AFFERENTS TO BASAL FOREBRAIN CHOLINERGIC PROJECTION NEURONS: AN UPDATE

Lászlo Záborszky¹, William E. Cullinan¹ and Alex Braun²

¹Departments of Otolaryngology, Neurosurgery and Neurology

University of Virginia Health Science Center, Charlottesville, VA 22908

²Department of Pathology, State University of New York at Stony Brook, New York 11780

INTRODUCTION

            The basal forebrain cholinergic projection (BFC) system has been the focus of considerable attention as a result of evidence implicating it in a number of behavioral functions, including arousal, sensory processing, motivation, emotion, learning, and memory (Deutsch, l983; Buzsaki et al., l988; Richardson and DeLong, 1988; Durkin, l989; Rolls l989, Steriade and McCarley, l990). Moreover, neuropathological changes in the BFC have been reported in a surprisingly large number of neurological diseases, including Alzheimer's and Parkinson's diseases (for ref. see Coyle et al., l983; Mesulam and Geula, l988; Arendt et al., l989). BFC neurons in the rat are dispersed across a number of classically defined territories of the basal forebrain, as illustrated from a series of coronal sections in Fig. 1. However, using a computer graphic three-dimensional reconstruction technique (Schwaber et al., 1987) or manual reconstruction from camera lucida drawings (Fig. 2) it is evident that BFC neurons form a continuum, rather than being arranged as distinct nuclear groups. 

            Although there is considerable species variation in the precise locations of cholinergic projection neurons in the basal forebrain, the efferent projections of these cells follow basic organizational principles in all vertebrate species studied. Thus, neurons within the medial septum and nucleus of the vertical limb of the diagonal band (MS/VDB; also termed Ch1/Ch2 according to the classification of Mesulam et al., 1983b) provide the major cholinergic innervation of the hippocampus; cholinergic cells within the horizontal limb of the diagonal band  and magnocellular preoptic nucleus (HDB/MCP; Ch3) project to the olfactory bulb, piriform, and entorhinal cortices; cholinergic neurons located in the ventral pallidum, sublenticular substantia innominata (SI), globus pallidus, internal capsule, and nucleus ansa lenticularis, collectively termed the nucleus basalis  (Ch4), project to the basolateral amygdala, and innervate the entire neocortex according to a rough medio-lateral and antero-posterior topography (Sofroniew et al., 1982; Armstrong et al., 1983; Mesulam et al., l983a,b; Lamour et al., l984b; Rye et al., l984; Woolf et al., l984; Amaral and Kurz, l985; Carlsen et al., l985; Wainer et al., l985; Woolf et al., l986; Záborszky et al., 1986a; Luiten et al., l987; Nyakas et al., l987; Sofroniew et al., l987; Fisher et al., l988; Gaykema et al., 1990).  In the primate the corticopetal cholinergic cells  (Mesulam et al., 1983b; Mesulam et al., 1986a; see also Butcher and Semba, 1989; Heimer et al., 1991a) are subdivided according to the topography of their projections. Thus, the anteromedial sector (Ch4am) projects to medial cortical areas including the cingulate gyrus; the anterolateral compartment (Ch4al) to ventral orbital, frontal, and parietal opercular regions, as well as the amygdala; the intermediate sector (Ch4i) to lateral frontal, parietal, peristriate and temporal regions including the insula; and the posterior sector (Ch4p) to superior temporal and temporopolar areas (Mesulam et al., l983a, l986a; Mesulam and Geula, l988).

            Despite the wealth of data on the topography of the efferent projections of BFC neurons, information concerning the afferent connections of these cells has been more elusive. The reasons for this are easily appreciated in view of the anatomical complexity of the basal forebrain, in which cholinnergic neurons are intermingled among numerous non-cholinergic cells (Záborszky et al., l986a; Walker et al., 1989), and are distributed in close proximity to several major ascending and descending fiber systems (for review see Záborszky, l989a). Therefore the verification of actual synaptic contact between the afferent fiber systems and the cholinergic projection neurons requires appropriate combinations of double immunocytochemical methods at the ultrastructural level, in which the afferent system and the cholinergic nature of postsynaptic target can be unequivocally determined (Záborszky and Heimer, l989). The study of these inputs is further complicated by the morphological characteristics of these neurons. For example, several studies suggested that the dendrites of BFC neurons extend for very long distances (Semba et al., l987; Brauer et al., 1988; Dinopoulos et al., 1988), and our own experiments involving combinations of Golgi labeling and choline acetyltransferase (ChAT) immunocytochemistry (Fig. 3) have confirmed this point. Also, synaptic input to the cell bodies and proximal dendrites of these cells is notably sparse, although it increases on more distal dendritic segments (Ingham et al., l985; Dinopoulos et al., 1986). Thus, a complete characterization of the afferents of the BFC cells will need to take these factors into account. This information is prerequisite to the design of pharmacological and behavioral investigations of BFC function.

            This review will survey data regarding afferents to the basal forebrain with special reference to potential inputs to BFC neurons, including their transmitters, as well as summarize the current state of knowledge from ultrastructural studies of identified afferents to these cells. Finally, we will discuss some possible functional roles of BFC neurons in behaviors as they may relate to specific neural circuits.

CORTICAL AFFERENTS

            Studies in monkeys and cats (Mesulam and Mufson, 1984; Irle and Markowitsch, l986) are consistent with the notion that basal forebrain areas rich in cholinergic neurons receive only a restricted cortical projection, originating from so called paralimbic cortical areas (Mesulam et al., l986b), including the orbitofrontal cortex, the anterior insular cortex, temporal polar, medial inferotemporal region, entorhinal, piriform, and perirhinal cortices. BFC neurons do not appear to receive direct input from primary sensory and motor cortex or from most higher order association areas. In contrast, in a study in the rat involving wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injections into different cortical areas (Saper, l984), it was suggested that cortical projections to BFC neurons originate in widespread cortical areas, and that these projections are reciprocal in nature to the corticopetal projection of the BFC system. However, data from recent studies in the rat, in which retrograde tracers were delivered to different regions of the BFC system, do not support this concept (Lamour et al., 1984b;  Haring and Wang, l986; Grove, l988; Jones and Cuello, l989; Semba and Fibiger, l989; Carnes et al., l990), but rather suggest a restricted origin of cortical input to basal forebrain areas containing cholinergic neurons in rodents, similar to primates. Indeed, our preliminary light microscopic experiments in the rat, involving anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) from different cortical areas (Cullinan and Záborszky, in preparation), are consistent with the notion that cortical inputs to the BFC are restricted to a number of allocortical regions, including  orbital areas, insular cortex, and perhaps the piriform cortex. One reason for the discrepancy with the results of Saper (l984) appears to be that many corticofugal axons of neocortical origin descending in the internal capsule, although located in close proximity to corticopetal cholinergic neurons, are in most instances smooth and devoid of varicosities, while axons from allocortical regions showed profuse terminal arborizations in some portions of the basal forebrain, where they could be seen to approximate cholinergic neuronal elements in patterns suggestive of synaptic contact.

            In the rat, the pattern of input to the basal forebrain from the various allocortical regions investigated appears to be restricted. For example, terminal arborizations of orbitofrontal axons were found mainly in the ventral portions of the MCP and HDB (Fig. 4). Interestingly, the forebrain regions which receive inputs from allocortical areas correspond well with the location of BFC neurons projecting to the same cortical areas, suggesting a reciprocity between BFC neurons and allocortical areas.

            Although the possibility cannot be excluded that a proportion of the cholinergic neurons receiving allocortical input project to  cortical

regions, other than allocortex, it is clear that large portions of the cortex are not influenced from the  allocortex  via BFC cells. This is

particularly true for many neocortical areas (e.g. sensorimotor, auditory), which receive cholinergic projections from BFC neurons located primarily in the internal capsule, globus pallidus, and peripallidal regions, areas which are apparently not reached by projections from allocortical regions. While it has been suggested that in the primate paralimbic cortical areas may influence not only their own cholinergic innervation, but also that of wide-spread cortical regions by virtue of their projections to the BFC (Mesulam and Mufson, l984), these conclusions were based on autoradiographic data, in which fibers of passage are not clearly distinguished from terminals. Therefore, the extent to which paralimbic cortical afferents might control the BFC system in the primate remains to be disclosed. On the other hand, cortical areas may indirectly influence their own cholinergic input through the striatopallidal system (see below), or through cortico-cortical connections. 

            The behavioral specializations of the orbitofrontal cortex are remarkably similar in rodents and primates, including humans, and are thought to include the regulation of autonomic functions, feeding, species-specific social-affective behaviors, motivation, and some aspects of learning and memory (Kolb, l984; Goldman-Rakic, l987; Fuster, l989; Sesack et al., 1989). Monkeys with orbitofrontal lesions were particularly impaired on behavioral tasks requiring the frequent making and breaking of stimulus-reward associations (Jones and Mishkin, 1972). In the absence of the orbitofrontal cortex, these animals continue to respond to inappropriate (unrewarded) stimuli, similar to humans with frontal lobectomy. 

            Electrophysiological experiments in primates have revealed that basal forebrain, possibly cholinergic neurons, similar to many orbitofrontal units, respond to a range of visual and auditory stimuli that have been reinforced (Richardson and De Long, l988; Rolls, l989; Wilson and Rolls, l990a,b). It has been suggested that this information is conveyed to the basal forebrain through the orbitofrontal cortex (Rolls, l989).

            Behavioral studies in primates have shown that the dorsolateral prefrontal cortex, or in rats the medial prefrontal cortex, is critically concerned with an animal's ability to connect events across time, as ablations of this region result in severe deficits in performance on delay tasks (Kolb, l984; Goldman-Rakic, 1987; Fuster, l989). Electrophysiological studies in behaving monkeys revealed that prefrontal units which participate in different phases of behavior organization show a topographical distribution. Units encoding the sensory cue (both its specific sensory nature and its behavioral significance), are located rostrally in the prefrontal cortex; other units, which discharge in relation to the anticipatory motor action, or engaging in the rapid relay between the first two categories of units, are located more caudally towards the premotor and motor areas. Finally, units which are related to reward or punishment concentrate in orbital areas and are intermingled with units responding to gustatory and olfactory inputs (Rosenkilde et al., 1981; Fuster et al., 1982; Thorpe et al., l983; Innoue et al., 1985). Although the exact mechanism by which these different units participate in the temporal organization of behavior is unclear, the cholinergic system, with afferents from the orbitofrontal cortex and probable projections back to the prefrontal cortex, is likely to influence these processes. Since corticofugal projections are thought to be primarily excitatory (Fonnum et al., l981; Giuffrida and Rustioni, l988), and a facilitatory role has been typically ascribed to acetylcholine (ACh) from physiological studies, feedback through the BFC system could conceivably hold the information about previously experienced stimuli current or 'on line' in prefrontal-cortical circuits over the delay period (while the stimulus is absent) to guide appropriate responses. This notion is consistent with the results of pharmacological and lesion studies, as well as neuropsychiatric data, indicating that disruption of the BFC system is associated with deficits in memory functions (Drachman and Leavitt, 1974; Bartus et al., 1982).

STRIATAL INPUT

Ventral striatal afferents

            The nucleus accumbens, together with the ventral part of the caudate putamen, the olfactory tubercle, and the striatal cell bridges that connect these structures, form the ventral striatum (Heimer and Wilson, l975). A major output of the ventral striatum is directed to the ventral extension of the globus pallidus known as the ventral pallidum, in a topographically organized manner (Heimer and Wilson, l975; Nauta et al., l978; Mogenson et al., l983; Haber et al., l990; Parent, l990; Heimer et al., l991a,b).

