Dissecting the contribution of vagal subcircuits in sepsis-induced brain dysfunctions.

Abstract

Sepsis, a life-threatening syndrome caused by a dysregulated host response to infection, induces a range of acute effects on the brain, including sickness behaviour and sepsis-associated encephalopathy. In addition, sepsis can lead to durable changes in neuronal circuits, resulting in long-term impairments such as post-traumatic stress disorder (PTSD). These brain dysfunctions are not directly caused by brain infection but result from peripheral inflammatory signals relayed to the brain via neural and humoral pathways. The vagal complex in the brainstem, composed of the nucleus of the solitary tract (NTS) and the area postrema, plays a crucial role in sensing and relaying these signals. Notably, the activation of the vagal complex triggers neurovegetative, neuroendocrine, and behavioural responses to infection. Chronic electrical vagus nerve stimulation has been used clinically to treat various brain disorders and is being investigated for its potential to alleviate inflammation and immune diseases through the anti-inflammatory reflex. However, a deeper understanding of the involvement of the vagus nerve and downstream brain circuits in sepsis-induced brain activation and dysfunction is needed to optimize therapeutic strategies. To investigate the role of the vagal complex in sepsis-induced brain dysfunction, various techniques were employed to manipulate vagus nerve activity and downstream circuits in a rodent model of sepsis by caecal ligation and puncture. Subdiaphragmatic vagotomy and pharmacogenetic manipulation of NTS and nodose (i.e. vagus sensory neurons) were implemented, revealing that vagotomy effectively reduced acute brain activation, inflammatory responses, and sickness behaviour triggered by sepsis. Additionally, transient activation of NTS neurons had a significant impact on inflammatory responses, sickness behaviour, and long-term PTSD-like consequences. This study underscores the complex interplay among the vagus nerve, brain circuits, and systemic inflammation during sepsis, emphasizing the critical importance of understanding these interactions in the development of targeted therapeutic interventions.