Fig. 3: Hypothesized molecular, cellular, and circuit changes in the cerebral cortex as LC-NE neurons progressively degenerate.

Before cell death in the LC region at a late stage of the disease, LC neurons likely show altered neuronal firing (i.e., compensatory), NE release alterations (i.e., compensatory), and loss of LC projections to the cortex at early stages (upper). Dysfunctional NE neurotransmission can alter local NE levels in the cortex, which may subsequently induce the sensitization of noradrenergic receptors in cortical neurons (i.e., compensatory). Importantly, altered expression levels and function of NE transporters will likely trigger secondary effects to cortical dopaminergic neurotransmission (e.g., a larger volume of DA diffusion in the cortex and prolonged DA receptor stimulation, dashed arrow) due to low dopamine transporter expression in the cortical regions.