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

The experimental study was published in the journal Brain, in an article titled, “Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviors.” The study identifies both a dedicated circuit for anxiety following sepsis and a potential pharmacological treatment that could help treat patients who are suffering from “long COVID.”

The brain has two ways of detecting and regulating systemic or local inflammation: humoral components such as circulating mediators of inflammation that inform specific regions of the brain, and afferent sensory nerves that detect and transmit localized inflammatory signals to the brain. For example, vagus, the tenth cranial nerve, uses receptors to detect digestive or pulmonary inflammation.

Specific neural networks perceive and integrate humoral and neural messages and orchestrate a coordinated defense through the autonomic nervous system and the limbic system, involving neuroendocrine, autonomic, and behavioral elements.

When the neuroendocrine system is activated, the main stress hormone, cortisol, is released. When the autonomic response is triggered, it activates both the sympathetic and vagal systems. The latter is believed to induce a local anti-inflammatory response. In addition, behavioral responses alter mood, attention, sleep, and appetite.

This high-level intervention aims to control inflammation to preserve the body’s integrity (homeostasis). But sometimes this regulation gets out of hand, resulting in immunological and/or psychological disorders that could prove life-threatening.

Sepsis, defined as “a deregulated host response to infection,” is the most common condition capable of inducing this defense strategy against inflammatory stress. Sepsis causes significant mortality and morbidity and poses a major public health issue.

Even after recovering from sepsis, the patient often suffers long-term psychiatric symptoms including anxiety and post-traumatic stress disorder (PTSD), collectively referred to as “post-sepsis syndrome” whose underlying neurobiology remains unclear. This long-term mental health malaise following sepsis increases suicide risk and impacts the patients’ personal, social, and professional lives.

“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,” said Tarek Sharshar, MD, PhD, professor and head of the Sainte-Anne neurology department, and who is an author of the current study.

In the current study, a team of scientists from the perception and memory laboratory at the Pasteur Institute in Paris and clinicians from the department of neurological resuscitation at the Paris Psychiatry and Neurosciences University Hospital Group (GHU) used pharmaceutical and pharmacogenetic techniques to identify a dedicated neural circuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, which when activated in the first few hours of sepsis induces anxiety-like behavior in a mouse model of sepsis, two weeks after the infection has cleared.

To assess the neurobiological mechanisms of long-term behavioral disorders following sepsis, the investigators used an established mouse model of sepsis where inflammation (peritonitis) of the extensive membrane lining the abdominal cavity (peritoneum) is induced using ligation and puncture of the cecum, a pouch at the junction of the small and large intestines.

“We showed that mice that recovered from sepsis further developed anxiety-related behaviors associated with an exaggerated fear memory. In the brain, sepsis induces an acute pathological activation of a specific neuronal subpopulation of the central nucleus of the amygdala (CeA),” the researchers noted.

Using the neuromodulatory drug levetiracetam or a pharmacogenetic approach based on the conditional expression of an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drugs), the investigators temporarily silenced CeA neurons projecting to the vBNST (ventral bed nucleus of stria terminalis) during the acute phase of sepsis.

These treatments, the authors showed, prevented the subsequent development of anxiety-related behaviors in the mouse model of sepsis.

The researchers concluded, “Dampening the activation of brain anxiety circuits during sepsis might constitute a novel preventive approach to preclude the post-infection psychiatric outcomes.”

Pierre-Marie Lledo, PhD, professor at the Pasteur Institute and CNRS, who is a senior author of the study said, “This discovery paves the way for new therapeutic strategies for sepsis. We observed that administering an agent capable of preventing the hyperactivation of this circuit reduces the risks of developing anxiety disorders.”

The authors believe this effect is partly linked to reduced activation of the vagal afferent integration center. The pharmacological treatment to dampen this anxiety-inducing circuit is poised to be tested in a multicenter randomized trial that could validate the link between neuroinflammation and psychiatric disorders in humans and provide a treatment for patients suffering from long COVID.

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