Cholinergic basal forebrain transplants restore diminished metabolic activity in the somatosensory cortex of rats with acetylcholine depletion

Abstract

It has been known for several years that stimulus-evoked metabolic activity is reduced in the somatosensory cortex of animals with basal forebrain lesions that deplete the neocortex of acetylcholine (ACh). During 2-deoxyglucose (2-DG) experiments, animals with unilateral basal forebrain lesions demonstrate a decreased response to somatic stimulation, while background metabolic activity in the surrounding cortical regions remains normal. In an attempt to ameliorate these deficits, we examined the ability of embryonic cholinergic basal forebrain transplants inserted into neocortex to innervate surrounding cortical regions and restore functional 2-DG activity in adult host rats previously depleted of ACh by basal forebrain lesions. To accomplish this goal, a series of experiments were conducted in which we (1) depleted the cerebral cortex of ACh by injecting an excitotoxin into the rat basal forebrain, (2) transplanted embryonic basal forebrain or embryonic neocortical (control) tissue into the ACh-depleted cortex and, (3) 6-12 months later, used the 2-DG metabolic mapping technique to examine effects of the transplants on metabolic activity evoked by whisker stimulation in rat somatosensory (barrel) cortex. Histochemical analysis revealed that acetylcholinesterase (AChE) staining within 2 mm of the basal forebrain transplants was similar in density to the contralateral normal hemisphere. AChE staining farther than 2 mm from the basal forebrain transplants and throughout hemispheres containing neocortical (control) transplants was greatly reduced, with few AChE-positive fibers present, a finding typical of cerebral cortex in basal forebrain-lesioned animals. Stimulus-evoked 2-DG uptake in barrels adjacent to the basal forebrain transplants, and therefore within AChE-rich territory, was similar to that in corresponding barrels identically activated in the contralateral hemisphere. 2-DG activity was reduced, however, in stimulated barrels outside the region of dense AChE-positive staining, as well as in all activated barrels in hemispheres containing control transplants of embryonic neocortex. These results indicate that transplantation of cell suspensions containing embryonic cholinergic basal forebrain, but not neocortex, can ameliorate basal forebrain lesion-induced deficits in functional activity, and that the restoration of activity is influenced by proximity to the transplant.