beta-amyloid((1-42))-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex

Ample experimental evidence suggests that beta -amyloid (A beta), when inje cted into the rat magnocellular nucleus basalis (MBN), impels excitotoxic i njury of cholinergic projection neurons. Whereas learning and memory dysfun ction is a hallmark of A beta -induced cholinergic deficits, anxiety, or hy poactivity under novel conditions cannot be attributed to the loss of choli nergic MBN neurons. As mood-related behavioral parameters are primarily inf luenced by the central serotonergic system, in the present study we investi gated whether A beta ((1-42)) toxicity in the rat MBN leads to an altered s erotonergic innervation pattern in the rat basal forebrain and cerebral cor tex 7 days postsurgery. A beta infusion into the MBN elicited significant a nxiety in the elevated plus maze. A beta toxicity on cholinergic MBN neuron s, expressed as the loss of acetylcholinesterase-positive cortical projecti ons, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreas ed concentrations of both serotonin and 5-hydroxyindoleacetic acid, and dec line of cortical 5-HT1A receptor binding sites indicated reduced serotonerg ic activity in the somatosensory cortex. In conclusion, the A beta -induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat ba sal forebrain and cerebral cortex. We assume that enhanced serotonin immuno reactivity in the damaged MBN indicates intrinsic processes facilitating ne uronal recovery and cellular repair mechanisms, while diminished cortical s erotonergic activity correlates with the loss of the subcortical cholinergi c input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex. (C) 2001 Academic Press.