Noradrenergic hyperactivity after partial fornix section: role in cholinergic dependent memory performance

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.

Dissecting the Fornix in Basic Memory Processes and Neuropsychiatric Disease: A Review

“…There is some material specificity in the expected direction, with left fornix damage tending to lead to verbal memory deficits and right fornix damage being more associated with visual memory deficits (Gaffan et al, 1991;McMackin, Cockburn, Anslow, & Gaffan, 1995). However, it is worth noting that the extent of damage is more predictive of deficits than the lesion location on both verbal and visual tasks (Korematsu, Hori, Morioka, & Kuratsu, 2010;Sara, Dyon-Laurent, Guibert, & Leviel, 2004 for an animal model).…”

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

“…These researchers postulated that the negative correlation between ChAT activity and NE turnover suggested that hyperactivity in the remaining noradrenergic neurons inhibited proper functioning of the remaining cholinergic neurons. 236 This is a remarkably similar pathology to that seen in AD and warrants further exploration. It is important to note that the suspected mechanism of noradrenergic inhibition on the cholinergic system operated through the α 2 receptors located on cholinergic terminals.…”

“…It was found that choline acetyltransferase (ChAT) activity was reduced by 50%, correlating negatively with the number of errors the rats made in a maze task, while hippocampal NE also decreased by 50%. 236 Interestingly, there was no decrease, and in fact a slight increase in the noradrenergic metabolite methylhydroxyphenylglycol (MHPG), suggesting a net increase in NE turnover despite the decrease in noradrenergic cells. These researchers postulated that the negative correlation between ChAT activity and NE turnover suggested that hyperactivity in the remaining noradrenergic neurons inhibited proper functioning of the remaining cholinergic neurons.…”

“…It is important to note that the suspected mechanism of noradrenergic inhibition on the cholinergic system operated through the α 2 receptors located on cholinergic terminals. [236][237][238][239] The dynamic relationship between these two neuromodulatory systems remains substantially uncharacterized, and limited work has been done explaining the precise mechanisms underlying adrenergic hyperactivation following LC disruption. There is evidence, however, that many of the mechanisms beneficial to memory storage occur with moderate levels of NE, while higher levels tend to impair memory storage.…”

Bayesian Models of Attention

“…Due to this antagonism, depleting the ACh level in the model has somewhat similar effects to enhancing NE; and depleting NE is similar to enhancing ACh. Intriguingly, Sara and colleagues have found similarly antagonistic interactions between ACh and NE in a series of learning and memory studies (Sara, 1989;Ammassari-Teule, Maho, & Sara, 1991;Sara, Dyon-Laurent, Guibert, & Leviel, 1992;Dyon-Laurent, Romand, Biegon, & Sara, 1993;Dyon-Laurent, Hervé, & Sara, 1994). They demonstrated that learning and memory deficits caused by cholinergic lesions can be alleviated by the administration of clonidine (Sara, 1989;Ammassari-Teule et al, 1991;Sara et al, 1992;Dyon-Laurent et al, 1993), a noradrenergic α-2 agonist that decreases the level of NE (Coull, Frith, Dolan, Frackowiak, & Grasby, 1997).…”