A Protocol for the Induction of Posttraumatic Stress-Disorder (PTSD)-like Behavior in Mice

Graeme Preston; Tamas Kozicz

doi:10.3791/63803

JoVE Journal > Behavior

행동분석학

A Protocol for the Induction of Posttraumatic Stress-Disorder (PTSD)-like Behavior in Mice

Published: July 28, 2022

doi:

10.3791/63803

Graeme Preston¹, Tamas Kozicz¹

¹Department of Clinical Genomics,Mayo Clinic

Summary

In this study, post-traumatic stress disorder (PTSD)-like behavior is induced in mice using two sessions of inescapable electric foot shock. PTSD-like and resilient animals are identified using several assays for PTSD-specific behaviors.

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that precipitates in ~10% of individuals exposed to a traumatic event (TE). Symptoms include recurrent and intrusive thoughts, sleep disturbance, hypervigilance, exaggerated startle, and reckless or destructive behavior. Given the complex and heterogeneous nature of the disease, animal models for PTSD-like symptomatology are of increasing interest to the field of PTSD research. Because resilience to PTSD-like symptomatology is an important epidemiologic aspect of PTSD, animal models that resolve vulnerable and resilient animals are of particular value. Due to the complex nature of the PTSD phenotype and the potential overlaps between PTSD-like behavior and behaviors associated with other stress-induced psychopathologies such as anxiety or depression, animal models that utilize multiple readouts for PTSD-like behavior are also of increasing value. We utilize a paradigm developed by Lebow et al. 2012 for the induction and identification of PTSD-like symptomatology in mice. This paradigm utilizes inescapable electric foot shock, administered in two decontextualized sessions over two consecutive days. Stressed mice perform four behavioral tests – dark/light transfer, marble burying, acoustic startle, and home cage activity – to generate five behavioral readouts of PTSD-like behavior: % risk assessment (%RA), % marbles buried (%MB), % prepulse inhibition (%PPI), latency to peak startle amplitude (LPSA), and % light phase activity (%LPA). PTSD-like symptomatology is characterized by decreased %RA, increased %MB, decreased %PPI, decreased LPSA, and increased %LPA. The 20% of animals displaying the most PTSD-like behavior in each test are awarded a certain number of points depending on the test, and animals scoring sufficient points are designated as PTSD-like, while animals scoring no points are designated PTSD-resilient. This paradigm identifies PTSD-like behavior in ~15% of animals, a rate comparable to that observed in humans. This protocol represents a robust and reproducible paradigm for the induction of PTSD-like behavior in mice.

Introduction

Post-traumatic stress disorder (PTSD) is debilitating psychopathology that can precipitate in individuals who have been exposed to a traumatic event (TE)¹. According to the DSM-V, TE exposure may take many forms, including direct or repeated indirect exposure to a real or perceived threat of death, bodily harm, or sexual violence to oneself or to another². PTSD symptomatology is characterized by intrusive negative thoughts and recollections, hyperarousal, hypervigilance, increased risk-taking behavior, and disrupted sleep cycles³. Lifetime prevalence of TE exposure worldwide is relatively high at approximately 64%-70%³, though lifetime prevalence of PTSD remains comparatively low, at ~1.3%-12%⁴. This disparity in the prevalence of TE exposure relative to PTSD precipitation suggests a strong gene x environment interaction in vulnerability to PTSD. Given the current absence of a reliable vertebrate model of PTSD-like behavior, the field relies on behavioral paradigms for the induction of PTSD-like symptomatology⁵.