            In rat, many cholinergic projection neurons invade the ventral pallidum and dorsal pallidum (or globus pallidus), or the narrow spaces between fiber bundles of the internal capsule, and it was suggested based upon light microscopic data (Grove et al., l986) that cholinergic neurons share to some extent the afferents of neighboring noncholinergic pallidal neurons. In experiments using PHA-L tracing and ChAT immunocytochemistry at the ultrastructural level (Cullinan and Záborszky, in preparation) we confirmed our preliminary electron microscopic degeneration data (Záborszky et al., l984b; Fig. 5) that nucleus accumbens axons establish synaptic contact with ventral pallidal cholinergic neurons. Since the majority of the PHA-L labeled neurons at the injection site in the nucleus accumbens in our study were also immunopositive for calcium binding protein (calbindin D₂₈), a marker for a subpopulation of GABAergic neurons in this region, it is likely that the neurotransmitter involved in this projection is, in large part, GABA. Indeed, terminals containing the enzyme glutamic acid decarboxylase (GAD), the GABA synthesizing enzyme, have been confirmed to terminate on cholinergic neurons in the ventral pallidum (Záborszky et al., l986b). Substance P and enkephalin are also transmitter candidates for these inputs, as lesions of the nucleus accumbens result in decreases in immunostaining for these substances in the ventral pallidum (Walaas and Fonnum, 1979; Záborszky et al., l982; Haber and Nauta, l983), and substance P and enkephalin containing terminals have been found to contact cholinergic neurons in pallidal regions (Bolam et al., l986; Martinez-Murillo et al., l988a). These substances may be co-localized with GABA, since striatal neurons have been shown to co-localize GABA and either substance P or enkephalin (Penny et al., l986).

            In autoradiographic (Mesulam and Mufson, l984; Haber et al., l990) and limited PHA-L tracing experiments in primates (Haber et al., l990) it has been suggested that axons originating from the nucleus accumbens and ventromedial portions of the caudate and putamen innervate the nucleus basalis. The extent to which these fibers terminate in this region or merely pass through, however, remains to be more fully disclosed.

            The possibility that cholinergic neurons receive ventral striatal input in primates, together with the observations of a topographical organization within corticostriatal projections (Phillipson and Griffiths, l985; Goldman-Rakic and Selemon, l986; McGeorge and Faull, 1989), ventral striatal projections (Haber et al., l990; Heimer et al., 1991b), and in the BFC system, may be of interest in the light of recent ideas about the functional organization of forebrain circuits that involve the cortex and basal ganglia. Alexander et al. (l986) have suggested that in primates distinct regions of the frontal cortex, basal ganglia, and the thalamus are connected through parallel, functionally segregated circuits. Cholinergic neurons receiving ventral striatal input may be part of such channels, however these would provide an extrathalamic outflow to the cortex. Several of such distinct circuits can be envisaged (Fig. 6, upper row), although more detailed data are needed, particularly with respect to the input-output relations of identified BFC neurons. Since the corticostriatal as well as the hippocampoor amygdalofugal projections are most probably excitatory (Fonnum et al., 1981; Christie et al., 1987; Fuller et al., l987), and the input from the ventral striatum to the cholinergic neurons is likely to be inhibitory, the activation of this corticostriatal link would appear to result in reduced cholinergic activity in the cortical target areas.  

            In rat, medial and lateral parts of the prefrontal cortex, (anterior cingulate, prelimbic, agranular insular) the perirhinal, entorhinal cortices, the amygdala and the hippocampus project to the ventral striatum in a topographical fashion (Krayniak et al., 1981; Kelley and Domesick, 1982; Kelley et al., l982; Phillipson and Griffith, l985; Swanson and Köhler, l986; Fuller et al., l987; Groenewegen et al., l987; Sesack et al., l989; Witter et al., l989; Groenewegen et al., 1990), and the projections from the ventral striatum to the pallidal complex also maintain a high degree of topographical organization (Gerfen, l985; Heimer et al., 1991a,b). Cholin-nergic neurons of the ventral pallidum project to the basolateral amygdala (Carlsen et al., l985), and to the medial prefrontal cortex and an adjoining medial strip of the motor cortex as well as allo(piriform and entor-hinal cortex) and periallocortical (insula) regions (Saper, l984; Haber et al., l985; Luiten et al., l987). Thus it appears that cholinergic neurons within the ventral pallidum may also participate in cortico-striatopallido-cortical loops (Fig. 6, lower row). In view of the fact that afferents from different cortical areas and the amygdala project to the striatum in a complicated, often overlapping or interdigitating fashion (Groenewegen et al., l990) in rats, similar to monkeys (Selemon and Goldman-Rakic, l985), and since the topography of the cholinergic projection neurons in the VP is not well understood, two-chain tracing/immunocytochemical experiments are required to determine whether such pathways involving cholinergic projections exist as proposed in Fig. 6.

Dorsal striatal input

            The significance of striatal input to pallidal cholinergic neurons would appear to vary according to the species. In primates, only a small number of cholinergic cells are located in the internal and external medullary laminae of the globus pallidus, or are embedded within the fibers of the internal capsule, in addition to the few neurons found within the globus pallidus proper (Mesulam et al., l983a; Saper and Chelimsky, l984; Everitt et al., 1988; Mufson et al., l989). It is not clear, however, whether these neurons are reached by striatofugal fibers from the dorsal striatum, or only by aberrant fibers from the stria terminalis (Price and Amaral, l981; Price et al., l987). In contrast, in rat, a considerable population of corticopetal cholinergic neurons are located in the globus pallidus, internal capsule and peripallidal areas, and it has been suggested that cholinergic neurons in these areas receive striatal input from the medial striatum (Grove et al., l986; Shu et al., 1988). In rat, corticostriatal projections from prefrontal, auditory, visual cortices, hippocampus and the amygdala project to the medial part of the dorsal striatum in a topographical manner (e.g. Beckstead, l979; McGeorge and Faull, l989). Due to the complex compartmental terminations of the different afferents in the dorsal striatum (e.g. Gerfen, 1984; Donoghue and Herkenham, 1986; Faull et al., l986; Gerfen, l989), it is unclear which afferents might reach those striatal cells, which in turn, project to cholinergic neurons in the globus pallidus.

            In summary, striatal afferents to BFC neurons may constitute a way by which different cortical regions indirectly control the cholinergic input they receive. Future studies should identify the specific neuronal elements involved in these circuits, and determine how this indirect cortical control may be related to the more direct cortical control of cholinergic function.

HIPPOCAMPAL AFFERENTS

            The majority of hippocampal projections to the septum in rat (Swanson and Cowan, l979; Groenewegen et al., 1987) course through the fimbria-fornix and terminate on spiny multipolar neurons (Alonso and Frotscher, l989) and GABAergic neurons (Leranth and Frotscher, l989) in the lateral septal nucleus. It has been suggested that lateral septal neurons establish synaptic contacts with cholinergic and GABAergic neurons in the medial septum which in turn project back to the hippocampus, but that hippocampopetal neurons in the MS/VDB do not receive afferents from the hippocampus directly (Köhler et al., l984; Freund and Antal, l988; Leranth and Frotscher, l989). Light microscopic tracing studies in primates (Aggleton et al., l987) and rodents (Carnes et al., l990) suggested that hippocampal efferents en route to the lateral hypothalamus and amygdala may terminate on neurons in the MS/VDB complex and medial part of the SI, however, the notion that cholinnergic hippocampopetal neurons receive direct input from the hippocampus remains questionable and requires confirmation. 

AFFERENTS FROM THE AMYGDALA

            Autoradiographic studies in primates and rodents have shown that fibers originating from different amygdaloid nuclei course through the HDB and SI as part of the ventral amygdalofugal pathway en route to other brain regions, including the hypothalamus, thalamus, striatum, and prefrontal cortical areas (Krettek and Price, l978; Price and Amaral, 1981; Russchen et al., l985a,b; de Olmos, 1990). Although the extent to which these projections terminate in the SI was unclear due to the limitations of the autoradiographic method, experiments using the PHA-L technique have shown that amygdaloid fibers have varicosities along their trajectory through the SI (Russchen and Price, l984; Russchen et al., l985a). In double-labeling experiments at the electron microscopic (EM) level in the rat, we have shown that fibers from the basolateral amygdaloid nucleus form synapses on dendrites of both cholinergic and noncholinergic cells in the ventral pallidum (Záborszky et al., 1984a).  The extent to which BFC neurons outside of the ventral pallidum receive amygdaloid afferents remains to be determined, as do the projection targets of those cells which may receive this input. The available evidence, however, suggests  that the amygdaloid complex as a whole is reciprocally connected with the BFC system in both rat and primate, but that this reciprocity is not exact.

            Neurons of the amygdala receive specific multimodal sensory information (Aggleton et al., l980; Turner et al., 1980; van Hoesen, l981; Ruschen et al., l985a,b; Amaral, l987; LeDoux, l987) and participate in stimulus-reward-associative learning (Gaffan and Harrison, 1987; Nishijo et al., 1988; LeDoux et al., l990). It is likely that  a subpopulation of BFC neurons participate in similar processes through amygdaloid input.

            It is interesting to note that polysensory paralimbic cortical areas, including the temporal pole, inferotemporal, orbitofrontal, perirhinal and entorhinal cortices,  which project to the amygdaloid nuclei, also project to the SI in primates (Aggleton et al., l980; Turner et al., 1980; van Hoesen, l981; Russchen et al., 1985a,b). Similar interconnections are also known in rat (Witter et al., l989; Groenewegen et al., l990). Therefore, from a functional point of view, it will be important to examine the possible convergence of cortical and amygdaloid  inputs to the same cholinergic neuron.

            Based upon hodological and chemoarchitectural characteristics, certain parts of the amygdala, the SI, and bed nucleus of the stria terminalis (BSt) constitute a morphological and perhaps functional entity, as originally suggested by de Olmos et al. (l985), and discussed recently in several papers (Alheid and Heimer, l988; Moga et al., l990; Heimer et al., l991a; Heimer and Alheid, this volume). In particular, the lateral BSt-SI-central nucleus of the amygdala share many connections. Similarly, an affiliation between the medial segment of the BSt and medial nucleus of the amygdala and an intervening portion of the SI has been suggested. The results of a PHA-L tracing study (Grove, 1988) have suggested that the lateral BSt and the central amygdala project to the more dorsal SI/ventral part of globus pallidus, while the medial BSt, medial and basomedial amygdaloid nuclei project to more ventral parts of the SI. Cholinergic projection neurons located within these subdivisions may thus subserve different functional roles accordingly.

