Meowza, that scared me!

April 5, 2022

Written by: Omer Zeliger

Approximately 8% of Americans will experience PTSD, or post-traumatic stress disorder, following a traumatic experience throughout their lifetime ¹. People with PTSD reexperience their trauma (often through flashbacks and nightmares), which is often paired with a general increase in anxiety or tension and leads them to avoid any reminders of their trauma². These symptoms can persist anywhere from a few months to over a decade³ and frequently interfere in daily life, straining relationships and impeding the ability to go to work. Patients can try to alleviate their symptoms with treatments like therapy or medication^2,4. However, almost a quarter of people do not respond to medication and nearly twice that many don’t see substantial improvement in therapy⁴.

Studies into the causes and treatments of PTSD are constantly ongoing in order to bring patients better outcomes. To learn about the underlying neurobiology of PTSD, scientists often model PTSD in animals. However, studying PTSD in animals has unique challenges – after all, you can’t ask a mouse whether it’s been having nightmares. To make up for this, scientists for the last two decades have been modeling PTSD in rodents using a paradigm called fear conditioning.

To fear condition a mouse, scientists teach them to associate a harmless cue, like a sound or a flashing light, with an instinctively unpleasant cue, such as the smell of a cat (a predator) or a mild electric shock. This sort of teaching comes from Pavlov’s experiments where he taught dogs to associate the sound of a bell with food. After several days of ringing the bell before giving them food, the dogs began to drool when they heard ringing; they had learned to react to the sound the same way they reacted to the food. Fear conditioning mice follows the same principle. After pairing them together a few times, mice will learn that the sound precedes the shock and, just like Pavlov’s dogs, will respond to the sound the same was they would to the shock: by freezing in place in fear. This type of fear conditioning mimics many of the hallmarks of PTSD; following a stressful event, the mouse will respond to the previously harmless cue with anxiety.

Researchers can then test what factors might predispose someone to PTSD and how different treatments affect fear conditioning. For example, one study found that rats who received cocaine before fear conditioning had a harder time unlearning the association⁵. Other studies show that long-term use of SSRIs (drugs often used to treat anxiety and depression) can reduce fear conditioning⁶. These studies help to reveal neurotransmitter systems and brain circuits that can either increase or decrease likelihood that someone will suffer from PTSD. In one case, animal research describing how specific areas of the brain changed their activity after fear conditioning⁷ let scientists decades later develop modern experimental treatments like teaching PTSD patients to consciously influence activity in those very same areas⁸.

Fear conditioning in animal models can’t capture all the nuances of human PTSD, and it’s important to be careful about generalizing from one to the other. One crucial aspect of PTSD is that the patient’s fear and anxiety are so hyperactive that they get in the way of daily life, while fear conditioning in mice is an adaptive response meant to help them escape potential danger⁶. Scientists continue to debate when and how this model should be used to study PTSD⁴, using variations on basic fear conditioning – ranging from injecting the stress hormone corticosterone after fear conditioning to associating the shock with an environment rather than a sound – to better capture different facets of the disorder.

Just as mouse research can contribute to our understanding of human disorders, findings in humans can help us expand and refine our animal models. For example, if studies find that people with a particular genetic mutation are more susceptible to PTSD⁹, then scientists can replicate that mutation in mice to investigate how the gene affects fear conditioning and whether mice with that mutation might respond better to some treatments than others. The more we learn about PTSD, the better and more accurate researchers can create PTSD models in mice, and the reverse is also true; more accurate and informative animal models lead to new avenues of treatment and understanding.

References:

1. Kilpatrick, DG et al. (2013) National Estimates of Exposure to Traumatic Events and PTSD Prevalence Using DSM-IV and DSM-5 Criteria. J Trauma Stress 26(5):537-547.
2. National Institute of Mental health. “Post-Traumatic Stress Disorder.” National Institute of Mental Health, 2020.
3. Watson, P (2019) PTSD as a Public Mental Health Priority. Curr Psychiatry Rep 21(7):61.
4. Bienvenu TCM et al. (2021) The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Neuron 109(15)2380-2397.
5. Lguensat A et al. (2021) The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Brain Struct Funct 226(7)2219-2241.
6. Burghards NS & Bauer EP (2013) The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Neuroscience 247:253-272.
7. Tang J et al. (2001) The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Brain Res 919(2):232-241.
8. Zotev V et al. (2018) The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Neuroimage Clin 19:106-121.
9. Nievergelt CM et al. (2019) International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nat Commun 10(1):4558.

Cover image by Moloch2511 via Pixabay.