Molecular Changes in the Brain in the Aftermath of a Traumatic Event May Help Explain Long-Term Susceptibility or Resilience

Summary: In mice genetically more susceptible to PTSD following a stressful event, researchers found an increased expression of cortisol receptors on neurons in the CA1 region of the dorsal hippocampus. Those increased receptors enabled an elevated expression of the HCN1 protein and TRIP8b, reducing neural excitability.

Source: Medical College of Georgia at Augusta University

Social avoidance is a common symptom of PTSD, and scientists working to better understand why have laboratory evidence that while stress hormone levels consistently increase in the immediate aftermath of a traumatic event, there can be polar opposite consequences in parts of the brain down the line.

In response to a significant stressor and a subsequent surge of stress hormones, some rodent models experience the expected short-term increase in the excitability of neurons in areas of their brain key to memory and to how they see their environment, as part of the natural instinct to fight or flee.

Other genetically identical mice instead experience a decrease in neuron excitability in this key area called the dorsal hippocampus, Dr. Chung Sub Kim, neuroscientist at the Medical College of Georgia at Augusta University, and his colleagues report in the journal Molecular Psychiatry.

Too little neuronal activity in the hippocampus has been linked to PTSD in humans; and detailed brain imaging of people with PTSD indicates structural and functional changes in key brain areas, like the hippocampus.

Glucocorticoid receptors for the stress hormone cortisol are highly expressed in the hippocampus and have been shown to be more highly expressed in PTSD patients than controls when they reexperience stressful situations.

“We are trying to answer the question as to why hippocampal activity is decreased in PTSD or depressed patients,” Kim says. “We know it happens, but the mechanism we don’t know.”

One of the things they are finding is that, like humans, some mice just seem more susceptible to a lasting impact from a major and/or chronic stressor and that both their behavior and internal molecular response to stress are distinctive from their more resilient peers.

“One was affected directly by stress, and another not so much,” Kim says. 

To mimic stressful scenarios like a bullied child or armed robbery, the scientists created a scenario where a male mouse, which is naturally aggressive, established his territory, then repeatedly attacked another mouse who ventured into that territory.

Again, somewhat like human victims, some of the mice did not seem phased after the attack, rather were still naturally inquisitive about the other mouse; while the susceptible mouse clearly avoided The aggressor.

In the “susceptible” mice, Kim and his colleagues found increased expression of receptors for stress hormones on neurons in the CA1 region of the dorsal hippocampus of their brain. Those plentiful receptors appeared in turn — and perhaps counterintuitively — to enable elevated expression of the protein HCN1, a natural modulator of neuron activity and connectivity already found in naturally high levels in the hippocampus.

HCN1 is a major research focus for Kim, who has evidence that even a single episode of significant stress can further increase HCN1 expression in the CA1 region of the dorsal hippocampus and bring neuron excitability down. Also increased in the susceptible rodents was the protein TRIP8b, which regulates HCN channel levels.

“Stress changes everything,” Kim says.

The scientists found that this cascade resulted in an increase as well in another natural tamping down mechanism, called hyperpolarization-activated current, which was known to be increased by stress but just how was unknown. Again, the changes were specific to the dorsal — in humans the back part — portion of the hippocampus.

Even months later, these levels which drove down neuron excitability remained high, and the susceptible mice continued to avoid contact with the aggressive male mouse. The reduced neuron excitability did not change even in response to direct application of a stress hormone to the neurons, which again should increase neuron excitability.

The susceptible mice also experienced impaired spatial working memory, which for humans is basically trouble remembering where you left your car keys and how to get to work.

The clearly different expression of the HCN1 protein in this region of the hippocampus may be the molecular mechanism driving susceptibility to social avoidance, Kim and his colleagues write.

“They have some malfunction in hippocampal information processing,” he says. Whether those changes are permanent is not certain but at three months, a long time in mouse years, they were still present: The average mouse lives maybe two to three years, while the average human in the U.S. lives into their late 70s.

But in the “resilient” mice, expression of the stress hormone receptor and HCN channel did not increase, but neuron excitability did, in the immediate aftermath of stress.