HYPOTHALAMIC AFFERENTS

            The possibility of hypothalamic input to the general forebrain regions containing cholinergic projection neurons was suggested from a number of autoradiographic studies (Conrad and Pfaff, l976a,b; Saper et al., l976; Swanson, l976; Saper et al., 1978; Krieger et al., l979; Saper et al., l979; Berk and Finkelstein, l982; Mesulam and Mufson, l984; Saper, 1985), although this issue remained somewhat unclear due to the difficulty in distinguishing fibers from terminals with the autoradiographic technique. More recent experiments using the anterograde tracer PHA-L have confirmed the presence of projections to these regions from several hypothalamic nuclei (ter Horst and Luiten, l986; Simerly and Swanson, 1988) and a light microscopic double-labeling study investigated the distribution of hypothalamic afferents to cholinergic cells in the SI (Grove, l988). We  recently have mapped the distribution of hypothalamic axons originating from various portions of the

caudal lateral hypothalamus and from different medial hypothalamic cell groups in relation to the BFC system in its entirety (Cullinan and Záborszky, l991). Inputs to the cholinergic projection system were distributed in a manner reflecting the gross topography of the ascending hypothalamic projections. Axons originating from neurons in the far-lateral hypothalamus reach cholinergic neurons in a zone which extends from the dorsal part of the SI caudolaterally, to the lateral portion of the bed nucleus of the stria terminalis rostromedially, encompassing a narrow band along the ventral part of the globus pallidus and medial portion of the internal capsule. Axons originating from cells in the more medial portions of the lateral hypothalamus reach cholinergic cells primarily in more medial and ventral parts of SI, and in the magnocellular preoptic nucleus and HDB. Finally, axons from medial hypothalamic cells, particularly the anterior hypothalamic and medial preoptic areas, appear to contact cholinergic neurons primarily in the medial part of HDB, and in the MS/VDB complex (Fig. 15D-F). Electron microscopic double-labeling experiments confirmed contacts between labeled terminals and cholinergic neurons in the HDB and SI, both from the lateral and medial hypothalamus (Záborszky and Cullinan, l989, Cullinan and Záborszky, l991; Fig. 7). A comparison of the topography of corticopetal and hippocampopetal neurons (Mesulam et al., l983a; Rye et al., l984; Woolf et al., l984; Amaral and Kurz, l985; Woolf et al., l986) with our findings suggests that corticopetal cholinergic neurons are innervated by lateral hypothalamic neurons, while hippocampopetal cholinergic neurons located largely within the MS/VDB complex are likely to receive input mainly from medial hypothalamic groups.

            Considering the fact that lateral hypothalamic neurons receive both general and special viscerosensory information (Fulwiller and Saper, l984) either directly from the nucleus of the solitary tract or through the parabrachial nucleus, it is possible that this integrated viscerosensory input reaches BFC neurons through lateral hypothalamic projections. The significance of afferents from the medial hypothalamus is less clear, as this region is thought to participate in the control of a number of neuroendocrine, autonomic, and behavioral mechanisms (Záborszky, l982; Swanson, 1987). A recent review (McGinty and Szymusiak, l990) suggested that inhibitory  input from preoptic neurons to basal forebrain  cholinergic neurons could be involved in thermoregulatory and hypnogenic mechanisms. Interestingly, in our combined electron microscopic study (Cullinan and Záborszky, l991), we have  identified symmetric synaptic contacts on cholinergic neurons in the basal forebrain originating from the medial preoptic-anterior hypothalamic area, suggesting an inhibitory influence.

THALAMIC AND SUBTHALAMIC PROJECTIONS

            Studies in the rat involving the delivery of retrograde tracers into the SI/globus pallidus area resulted in labeling of neurons within the parafascicular nucleus (Grove, l988; Jones and Cuello, l989; Carnes et al., l990), while injections into more caudoventral parts of the SI produced retrograde labeling in the paratenial, paraventricular, central medial, rhomboid and reuniens thalamic nuclei (Grove, l988; Carnes et al., l990). The interpretation of these results is confounded by technical difficulties, however, since these tracers often involve uptake by fibers of passage, and axons from intralaminar and medial thalamic nuclei, as components of the inferior thalamic radiation, pass through the internal capsule and globus pallidus en route to the striatum and cortex (Herkenham, l978, l979; Beckstead, 1984; Kelley and Stinus, l984; Royce and Mourey, l985).

            Using the autoradiographic tracing method, Ricardo (l981) described a significant projection from the zona incerta to several rostral forebrain structures including the SI, ventral pallidum, and globus pallidus. Since the labeling in these structures appeared to represent an end-point, it is likely that many fibers actually establish synaptic contact in these regions. Both the zona incerta and the intralaminar thalamic nuclei are known to receive significant projections originating from several levels of the brainstem reticular formation, to project upon widespread regions of the cortex (Macchi and Bentivoglio, l986), and have been implicated in the modulation of cortical activity (Steriade and McCarley, l990). In view of evidence implicating the BFC system in arousal (see below), it will be important to determine whether brainstem reticular influences upon the cortex are also mediated through a subthalamic relay to the BFC system.

BRAINSTEM AFFERENTS

            Following knife cuts at the meso-diencephalic border, degenerating terminals were found in synaptic contact with BFC neurons (Fig. 8A,B), and this intervention also resulted in a decrease of ChAT (choline acetyltransferase) activity in forebrain areas rich in cholinergic cell bodies (Záborszky et al., l986c). Although this preliminary study did not reveal the origin or chemical specificity of afferents, it was the first direct evidence of brainstem input to BFC neurons, and further suggested that removal of brainstem afferents may induce transynaptic changes in these cells. Since this report we have confirmed the presence of locus coeruleus terminals on BFC neurons. Several other brainstem afferent systems are also potentially important, since they might mediate the effects of reticular activation upon the cortex.

Peripeduncular Area

            The peripeduncular area (PPa) is located ventrally and medially to the anterior part of the medial geniculate body (MGB), abutting the dorsal end of the cerebral peduncle and the substantia nigra pars lateralis. It contains several cell groups such as the peripeduncular nucleus (PP) and the posterior intralaminar nucleus, which as parts of the "adjunct" auditory system receive acoustic signals from different auditory relay stations, although with less topographic and modality specificity (LeDoux et al., l985; Arnault and Roger, l987; LeDoux et al., 1990). Using  the autoradiographic tracing method in primates, Jones et al. (l976) suggested that the PP projects to the large aggregated neurons of the SI and medullary laminae of the globus pallidus. In the rat, retrograde tracing experiments (Jones and Cuello, l989), as well as anterograde tracing studies using PHA-L (Grove, l988), have confirmed that neurons located in the PPa project rather specifically to the vicinity of BFC neurons in the caudal part of the globus pallidus, adjacent to the internal capsule. Since the same group of cholinergic neurons which are likely to receive input from the PPa have been  shown to project to the auditory cortex (Rye et al., l984), the PPa may provide a relay through which a subpopulation of cholinergic neurons participates in auditory sensory processing (Fig. 9A).

Parabrachial Nucleus

            The brachium conjunctivum is surrounded by several cytoarchitectonically distinct cell groups along its course through the dorsolateral pons (Fulwiler and Saper, l984). Both the medial and lateral nuclei have widespread ascending projections innervating different hypothalamic, amygdaloid and thalamic nuclei, basal forebrain and cortical areas (Saper and Loewy, 1980; Fulwiller and Saper, l984; Semba et al., l988; Vertes, 1988; Jones and Cuello, 1989).  Following PHA-L injections into the lateral segment of the parabrachial nucleus (PB), varicose fibers were evident throughout the dorsal part of SI, lateral BSt, and lateral part of the central nucleus of the amygdala (Grove, 1988).

            The parabrachial nucleus relays both specific (gustatory) and general (respiratory, cardiovascular, gastrointestinal) viscerosensory input from the nucleus of the solitary tract (NTS) to the viscerosensory nuclei of the thalamus, and the insular cortex (Saper, l982; Block and Schwartzbaum, l983; Cechetto and Saper, l987; Ruggiero et al., l987). Cholinergic cells in the SI may receive specific viscerosensory input through the medial PB, since it is this region of the PB that receives afferents from the rostral, gustatory part of the NTS (Norgren, l978), and is where many of the labeled cells were found following injections of retrograde tracers in the SI (Fullwiller and Saper, l984). However, BFC neurons in the SI may also receive general viscerosensory input from the lateral PB, since the lateral PB receives input from the caudomedial, general viscerosensory portion of the NTS (Ricardo and Koh, 1978; Milner et al., l984), and this portion of the parabrachial nucleus contained retrogradely labeled cells backfilled from the SI (Fullwiller and Saper, 1984; Moga et al., l990). Interestingly, neurons in the SI also appear to receive direct input from the caudal NTS area, therefore cholinergic neurons may receive general viscerosensory input both directly, and to some extent indirectly through the PB, but are likely to receive gustatory input mainly indirectly through the PB relay.

            Information relayed through the BFC system from the PB is likely to reach, among other cortical regions, the insular cortex. The insular cortex  receives highly processed viscerosensory information from the thalamus (Cechetto and Saper, l987). Viscerosensory information relayed through the BFC system to the insular cortex might thus provide a primitive representation of the stimulus. These relationships are illustrated in the simplified circuit diagram of Fig. 9. It should be added that the PB and caudal NTS also project to the central nucleus of the amygdala (Saper, l982; Shipley and Geinisman, l984; de Olmos, 1985), which is itself a likely source of input to BFC neurons in the SI. Thus, a certain population of cholinergic neurons in the SI might participate in a complex neural circuit implicated in viscerosensory information processing, conditioned taste aversion, (Lasiter et al., l985) and affective evaluation of the stimulus (LeDoux, 1987). According to recent studies, information from the NTS is relayed through the  PB in a much more  complicated fashion (Herbert et al., l990; Moga et al., 1990). It will be a challange for future studies to identify whether cholinergic cells indeed participate in such circuits and if so what type of specific information they receive.

Pedunculopontine-Laterodorsal Tegmental Nuclei

            The pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT) in the mesopontine tegmentum represent the primary sources of cholinergic projections to the thalamus (Sofroniew et al., 1985; Levey et al., l987; Pare et al., l988; Steriade et al., l988). In addition, a cholinergic projection to the medial prefrontal cortex from the LDT has been described (Satoh and Fibiger, l986), and it has been suggested that a subpopulation of cholinergic neurons, mainly in the magnocellular preoptic nucleus (MCP), may receive cholinergic input from the LDT/PPT area (Woolf and Butcher, 1986; Satoh and Fibiger, l986; Semba et al., l988; Jones and Cuello, 1989).

            The majority of neurons in these areas that project to the thalamus display tonic discharge patterns and increment firing rates that precede the earliest change from EEG synchronization during quiet sleep to EEG  desynchronization during REM sleep (Steriade and McCarley, l990). The PPT/LDT may thus be considered the best candidate for inducing EEG desynchronization, which parallels increased ACh release (Kanai and Szerb, l965; Jasper and Tessier, l971). A cholinergic/cholinergic interaction in the basal forebrain would also be congruent with the original concept that stimulation of the midbrain reticular formation could evoke desynchronization of the EEG (Moruzzi and Magoun, 1949). Despite intensive efforts, however, there is no convincing evidence for a significant cholinergic projection to BFC neurons (see also Hallanger and Wainer, l988). In contrast, a preliminary electron microscopic study has suggested that the ascending cholinergic axons from the mesopontine tegmentum establish synaptic contact with non-cholinergic neurons of the basal forebrain (Hallanger et al., l988).

Ventral Tegmental Area-Substantia Nigra-Retrorubral Field           

            Using autoradiographic tracing from the dopaminergic ventral tegmental area (VTA), substantia nigra (SN) and retrorubral field (RRF), labeled fibers were traced through basal forebrain areas rich in cholinergic cells (Fallon and Moore, l978; Beckstead, 1979; Simon et al., l979; Vertes, l988). Retrograde tracing studies have confirmed the presence of labeled cells primarily in the VTA after tracer injections into the VDB/HDB area, while tracer injections into the cholinergic rich region of the globus pallidus (Haring and Wang, 1986; Hallanger and Wainer, l988;  Martinez-Murillo et al., 1988b; Semba et al., 1988; Jones and Cuello, l989) resulted in a large number of retrogradely labeled cells in the SN and RRF. In the substantia nigra the majority of the cells were in the zona compacta (SNc), with few seen in the pars reticulata. The simultaneous detection of retrogradely labeled cells and dopaminergic neurons using an antibody against tyrosine hydroxylase (TH) revealed that almost all retrograde neurons in the SNc were double labeled, while in the VTA and RRF 75-82% of the retrogradely labeled cells contained TH (Jones and Cuello, l989). Since many dopaminergic axons in the globus pallidus and other forebrain areas represent fibers of passage toward the striatum, septum, and cortex, further studies are needed to determine the origin and distribution of putative dopaminergic input to BFC neurons. 

