Hepatic encephalopathy (HE) describes the deterioration of brain function in patients with acute or chronic liver failure. This entity, typified by cognitive, behavioral and motoric deficits, relates to neuronal death, the origin of which is unknown in HE. About 80% of patients suffering from liver cirrhosis are at risk to develop HE, resulting in high morbidity and mortality, reduced quality of life and a high economic burden. Current therapies only give symptom control and do not halt neuronal damage. It has been proposed that HE is a gliopathy, referring to the aberrant neuronal function as a secondary effect to astrocyte dysfunction. HE is indeed associated with astrocytic changes, the prime factor being the accumulation of ammonia, that can only be metabolized in the brain by astrocytes. Interestingly, ammonia has been revealed as an endoplasmic reticulum (ER) stress inducer. Any condition interfering with ER function leads to an ‘unfolded protein response’ and an ‘integrated stress response’, two cellular programs aimed at protecting against cell death. Excessive stress however induces apoptosis and inflammation. Our preliminary work in HE shows that neurobehavioral deficits in HE can be prevented by the ER stress inhibitor TUDCA, that targets the brain. The aim of this project is therefore to further evaluate ER stress in the neurogliovascular unit, with a focus on astrocytes, and to verify the therapeutic potential of ER stress modulation.