Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours.

Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown. Using a reference mouse model of sepsis, we showed that mice that recovered from sepsis further developed anxiety-related behaviours 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 circuit tracing and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and in the responsiveness of these central amygdala neurons projecting to the ventral bed nucleus of the stria terminalis. The transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the anti-epileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviours. Specific inhibition of brain anxiety and fear circuits during the sepsis acute phase constitutes a preventive approach to preclude the post-infection psychiatric outcomes.

Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19?

The absence of a specific treatment for SARS-CoV-2 infection led to an intense global effort in order to find new therapeutic interventions and improve patient outcomes. One important feature of COVID-19 pathophysiology is the activation of immune cells, with consequent massive production and release of inflammatory mediators that may cause impairment of several organ functions, including the brain. In addition to its classical role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) has immunomodulatory properties, downregulating the inflammatory response by central and peripheral mechanisms. In this review, we describe the roles of 5-HT in the regulation of systemic inflammation and the potential benefits of the use of specific serotonin reuptake inhibitors as a coadjutant therapy to attenuate neurological complications of COVID-19.

Central leukotrienes modulate fever tolerance to LPS in rats.

Leukotrienes mediate several inflammatory events such as neutrophil chemoattraction, leukocyte adhesion, and central-release of cytokines and fever. However, there is no information available about their putative role in lipopolysaccharide (LPS) tolerance. The rational of the present study was to find out if central leukotrienes are involved in the development of LPS tolerance. Thus, we inhibited central leukotriene synthesis in tolerant rats using a pharmacological tool, i.e., a selective inhibitor of leukotriene synthesis MK-886 injected into the third ventricle (3V) of rats. Body core temperature (Tb) was measured using a datalogger placed inside the abdominal cavity. A low-dose of LPS (100 µg/kg ip) was given for 4 consecutive days to induce LPS tolerance. At day 4, rats received a microinjection of MK-886 into the 3V immediately before LPS, whereas control groups were treated with vehicle (saline). We observed that LPS failed to induce plasma cytokines surges, increased hypothalamic PGE2 levels and fever 3 days post LPS treatment, aptly characterizing the tolerance. When MK-886 was given to control rats treated with saline, no significant change in Tb was observed. However, a full LPS-induced fever was observed in tolerant rats pretreated with MK-886, which was associated with an enhancement in the hypothalamic PGE2 levels, that were not accompanied by plasma cytokines (IL-1ß, and IL-6) and PGE2 surges. These data are consistent with the notion that central leukotrienes play a role in fever tolerance to LPS.