Locus Coeruleus

            Evidence from autoradiographic and retrograde tracing studies has suggested projections to forebrain areas rich in cholinergic projection neurons from the locus coeruleus (Semba et al., 1988; Jones and Cuello, 1989). However, since axons from the locus coeruleus are known to pass through the basal forebrain areas en route to the cortex (Jones and Moore, l977; Jones and Yang, l985), these data are of limited value in determining the extent to which these projections terminate in the basal forebrain and contact BFC neurons. In a PHA-L study (Záborszky et al., in preparation) in which the majority of the labeled cells at the injection site were localized within the locus coeruleus, labeled varicosities were detected in direct apposition to cholinergic projection neurons in extensive basal forebrain areas, including the MS/VDB complex, HDB and SI. In contrast, cholinergic neurons in peripallidal regions appear to receive very few contacts. Results of experiments at the electron microscopic level indicate that cholinergic neurons are indeed contacted by locus coeruleus axons, and that an individual locus axon can establish synaptic contacts with both cholinergic and non-cholinergic neuronal elements (Záborszky et al., in preparation).

            Locus coeruleus neurons are activated by a wide variety of afferent stimuli, including auditory, visual, somato and viscerosensory (Aston-Jones and Bloom, l981; Foote et al., l983), as well as stressful and/or aversive stimuli (Abercrombie and Jacobs, l987, Jacobs, l987), although there is controversy concerning whether this nucleus receives afferent information from widespread (Cederbaum and Aghajanian, l978) or restricted (Aston-Jones et al., l986) areas. Locus coeruleus cells, similar to dorsal raphe serotonergic neurons, show pacemaker-like activity and state-related modulation of discharge, which is highest in the waking state and decreases in slow wave sleep. Arousing stimuli are accompanied by bursting activity of these neurons (Steriade and McCarley, l990). Electrophysiological studies have shown that noradrenergic activation often leads to enhanced efficacy of synaptic transmission for other afferents that converge upon the same postsynaptic neuron (Foote et al., l983; Björklund and Lindvall, l986). Locus coeruleus axons may therefore participate in selective attention by filtering out irrelevant stimuli and thus increase the signal-to-noise ratio of behaviorally significant stimuli. In view of the fact that similar physiological mechanisms have been described generally for the action of acetylcholine on its target neurons, as well as morphological evidence that locus coeruleus axons terminate on BFC neurons, these effects may be mediated both indirectly through the connections of the locus coeruleus with the BFC system, as well as directly through its widespread corticopetal projections. An important difference between BFC and locus coeruleus mediated arousal is that locus coeruleus neurons virtually cease discharge with the advent of REM sleep (Steriade and McCarley l990).

            Phasic activation of cholinergic neurons by noradrenergic afferents has been implicated in certain memory processes (Durkin, l989), which is compatible with the observation  that LC neuronal activity is increased during conditioning (Jacobs, l987).        

Raphe Nuclei

            The results of retrograde tracing experiments have suggested projections from the raphe nuclei to areas containing BFC neurons (Semba et al., l988; Vertes, 1988; Jones and Cuello, l989; Carnes et al., 1990). Consistent with data from autoradiographic studies (Azmitia and Segal, l978; Vertes and Martin, l988), it appears that the MS/VDB complex receives projections mainly from the median raphe nucleus (MR; B8 serotonergic cell group of Dahlström and Fuxe, l964), while inputs to the MCP/HDB and SI/globus pallidus regions originate from the dorsal raphe nucleus (DR; B7 cell group). Additional projections have been described from the caudal linear, interfascicular, magnus, pontine raphe nuclei, and from neurons within the B9 serotonergic cell group in the mesopontine ventral tegmentum (Molliver, l987; Semba et al., 1988; Vertes, l988; Jones and Cuello, l989). Using concurrent immunostaining for serotonin (5-HT), Jones and Cuello (l989) revealed that after large WGA-HRP injections into the globus pallidus/SI area, about 85% and 61% of retrogradely labeled neurons were also 5-HT-positive in the DR and MR, respectively. On the other hand, in the B9 cell group only 15% of the retrogradely labeled neurons contained 5-HT. Interestingly, in the same study, the remaining neurons (l5%) in the DR were positive for tyrosine hydroxylase (TH), indicating a dopaminergic input to the area of globus pallidus/SI from this region. In double-labeling experiments involving ChAT and PHA-L, we have found light microscopic evidence suggesting input to BFC neurons from the DR (Fig. 10). Confirmation of synaptic input remains to established at the electron microscopic level.

            There have been several reports that MR stimulation produces hippocampal desynchronization and inhibition of the bursting discharge of the septal pacemaking cells (i.e. those neurons directly involved in controlling the rhythmical slow-wave [theta] activity of the hippocampus; Assaf and Miller, l978; Vertes, l981).  MR-elicited desynchronization appears to be a serotonin mediated effect (McNaughton et al., 1980). Although the MR can influence the hippocampus directly, it is possible that it also may indirectly influence it through GABAergic or cholinergic septohippocampal neurons, both of which may be involved in pacing hippocampal theta (Stewart and Fox, l990). However, there is no direct morphological evidence to date for such connections.

            DR presumably serotonergic neurons show pacemaker-like activity and state-related modulation of discharge (for ref. see Jacobs, 1987; Jacobs et al., l990; Steriade and McCarley, l990). Phasic sensory (visual and auditory) stimulation produces an excitation followed by  inhibition in these  units (Jacobs, l987). Injections of 5,7-DHT into brainstem serotonergic cell groups produced  a severe reduction of the low-voltage fast activity in the neocortex that paralleled the extent of serotonin depletion in the forebrain (Vanderwolf et al., l990). Moreover, Vanderwolf and colleagues (Vanderwolf, l988; Vanderwolf et al.,l990) and Riekkinen et al. (l990) have reported that combined cholinergic and serotoninergic blockade in rat have potentiating effects  on suppressing cortical arousal.  Such animals also show severe memory impairments (Nilsson et al., 1988; Richter-Levin and Segal, 1989). An interaction between the serotonergic and cholinergic systems could take place at the level of the target in the cortex and/or at the cholinergic cell body level in the basal forebrain. Our preliminary morphological (Fig.10C) and biochemical data (Záborszky and Luine, l987) are suggestive of a basal forebrain  interaction.

Reticular Formation

            The demonstration by Moruzzi and Magoun (l949) that the reticular formation (RF) is involved in controlling the cortical EEG focused attention on the course and termination of ascending reticular projections. After the initial Golgi and degeneration studies (Nauta and Kuypers, l958; Scheibel and Scheibel, l958), several subsequent papers used autoradiography (Edwards and de Olmos, l976; Zemlan et al., l984; Eberhart et al., 1985; Jones and Yang, l985; Vertes et al., l986; Vertes and Martin, l988) or retrograde techniques (Semba et al., l988; Vertes, l988; Jones and Cuello, l989) to trace the ascending projections from the brainstem RF. The reader should consult with the original papers or the review by Vertes (l990a) for further details. Here we will summarize only data relevant to basal forebrain projections.

            In general, long ascending reticular fibers travel through the central tegmentum and are collected at the caudal diencephalon in Forel's fields. From this broad band of fibers, three main fiber systems emanate: a dorsal one coursing into the thalamus to innervate the intralaminar (parafascicular, paracentral, central, lateral), midline (rhomboid, reuniens, paraventricular, intermediodorsal), posterior, ventromedial, and dorsomedial nuclei; an intermediate group of fibers, as the rostral continuation of Forel's fascicle, passes through the subthalamus, giving off fibers to the zona incerta and reticular thalamic nucleus, with some fibers reaching the basal ganglia; and a ventrolateral pathway, which travels mainly within the medial forebrain bundle (MFB) to innervate the basal forebrain. Although the different subnuclei of the RF show overlapping projections, the more rostral the fibers originate, the stronger the ascending projection. For example, the medullary parvicellular reticular nucleus innervates mostly the lateral pontomedullary tegmentum, with only a few fibers reaching the mesencephalic RF, and none reaching further rostrally. In contrast, the nuclei gigantocellularis (Gc), pontis caudalis (RPc), pontis oralis (RPo), and the midbrain reticular formation (MRF), give rise to progressively heavier projections. Thus, only a few labeled fibers were detected in the medial portion of the HDB and VDB from the Gc. In contrast, the whole MS/VDB and medial two thirds of the ventral pallidum/HDB area are innervated by the RPo. Finally, the MRF innervates the entire ventral pallidum, globus pallidus, MS/VDB complex, parts of the caudate-putamen, the central amygdaloid nucleus, lateral BSt, and medial prefrontal and suprarhinal cortices (Jones and Yang, 1985).

            Retrograde studies suggest that ascending projections from more rostral portions of the RF (e.g. MRF) project more dorsally in the basal forebrain, and may reach BFC neurons in the SI/globus pallidus, while more caudally located RF cell groups project mainly to the more ventral parts of the basal forebrain, such as the HDB.

            The pontine RF appears to serve a prominent role in the generation of the hippocampal theta rhythm. Petsche et al. (1962) first suggested that discharges of a population of MS/VDB cells are phase-locked with the hippocampal theta, and showed further that these septal "pacemaking" cells were activated by high frequency stimulation of the brainstem RF. Vertes (l977, l979, 1990b) has identified, in the freely moving rat, a subset of RPo neurons  that fire selectively during those states in which the theta rhythm is present (waking, REM sleep). It is not clear, however, whether these reticular axons directly contact cholinergic or GABAergic septohippocampal neurons, or local interneurons in the septum.

            On the other hand, Steriade and colleagues (Steriade, l970; Steriade and Llinas, l988; Steriade and McCarley, l990) proposed that MRF projections to the  intralaminar thalamic nuclei may be critically involved in the tonic activation processes related to EEG desynchronization during waking and REM sleep. Although there is considerable evidence for thalamic involvement, it is likely that the MRF projections to areas rich in BFC neurons may be a route by which MRF acts upon the cortex (Buzsaki et al., l988). PHA-L injections into the MRF result in massive projections in the lateral part of SI (unpublished data), although the question of whether these fibers contact BFC neurons awaits investigation at the EM level. Brainstem activation of BFC might also come from the RPc, which has been implicated in REM sleep (Greene et al., l989), although this possibility has yet to be investigated.

Lateral Tegmental and Dorsal Medullary Catecholaminergic Cell Groups

            Intermingled with other transmitter-containing neurons in the lateral and dorsal medullary-pontine RF, several catecholaminergic cells were identified by Dahlström and Fuxe (1964). The basal forebrain projections from these areas are summarized below.

            A7 area.   The A7 noradrenergic cell group, which is located between the ventrolateral border of the superior cerebellar peduncle and the lateral lemniscus, constitutes a continuation of the A5 cell group. Although in combined lesion-biochemical experiments it was reported that ascending noradrenergic fibers from the area of the A7 cell group contribute to the innervation of the hypothalamus (Palkovits et al., 1980), due to the fact that fibers originating from more caudal noradrenergic cell groups project through the A7 area, these results must be interpreted with caution. It is thus not clear at present whether the A7 cell group projects to the basal forebrain.

            A5 area.   The A5 noradrenergic cell group area (Dahlström and Fuxe, l964) is located in the caudal pons, dorsolateral to the superior olive. The projections of the A5 noradrenergic cell groups have been described recently by Byrum and Guyenet (l987). Noradrenergic neurons from this region project to several hypothalamic, thalamic, and limbic nuclei, and it is possible that a subpopulation of BFC neurons in the caudal SI receive such input. In view of the widespread interconnections of the A5 group with basal forebrain regions involved in cardiovascular regulation (Guyenet and Byrum, l985), it is possible that this information also reaches the BFC system.