PTSD is a complex and highly heterogeneous psychiatric disorder, and developing a robust and reliable animal model for PTSD-like symptomatology has been challenging. Commonly used readouts for PTSD-like behavior, such as freezing, are also symptomatic of other trauma-induced psychopathologies, namely, anxiety, and depression⁶. This is further complicated by the high comorbidity between PTSD and depression². Recent investigations have shown that rats that have witnessed traumatic events display increased anxiety and depression behaviors⁷^,⁸^,⁹, further demonstrating the importance of assessing PTSD-specific behaviors when utilizing behavioral models of PTSD in rodents. Additionally, resilience to PTSD-like symptomatology following traumatic event exposure is a significant epidemiologic feature of PTSD, as lifetime incidence of traumatic event exposure worldwide far outstrips lifetime prevalence of PTSD. Historically, behavioral models for induction of PTSD-like behavior, such as those investigating fear memory¹⁰^,¹¹, did not resolve PTSD-like animals from trauma-exposed controls (PTSD-resilient animals), treating all trauma-exposed animals as PTSD-like, and commonly used few behavior readouts, such as freezing, that are either not specifically symptomatic of PTSD or are symptomatic of other trauma-induced psychopathologies such as anxiety or depression¹². While these paradigms are effective in investigating neural circuits of fear memory, the lack of a robust and specific assessment of PTSD-like behavior may impact the translation of these data. The current state of the field, therefore, focuses on paradigms utilizing multiple PTSD-specific behavioral readouts to identify both PTSD-like and resilient animals¹².

We utilize a recently developed paradigm for the induction of PTSD-like behavior in mice which identifies both PTSD-like and resilient animals using a series of four behavioral tests to assay five PTSD-like behavioral readouts¹³^,¹⁴. PTSD-like behavior is induced using decontextualized electric foot shock across two sessions. Animals are first exposed to a severe Trauma session on the first day, followed by a relatively mild Trigger session the following day (Figure 1). This combination has been shown to significantly increase the precipitation of PTSD-like behavior. This paradigm utilizes an acute stress model for PTSD induction rather than chronic stress (which may induce a more depressive phenotype¹⁵) or traumatic brain injury (which may result in a distinct PTSD-like phenotype¹⁴). Similarly, the behavioral readouts utilized to identify PTSD-like behavior in this paradigm – reduced risk-taking behavior, increased marble burying, reduced prepulse inhibition, reduced latency to peak startle amplitude, and increased light phase activity (Figure 1) – are specific to PTSD-like behavior, rather than to other trauma-induced psychopathologies such as anxiety or depression. Additionally, the use of multiple behavioral readouts, and the need for animals to display multiple PTSD-like behaviors in order to be designated PTSD-like, increases the likelihood that animals designated PTSD-like are truly displaying a PTSD-like phenotype. Together, these features of the protocol ensure that this paradigm is a robust and reliable means for inducing PTSD-like symptomatology in mice.

Protocol

All procedures described here are approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC).

1. Animals and housing

House 10-week-old male C57BL/6J mice 4-to-a-cage in standard housing conditions (standard microisolator cage, 70 °F room temperature (RT), food and water ad libitum, 12 h/12 h light/dark cycle).

2. PTSD-induction

Trauma session
1. Prepare the fear conditioning equipment and chamber.
  1. Program the trauma protocol in the fear conditioning software. Set a total time to 5100 s (85 min). Add white light from Time 0 s – Time 5,100 s. Add fourteen 1 s currents at a random inter-trial interval (ITI). Adjust the current to 1.0 mA.
  2. Wipe down all interior surfaces of each fear conditioning chamber with 1% acetic acid solution.
  3. Turn the light of the procedure room out and turn on a lamp equipped with a red-light bulb to light the room.
  4. Transport the animals to be assayed directly to the procedure room under an opaque covering.
  5. Allow the animals to acclimate to the procedure room for 30 min in the dark with 65 db(A) white noise.
  6. Place each animal into a fear conditioning chamber, make sure the chamber is latched, and start the protocol using the fear conditioning software.
  7. When the protocol has finished, remove the animals from the fear conditioning chambers and return them to their cage. If additional cages of animals are to be assayed on the same day, transport the trauma-exposed animals to a recovery room separate from the home cage room to prevent traumatized animals from communicating information to the trauma-naïve animals.
2. Clean the interior of the fear conditioning chambers with 70% ethanol. If additional animals are to be assayed, clean the interior of the chamber with 1% acetic acid and repeat the protocol until all animals have been assayed.
3. Trigger session
  1. Program the trigger protocol. Set the total time to 300 s (5 min). Add 1 s currents at times 60 s, 120 s, 180 s, 240 s, and 300 s. Adjust the current to 0.7 mA.
  2. Install A-frame plexiglass inserts into the fear conditioning chamber and wipe down all the interior surfaces with 10% ethanol. Place a white noise machine into each sound-attenuating cubicle and adjust sound output to 70 dB(A).
  3. Transport the animals uncovered to the fear conditioning procedure room via an indirect route, which takes longer than the direct route taken for the trauma session.
  4. Allow animals to acclimate to the fear conditioning room for 30 min.
  5. Place each animal into a fear conditioning chamber, turn on the white noise machine, and start the protocol.
  6. When the protocol has finished, remove the animals from the fear conditioning chambers and return them to their cage.
  7. Clean the interior of the fear conditioning chambers with 70% ethanol. If additional animals are to be assayed, clean the chamber interior with 10% ethanol. If no additional animals are to be assayed, clean the chamber interior with 70% ethanol.

