Thomas O'Gorman

Summer Research Description: Sepsis-induced delirium is a dangerous acute condition that affects up to 75% of people treated in an intensive care unit (ICU) characterized by changes to sleep/wake architecture and short- and long-term cognitive impairments. The M1 muscarinic acetylcholine receptor (M1 mAChR) has been linked to the anti-inflammatory response, prompting the investigation of novel pharmacological intervention at this site to reduce inflammation and the associated risk of delirium. Lipopolysaccharide (LPS), a bacterial endotoxin that causes systemic inflammation, and a novel M1 mAChR positive allosteric modulator (PAM) developed at the VCNDD will be administered to wild type and choline transporter knockdown (CHT Het) mice. CHT Het mice function as a demand-dependent model of cholinergic hypofunction, only showing deficits after sustained activation of the acetylcholine system, such as during an anti-inflammatory response. We hypothesize that the administration of the M1 PAM will reverse the negative effects of the LPS sickness response and restore cognitive functioning by boosting endogenous acetylcholine functioning. The restoration of sleep/wake architecture and cognitive prowess will be measured through electroencephalography (EEG) and learning paradigms. Improved cognition and sleep in this mouse model will support M1 mAChR activation for the treatment of delirium and associated cognitive impairments.