            A2 area. The A2 noradrenergic cell group is located in the caudal portion of the nucleus of the solitary tract (NTS). It has been estimated that at least 90% of all nucleus commissuralis (caudal, noradrenergic part of the NTS) neurons projecting through the MFB are catecholaminergic (Moore and Guyenet, 1983). Projections from this caudal part of the NTS in rat were followed to the lateral PB area, SI, central amygdala and lateral BSt (Norgren, l978; Ricardo and Koh, l978). It is thus possible that BFC cells receive general viscerosensory input from the vagal nerve mediated through noradrenergic afferents. On the other hand, different peptides such as enkephalin, somatostatin, or substance P have been localized in ascending projections from the caudal NTS (Riche et al., l990; Sawchenko et al., 1990), and are known to be present in fibers within forebrain regions containing BFC neurons. Therefore, it is possible that BFC neurons receive some peptidergic projections from the NTS.

            Several studies have shown that serotonin applied directly to the area of the  NTS and immediate surrounding region of the lower medulla elicits cortical synchronization and/or sleep. It has further been proposed that serotonin afferents to the NTS responsible for triggering slow wawe sleep may primarily arise from the area postrema (for ref. see Vertes, l990b). It is unclear  whether information relayed to the cortex from this "medullary sleep center" is mediated  via BFC or other basal forebrain neurons.

            A1 area.   The A1 noradrenergic cell group area (Dahlström and Fuxe, 1964) is located caudally within the ventrolateral medulla. The projections from the A1 area differ significantly from those of each of the reticular nuclei discussed above (McKellar and Loewy, l982; Vertes et al., l986). Although some fibers project to the midline thalamus, zona incerta and rostral intralaminar thalamic nuclei, a considerable proportion of fibers ascend in the medial forebrain bundle (MFB) and terminate in various hypothalamic nuclei, as well as in areas containing BFC neurons such as the SI, and MS/VDB complex. Using PHA-L tracing from a region which included the A1 catecholaminergic cell group (Fig. 11), labeled fibers could be traced to the vicinity of BFC neurons in the medial HDB and ventral part of the globus pallidus, although confirmation of synaptic contacts awaits ultrastructural examination.

TRANSMITTER-SPECIFIC AFFERENTS

GABA

            GABAergic synapses on cholinergic projection neurons were first described in the ventral pallidum (Záborszky et al., 1986b), and have since been identified on corticopetal, presumably cholinergic neurons in the globus pallidus (Ingham et al., l988), on septal cholinergic neurons (Leranth and Frotscher, l989), and on cholinergic cells in the anterior amygdaloid area (Nitecka and Frotscher, l989). GABAergic boutons form symmetric membrane specializations (Fig. 14D), which in some areas comprise over half of the input to the perikarya and proximal dendrites (Ingham et al., l988). In the ventral pallidum, a significant proportion of GABAergic terminals comes from the nucleus accumbens, since lesions of this structure result in a significant decrease of GAD in the ventral pallidum (Walaas and Fonnum, l979; Záborszky et al., l982). Another source of GABAergic terminals may be local GABAergic neurons, such as postulated for the septum (Leranth and Frotscher, l989).

            There is ample evidence that the turnover rate of hippocampal acetylcholine (ACh), as well as theta activity, can be manipulated by intraseptal administration of GABAergic agents (Wood and Cheney, 1979; Costa et al., l983; Allen and Crawford, l984; Blaker et al., l986). Changes in cortical acetylcholine turnover rate (ACh_TR), sodium dependent high affinity choline uptake (SDHACU), or cortical ACh output, have also been reported following muscimol injections into the SI (Wood and Richard, l982; Wenk, l984; Blaker, l985; Casamenti et al., 1986; Wood and McQuade, l986). The pharmacological studies have indicated further that muscimol acts through GABA-A receptors located on the cholinergic neurons (Blaker et al., l986). It has been also suggested that other septal neurotransmitters such as dopamine, glutamate, and ß-endorphin modulate ACh_TR indirectly through their influences on GABAergic interneurons (Costa et al. 1983). Whether the GABAergic link indeed acts as a "final common pathway" (Chrobak et al., l989) for these afferents in the regulation of septohippocampal neurons is unresolved, since it is unknown whether GABAergic interneurons which receive such afferents project, in turn, to septohippocampal or corticopetal cholinergic neurons.

            GABAergic input to BFC neurons may have functional significance with respect to learning and memory processes, as pharmacological manipulation of GABA-A receptors within the medial septum or nucleus basalis has been shown to affect performance on working memory tasks, as well as in inhibitory avoidance behavior (Nagel and Houston, 1988; Chrobak et al., 1989). Also, enhancement of cholinergic function through pharmacological disinhibition of the GABAergic-cholinergic interaction has been suggested as a therapy for dementia of the Alzheimer's type (Sarter et al., 1988, 1990).

Acetylcholine

            It has been generally noted that cholinergic neurons do not receive significant cholinergic input (Ingham et al., l985; Armstrong, 1986; Dinopoulos et al., l986; Záborszky et al., 1986b; Bialowas and Frotscher, l987; Martinez-Murillo et al., 1990).  We have occasionally found ChAT-immunoreactive boutons in contact with cholinergic cell bodies or proximal dendrites in the SI, and these synapses were usually of the symmetric type (Fig. 14). Since symmetric type synapses have generally been associated with inhibitory synaptic effects (Peters et al., l976), this finding is not readily compatible with electrophysiological studies which have indicated that the majority of septohippocampal or corticopetal neurons are excited by the iontophoretic application of ACh  (Lamour et al., l984a; 1986). These effects might be explained by an action through inhibitory interneurons, however. Also, physiological studies have indicated that the action of ACh within the CNS is quite diverse, and may largely depend upon the nature of the postsynaptic receptor (Nicoll, l988).  

            The origin of cholinergic axons in the basal forebrain remains unclear. One possible source is the ascending cholinergic projection from the PPT/LDT (Satoh and Fibiger, l986), although a PHA-L study did not find evidence for terminations on BFC neurons, but rather, on non-cholinergic cells (Hallanger et al., 1988). In another study, physiologically identified corticopetal neurons in the SI were observed to have local axon collaterals (Semba et al., l987), however, since the chemical nature of these neurons was not confirmed it is unclear whether they were indeed cholinergic.

Glutamate

            It has been suggested that amygdalofugal axons use glutamate as transmitter, as evidenced by decreases in glutamate uptake in the SI following amygdaloid lesions (Francis et al., l987), as well as by the presence of ³H-D-Asp containing cell bodies in the amygdala after injection of this tracer into the ventral pallidum (Fuller et al., l987). We have found that asymmetric contacts are formed on BFC neurons by amygdalofugal axons (Záborszky et al., 1984a), although the transmitter of these terminals was not identified. In addition, hippocampal efferents to the lateral septum apparently use also glutamate as a transmitter, as evidenced by decreases in glutamate uptake after surgical lesions of the fimbria (Fonnum and Walaas, 1978). Injections of glutamate in the SI significantly increased cortical SDHACU (Wenk, 1984), suggesting that corticofugal axons are also likely to be glutamatergic. A recent retrograde tracing study injecting  ³H-D-Asp into different basal forebrain areas containing BFC neurons suggests a more widespread origin of glutamatergic projection to basal forebrain areas, including the intralaminar thalamic nuclei, lateral septum, habenula, and several hypothalamic and brainstem sites (Carnes et al., l990). Glutamic acid has been shown to cause rapid depolarization of cultured cells from the nucleus basalis (Nakajima et al., 1985), although the identification of glutamate in synapses on BFC neurons awaits ultrastructural double-labeling studies.

Substance P

            Substance P-containing terminals have been found to contact BFC neurons in the ventral pallidum and ventromedial globus pallidus (Bolam et al., 1986). Such synapses were detected on the proximal dendrites and cell bodies of cholinergic neurons. It has been estimated that as many as one-third of the observed contacts contained substance P. The majority of immunoreactive terminals formed symmetrical synaptic specializations. However, a few boutons formed asymmetric contacts with the proximal dendrites of cholin-ergic neurons. Individual cholinergic neurons apparently receive multiple substance P-containing terminals. A light microscopic study performed on human tissue has suggested that substance P innervation of acetylcholine esterase (AChE)-positive nucleus basalis neurons is heterogeneous, since in some areas all AChE-positive cell bodies were in possible contact with approximately 5-20 substance P-immunoreactive terminal-like structures, while in other areas AChE positive neurons were entirely devoid of such putative contacts (Beach et al., 1987). One potential site of origin of substance P-containing terminals to BFC neurons in the ventral pallidum or ventromedial globus pallidus is the nucleus accumbens, since lesions of this region cause a reduction of substance P immunostaining in the ventral pallidum (Záborszky et al., 1982; Haber and Nauta, l983). However, the different morphological types of substance P synapses, as well as the fact that several other structures which project to the areas containing BFC neurons also contain substance P-positive cells, suggests other potential input sources, including the amygdala, BSt, hypothalamus, and the pontine tegmentum (see Beach et al., l987).

            Iontophoretic application of substance P has been shown to produce increased excitability of cholinergic neurons from cultures of the medial septum and diagonal band, an effect caused by inhibition of inward rectifying K-channels (Nakajima et al., 1985, l988). Moreover, intraseptal application of substance P facilitates performance in passive avoidance behavior (Staubli and Huston, l980). These findings are in apparent contradiction to the effects of intraseptal administration of substance P on hippocampal ACh_TR, which has been found to be inhibitory (Malthe-Sorensen et al., l978a). Studies on the effects of muscimol and substance P on the ACh_TR in different regions of the hippocampus suggest that these two substances control two different projections from the septum to the hippocampus (Blaker et al., l984). Namely, septal administration of substance P in the MS/VDB resulted in reduction of ACh_TR only in the dorsal hippocampus, while muscimol affected only ACh_TR in the ventral hippocampus. Considering the topographical arrangement of cholinergic neurons projecting to the dorsal versus the ventral hippocampus (Amaral and Kurz, l985), it is possible that distinct populations of cholinergic neurons in the septum receive GABA or substance P input. At present, however, direct morphological data are lacking for such a possibility. Similar to septal injections, administration of substance P into the region of the nucleus basalis in rat facilitates performance of an inhibitory avoidance task (Kafetzopoulos et al., 1986; Nagel and Huston, 1988).

Enkephalin

            An immunocytochemical double-labeling experiment has shown that enkephalin-positive terminals contact with cholinergic dendrites in the globus pallidus (Chang et al., l987), although these were reported to be few. Another study (Martinez-Murillo et al., l988a) found somewhat more enkephalin-positive terminals in contact with AChE-positive neurons in the globus pallidus and internal capsule. Although technical factors can limit the detection of enkephalinergic/cholinergic interactions, these studies appear to suggest that there is little monosynaptic interaction between enkephalinergic terminals and cholinergic neurons.

            Injections of enkephalin or its derivatives to the SI have been shown to reduce neocortical SDHACU by approximately 50% (Wenk, l984), and produce naloxone-reversible locomotor hyperactivity (Baud et al., l988). In another study, however, local delivery of enkephalin derivatives into the SI failed to induce changes in cortical ACh_TR, although a significant decrease resulted after parenteral administration (Wood and McQuade, l986). On the other hand, septal injections of enkephalin have been found to cause a significant decrease in hippocampal ACh_TR (Costa et al., l983). Clearly, the role of enkephalin in modulating cortical or hippocampal cholinergic activity requires clarification in further anatomical and pharmacological studies.

Somatostatin

            Somatostatin has been found in axon terminals in contact with BFC neurons in the SI (Záborszky, l989a). The synapses observed were of the symmetric type, and were found primarily on proximal dendrites (Fig. 14B). The results of a high magnification light microscopic analysis of the distribution of putative contact sites suggest that BFC neurons in the SI and MCP/HDB may receive a rather diffuse innervation (Záborszky et al., in preparation). At least a proportion of such terminals are likely to originate from local interneurons.