3. Behavioral assessment

Dark/light transfer
1. Arrange the light/dark transfer box under the ceiling-mounted camera. Zoom in the camera until the light/dark box fills the field of view and adjust the focus such that the image is clear. Place a piece of opaque plastic over the doorway connecting the light and dark arenas.
  1. Define the light arena and risk assessment area (a 1-inch x 3-inch area directly outside the door in the light arena) in the movement tracking software.
  2. Adjust the lighting in the bright arena to 1,000-1,100 lux.
  3. Transport the animals to the procedure room and allow the animals to acclimate for 30 min.
  4. Place each animal into the dark arena and replace the lid. Remove the doorway separating the light and dark chambers and record the animal's movement for 5 min.
  5. Remove the animal from the apparatus and clean all surfaces with 70% ethanol.
  6. Calculate the % risk assessment for each animal by dividing the time spent in the Risk Assessment Area by the total time spent in Light Arena.
  7. Return all the animals to their home cages. Clean the light/dark box thoroughly with 70% ethanol.
Marble burying test
1. Perform the marble-burying test in a standard rat microisolator cage or similar enclosure. Fill each cage with 5 cm fresh bedding. Arrange the cages on the bench of the procedure room and adjust the lights to <10 lux.
2. Arrange 20 clean black glass marbles in an evenly spaced 5 x 4 grid across the bottom of each cage.
3. Transfer the animals to the marble-burying procedure room to allow the animals to acclimate for 30 min.
4. Place each animal into a marble-burying arena for 25 min. After 25 min, remove each mouse from its arena and return it to its cage.
5. Calculate the % of marbles buried by dividing the number of buried marbles by 20.
Acoustic startle response
1. Define the startle, no stimulus, and prepulse startle trials in the startle response software.
  1. Define the 120 dB(A) startle stimulus to emit a 40 ms tone of 120 dB(A) while measuring startle amplitude.
  2. Define the 75 dB(A), 80 dB(A), and 85 dB(A) prepulse stimuli to emit either a 40 ms tone of 75 dB(A), 80 dB(A), or 85 dB(A), respectively, followed by a 40 ms tone of 120 dB(A) while measuring the startle amplitude.
  3. Define the no startle stimulus to emit a 40 ms tone of 65 dB(A) (background) while measuring startle amplitude.
2. Define the acoustic startle response session.
  1. Set the background to the analog level correlating to 65 db(A).
  2. Add seven 120 db(A) startle trials at the beginning of the session, followed by an additional ten 120 db(A) startle trials randomly interspersed with twelve no stimulus trials, twelve 75 db(A) prepulse trials, twelve 80 db(A) prepulse trials, and twelve 85 db(A) prepulse trials, followed by a final seven 120 db(A) startle stimuli.
3. Transfer the animals to a room adjacent to the acoustic startle response procedure room and allow the animals to acclimate for 30 min.
4. Following the 30 min acclimation, transfer the animals to be assessed to the procedure room in the dark.
5. Place each animal into the restrainer in the acoustic startle unit, replace the inserts to restrain each animal, and close the door of the sound-attenuating cubicle. Ensure that the inserts are positioned such that the animal is centered over the vibration sensor but is still able to turn around freely.
