The brain is able to sense and regulate localized or systemic inflammation using two communication pathways. The first, humoral, involves specific brain structures that allow circulating inflammatory mediators to enter the brain. The second, neural, involves nerves whose sensory afferents transmit the inflammatory signal detected at the local level.
The vagus nerve therefore uses identified receptors to detect digestive or pulmonary inflammation. Specific brain structures and networks perceive and integrate these humoral and neural messages and orchestrate a regulatory response involving neuroendocrine, autonomic and behavioral elements. These corrective interventions are controlled by the hypothalamus and pituitary respectively – the autonomic nervous system and the limbic system. Neuroendocrine activation is characterized by the release of cortisol, the main stress hormone. The autonomic response involves the combined activation of the sympathetic and vagal systems, the latter thought to induce a local anti-inflammatory response. Behavioral changes affect mood, attention, sleep and appetite. The goal of the overall response is to control inflammation in order to preserve bodily integrity, or homeostasis. But in certain circumstances, it can be unsuitable and lead to immunological and/or psychic disorders.
A severe infection known as sepsis is the most common condition capable of inducing this defense strategy against inflammatory stress. Sepsis is the leading cause of death worldwide and represents a major public health issue. What makes matters worse is that sepsis is also associated with chronic psychological disorders such as anxiety, depression, and post-traumatic stress disorder. These conditions significantly increase the risk of suicide and have a lasting impact on the personal, social and professional lives of patients. “No preventive treatment has so far demonstrated its effectiveness, probably due to a lack of knowledge of the pathophysiology of these disorders, in particular the neural networks involved in their appearance”, explains Professor Tarek Sharshar, Head of from the Sainte-Anne neurology department. .
In an experimental study published in the journal Brain, a team of scientists from the Institut Pasteur (Perception and Memory laboratory) and clinicians from the Groupe Hospitalier Universitaire de Psychiatrie et Neurosciences (GHU) in Paris (Service de Réanimation Neurologique) used pharmacogenetic techniques to identify a dedicated neural circuit comprising the central nucleus of the amygdala and the nucleus of the bed of the stria terminalis. Activation of this circuit in the first hours of sepsis induces anxious behavior two weeks after the disappearance of the infection. This behavior seen in mice mimics the post-traumatic stress disorder seen in patients recovering from sepsis.
“This discovery opens the way to new therapeutic strategies for sepsis: we have observed that the administration of an agent capable of preventing the hyperactivation of this circuit reduces the risk of developing anxiety disorders”, explains Prof. Pierre-Marie Lledo, Pasteur Institute and CNRS. This effect is thought to be partly related to reduced activation of the vagal afferent integration center.
This study is particularly interesting because it identifies both a circuit dedicated to post-sepsis anxiety and a potential pharmacological treatment. The latter will soon be tested in a multicenter randomized therapeutic trial. By revealing the link between neuroinflammation and psychiatric disorders, this research resonates with the current context of the COVID-19 pandemic and long COVID.
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