            Cysteamine-induced release of somatostatin has been shown to lead to significant impairment of cognitive processes such as on retention in passive avoidance tasks (Vecsei et al., 1984; Haroutunian et al., 1987). Since combinations of nucleus basalis lesions and cysteamine depletion in rats did not lead to any greater impairment of mnemonic function than that produced by ablation of the nucleus basalis alone, it was suggested that the amnesia produced by the cysteamine-induced release of somatostatin is mediated through the BFC system (Haroutunian et al., l989). Our morphological demonstrations of symmetric synapses on cholinergic corticopetal neurons suggests that somatostatin released at these synapses may inhibit cholinergic function in target areas. Somatostatin has been reported to inhibit ACh release from cholinergic neurons of the myenteric plexus (Yau et al., l983), although it has been shown that intraventricular injection of somatostatin increases hippocampal Ach_TR (Wood et al., l979). The functional impact of such somatostatinergic/cholinergic interactions in the basal forebrain remains to be elucidated.

Neuropeptide Y

            Neuropeptide Y (NPY) has been found in axon terminals in synaptic contact with BFC neurons in the SI (Záborszky and Braun, l988). In many cases, multiple NPY-containing boutons were found to encompass cholinergic cell bodies. The synapses were always of the symmetric type. Similar to somatostatin, at least a proportion of NPY terminals are likely to be derived from local interneurons. Light microscopic observations have suggested that a single peptidergic neuron (NPY or somatostatin), with its locally arborizing axon collaterals, may innervate a number of BFC neurons. Conversely, a single BFC neuron may receive axon terminals from several NPY or somatostatin cells (Záborszky, 1989b).

            It has recently been demonstrated that intraventricular NPY administration modulates retention of foot-shock avoidance in a dose and time-dependent manner (Flood et al., l987). Post-training administration of NPY to the septum or hippocampus also has been demonstrated to affect performance on a learning task (Flood et al., 1989). Whether these effects are mediated in part through the BFC system is presently unknown. Clearly, detailed anatomical and pharmacological studies are necessary to reveal the possible significance of NPY-cholinergic interactions in the basal forebrain.

Other Peptides

            Various peptide-containing fiber systems are differentially distributed in the basal forebrain (for ref. see Palkovits, l984). As a result, different populations of BFC neurons are likely to be contacted by different afferent peptidergic fibers (Záborszky, l989b). For example, the majority of BFC neurons in the rostral globus pallidus and ventral pallidum may receive a rich neurotensin innervation (see Fig. 12), but appear to be contacted only occasionally by other peptidergic afferents. BFC neurons in the SI appear to receive a substantial input from a number of different peptidergic systems, including  NPY, somatostatin and neurotensin.

            The possibility of a rich innervation of a subpopulation of BFC neurons by neurotensin fibers is supported by a study reporting localization of radiolabeled neurotensin binding sites on AChE-positive neurons in the area of the nucleus basalis (Szigethy et al. l990). Since intraventricular administration of neurotensin in the rat has been shown to modulate hippocampal ACh_TR (Malthe-Sorenssen et al., l978b), as well as to affect performance in a conditioned avoidance paradigm (van Wimersma Greidanus et al., l982), it is possible that neurotensin modulation of BFC output may have a role in memory processes.

            Vasopressin axons emanating from the hypothalamic paraventricular nucleus  en route to the posterior pituitary cross cholinergic dendrites of the SI or HDB, and boutons containing large neurosecretory vesicles are occasionally found in synaptic contact with distal cholinergic dendrites (unpublished data, Fig. 14C). The functional significance of such connections is presently unclear.           

            Galanin has been shown to be present in neurons in the area of the basal nucleus of Meynert in the normal human brain, both in local circuit neurons, and in a number of cholinergic projection neurons. In addition, local galanin interneurons appear to innervate cholinergic cells (Chan-Palay, l988). Lesion studies suggest that most medial septal neurons that contain both galanin and acetylcholine project to the ventral hippocampus (Melander et al., l986). In the ventral hippocampus exogenously administered galanin appears to attenuate scopolamine-stimulated ACh release (Fisone et al., l987), and inhibit the muscarinic stimulation of phosphoinositide turnover (Palazzi et al., l988). Galanin also has  been shown as an inhibitory peptide affecting myenteric cholinergic neurons (Yau et al., l986), although no data are yet available for their central action at the level of the cholinergic neurons in the basal forebrain. In Parkinson's disease and Alzheimer's disease, there is an apparent hyperinnervation of surviving cholinergic neurons, and it has been proposed that this hyperinnervation reflects plasticity in response to altered (diminished) cholinergic function. However, since galanin might act as an inhibitory transmitter, the effect might be a further deterioration of the cholinergic metabolism (Chan-Palay, l988). Behavioral studies in rats suggest that galanin acts as an inhibitory modulator of ACh, having no direct effect of its own, but partially blocking the facilitatory actions of ACh on working memory (see Crawley and Wenk, 1989).

            In addition to galanin, studies have indicated changes in levels of somatostatin, neurotensin, NPY and a-melanocyte-stimulating-hormone in the basal forebrain areas rich in cholinergic neurons in Alzheimer's disease (Ferrier et al., 1983;  Allen et al., l984; Arai et al., l986; Constantinidis et al., 1988). It is interesting to note that in Alzheimer's disease, individual sectors of the nucleus basalis are affected differentially, with concomitant pathological changes in the corresponding cortical projection areas (Arendt et al., l985). Our findings (Záborszky, l989b) may be relevant in this context, in that specific populations of cholinergic neurons are likely to be contacted and modulated by specific sets of peptidergic afferents. It will therefore be important to determine whether  altered peptidergic innervation in the basal forebrain is correlated with the pathological changes in subsets of nucleus basalis neurons in Alzheimer's disease.

Catecholamines

            Noradrenaline/Adrenaline.   We have recently mapped the distribution of dopamine-ß-hydroxylase (DBH) positive varicosities in relation to BFC system at the light microscopic level. With the exception of those neurons in the dorsal part of the globus pallidus and internal capsule, cholinergic neurons are approximated by DBH-positive varicosities in most portions of the BFC system. In some cases, particularly within the caudal SI, distal segments of cholinergic dendrites appeared to receive repetitive contacts in the form of a "climbing" arrangement.  The distribution of DBH-positive fibers/terminals in relation to BFC neurons at the level of the anterior commissure is shown in Fig. 13A. Parallel experiments at the EM level confirmed synaptic contact between DBH-positive terminals and cholinergic neurons (Záborszky et al., l991). Fig. 13B illustrates the distribution of PHA-L labeled fibers in relation to BFC neurons following PHA-L injection in the locus coeruleus, suggesting that at least  part of the noradrenaline innervation of the basal forebrain originates in the locus coeruleus. The results of these studies have suggested that the overall noradrenergic innervation of the BFC system is rather diffuse (see Fig. 15C), particularly from the locus coeruleus (Fig. 15B), although the input is apparently not entirely uniform. Regional variations in the type and distribution of labeled fibers further suggested contributions to the innervation of the BFC from noradrenergic cell groups such as the A1 and A2 groups.

            Parenteral administration of amphetamine increases ACh_TR in the hippocampus (Costa et al., l983). This response is likely to be mediated in part through noradrenergic terminals on septal BFC cells, since the response is prevented by intraseptal injection of phenoxybenzamine, an irreversible a-adrenergic blocker (Costa et al., l983), or by 6-OHDA lesions of the ventral or dorsal noradrenergic bundles (Robinson, l986, l989). Furthermore, it is suggested that this noradrenergic input phasically activates the septohippocampal cholinergic neurons during working memory testing (Durkin, l989). Other pharmacological experiments also have implicated noradrenergic-cholinergic interactions in memory related processes (Mason and Fibiger, l979; Decker and Gallagher, l987; Decker and McGaugh, l989; Decker et al., l990; Haroutunian et al., l990), although the site(s) of such interactions were not determined. The present findings might provide a morphological basis for such effects.

            Dopamine.  Biochemical, pharmacological, electrophysiological, histofluorescence, and combined retrograde immunohistochemical/tracing studies have suggested dopaminergic innervation of forebrain regions containing BFC neurons (Brownstein et al., 1974; Versteeg et al., l976; Lindvall and Björklund, l979; Haring and Wang, l986; Martinez-Murillo et al., l988b; Semba et al., l988;  Jones and Cuello, l989; Napier and Potter, l989; Napier et al., this volume). We recently mapped the distribution of TH-positive axonal varicosities in relation to cholinergic neurons (Záborszky et al., l991). Due to the fact that the TH antibody used in our study labeled many fibers in the basal forebrain that were also DBH-positive, interpretation of these data requires caution. However, in areas such as the ventromedial globus pallidus and the internal capsule, where few or no DBH-positive terminals were present, it is likely that TH varicosities represent dopaminergic terminals, and preliminary EM evidence indicates that TH axons in these regions establish symmetric synapses with BFC cells.

            Pharmacological studies suggested that septohippocampal BFC neurons are under a tonic inhibitory dopminergic influence from the ventral tegmental area, and that this inhibitory effect of dopamine on hippocampal ACh_TR is mediated through the septum via GABAergic interneurons (Robinson et al., l979; Costa et al., l983; Gilad et al., 1986). An indirect dopaminergic influence on the corticopetal cholinergic neurons has also been suggested (Casamenti et al., l986). Several recent pharmacological studies have suggested that dopaminergic/cholinergic interactions play some role in cognitive functions, including spatial memory performance (Galey et al., l985; McGurk et al., l988; l989; Levin et al., l990). A definitive answer to the question of direct dopaminergic/cholinergic interactions in the basal forebrain awaits double-labeling studies using antisera for ChAT and dopamine. In addition, further morphological and biochemical studies may reveal the significance of a possible GABAergic mechanism mediating this interaction.

Clinical Significance of Catecholaminergic/Cholinergic Interaction

            Studies on aging and age related disorders such as Alzheimer's disease and Parkinson's disease suggest that the disruption of catecholaminergic/ cholinergic interaction in these conditions may contribute to the cognitive decline observed. In aged rodents, nonhuman primates, and humans, reductions in forebrain catecholaminergic markers have been reported (Carlsson, l987; Morgan et al., l987), as has cell loss within the substantia nigra and locus coeruleus (Brody, l976; McGeer et al., 1977; Chan-Palay and Asan, l989a). Forebrain catecholaminergic markers are also reduced in Alzheimer's disease (for ref. see Mann, l988) and neuronal loss has been reported within the locus coeruleus and ventral tegmental area (Forno, l978; Tomlinson et al., 1981; Ichimaya et al., l986; Price et al., l986; Palmer et al., l987; Chan-Palay and Asan, l989b). In Parkinson's disease, in addition to the well known degeneration of the substantia nigra, neuronal loss within the locus coeruleus and reductions of forebrain noradrenaline levels have been demonstrated (Mann and Yates, 1983; Chan-Palay and Asan, 1989b). Reductions in forebrain presynaptic cholinergic markers and cell loss in the nucleus basalis have been reported not only in Alzheimer's diseases but also in aging, as well as in Parkinson's disease  (McGeer et al., l984; Decker, l987; Fisher et al., l989; Jellinger, l990). The extent to which reductions in catecholaminergic and cholinergic markers are independent or related processes is unclear. However, the fact that 6-OHDA lesions of the ascending catecholaminergic bundle result in a decrease in ChAT activity in forebrain areas rich in cholinergic cell bodies (Záborszky and Luine, l987; Záborszky et al., l991) suggests a catecholaminergic influence on BFC neurons. The lack of this influence could be a factor in the metabolic deterioration of the BFC in Alzheimer's  disease, Parkinson's disease, or aging, a notion consistent with a recently proposed theory of transynaptic systems degeneneration in neurological diseases (Saper et al., l987).

