Neural circuits and drugs for post-sepsis anxiety identified in mice

French scientists have identified a dedicated neural circuit responsible for anxiety-like behavior in an established mouse model of sepsis that corresponds to the psychiatric symptoms seen in patients recovering from sepsis.

Experimental study published in journal brainIn the article titled, “Silencing of the amygdala circuit during sepsis prevents the development of anxiety-related behaviors.. This study identifies both a dedicated circuit for post-sepsis anxiety and pharmacological treatments that may help treat patients suffering from “long COVID.”

There are two ways in the brain to detect and regulate systemic or localized inflammation. It is a humoral component such as a circulatory mediator of inflammation that notifies specific areas of the brain, and an afferent sensory nerve that detects and transmits local inflammatory signals to the brain. For example, the tenth cranial nerve, the vagus nerve, uses receptors to detect gastrointestinal or lung inflammation.

Specific neural networks recognize and integrate humoral and neural messages and coordinate coordinated defenses, including neuroendocrine, autonomic, and behavioral elements, through the autonomic and limbic systems. increase.

When the neuroendocrine system is activated, the main stress hormone, cortisol, is released. When the autonomic nervous system is triggered, both the sympathetic and vagal nervous systems are activated. The latter is thought to elicit a local anti-inflammatory response. In addition, behavioral responses change mood, attention, sleep, and appetite.

This high level of intervention aims to control inflammation and maintain the integrity of the body. However, sometimes this regulation becomes unmanageable and causes potentially life-threatening immunological and / or psychological disorders.

Sepsis, defined as “unregulated host response to infection,” is the most common condition that can elicit this defense strategy against inflammatory stress. Sepsis causes significant mortality and morbidity and causes major public health problems.

Even after recovering from sepsis, patients often suffer from long-term psychiatric symptoms, including anxiety and post-traumatic stress disorder (PTSD). PTSD is collectively referred to as “post-sepsis syndrome,” and the underlying neurobiology remains unknown. This long-term mental health malaise after sepsis increases the risk of suicide and affects the patient’s personal, social and professional life.

“So far, prophylactic treatment has not been proven to be effective, probably due to a lack of understanding of the pathophysiology of these disorders, especially the neural network involved in their development. “Tarek Sharshar, MD, professor and director, said. The Sainte-Anne Department of Neurology and the author of the current study.

In the current study, a team of scientists from the Institute of Perception and Memory at the Pasteur Institute in Paris and clinicians from the Department of Neuroresuscitation at the Paris Psychiatry and Neuroscience University Hospital Group (GHU) have used pharmaceutical and pharmacogenetic techniques. The neural circuit, including the central nucleus of the tonsils and the stria terminalis, dedicated to use, is activated in the first few hours of sepsis and is anxious in a mouse model of sepsis two weeks after the infection is resolved. Induces behavior like.

To evaluate the neurobiological mechanism of long-term behavioral disorders after sepsis, researchers have found that extensive membrane inflammation (peritonitis) that lines the abdominal cavity (peritoneum) is induced using cecal ligation and puncture. An established mouse model of sepsis was used. A pouch at the junction of the small and large intestines.

“Mice recovered from sepsis have been shown to further develop anxiety-related behaviors associated with exaggerated fear memory. In the brain, sepsis is acute in a particular neuronal subpopulation of the central nucleus of the amygdala (CeA). Induces pathological activation of the disease, “the researchers say.

Using a pharmacogenetic approach based on the conditional expression of the neuromodulator levetiracetam or inhibitory DREADD (designer receptor exclusively activated by designer drugs), researchers used vBNST (demarcation line) in the acute phase. The CeA neurons that project to the abdominal nucleus) were temporarily silenced for septicemia.

The authors showed that these treatments prevented the subsequent development of anxiety-related behaviors in a mouse model of sepsis.

The researchers concluded that “weakening the activation of the brain anxiety circuit during sepsis may constitute a new prophylactic approach to eliminate post-infection psychiatric consequences.”

Dr. Pierre-Marie Lledo of CNRS, a professor at the Pasteur Institute and the lead author of the study, said: It has been observed that administration of drugs that can prevent overactivation of this circuit reduces the risk of developing anxiety disorders. “

The authors believe that this effect is partly associated with reduced activation of the vagal afferent integration center. Pharmacological treatments to weaken this anxiety-inducing circuit are ready to be tested in a multicenter randomized trial that can validate the association between human neuroinflammation and psychiatric disorders and provide treatment to patients suffering from long COVID. Is done.