Defining the inflammatory pathophysiology of depression in cirrhosis using an in vitro model of human hippocampal neurogenesis

Background: Liver disease is the only common cause of death that is increasing in numbers in the UK, and is the biggest killer of people aged 35 - 49. Once individuals develop severe scarring of the liver, known as ‘cirrhosis’, there are no proven medications to reverse this. Depression is a worldwide problem and is more common in patients with cirrhosis (18-58%) compared to the general population (10%). Many different health conditions cause cirrhosis; increased rates of depression are seen in all causes. Depression in cirrhosis reduces quality of life and survival, and increases the likelihood of frequent admissions to hospital. The body creates inflammation to fight infection. However, there is too much inflammation in the bloodstream in cirrhosis, termed ‘systemic inflammation,’ which is harmful and can worsen liver disease and its complications. Systemic inflammation is also seen in individuals with depression, and may contribute towards the high rates of depression in patients with cirrhosis. However, this has not been investigated. Investigating the underlying driver(s) for the increased rates of depression in cirrhosis is an unmet need, as treating depression effectively in patients with cirrhosis will improve their quality of life and survival. Systemic inflammation can access the brain and detrimentally affect brain processes involved in mood. Specifically, this may reduce neurogenesis, the formation of new neurons (or nervous system cells), in the hippocampus, a small structure in the front of the brain that is responsible for memory, learning and emotion. However, we do not yet know how systemic inflammation reduces neurogenesis. I propose that the high rate of depression in patients with cirrhosis is due to increased systemic inflammation, and I hypothesise that this is due to a reduction in hippocampal neurogenesis. Objectives: To determine if there is greater inflammation in the blood of patients with cirrhosis and depression, than in those with cirrhosis without depression. To investigate if systemic inflammation in patients with cirrhosis and depression reduces hippocampal neurogenesis. To work out how systemic inflammation in patients with cirrhosis and depression reduces hippocampal neurogenesis. Methods: I will use stored blood samples from patients with cirrhosis with and without depression. I will perform laboratory work first to measure levels of inflammation in the blood of both patient groups, and compare them. I will then investigate how blood from these patients affects brain cells. These experiments will be performed in a laboratory dish, and not on living organisms. Potential applications and benefits: If I can discover how bloodstream inflammation contributes to depression in cirrhosis, this could identify new treatments. This would lead to further research studies to confirm if these treatments work. Ultimately, this could lead to improved quality of life and survival in this growing patient population and could influence clinical practice guidelines in the future. Effectively treating depression in cirrhosis would also reduce carer burden, alongside pressure on the NHS and economy. This work will also stress the importance of addressing mental health in cirrhosis, which will help to reduce stigma. Results will be circulated through journals, international conferences, patient networks and social media.