6. Start the protocol using the startle response software.
7. When the protocol concludes, remove all the animals from the acoustic startle apparatus to the transfer cage.
8. Clean the animal restrainer by thoroughly wiping down the interior surfaces with 70% ethanol.
9. Calculate latency to peak startle the amplitude by averaging the time to max velocity values for all 120 dB(A) startle stimuli for each animal.
10. Calculate the % prepulse inhibition. Calculate the average Vmax value for 120 dB(A) startle stimuli, no startle, 75 dB(A) startle stimuli, 80 db(A) startle stimuli, and 85 dB(A) startle stimuli. Calculate the net average startle amplitude by subtracting the average Vmax for no startle stimuli from the average Vmax for 120 dB(A). Calculate the % prepulse inhibition for the 75 db(A), 80 dB(A), and 85 dB(A) prepulse startles by dividing each average prepulse Vmax by the average 120 dB(A) Vmax, subtracting that ratio from 1 and multiplying by 100. Calculate the average % pre-pulse inhibition by averaging the 75 dB(A), 80 dB(A), and 85 db(A) % pre-pulse inhibitions.
Home cage activity
1. Perform the home cage activity in microisolator cages with modified lids fitted with passive infrared sensors which detect animal movement. Replace the standard water bottles with 50 mL conical tubes fitted with a stopper sipper to reduce the area of the cage bottom obstructed from the view of the motion sensor. Place a limited amount of food (50-75 g) into the wire cage insert to reduce obstruction of the motion sensor.
2. Transport the animals to the home cage activity room following the acoustic startle response test.
3. Place each animal into a modified microisolator cage and ensure that the IR sensor is reading movement. Replace the wire cage top and lid.
4. Check the animals daily over the course of the assay to ensure each animal has sufficient access to both food and water.
5. House the animals in the home cage activity cages for 3 light/dark cycles (72 h).
6. Following the 72 h period, stop the recording and remove all the animals from their home cages.
7. Calculate the % light phase activity by dividing the total number of activity bouts during the second and third light phases by the total number of activity bouts of the last 48 h of monitoring.
Scoring and inclusion
1. Calculate the Z value for % risk assessment, % marbles buried, average % prepulse inhibition, latency to peak startle amplitude, and % light phase activity readout for each animal by subtracting the mean value for that behavioral test in that cohort and then dividing by the standard deviation of that behavioral test in that cohort.
2. Award points to the top 20% most PTSD-like animals for each behavioral readout. The top 20% of animals displaying the lowest % risk assessment, highest % marbles buried, lowest average % prepulse inhibition, lowest latency to peak startle amplitude, and highest % light phase activity, receive 3, 1, 2, 3, and 1 points respectively (Table 1).
3. Add all of the points received by each animal in the behavioral tests. Designate the animals receiving 5 points or more as PTSD-like, and designate the animals receiving 0 points as resilient.