“There are clearly physical differences in the response to stress in the two mice that correlate with their behavior,” Kim says, even though you would not suspect the differences in these genetically identical rodents. 

This shows a brain
Too little neuronal activity in the hippocampus has been linked to PTSD in humans; and detailed brain imaging of people with PTSD indicates structural and functional changes in key brain areas, like the hippocampus. Image is in the public domain

More work still needs to be done to understand exactly why some mice are resilient and others are susceptible to emotional trauma, the scientists write.

In the mouse, the dorsal hippocampus is more linked to learning and memory while the ventral hippocampus is linked to emotion-related reactions like anxiety, Kim and his colleagues write. Comparatively speaking, the dorsal hippocampus has less neuron excitability and is clearly the most reactive to chronic stress.

HCN channels are involved in a variety of physiologic processes like sleep and wake states, taste and fear learning. Work by Kim and others has found evidence of a link between HCN channels and mental diseases, including depression and anxiety.

The adrenal gland releases cortisol and adrenaline as well in response to a fearful situation like someone threatening you. The increase helps prepare the body for the so-called protective flight or fight response, by making adjustments like increasing levels of glucose, which your body uses as fuel, while suppressing functions like digestion and reproduction, which are not considered essential in that moment.  

PTSD has also been shown to produce changes in the amygdala, which helps perceive and store memories of emotions like anger, fear and sadness and recognize threat; and the medial prefrontal cortex, which is thought to be important to cognitive functions like attention, habit formation and long-term memory.

About this PTSD research news

Author: Toni Baker
Source: Medical College of Georgia at Augusta University
Contact: Toni Baker – Medical College of Georgia at Augusta University
Image: The image is in the public domain

Original Research: Open access.
Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons” by Jiwon Kim, Yun Lei, Xin-Yun Lu & Chung Sub Kim. Molecular Psychiatry


Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons

While chronic stress increases hyperpolarization-activated current (Ih) in dorsal hippocampal CA1 neurons, the underlying molecular mechanisms are entirely unknown.

Following chronic social defeat stress (CSDS), susceptible mice displayed social avoidance and impaired spatial working memory, which were linked to decreased neuronal excitability, increased perisomatic hyperpolarization-activated cyclic nucleotide-gated (HCN) 1 protein expression, and elevated Ih in dorsal but not ventral CA1 neurons.

In control mice, bath application of corticosterone reduced neuronal excitability, increased tetratricopeptide repeat–containing Rab8b-interacting protein (TRIP8b) and HCN1 protein expression, and elevated Ih in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional Ih was mediated by the glucocorticoid receptor (GR), HCN channels, and the protein kinase A (PKA) but not the calcium/calmodulin-dependent protein kinase II (CaMKII) pathway.

Three months after the end of CSDS, susceptible mice displayed persistent social avoidance when exposed to a novel aggressor. The sustained behavioral deficit was associated with lower neuronal excitability and higher functional Ih in dorsal CA1 neurons, both of which were unaffected by corticosterone treatment. Our findings show that corticosterone treatment mimics the pathophysiological effects of dorsal CA1 neurons/region found in susceptible mice.

The aberrant expression of HCN1 protein along the somatodendritic axis of the dorsal hippocampal CA1 region might be the molecular mechanism driving susceptibility to social avoidance.

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  1. This is very interesting . I have had a series of stressors in my life I feel have shaped my brain function . Over the years I have started to connect dots . It started with seeing an alternative Dr in Chicago 20 yrs ago where she found adrenal gland issues and suggested it was my hypothalamus where she provided adrenal supplements and licorice extract under the tongue twice a day. Life continues . Now I get into a relationship with a type A male and I literally have a situation where it seems in high stress (or what seems to be ) i start shutting down mentally in stressful conversations or situations . I describe it as “going fetal”. I do a blood and saliva panel test 5 yrs ago and my cortisol levels are consistently below low throughout the day . Drs don’t know how to manage this and suggest nothing. Yet it impacts many fibers of my life . But the only solution I am told is to take ashygawanda or reduce stress . i am intention in my efforts now that I have gathered more information on my behaviors throughout the years but I feel there is so much more valuable and useful research on this subject .

