Basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS neurons in the rat neocortex: cellular basis for cortical blood flow regulation

Stimulation of basal forebrain neurons results in local increases in cortical cerebral blood flow that are dependent upon cholinergic and nitrergic mechanisms. In the present study, we investigated the possibility that basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS interneurons in the rat cerebral cortex. We performed quisqualic (QUIS) acid lesions of the basal forebrain and evaluated their effects on cortical NOS immunostained nerve terminals, with emphasis on those associated with microvessels and NOS interneurons, both at the light and/or electron microscopic levels. The results show that basal forebrain NOS neurons provide about one third of the overall cortical NOS innervation. Further, the data indicate that basalocortical NOS fibres establish privileged associations with microvessels and NOS neurons, as respective denervations of 60 and 45% were observed following lesion. At the electron microscopic level, most perivascular NOS neuronal elements corresponded to nerve terminals and a majority (similar to 25%) of these were located in the immediate vicinity of the blood vessels, similar to the perivascular distribution reported previously for classic neurotransmitters/neuromediators. NOS terminals abutting on cortical NOS neurons were primarily nonjunctional. Altogether, these results raise the possibility that not only cholinergic but also nitrergic basal forebrain neurons are involved in the flow response observed following stimulation of the basal forebrain. Further, they suggest interactions between basalocortical and intracortical NOS neurons. We conclude that these interactions are involved in the spatial and temporal regulation of cortical perfusion following basal forebrain activation, and that they may become dysfunctional in pathologies such as Alzheimer's disease which affects both the basal forebrain and the cortical NOS neurons.