Silencing amygdala circuits during sepsis prevents development of anxiety-related behaviors Summary Sepsis is a life-threatening condition induced by a dysregulated host response to a severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, the neurobiological mechanisms of which remain unknown. Using a baseline mouse model of sepsis, we show that mice that recovered from sepsis developed even more anxiety-related behaviors associated with an exaggerated fear memory. In the brain, sepsis induced an acute pathological activation of a specific neuronal population of the central nucleus of the amygdala , which projects to the ventral bed nucleus of the stria terminalis. Using viral-genetic circuitry and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and responsiveness of these central amygdala neurons that project to the ventral bed nucleus. the stria terminalis. Transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the antiepileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviors. Specific inhibition of anxiety and fear brain circuits during the acute phase of sepsis constitutes a preventive approach to avoid post-infection psychiatric outcomes. |
Comments
The brain is able to detect and regulate systemic or localized inflammation through the use of two communication pathways. The first, humoral, makes use of 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 locally.
Therefore, the vagus nerve uses identified receptors to detect digestive or lung inflammation. Specific brain structures and networks perceive and integrate these humoral and neural messages and orchestrate a regulatory response that involves neuroendocrine, neurovegetative and behavioral elements. These corrective interventions are controlled respectively by the hypothalamus and pituitary gland, 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 combined activation of the sympathetic and vagal systems, and the latter is 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 to preserve body integrity or homeostasis. But in some circumstances, it may be maladaptive and may lead to immunological and/or psychological 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 challenge. 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 patients’ personal, social and professional lives.
"Until now, no preventive treatment has proven to be effective, probably due to the lack of understanding of the pathophysiology of these disorders, especially the neural networks involved in their appearance," explains Professor Tarek Sharshar, head of the Department of Neurology at Sainte -Anne. .
In an experimental study published in the journal Brain , a team of scientists from the Institut Pasteur (Perception and Memory Laboratory) and doctors from the Group of the Paris University Hospital of Psychiatry and Neurosciences (GHU) (Department of Neurological Resuscitation) used pharmacogenetic techniques to identify a neural circuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Activation of this circuit in the first hours of sepsis induces anxious behavior two weeks after the infection has cleared. This behavior observed in mice mimics post-traumatic stress disorder seen in patients recovering from sepsis.
"This discovery paves the way for new therapeutic strategies for sepsis: we observe that the administration of an agent capable of preventing hyperactivation of this circuit reduces the risks of developing anxiety disorders," explains Professor Pierre-Marie Lledo, Institut Pasteur and CNRS. This effect is thought to be related in part to reduced activation of the vagal afferent integration center.
This study is of particular interest because it identifies both a dedicated circuit for 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.
Discussion
The major advance of this study concerns the preclinical validation of a therapeutic approach capable of buffering the post-infection anxiety-related syndrome by preventative administration of the neuromodulatory drug LEV only during the infection phase. Our results showed that acute treatment with LEV alone during the first 48 h after CLP is sufficient to alleviate long-term behavioral alterations in mice .
Given that application of LEV in brain slices can directly reduce synaptic transmission induced by neuronal hyperactivation while preserving baseline transmission, and considering that we did not observe any peripheral anti-inflammatory effect of LEV, we believe that, in our model, the site LEV’s action is primarily in neural circuits. This drug has all the favorable characteristics to be considered for human trials (it is well tolerated, easy to administer and monitor, and it is economical).
Similarly, several proposed drugs for PTSD are prescribed to sepsis survivors, including β-blockers, α2-adrenoceptor agonists, corticosteroids, or ketamine, but the clinical benefit of these drugs for prevention of PTSD Post-sepsis PTSD remains highly controversial. Surprisingly, sepsis-induced EEG and neurophysiological changes have never been a therapeutic target in experimental studies or clinical trials until now, while a wide range of antiepileptic medications are available.
