No abstract

Rats with unilateral or bilateral partial section of the fornix were impaired on an eight arm radial maze task. Neurochemical analysis of hippocampal tissue four weeks after the lesions revealed a 50% reduction of choline acetyltransferase (ChAT) activity. The cholinergic marker was correlated negatively with the number of errors in the maze; the lower the ChAT activity, the higher the error score. The fornix lesion also induced a 50% reduction in norepinephrine (NE), but no change in the noradrenergic metabolite methylhydroxyphenylglycol (MHPG), suggesting a net increase in turnover of NE in these animals. Additional lesion of the noradrenergic system with the neurotoxin DSP4 reduced both MHPG and NE levels by more than 90%, compared to nonlesioned controls, and reversed the behavioral deficit. This treatment had no further effect on cholinergic markers. There was a significant negative correlation between ChAT activity and the index of NE turnover, suggesting that hyperactivity in the noradrenergic system after fornix section inhibits the spared cholinergic function and thus exacerbates the cognitive deficit. The pattern of neurochemical results bear a striking resemblance to those seen in some Alzheimer's patients and suggest that an equilibrium among neurotransmitters is important to cognitive function.

Previous studies have shown that, in addition to partial damage to the cholinergic system, partial fornix section causes changes in the noradrenergic (NA) system and an increase in NA activity in the dorsal hippocampus. Behaviorally, this NA hyperactivity contributes to the deficits observed in the radial arm maze, since a reduction of NA activity restores the performance of rats with a partial fornix lesion. The reorganization of the NA system after partial fornix section should modify its responsiveness, and the present series of experiments examines these changes. In the first experiment, sensitivity to the sedative effects of the alpha 2 agonist clonidine was evaluated by determining a dose-response curve to clonidine in a hole board. Rats with partial fornix lesion were resistant to the sedative effects of clonidine, suggesting differences in alpha 2-receptor sensitivity. In the second experiments, rats were submitted to a test for novelty-seeking behavior in the hole board with objects placed in some holes. Rats with fornix sections spent more time in contact with novel objects than the control rats, a behavior which has previously been observed in hyper-noradrenergic animals. Finally, single-unit recording of locus coeruleus (LC) cells in anesthetized rats showed there were no effects of the partial fornix lesion either on spontaneous firing rate of LC cells or on their responsiveness to clonidine. These last results suggest that the behavioral differences and differences in NA activity observed after partial denervation are a result of local regulation of release at the NA terminals and are not due to changes in the cell bodies within the LC.

Previous experiments revealed that the cholinergic deficit in rats with a partial fornix section was accompanied by an increase in turnover of noradrenaline (NE) in the hippocampus. This noradrenergic hyperactivity contributed to the cognitive deficit in lesioned rats, probably by interaction with the cholinergic system. The present experiment examines the reorganization of the noradrenergic system after the damage induced by partial fornix section and attempts to determine if the increase in NE turnover is of locus coeruleus (LC) origin, or if it is a result of local regulation at the noradrenergic terminals. Rats were submitted to knife-cut section of the fornix, resulting in a decrease in choline acetyltransferase activity in the hippocampus, correlated with a significant behavioral deficit in a spatial memory task. Lesioned rats learned a nonspatial memory task normally. Sections of brains of these rats were submitted to quantitative autoradiography. [125I]Iodopindolol binding was assessed in the dorsal and ventral hippocampus to determine availability of beta receptors. This was found to be significantly lower in lesioned rats. [125I]Iodoclonidine was used to determine alpha 2 receptors binding in dorsal and ventral hippocampus and in LC. There was no difference in alpha 2 receptors in LC, a significant decrease in dorsal regions of the hippocampus, and a significant increase in ventral regions. Muscarinic M1 receptors in the hippocampus showed no changes after the lesion.