Activation of Basal Forebrain Afferents Following Systemic Inflammation

Sepsis is a large-scale immune response typically due to an imbalance of pro- and anti-inflammatory responses due to some type of infection or insult. Around 1.7 million adults in the United States will develop it each year, making it the leading cause of increased morbidity and mortality in hospitals. Sepsis can lead to many different symptoms, one of which is delirium. Delirium is a mental state of confusion and disorientation and involves delusions, hallucinations, memory issues, and most commonly inattention. Delirium is more prevalent in older individuals which leads to further complications and a higher likelihood of development of long-term cognitive decline and dementia. There is limited information on the mechanisms of sepsis and the development of delirium, and no treatment options exist yet. It is believed that the basal forebrain cholinergic system, known to be dysfunctional in Alzheimer’s disease, is also involved in causing delirium and those cognitive effects. This project examines the activation of the basal forebrain afferents that might lead to more understanding of what brain regions are involved in delirium and why it is more prevalent in aged individuals with the expectation that aged individuals will have less activation in regions controlling attention and memory functions. Young adult (2 to 4 months) and aged (22 to 26 months) male and female F344 x Brown Norway F1 hybrid rats had cholera toxin B (CTb), a retrograde neuronal tract tracer, injected into the basal forebrain region. After two weeks, they were injected with 0.1 mg/kg of either sterile saline or lipopolysaccharide (LPS), a major component of the outer membrane of gram negative bacteria, that induces systemic inflammation. Two hours later, the brains were harvested and coronally sectioned (50 µm) before immunohistochemical analysis. Sections in the prefrontal cortex were stained for cFos, a neuronal activation marker, and CTb. Analysis was completed in the prelimbic cortex and infralimbic cortex using a defined area of 0.49 mm2. The infralimbic cortex showed no significant changes, whereas the prelimbic cortex was less activated in aged animals, along with males after LPS administration. Future analysis will look at more brain regions, including the agranular insular cortex and the hypothalamus.