Cholinergic innervation of the primate hippocampal formation: II. Effects of fimbria/fornix transection

Abstract

The distribution of choline acetyltransferase (ChAT)-immunoreactive and acetylcholinesterase (AChE)-positive fibers and terminals was analyzed in the hippocampal formation of macaque monkeys subjected to transection of the fimbria/fornix. Cases with either unilateral or bilateral transections were prepared, with post transection survival times ranging from 2 weeks to 1.5 years. The fimbria/fornix transection resulted in a dramatic decrease in the number of cholinergic fibers in most regions of the hippocampal formation. Some hippocampal regions, however, showed relatively greater sparing of ChAT- or AChE-positive fibers. In practically all regions of the hippocampal formation, residual AChE-positive fibers were more abundant than ChAT-immunoreactive fibers. In animals with unilateral lesions, the distribution patterns and density of AChE and ChAT staining on the side contralateral to the lesion were generally similar to those of sections from unlesioned control brains. The largest decreases in the densities of positive fibers were observed in the dentate gyrus, CA3 and CA2 fields of the hippocampus, subiculum, parasubiculum, and medial and caudal parts of the entorhinal cortex. Fibers were relatively better preserved in the rostral or uncal portion of the hippocampus and dentate gyrus and in the rostral portion of the entorhinal cortex. The presubiculum demonstrated remarkable sparing that contrasted with the almost complete loss of fibers in the parasubiculum. Interestingly, animals killed approximately 1.5 years after the fornix transection showed essentially the same pattern of fiber loss as the cases with shorter survival periods. This indicates that the residual ChAT-immunoreactive fibers, many of which reach the hippocampal formation through a ventral cholinergic pathway, are not capable of reinnervating the denervated portions of the hippocampal formation. This appears to distinguish the monkey from the rat, for which substantial sprouting and reinnervation of cholinergic fibers have been reported after similar lesions.

Animal models in the drug discovery pipeline for Alzheimer's disease

“…Focal neurotoxic, electrolytic or mechanical lesions of the cholinergic centres of the basal forebrain, as well as more general lesions of all the cholinergic neurons of the basal forebrain, are most frequently used to obtain such models. Focal lesions are especially directed at the nucleus basalis magnocellularis (Lescaudron and Stein, 1999; Vale‐Martínez et al ., 2002), the rodent analogue of the human nucleus basalis of Meynert, the septal area (Mulder et al ., 2005), or consist of fimbria/fornix transection leading to septo‐hippocampal cholinergic denervation (He et al ., 1992; Alonso et al ., 1996). Lesioning can be achieved by surgical or electrolytical procedures, and intraparenchymal or intracerebroventricular microinjections of neurotoxic substances, such as quinolic, kainic, N‐methyl‐D‐aspartic, ibotenic and quisqualic acids, the cholinotoxin AF64, and the immunotoxin 192 IgG‐saporin (for review, see Toledana and Álvarez, 2010).…”

Retrieving Memories via Internal Context Requires the Hippocampus

“…Excitotoxic lesions of the hippocampus selectively destroy neurons in the dentate gyrus and Ammon's horn while sparing fibers of passage. The two types of lesions also cause different types of unintended damage (McClelland et al, 1995;Alonso et al, 1996;Aggleton and Saunders, 1997). Although fornix and hippocampal lesions typically have similar effects on learning and memory, they can also differ (O'Keefe et al, 1975;O'Keefe and Nadel, 1978;McDonald et al, 1997).…”

Cholinergic dysfunction in vascular dementia

“…The cholinergic supply to the hippocampus originates in the medial septal nucleus (Ch1) and the vertical limb of the nucleus of the diagonal band of Broca (Ch2) [51]. The main efferent is the septohippocampal pathway that projects mainly to the uncal portion of the hippocampus, the parasubiculum, and the entorhinal cortex; the lowest densities of labeled ACh fibers are in CA1 [52].…”