Reconciling Cholinergic and inflammatory hypotheses of delirium: acute and lasting effects of systemic inflammation on chronic neurodegeneration.

Delirium causes acute psychological impairments and accelerates the process of cognitive decline and is highly prevalent in aging and dementia. Delirium is commonly caused by systemic infection, surgery or injury and we have exploited these interactions of systemic inflammation with ongoing dementia to develop the first animal model of delirium during dementia. However, delirium caused by administration of anti-cholinergic drugs has led to a consensus view of delirium as an acute cholinergic def iciency. Here we propose a mouse model of delirium during dementia that reflects its multi-factorial etiology and attempts to reconcile inflammatory and cholinergic hypotheses of delirium. By superimposing systemic inflammation upon prior pathology in the basal forebrain cholinergic nuclei, presumed to be hypoactive in delirium, we will investigate the cognitive, neurochemical and inflammatory consequences of these insults. Both models are founded on the concept, which we originally described, t hat microglia are primed by chronic neurodegeneration to produce exaggerated responses to subsequent inflammatory stimulation. We will further investigate the nature of microglial priming and its contribution to the acute delirium-like episode and to exacerbation of underlying pathology and resulting long-term cognitive decline post-delirium. The involvement of interleukin-1beta and interferon-beta in cognitive and pathological exacerbations will be investigated in detail.