INFORMATION PROCESSING IN THE BASAL FOREBRAIN

            Recent attempts to assess inputs to BFC neurons have employed double-labeling approaches involving ChAT immunocytochemistry combined with either tracing or transmitter identification at the electron microscope level (Záborszky et al., l984a; Ingham et al., l985; Bolam et al., 1986; Záborszky et al., 1986b; Chang et al., 1987; Ingham et al., 1988; Martinez-Murillo, et al., 1988a; Záborszky and Cullinan, 1989; Záborszky et al., 1991). Fig. 14 shows several examples of synapses on identified cholinergic neurons. As suggested in the schematic drawing of Fig. 14A, various inhibitory synapses appear to show a preferential distribution on the cell body or proximal part of the dendrite. These terminals are likely to originate mainly from local interneurons. On the other hand, excitatory inputs from more distant areas apparently concentrate on more distal dendritic segments. This afferent "synaptic topography" (Smith and Bolam, l990) based on the available data may represent a first level of integration of afferent information. However, since the number of synapses and/or their types  may vary according to the location and/or the target of the cholinergic neuron, the minimum operational network for corticopetal cholinergic neurons remains to be established. Another level of interaction between inputs may be represented through local GABAergic and peptidergic interneurons (Záborszky, l989a,b), which project to cholinergic neurons. Although the exact divergence-convergence relationships of these interneurons, as well as their afferents are unknown, it is likely that such an interactive system signifies complex processing of information  through the cholinergic system prior to its reaching the cortex.  

ORGANIZATION OF AFFERENTS

            For practical purposes only a limited number of neurons with their afferent inputs can be reconstructed at the ultrastructual level. To assess the organization of different afferent systems in relation to the cholinergic projection system in its entirety, we mapped the  potential sites of contact under high resolution light microscopy (e.g. Fig. 15). Although this technique is subject to several limitations (see Cullinan and Záborszky, 1991), it does appear to provide insight into the pattern of innervation from a given brain region (see Fig. 15).

            On the basis of data using this "double strategy" of identifying terminals on single cells, as well as mapping their quasi 3-D distribution,  (Záborszky and Cullinan, l989;  Cullinan and Záborszky, l991; Záborszky et al., l991), a number of organizational principles have emerged that are likely to be relevant not only to the cases studied, but with respect to afferents to the BFC system in general: 1) Inputs to the BFC system are  apparently non-specific. In all cases examined, labeled terminal varicosities detected in the basal forebrain were related to both cholinergic and non-cholinergic elements. Indeed, the vast majority appeared to be associated with elements that were non-cholinergic. These observations support the notion that cholinergic neurons do not maintain afferent connections distinct from neighboring non-cholinergic cells, but rather, participate to some extent in the circuitry of the forebrain regions in which they are located, as has been suggested by Grove et al., (l986). 2) The distribution patterns of various terminals on the BFC sytem correspond to the general topographical arrangement of basal forebrain fibers. For example, fiber contingents coursing through certain compartments of the MFB tend to have terminations in the rostral forebrain corresponding to the same compartment. Moreover, projections in which fibers ascend through multiple MFB compartments tend to innervate the forebrain in a more diffuse fashion. A precise localization of different ascending brainstem fiber systems in relation to the compartments of the MFB (see Satoh and Fibiger, 1986) may therefore be of value in defining inputs to chemically specific cells in the basal forebrain, including BFC neurons. 3) Afferents to the BFC system may be restricted or relatively diffuse. The majority of afferents examined in our experiments showed a preferential distribution towards subsets of BFC neurons. For example, inputs from paralimbic cortical areas were confined to subterritories of the basal forebrain, and similarly, those from the hypothalamus or the ventral striatum reached subpopulations of these neurons. In addition, the distribution of several peptides and other afferents (see Semba and Fibiger, l989; Záborszky, l989b) to the basal forebrain suggest that they might contact subpopulations of BFC cells. Thus, the emerging view is that different subsets of these cells receive different combinations of afferents according to their location in the basal forebrain.  On the other hand, noradrenergic afferents, particularly those from the locus coeruleus,  apparently contact extended portions of the BFC system. Other afferents, particularly those which comprise "diffuse corticopetal systems" (Saper, 1987), such as the raphe nuclei, might similarly be expected to maintain a diffuse or generalized relationship to the BFC system.  

             It has been suggested by several authors that BFC neurons receive afferents from those fiber systems with which they are associated in the basal forebrain. Recent morphological data obtained with the PHA-L technique, however, have underscored the distinction between terminal fields and fibers of passage in these areas (Grove, l988; Cullinan and Záborszky, l991). For example, in some cases, fibers completely devoid of terminal varicosities were noted to course through areas rich in BFC cells. On the other hand, the detectability of afferents to cholinergic neurons was usually proportional to the density of terminals present in a given area. Clearly, a more complete understanding of the afferent connections of the BFC system will require the disclosure of those sources which elaborate significant terminal networks in the forebrain areas containing these neurons.

BEHAVIORAL AFFILIATIONS OF BFC NEURONS AS RELATED TO SPECIFIC CIRCUITS

            Various authors have emphasized the role of the BFC system in arousal, sensory processing, emotion, motivation, learning, memory and motor functions. These processes may occur serially, even if they are often interactive.  Much connectional information is needed to establish the possible role of the BFC in these functions, although as discussed below, these processes may be mediated by distinct neural circuits involving BFC neurons.

Arousal

            Moruzzi and Magoun (l949) demonstrated that electrical stimulation of the midbrain reticular formation (MRF) evokes a general cortical EEG desynchronization similar to natural arousal. Since no direct connections exist between the MRF and the cortex, the facilitatory effect of MRF stimulation on the cortex was thought to be mediated partially through the thalamus and through an ill-defined extrathalamic route (Lindsley et al., l949; Starzl et al., 1951). Although there is considerable evidence for the involvement of the intralaminar thalamic nuclei on cortical arousal  (see reviews by Steriade, 1970; Steriade and Llinas, 1988; Steriade and McCarley, 1990), a growing number of studies have suggested that at least part of the effect of MRF stimulation on cortical or hippocampal activation is mediated through the BFC system (Dudar, 1977; Buzsaki et al., l988; Semba, this volume).

            Several data have been taken in support of a role of the BFC in cortical activation. 1) Cortical release of ACh is closely related to level of EEG arousal (Kanai and Szerb, l965; Celesia and Jasper, l966; Collier and Mitchell, l967; Szerb, l967; Jasper and Tessier, l971). 2) Data correlating behavioral states with EEG-related discharge profiles of nucleus basalis neurons (Pirch et al., 1986; Detari and Vanderwolf, 1987; Buzsaki et al., l988; Szymusiak and McGinty, l989), together with electrophysiological evidence that ACh acts as a slow excitatory neurotransmitter in the neocortex (Sillito and Kemp, l983), have been taken as support for the hypothesis that the nucleus basalis provides a steady background of neocortical activity that may enhance the effects of other afferents to the neocortex.  3) Lesions of the basal forebrain lead to decreases in ACh activity in the cortex and reductions of electrical activity over the lesioned hemisphere (LoConte et al., l982). 4) EEG alterations with an increased tendency toward slow waves are seen in patients suffering from Alzheimer's disease (Coben et al., l983), in which loss of neurons in the nucleus basalis is reliably observed.

            An important  issue is thus what drives the BFC system, particularly since these neurons do not show pacemaker-like activity (Griffith, 1986, l988, this volume).  The question of how messages from the outside world (during the waking state) or from the millieu intérieur  (as during REM sleep) drive the BFC system remains largely unanswered. Since MRF stimulation evidently involves not only activation of cells, but of several passing fiber systems, various potential sources of afferents might be considered based upon the correlation between their discharge patterns and the EEG. For example, locus coeruleus axons appear to contact extended portions of the BFC system, and physiological studies have implicated the locus coeruleus in cortical arousal. Although direct projections from various other brainstem sites to BFC neurons are possible, the effects of MRF stimulation upon the cortex could be mediated in part through the lateral hypothalamus, which is known to receive brainstem afferents, as well as contact BFC neurons.

Sensory Processing, Motivation, Emotion, and Learning

            Sensory information passes through multi-synaptic pathways from primary sensory cortical areas, through multi-modal association areas, to the amygdala and hippocampus (Jones and Powell, l970; van Hoesen and Pandya, 1975; Turner et al., l980; Pandya and Yeterian, 1985; Amaral, l987; Heilman et al., l987). It has been suggested that cortico-amygdaloid connections are particularly important in the affective processing of sensory signals (see LeDoux, l987) and in stimulus-reinforcement associations (Jones and Mishkin, l972). The results of biochemical measurements of ChAT activity in various cortical regions suggested that sensory information is likely to come under progressively greater cholinergic influence as it is transferred from sensory association areas, to the multimodal association areas, and finally to the amygdala (Mesulam et al., 1986b). In other words, BFC neurons may gate cortico-limbic interactions. More specifically, Rolls and colleagues (Rolls, l989; Wilson and Rolls, l990a,b) proposed that cholinergic neurons from the orbitofrontal cortex and the amygdala receive information on the expected availability of reinforcement brought about through learning, and relay this information to widespread cortical areas to facilitate sensory, motor, or associative functions. Indeed, neuronal responsiveness in sensory cortex appears to be related to similar motivational changes in basal forebrain neurons (Steriade and McCarley, l990). It is unclear, however, how these motivational related events are transmitted to widespread cortical areas, since it appears that those BFC neurons that receive orbitofrontal input project to limbic cortical areas, rather than sensory or motor cortical regions.

            Studies involving  pairing of sensory stimulation with cortical application of ACh suggest that ACh can produce stimulus-specific modification of information processing in sensory cortical areas (Ashe et al., l989; McKenna et al., l989; Metherate and Weinberger, 1990). Furthermore, studies using  sensory stimulation in combination with nucleus basalis lesions (Satoh et al., 1987; Ma et al.,l989; Juliano et al.,l990) or basal forebrain stimulation (Pirch et al., l986; Rigdon and Pirch, 1986; Rasmusson and Dykes, 1988; Pirch et al., this volume), suggest that the enhancement of sensory-related cortical responses is correlated with activation of the BFC system.  Although more elaborate functional studies are necessary, the connectional data reviewed here are consistent with  the notion that sensory stimuli may reach specific cortical areas through relatively localized portions of the BFC system. For example, as discussed in the section on brainstem connections, auditory signals with weak tuning properties may reach a subpopulation of cholinergic neurons through the peripeduncular area. Such cholinergic neurons then would project to the auditory cortex (see Fig. 9A). A similar situation may exist for viscerosensory inputs as discussed and summarized in Fig. 9B. In this way, specific sensory cortical areas might receive a relatively primitive representation of the peripheral stimulus through the cholinergic system, and more precise information through the thalamic relay. This mechanism might allow for the release of ACh that is spatially and temporally coupled with the arrival of specific sensory signal through the thalamic relay nuclei.

            A similar coupling of ACh release with increased cell firing in the motor cortex may form the basis for learned motor performance  (Woody, 1982; Richardson et al., l988; Richardson and DeLong, l991), although the connectional basis for this is more uncertain.

CONCLUDING REMARKS

            Recent anatomical studies has suggested that afferents to BFC neurons may contact widespread portions of this system, or be relatively restricted. Generalized behavioral functions such as arousal may be mediated in part through relatively diffuse inputs, such as the noradrenergic afferents from the locus coeruleus. Restricted afferents may be related to more specific functions. However, generalized versus specific functions of this system may not be mutually exclusive alternatives, in that either mechanism might predominate depending upon the current or prevailing state of afferent control.

