Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

Abstract

A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The present study tested rats with highly selective lesions of cholinergic neurons in all major areas of the basal forebrain on a spatial working memory task in the radial arm maze. In postoperative testing, there were no significant differences between lesion and control groups in working memory, even with a delay period of 8 h, with the exception of a transient impairment during the first 2 d of postoperative testing at shorter delays (0 or 2 h). This finding corroborates other results that indicate that the cholinergic basal forebrain does not play a significant role in spatial working memory. Furthermore, it underscores the presence of intact memory functions after cholinergic basal forebrain damage, despite attentional impairments that follow these lesions, demonstrated in other task paradigms.The cognitive functions of the basal forebrain cholinergic system (BFCS) are of considerable interest, given the damage to this system associated with neuropathological conditions such as Alzheimer's disease (Perry et al. 1977(Perry et al. , 1978Bartus et al. 1982Bartus et al. , 1985aBaxter and Gallagher 1997;Bartus 2000). Experimental lesion studies have attempted to address the question of which aspects of cognitive impairment in these human disease states, if any, can be attributed to loss of cholinergic neurons. The present study aims to further clarify the role of the BFCS in spatial cognition.The extent of acetylcholine loss in aged and demented subjects correlates with the extent of their cognitive impairment (Perry et al. 1977(Perry et al. , 1978Bartus et al. 1982). Experiments on animals have therefore examined the effects of BFCS lesions on spatial learning and memory tasks. These tasks are thought to effectively model the cognitive processes that are usually the first to deteriorate in aged and demented humans (Gallagher and Pelleymounter 1988). However, different BFCS lesion experiments have produced seemingly contradictory results. Early studies suggested an important role for this system in learning and memory. Rats with ibotenic acid lesions of the nucleus basalis magnocellularis/substantia innominata (nBM/SI), the component of the basal forebrain that projects predominantly to neocortex, were impaired on a preoperatively learned delayed nonmatching-tosample (DNMS) radial maze task (Bartus et al. 1985b(Bartus et al. , 1986. Similarly, lesions to the nBM/SI or medial septum/vertical limb of the diagonal band (MS/VDB; the component of the basal forebrain that projects predominantly to the hippocampus) also impaired learning and performance in spatial working memory in the radial arm maze (Hepler et al. 1985;M'Harzi and Jarrard 1992).However, studies using ibotenic acid ca...

Cholinergic suppression of glutamatergic synaptic transmission in hippocampal region CA3 exhibits laminar selectivity: Implication for hippocampal network dynamics

“…Other studies (Cahill and Baxter, 2001;Janisiewicz et al, 2004;Fletcher et al, 2007) have used 192 IgG-saporin to selectively lesion cholinergic neurons in the medial septum/diaganol band of Broca, the primary source of cholinergic innervation to the hippocampus. In contrast to the clear mnemonic effects of cholinergic antagonists, these selective lesion studies cause only transient impairments to spatial memory function (Vuckovich et al, 2004). However, saporin lesions of cholinergic hippocampal innervation do cause impairments of attentional parameters that are consistent with the selective modulation of synaptic transmission shown here (Baxter et al, 1997;Janisiewicz et al, 2004).…”

“…An extensive range of experiments using ACh agonists and antagonists (Davis et al, 1971;Ghoneim and Mewaldt, 1977;Kopelman, 1986;Hagan and Morris, 1988;Whishaw, 1989;Fibiger, 1991) indicate a vital role for ACh in the encoding of new memories. Selective lesions of the primary cholinergic input to the hippocampus using IgG-192 saporin have been shown to influence attention and various aspects of cognitive behavior (Baxter et al, 1997;Janisiewicz et al, 2004), including causing transient impairments of spatial memory function (Vuckovich et al, 2004), but they may not Corresponding Author: 5858 Horton Street, Suite 200, Emeryville, CA 94608, Email: tkremin@gallo.UCSF.edu, . Section Editor: Dr. Geoffrey Schoenbaum Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function

“…The first is that indirect projections from the hippocampal formation to the mammillary bodies via some other structure remain intact and, hence, might still support performance. While there are potential routes via the prefrontal cortex or septum to the mammillary bodies, the lack of consistent evidence that these relay sites are vital for the present tests of spatial working memory (e.g., Dias and Aggleton, 2000;Kirby and Rawlins, 2003;Vuckovich et al, 2004) makes this explanation less attractive. A more obvious possibility is that the direct projections from the hippocampal formation to the thalamus compensate for removal of the mammillary body relay.…”

Cholinergic Deafferentation of the Neocortex Using 192 IgG-Saporin Impairs Feature Binding In Rats

“…To quantify the reduction of cortical cholinergic input induced by our NBM cholinergic lesions, estimates of optical density in the frontal and parietal cortices and hippocampus were obtained from photomicrographs of AChE-stained brain sections using the software package Scion (Scion). For each rat, optical density values obtained from the three target brain regions were then normalized to raw striatal optical density values to eliminate the potential influence of different staining intensities across animals [see similar method used by Vuckovich et al (2004)]. Raw optical density values from the striatum did not differ between the NBM-and sham-lesioned groups (see Results).…”