Developmental regulation of adult cortical morphology and behavior: an animal model for mental retardation.
The purpose of this study was to examine the behavioral performance in adult mice which, as neonates, had received lesions to cortically projecting, cholinergic basal forebrain neurons. The nucleus basalis magnocellularis (nBM) provides the primary cholinergic innervation to cerebral cortex. Lesions in the nBM in neonatal mice result in transient cholinergic denervation and persistent abnormalities in cortical morphology and cytoarchitecture. These cortical abnormalities resemble pathologies observed in a number of developmental disabilities in humans, including Down Syndrome. Balb/CByJ mice received lesions to the nBM 12-24 hr after birth; littermates served as controls. Behavioral testing began 8 weeks after the lesion and included assessments of spontaneous motor activity, retention (a passive avoidance task) and cognition (the Morris swim task). Following behavioral testing, a subset of mice was killed for Nissl and acetylcholinesterase (AChE) histology. The cortical morphology in these brains was evaluated and ranked by the experimenter, who was blind to the lesion and behavioral studies. The lesioned mice exhibited increased spontaneous activity as compared to littermate controls. The lesioned mice were also severely impaired in performance of the retention and cognitive task; they showed decreased passive avoidance retention latencies and increased swim maze latencies as compared to controls. The brains of all of the lesioned mice exhibited cortical morphological abnormalities that ranged from slight to severe. Cortical AChE intensity and distribution in the brains of the lesioned mice, however, were comparable to those of controls. In correlation studies of behavioral and morphological data, motor activity did not correlate with either passive avoidance retention or swim maze latencies. Additionally, cortical cytoarchitectural abnormalities did not correlate with motor activity. Cortical cytoarchitectural abnormalities did, however, correlate with both passive avoidance and swim maze latencies, i.e. severely abnormal cortical morphology predicted low passive avoidance retention latencies and high swim maze latencies. These data indicate that cortical cytoarchitectural abnormalities resulting from nBM lesions in neonates correlate with impairments on the cognitive task, but not with the activity measures, in adult mice. Thus, in this lesion model, and by extrapolation in developmental disabilities in humans, structural changes in the cortex which result from transient disruption of cortical cholinergic innervation may lead to persistent cognitive impairments in adulthood.
School of Medicine, University of North Carolina, Chapel Hill.
E S
ES
Bachman
J
J
Berger-Sweeney
J T
JT
Coyle
C F
CF
Hohmann
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000201:enzymology / Q000254:growth & development*; D004195:Disease Models, Animal; D008607:Intellectual Disability / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000502:physiology; D012044:Regression Analysis
D000110:Acetylcholinesterase