    1. Gina, Thank you so much for sharing. While reading your story, I sat here shaking my head thinking, “Holy Sh*t! I know that feeling all too well!”
      In the second grade I was sexually assaulted by a member of the church while attending a local private catholic school. Immediately following the assault, I had to return to class and was unable to hold my bowels. Of course, the kids in my class made fun of me and bullied me pretty much everyday for the next 7 years. Trying to learn anything while my brain was in fight or flight proved to be impossible. The bullying then moved to the teaching staff, who concluded that I had problems paying attention. And I needed to take my education more seriously. There was only one teacher who saw what was going on and questioned the entire class about it (after excusing me to the Principal’s office…which I didn’t go to. Instead I stayed and listened to what went on). One person in the class spoke up and basically told the truth. Sadly, it was a week before leaving the school, and it made no difference at all.
      After leaving St. Mary’s, my life finally started to begin. But I would forever be scarred by those 7 years there…always. In high school, I was able to move forward, blocking out the trauma there. I concentrated on creating a new persona. This time, I would be just the opposite. If someone was cross with me or anyone who couldn’t stick up for themselves, I would stand up for us. I swore I would not back down ever again. I chose a career in Law Enforcement, and promised to look out for all who were spiritually smaller than I. I would end up pushing myself so hard that I would eventually end up disabled and retired.
      After a long hiatus to repair my broken body and spirit, I took a job as an instructor for a company that does scenario based Hostile Environment Trainings. The director of education was an ex military instructor from England. He apparently had something against me for he barely acknowledged my presence for 2 years. and if he did, it was always in a negative manner. I loved this job, so I would hold my tongue and cow-tow to him. For the next three years the attacks would increase. I started noticing that even if I wanted to say something to him in return, I just couldn’t. I found my brain would shut down, like I lost the ability to think…to react…to fight. I would barely sleep during the week, because I couldn’t. And I would pass out on Friday evening and stay in bed, useless to my family, the entire weekend. My body would be in so much pain. So much inflammation that you could visibly see it on me. I went to the ER so many times they started to think I was a hypochondriac. I would lie to my employer and tell them that I was allergic to the mold at the office and call out sick. Just to try to buy some time to figure out what the hell was wrong with me, and try to figure out how to beat it. I took a leave of absence and picked up another job. And it was about two weeks in when I noticed that I was feeling like my old self again. So, like an idiot, I went back to my old job. The first thing the director of education said to me was, “looks like you’ve put on some weight!” I instantly felt a huge rush of “sick” pouring onto me. Like, a bucket of pig’s blood fell from the sky above me. It was in that moment that I realized what was happening.
      I still haven’t figured out how to deal with it. I guess I really never figured out how to deal with being bullied. I got so used to laughing at myself along side of my aggressors, that it’s become how I deal with it (or don’t deal with it). It truly goes to show you how re-wired our brains become to try to protect ourselves from our aggressors. Kind of a messed up defense mechanism, if you ask me. Haha. Just wanted you to know that you’re not alone in this. Sending you a huge blast of positive energy! Stay strong!

    2. not so surprising; the adapt response is desensitization, detachment, feeling less experiencing less being more robotic entering a more superficial state and transitioning between layers of consciousness all of which enables living but feeling seeing being ‘there’ less. More floating less feeling. Easily explains the findings particularly the ones like the loss of keys etc.

      While of course like everything there’s natural predispositions combined with life’s to date ‘training and conditioning’, one would expect to find similar findings by upping the degrees of severity of the trauma, along with the frequency and repetition

    3. Wow at this time so much of what you have said puts me back k in a state of shock. I cannot describe ibre what you said because I’m still trying to hand over all my burdens without ease. I have now lost my father which had sone if bot too many answer that i will never hear. I know that you cannot fully understand or comprehend what I’m going through but might be able to help woth some type of acceptance going into this.

      We are strong together, I am a saved Christian so believe iron sharpens Iron. So I pray for you and hope that our paths have crossed only for good.

      I know that the only way to ovwr come evil is by good

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