When a pathogen invades the body, the immune system has to identify it and mount a response, which involves inflammation. That inflammation may be local, but it can also become widespread throughout the body. The immune system must be carefully regulated, or such inflammation can spiral out of control, and create a life-threatening situation known as sepsis. Even when people survive a septic infection, they may have lifelong symptoms; post-sepsis syndrome is thought to affect about 50 percent of those affected. Cases of sepsis are also on the rise, which is unsurprising as the world faces greater exposure to infectious microbes.
When sepsis occurs, the brain is not spared. Patients may exhibit a variety of neurological and psychological problems including delirium, coma, brain damage, anxiety, depression, sleep disruption, and post-traumatic stress disorder (PTSD).
Reporting in the journal Brain, researchers have now learned more about how sepsis impacts certain areas of the brain that have previously been linked to sepsis, the amygdala and brainstem.
"No preventive treatments have so far been demonstrated to be effective, probably because of a lack of understanding of the pathophysiology of these disorders, especially the neural networks implicated in their onset," noted co-corresponding study author Professor Tarek Sharshar, Head of the Sainte-Anne Neurology Department at the Pasteur Institute.
Two groups of neurons in the amygdala have been associated with anxiety, and fear learning. In this study, a mouse model of sepsis was used to investigate what happens to those regions during a septic infection. The mouse model displays many of the same signs of sepsis as humans, including severe inflammation and altered behaviors. Like people who have gotten over sepsis, mice that recovered also showed signs of PTSD, a disorder that affects a quarter to half of sepsis patients compared to about six percent of the general population.
The researchers identified a specific neural circuit in the brain, part of the central nucleus of the amygdala that interacts with the bed nucleus of the stria terminalis, which was triggered during the first few hours of sepsis. Sepsis led to persistent changes in how the neurons in that circuit responded to stimuli and alterations in their connectivity. The PTSD behaviors arose about two weeks after the infection cleared the body.
In additional work, the researchers inhibited this circuit in mice in two ways, with a drug and with a gene silencing approach. Both methods prevented the post-sepsis PTSD behaviors in the mouse model; the researchers suggested that they are reducing the activity in the vagal afferent integration center. The vagus nerve extends from the brain to the gut, and it has special receptors that can tell when gastrointestinal or lung inflammation is occurring.
The study authors are hopeful that this work will lead to new treatments for sepsis, because they identified a medication that can prevent hyperactivation in the neural circuit, and reduce the risk that anxiety disorders will develop. A trial is now being planned to determine whether the drug works in sepsis patients.
Sources: Pasteur Institute, Brain
