Molecular changes in the brain after a traumatic event may help explain long-term susceptibility or resilience

Summary: In mice genetically more susceptible to PTSD after a stressful event, the researchers found increased expression of cortisol receptors in neurons in the CA1 region of the dorsal hippocampus. These increased receptors allowed for elevated HCN1 and TRIP8b protein expression, reducing neuronal excitability.

Source: Medical School of Georgia at Augusta University

Social avoidance is a common symptom of PTSD, and scientists working to better understand why have laboratory evidence that, although levels of stress hormones consistently rise immediately after a traumatic event, there it can have opposite consequences for parts of the brain later on.

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

Other genetically identical mice instead experience a decrease in the excitability of neurons in this key area called the dorsal hippocampus, Dr. Chung Sub Kim, a neuroscientist at the Medical College of Georgia at Augusta University, and his colleagues leagues report in the magazine. 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 areas of the brain, such as 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 in controls when they re-experience stressful situations.

“We’re trying to answer the question of why hippocampal activity is reduced in patients with PTSD or depression,” says Kim. “We know it happens, but we don’t know the mechanism.”

One of the things they’re finding is that, like humans, some mice seem more susceptible to the long-lasting impact of a major and/or chronic stressor, and that both their behavior and internal molecular response to stress are different. of his more resistant colleagues.

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

To mimic stressful scenarios such as a child being bullied or an armed robbery, the scientists created a scenario in which a male mouse, which is naturally aggressive, established its territory and then repeatedly attacked another mouse that ventured into this territory

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

In the “susceptible” mice, Kim and his colleagues found increased expression of stress hormone receptors in neurons in the CA1 region of the dorsal hippocampus of their brains. These abundant receptors appeared in turn, and perhaps counterintuitively, to allow for elevated expression of the HCN1 protein, a natural modulator of neuronal activity and connectivity that is already found at naturally high levels in the hippocampus.

HCN1 is an important 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 reduce the excitability of neurons It also increased in susceptible rodents the TRIP8b protein, which regulates the levels of the HCN channel.

“Stress changes everything,” says Kim.

The scientists found that this cascade also resulted in an increase in another naturally occurring compression mechanism, called a hyperpolarization-activated current, which was known to be increased by stress, but how. Again, the changes were specific to the dorsal portion, in humans, of the posterior part of the hippocampus.

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

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

Kim and colleagues write that distinctly different expression of the HCN1 protein in this region of the hippocampus may be the molecular mechanism that drives susceptibility to social avoidance.

“They have some information processing malfunction in the hippocampus,” he says. It is not certain whether these changes are permanent, but at three months, a long time in mouse years, they were still present: the average mouse lives perhaps two to three years, while the average human in the United States lives to 70 years

But in the “resistant” mice, the expression of the stress hormone receptor and the HCN channel did not increase, but the excitability of the neurons did, immediately after the stress.

“There are clearly physical differences in the stress response in the two mice that correlate with their behavior,” says Kim, although you wouldn’t suspect the differences in these genetically identical rodents.

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 areas of the brain, such as the hippocampus. The image is in the public domain

More work is still needed 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 related to learning and memory, while the ventral hippocampus is related to emotion-related reactions such as anxiety, Kim and colleagues write. In comparison, the dorsal hippocampus has less neuronal excitability and is clearly the most reactive to chronic stress.

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HCN channels are involved in a variety of physiological processes such as sleep and wake states, taste and fear learning. Work by Kim and others has found evidence for a link between HCN channels and mental illness, including depression and anxiety.

The adrenal gland releases cortisol and adrenaline also in response to a fearful situation such as someone threatening you. The increase helps prepare the body for the so-called protective flight-or-fight response, making adjustments such as raising glucose levels, which your body uses for fuel, while suppressing functions such as digestion and reproduction, which are not considered essential at this time.

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

About this PTSD research news

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

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


Summary

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

While chronic stress increases the hyperpolarization-activated current (meh) in CA1 neurons of the dorsal hippocampus, the underlying molecular mechanisms are completely unknown.

After chronic social defeat stress (CSDS), susceptible mice showed social avoidance and impaired spatial working memory, which were related to decreased neuronal excitability, increased protein expression 1 activated by perisomatic hyperpolarization activated by cyclic nucleotides (HCN) and elevated protein expression. meh in dorsal but not ventral CA1 neurons.

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

Three months after completion of CSDS, susceptible mice showed persistent social avoidance when exposed to a new aggressor. The sustained behavioral deficit was associated with lower neuronal excitability and greater functionality meh in dorsal CA1 neurons, which were not affected by corticosterone treatment. Our results show that corticosterone treatment mimics the pathophysiological effects of dorsal CA1 neurons/region found in susceptible mice.

Aberrant expression of HCN1 protein along the somatodendritic axis of the CA1 region of the dorsal hippocampus could be the molecular mechanism driving susceptibility to social avoidance.

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