Multiple output pathways of the basal forebrain: organization, chemical heterogeneity, and roles in vigilance

Abstract

Studies over the last decade have shown that the basal forebrain (BF) consists of more than its cholinergic neurons. The BF also contains non-cholinergic neurons, including γ-aminobutyric acid-ergic neurons which co-distribute and co-project with the cholinergic neurons. Both types of neuron project, in variable proportions, to the cerebral cortex, hippocampus, thalamus, amygdala, and olfactory bulb, whereas descending projections to the posterior hypothalamus and brainstem nuclei are predominantly non-cholinergic. Some of the cholinergic and non-cholinergic projection neurons contain neuropeptides such as galanin, nitric oxide synthase, and possibly glutamate. To understand better the function of the BF, the organization of the multiple ascending and descending projections of BF neurons is reviewed along with their neurochemical heterogeneity, and possible functions of individual pathways are discussed. It is proposed that BF neurons belong to multiple systems with distinct cognitive, motivational, emotional, motor, and regulatory functions, and that through these pathways, the BF plays a role in controlling both cognitive and non-cognitive aspects of vigilance.

Introduction

The basal forebrain (BF) has received much attention in the last two decades primarily because of its cholinergic neurons and their suggested roles in learning and memory, and involvement in the pathophysiology of Alzheimer's dementia [15]. These cholinergic neurons project to the cerebral cortex, providing the main source of acetylcholine (ACh) released in the cortex. However, as the articles in this Special Issue indicate, it has become evident that the BF is also involved in other functions such as cortical arousal, attention, behavioural state control, reward, and plasticity. While these functions have often been associated with BF cholinergic neurons, it is now clear that not only cholinergic but also GABAergic and peptide-containing neurons are present in the BF and that some of these non-cholinergic neurons project to the cerebral cortex. Furthermore, as already noted in 1975 by Divac [61], the BF is a source of multiple descending projections. Descending BF axons are now known to innervate the thalamus, hypothalamus and brainstem, and they are predominantly non-cholinergic. The heterogeneity of BF neurons is seen not only in their anatomical features, but also in their neurophysiological properties, as revealed by both in vitro and in vivo electrophysiological investigation [122]; see also Detari, Griffith et al., and Szymusiak et al., this volume).

The increasing knowledge about the complexity of the organization and function of the BF would require reconsideration of some of the results in earlier behavioural studies that employed non-selective lesions, or stimulation or drug injections that would affect all BF neurons indiscriminately. Furthermore, relatively little is known about the organization and function of descending BF projections, despite the fact that these are probably as substantial as their ascending counterparts. Importantly, in view of the anatomical and physiological complexity, the simple view that cortically projecting cholinergic neurons account for all the functions so far associated with the BF is no longer warranted.

The goals of this review are to provide a summary of the current knowledge of the organization of the efferent pathways of the BF, with emphasis on neurochemical heterogeneity, and to consider possible roles of these multiple pathways in the control of vigilance and other functions. It is proposed that the BF plays a role as a site of integration of both cognitive and noncognitive aspects of vigilance through its ascending and descending projections. Due to page limitations emphasis is placed on the efferent pathways of the BF, in particular its anatomical aspects. Recent reviews are available for the afferent connections of the BF [216], [265], [275] (see also Záborszky and Duque, this issue).

The definition of the term BF in this article is as follows. While the BF literally means the ventral part of the forebrain, the term is often used in association with magnocellular cholinergic neurons located in that area, and the present article follows this convention. Specifically, the BF here refers to the ventral part of the forebrain the boundaries of which are defined by the presence of cholinergic neurons but whose cell population is not restricted to cholinergic neurons. The classically defined nuclei that belong to the BF include, in a rostral to caudal order, the medial septum, the nuclei of the vertical and horizontal limbs of the diagonal band of Broca, the ventral pallidum, the magnocellular preoptic area, the substantia innominata, and the magnocellular basal nucleus ([34], Fig. 1).