Representative Results

We expect to see animals displaying PTSD-like behavior in each behavioral test evenly distributed across all cohorts. A concentration of PTSD-like animals in any one cohort may indicate artifacts introduced either during the PTSD induction or behavioral testing. Animals scoring points in each behavioral readout are equally distributed across all cohorts tested (Figure 2). 7 of the 48 animals (14.6%) exposed to the PTSD-induction paradigm scored 5 or more points and were designated PTSD-like (Figure 3). A significantly higher number of animals were designated resilient. Retrospective assessment of PTSD-like and resilient animals shows that PTSD-like animals displayed significantly more PTSD-like behaviors in Marble Burying, Prepulse Inhibition, Latency to Peak Startle Amplitude, and Home Cage Activity. Additionally, PTSD-like animals displayed a very highly significantly more PTSD-like average behavioral Z (the average Z score across all behavioral tests) relative to resilient controls, indicating a high degree of behavioral synergy, decreasing the likelihood that animals were misidentified due to artifactually more PTSD-like behavior in some tests (Figure 4).

Figure 1: Timeline of behavioral protocols. PTSD-like behavior is induced via two sessions of the inescapable electric foot shock: a Trauma and Trigger session on days 1 and 2, respectively. Behavioral testing for PTSD-like behaviors is performed from days 8-15, with a dark/light transfer (DLT) test performed on day 8, a marble-burying test (MBT) performed on day 10, an acoustic startle response (ASR) test performed on day 12, and a home cage activity (HCA) test performed over days 13-15. Finally, animals are sacrificed on day 22. Please click here to view a larger version of this figure.

Figure 2: Behavioral test results for a 48-animal cohort of mice. Z scores for (A) % Risk Assessment, (C) % Marbles Buried, (E) Latency to Peak Startle Amplitude, (G) % Prepulse Inhibition and (I) % Light Phase Activity for 48 animal cohort, as well as each individual 8 animal cohort (B, D, F, H, and J, respectively). Z values have been scaled such that a more positive Z value indicates more PTSD-like behavior (decreased % risk assessment, increased % marbles buried, decreased latency to peak startle amplitude, decreased % prepulse inhibition, and increased % light phase activity). The 20% most PTSD-like animals in each behavioral test are indicated by red data points. Plotted data represent means and standard deviations (SD). Please click here to view a larger version of this figure.

Figure 3: PTSD symptom scores for 48 mice. 7 mice (~15%) scoring 5 points or more were designated PTSD-like, while 16 mice (~30%) scored no points and were designated resilient. Plotted data represent means and standard deviations (SD). Please click here to view a larger version of this figure.

Figure 4: Behavioral test results for PTSD-like (n = 7) and Resilient (n = 16) mice from 48 animal cohort. Z scores for % Risk Assessment (%RA), % Marbles Buried (%MB), % Pre-Pulse Inhibition (%PPI), Latency to Peak Startle Amplitude (LtPSA), % Light Phase Activity (%LPA), as well as the average Z value of all behavioral tests (Avg Z). Plotted data represent means and standard deviations (SD). Please click here to view a larger version of this figure.

Behavioral Test	Points (Top 20%)
% Risk Assessment	3
Marbles Buried	1
Latency to Peak Startle Amplitude	3
% Pre-Pulse Inhibition	2
% Light Phase Activity	1
Phenotype	Final Score
PTSD-Like	5+
Resilient	0

Table 1: Scoring and inclusion criteria for identifying PTSD-like and resilient animals. The top 20% most PTSD-like animals for each behavioral readout receive points for that readout. Animals scoring 5 points or more are designated PTSD-like, while animals scoring no points are designated resilient.

Day	Cohort n	Cohort n+1
1	Trauma
2	Trigger
3
4
5
6
7
8	LDT	Trauma
9		Trigger
10	MBT
11
12	ASR
13	HCA
14	HCA
15	HCA	LDT
16
17		MBT
18
19		ASR
20		HCA
21		HCA
22	Sac	HCA

Table 2: Example timeline of behavioral protocols when assaying multiple cohorts of animals. Experimental timelines for each cohort are staggered by 1 week. Light/dark transfer (LDT), marble-burying test (MBT), acoustic startle response (ASR), home cage activity (HCA), sacrifice (Sac).

Discussion

PTSD is a complex and heterogenous psychiatric disease. Unfortunately, there is currently no reliable animal model for PTSD-like behavior, and behavioral paradigms for the induction of PTSD-like behavior are the most reliable means of generating animals displaying a PTSD-like behavioral phenotype. The paradigm described here provides a robust and reliable means of precipitating a PTSD-like behavioral phenotype due to the use of acute trauma to precipitate PTSD-like behavior and multiple PTSD-specific behavioral readouts to identify PTSD-like animals. The PTSD-specific behaviors utilized in this paradigm are highly clinically relevant. Five points are available from the acoustic startle response test (three points for reduced latency to peak startle amplitude and two points for reduced % prepulse inhibition), and hyperarousal is the most significant self-reported symptom associated with reduced quality of life in individuals with PTSD¹⁶. Ultimately animals must display PTSD-like behavior in the top 20% of animals in at least two behavioral readouts in order to score sufficient points to be designated PTSD-like, decreasing the likelihood of an animal being incorrectly designated PTSD-like due to artifactually PTSD-like behavior in any one test.

