate with certain physiological phenomenon, such as Parasympathetic nervous system activity. (Scroll to the bottom to understand the difference between units of measurement) Common Frequency Domain HRV metrics include: High Frequency power (HF): frequency activity in the 0.15 - 0.40Hz range (green in the above chart) Low Frequency power (LF): frequency activity in the 0.04 - 0.15Hz range (yellow in the above chart) LF/HF Ratio: A ratio of Low Frequency to High Frequency. Some consider this indicative of Sympathetic to Parasympathetic Autonomic Balance, but that is controversial. Please see this article and this article for more information.
  13. On Day 1 of extinction training, the CS-US group exhibited increased freezing throughout the 30 CS presentations (Figure 1C). Fear acquisition was demonstrated in the CS-US animals compared to the CS by group differences in freezing during the first 4 CS presentations (71%  4 vs. 10%  3, p < 0.05) (Figure 1E). CS-US animals showed a significant reduction in freezing from Day 1–2, with a significant group x time interaction [F(1,17) = 20.68, p = 0.0003] (Figure 1E).
  14. Integrating wireless telemetry approaches, combined with animal behavioral measures (e.g., Pavlovian fear conditioning), provides a unique way to test the impact of pharmacological, behavioral (e.g., exposure therapy/extinction learning) or other non-invasive interventions (e.g., TMS) on cardiovascular autonomic responses to learned threats and emotional regulation.
  15. Integrating wireless telemetry approaches, combined with animal behavioral measures (e.g., Pavlovian fear conditioning), provides a unique way to test the impact of pharmacological, behavioral (e.g., exposure therapy/extinction learning) or other non-invasive interventions (e.g., TMS) on cardiovascular autonomic responses to learned threats and emotional regulation.
  16. In order to eliminate some of the confounds which may result from cardiovascular changes related to stress or other environmental factors, we developed a program for remote application in Ponemah™ (version 6.3) from Data Sciences International (DSI), St. Paul, MN, United States. The software is built as a standalone CS delivery remote connection scheduling software which can use any connected computer audio outputs in which conditioned stimuli (i.e., audible tones) can be delivered outside of a dedicated testing chamber in a home cage environment. 
  17. The software processes and stores this data as well as delivers the conditioned stimuli using native USB audio output channels PonemahTM software has the capability to send live signals over TCP These signals can be used by local software and processed in real-time for feedback to the animal
  18. This is important because memory cells are very long lived and can sensitize individuals to repeated hypertensive stimuli, thus contributing to end-organ damage.