Behavioral testing should be performed during the dark phase, which is the mouse's active phase, and no sooner than 4 h after the beginning of the dark phase to ensure that all animals are in a stable phase of their corticosterone cycle. It is therefore highly recommended that animals be housed on an inverted light/dark cycle, allowing behavioral testing to be performed during normal work hours. If animals are housed on an inverted light/dark cycle, animals should be allowed to acclimate to the inverted light/dark cycle for at least 14 days to ensure that their circadian rhythm has fully adjusted, preventing any artifacts. Because this paradigm involves the differential use of light in both the induction of PTSD-like behavior, as well as in multiple assays utilized to identify PTSD-like behavior, viz. the dark/light transfer and home-cage activity tests, this protocol may not be effective in mouse strains experiencing retinal degeneration (e.g., CD1, FVB).

The trauma and trigger electric foot shock sessions should be performed on consecutive days to maximize the traumatic effect. Conversely, behavioral tests should never be performed on consecutive days in order to prevent undue stress, which may create artifacts. It is recommended to sacrifice animals via live decapitation without anesthetic in order to prevent artifacts in post-mortem analysis. There is sufficient time between the home cage activity test and sacrifice to perform any additional behavioral or functional assays such as a restrained stress test for corticosterone response¹³.

Whenever possible, it is recommended to remain in the procedure room for the duration of each behavioral test to ensure that the test runs without issue. One exception is the acoustic startle response test. Due to the high noise levels involved with that test it is recommended to remain in the procedure room at least long enough to observe the test is running normally before leaving the procedure room.

This paradigm precipitates PTSD-like behavior in ~10%-15% of exposed animals, which closely matches the rate of PTSD in individuals exposed to a traumatic event⁴. Unfortunately, this relatively low rate of PTSD induction necessitates a large number of animals in order to generate a sufficient number of PTSD-like animals for post hoc analysis. For example, exposing 48 mice to the PTSD-induction paradigm will result in 5-7 PTSD-like animals identified. The PTSD-induction paradigm and behavioral tests used to diagnose PTSD-like behavior are both time- and equipment-intensive. It is, therefore, not practical to process all animals through the paradigm simultaneously. We, therefore, recommend exposing animals to the paradigm in cohorts of 8-16 animals, depending on the equipment availability, and staggering the experiment schedule of these animals by 1 week (Table 2).

It is important to note that PTSD-like animals are not identified based on absolute behavioral readouts but instead based on their behavior relative to the cohort as a whole. The inability of this paradigm to identify PTSD-like based on absolute behavioral readouts necessitates the use of relatively large cohorts of animals and may limit experimental designs to investigate the effects of therapies or transgenes on PTSD-like behavior.

Disclosures

The authors have nothing to disclose.

Acknowledgements

This work was made possible by the generosity of the Hayward Foundation and Marriot Family. We would also like to acknowledge the hard work and expertise of the Tulane University and Mayo Clinic IACUC committees and Departments of Comparative Medicine, as well as the Mayo Clinic Rodent Behavioral Research Facility.

Materials

Acetic acid, glacial	Sigma Aldrich	AX0073
Benchtop Balance	Fisher Scientific	01-913-925
Clocklab Data Collection Suite	Actimetrics	–	Home cage activity cages
Deciblemeter
Ethovision XT14 Software	Noldus	–	Movement tracking software
Ethyl alcohol	Sigma Aldrich	443611
Light/Dark Box	Noldus	–	Light/dark transfer box
Lux Meter
Monochrome GigE Camera	Noldus	–	Requires Ceiling Mounting Hardware Available from Noldus
NIR Video Fear Conditioning Package for Mouse [Standard, USB]	Med Associates	MED-VFC2-USB-M	Fear conditioning equipment and chamber. Package includes all equipment needed to assay 1 animal at a time.
Spray Bottle	Thermo Scientific	BirA500
SR LAB Software	San Diego Instruments	–	Startle response software
SR LAB Startle Response Unit	San Diego Instruments	–	Acoustic startle unit
Video Fear Coniditioning "Video Freeze " Software	Med Associates	SOF-843	Fear conditioning software
White noise machine	Med Associates	ENV-230

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