            It is also important to note that afferents to BFC neurons are non-specific, since neighboring non-cholinergic neurons are also apparently the recipients of a given afferent projection. These non-cholinergic cells may have efferent projections that parallel those of BFC neurons, or may constitute interneuronal populations, which in turn, innervate BFC cells. Thus, it is conceivable that such arrangements represent local integrative processing units related to specific functions, of which cholinergic neurons comprise a part.

            Thus, future anatomical studies should be directed at distinguishing subpopulations of BFC neurons with their input-output relationships and to define to what extent such cholinergic neurons together with other nearby non-cholinergic neurons participate in specific forebrain circuits. Such detailed anatomical data, together with the information outlined above and from other recent functional studies (e.g. Olton et al., l991; Richardson and DeLong, l991), should aid in the design of pharmacological, electrophysiological, and behavioral investigations of the functional roles of specific basal forebrain circuits.

ACKNOWLEDGEMENTS

            Particular thanks are due to Dr. Lennart Heimer, who gave continuous support and encouragement over many years.  Mr. F. Lee Snavely and Ms. Vinessa Alones have provided skillful assistance. The original research summarized in this review is supported by USPHS Grants Nos. 23945 and 17743.

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LEGENDS

Fig. 1.  A-F: Series of drawings made from coronal sections through a rat brain (rostral to caudal) that have been immunostained for ChAT (choline acetyltransferase), illustrating the distribution of cholinergic neurons (dots). Striatal cholinergic neurons (including those in the ventral striatum) have been omitted for simplicity. Abbrev. ac = anterior commissure; Acb = accumbens nucleus; BL = basolateral amygdaloid nucleus; BSt = bed nucleus  of the stria terminalis; CA = central amygdaloid nucleus; CP = caudate putamen; DM = dorsomedial hypothalamic nucleus; f = fornix; GP = globus pallidus;  HDB = horizontal limb of the diagonal band; ic = internal capsule; LSd = lateral septal nucleus, dorsal; LSi = lateral septal nucleus, intermediate; LV     = lateral ven-tricle; MCP = magnocellular preoptic nucleus; MS = medial septal nucleus; ot = optic tract; Rt = reticular thalamic nucleus; SI = sublenticular substantia innominata; sm = stria medullaris; VDB = vertical limb diagonal band nucleus; VM = ventromedial hypothalalamic nucleus; VP = ventral pallidum.

Fig. 2. Composite map illustrating the distribution of cholinergic projection neurons (dots). This drawing was composed from 6 camera lucida drawings which were aligned and superimposed to generate the final figure. Only the ventral outlines of the brain and the corpus callosum are indicated. The same technique is used to show the distribution of putative contact sites of different afferent systems in relation to the cholinergic neurons in Fig. 15. Cells between the arrows correspond to the area of the SI. Abbrev. See Fig. 1.

Fig. 3.  A: Golgi impregnated cholinergic neuron (method of Gabbott and Somogyi, l984) located medial to the substriatal gray. Neuron in boxed area is shown under higher magnification in B and C. D: Electron micrograph showing gold deposits (arrows) in the perikaryon, in addition to heavy immunostaining for ChAT. E: Low magnification view of the identified neuron (# 1) in the electron microscope.  Abbrev. CP = caudate putamen. Scale: B=10µm; E=2µm.

Fig. 4.  A: Camera lucida drawing (10x) from a double-labeled section illustrating the distribution of PHA-L labeled fibers in relation to cholinergic neurons following delivery of the tracer to the orbitofrontal cortex. B: Schematic drawing (from section adjacent to the one shown in A) illustrating the distribution pattern of PHA-L labeled terminals in apposition to cholinergic neurons from a section that was analyzed using high magnification light microscopy. Cholinergic neurons are represented by dots. Zones of putative contacts between PHA-L-positive terminals and cholinergic profiles are depicted as squares. Sections were screened using an ocular reticle (80x80 µm) at 63x, and contact sites were marked on a camera lucida drawing of the corresponding section using a proportional grid. Abbrev. see Fig. 1.

Fig. 5.  A: Degenerated terminal synapsing with a cholinergic dendrite in the ventral pallidum two days after lesion of the nucleus accumbens; b: for comparison a normal bouton. B,C: Degenerated terminals after a unilateral meso-diencephalic knife cut on cholinergic dendrites in basal forebrain. Arrows point to synaptic thickenings. Cholinergic profiles are indicated by asterisk. Bar scale: 1 µm.

Fig. 6.  Proposed forebrain circuits involving the cortex, basal ganglia and BFC neurons. Upper row: primate, lower row: rat. Data from Alexander et al. (l986), Groenewegen et al., (1990), Haber et al. (l990). Thick arrow marks the cholinergic link.  Abbrev. A = amyg-dala; ACg = anterior cingulate cortex; AId = dorsal agranular insular cortex; c-MD = mediodorsal thalamic nucleus, central part; d-GP = globus pallidus, dorsal part; dm-CAUD = caudate nucleus, dorsomedial part;  dm-VP = ventral pallidum, dorsomedial part; E = entorhinal cortex; GPi = globus pallidus, internal segment; H = hippocampus; l-ACb = nucleus accumbens, lateral part;  l-MD = mediodorsal thalamic nucleus, lateral part; l-VP = ventral pal-lidum, lateral part; LOF = lateral orbitofrontal cortex; m-ACb = nucleus accumbens, medial part; m-MD = mediodorsal thalamic nucleus, medial part; m-VP = ventral pallidum, medial part; MDmc = mediodorsal thalamic nucleus, magnocellular division; MOF = medial orbitofrontal cortex; PRE = prelimbic cortex; vl-CAUD = caudate nucleus, ventrolateral part; vm-CAUD = caudate nucleus, ventromedial part; vm-PUT; putamen, ventromedial part; VA = ventral anterior thalamus. 

Fig. 7. A: Low power electron micrograph of a reconstructed cholinergic neuron from the substantia innominata (arrow in B).  Boxed area in A is enlarged at inset in upper right corner, and show the synaptic contact of the PHA-L varicosity, indicated by an arrow in C. Arrowheads in the inset  denote sub-synaptic dense bodies. PHA-L was injected into the lateral hypothalamus. Asterisks in A and C mark the same vessel for orientation. Bar scale: A = 10 µm, inset = 1 µm. Reproduced from Záborszky and Cullinan (1989) by permission of Elsevier Science Publishers.

Fig. 8.  A,B: Degenerated terminals after unilateral meso-diencephalic knife cut on cholinergic dendrites (asterisks) in basal forebrain. Arrows point to postsynaptic thickenings. Bar scale: 1 µm.

Fig. 9.  A: Hypothetical circuit involving the auditory cortex, peripeduncular area (PPa), caudomedial (cm) striatum and cholinergic and noncholinergic neurons in the caudal (c) globus pallidus in rat. Heavy line on the right marks the putative cholinergic link. Other connections of the PPa are indicated on the left, including those with auditory subcortical relay stations (heavy lines). Data from  Arnault and  Roger (l987) and LeDoux et al. (1990). Abbrev. ACe = central amygdaloid nucleus; AL = lateral amygdaloid nucleus; CNf = cuneiform nucleus; DLL = dorsal nucleus of the lateral lemniscus; IC = inferior colliculus; PAG = periaqueductal gray; PPT = pedunculopontine tegmental nucleus; PRh = perirhinal cortex; VLL = ventral nucleus of the lateral lemniscus; VMH = ventromedial hypothalamic nucleus; Zi = zona incerta. B: Hypothetical circuit involving the insular cortex, thalamic viscerosensory nuclei, parabrachial nucleus, nucleus of the solitary tract, the central amygdaloid nucleus and cholinergic and noncholinergic neurons in the SI in the rat. Hyphenated lines represent weaker connections,  heavy line  the putative cholinergic link. Data from van der Kooy et al. (l984), Shipley and Geinisman (l984), Cechetto and Saper (l987), and Moga et al. (1990). Abbrev. PBl = lateral parabrachial nucleus; PBm = medial parabrachial nucleus; VPLpc = parvicellular ventroposterior lateral nucleus of the thalamus; VPMpc = parvicellular ventroposterior medial nucleus of the thalamus.

Fig. 10.  A: PHA-L injection site in the dorsal raphe nucleus. The same section stained for serotonin (5-HT) (A') reveals that many of the labeled neurons contain serotonin. B: A cholinergic neuron from the dorsal aspect of the HDB (arrow in D) is approached by PHA-L fibers with varicosities. C: Serotonin axon with varicosities in juxtaposition to cholinergic neurons in the same area of intact animal. Note the similar pattern of axonal arborization with respect to cholinergic neurons in B and C. Scale; A, A', and D = 100µm; B and C = 10µm. Abbrev. ac = anterior commissure; Aq = aqueductus cerebri; FStr = fundus striati; mlf = medial longitudinal fascicle.       

Fig. 11.  A: PHA-L injection site in the ventral medullary reticular formation. B: Enlarged view of the upper part of the box of A showing several PHA-L labeled neurons. Arrow points to a neuron which is double-labeled for dopamine-ß-hydroxylase (DBH). C: The same section as in B stained for DBH. A number of noradrenergic cells of the A1 group are visible in the lower half of the picture. D: Combined PHA-L/ChAT staining from the same case showing the distribution of PHA-L labeled fibers in the forebrain in relation to cholinergic neurons. Bar Scale; A = 500µm; C = 100µm. Star indicates the same vessel in B and C. Abbrev. f = fornix; GP = globus pallidus.        

Fig. 12.  A: Distribution of neurotensin-containing fibers/terminals and cholinergic cells at the level of the posterior part of the crossing of the anterior commissure. B: Schematic drawing from the same section showing that the ventral part of the globus       pallidus contains a number of cholinergic projection neurons which  are embedded in a heavy neurotensin-containing network. Bar Scale:  500µm. Abbrev. ac = anterior commissure; CP = caudate putamen; f = fornix; ic = internal capsule; MP = medial preoptic nucleus; Tu = olfactory tubercle; 3V = third ventricle.

Fig. 13.  A: Camera lucida drawing from a frontal section at the level of the anterior commissure stained for dopamine-ß-hydroxylase (DBH) fibers/terminals and cholinergic neurons using the nickel enhanced DAB/DAB technique. Only the most proximal portions of dendrites of cholinergic cells are drawn. B: Distribution of PHA-L labeled fibers in relation to cholinergic neurons at the same level as A after PHA-L injection in the locus coeruleus. Note that PHA-L labeled fibers/terminals from locus coeruleus may represent a portion of those found in the DBH/ChAT material. Abbrev.  ac = anterior commissure; HDB = horizontal limb of the diagonal band.

Fig. 14.  A: Topography of synaptic inputs to a typical cholinergic neuron in the SI. Compiled  from our data as well as that of Bolam et al. (l986); Chang et al. (l987) and Martinez-Murillo et al., (l988a, 1990). Putative inhibitory synapses are labeled by solid, excitatory contacts by open symbols. B: Somatostatin-containing bouton in synaptic connection with the dendrite. Double labeling with nickel enhanced DAB/DAB. C: Bouton containing large neurosecretory granula (small arrows) establishing synaptic contact with the distal dendrite. Single immunostaining for ChAT. D: GABAergic bouton labeled with ferritin (small arrow) establishes symmetrical contact with the cholinergic cell body. From the material of Záborszky et al. (1986) by permission of Willey and Liss. E: ChAT-positive bouton contacts proximal ChAT-positive dendrite. Single immunostaining enhanced with cobalt. F: DBH-positive bouton establishes asymmetric synapse with a cholinergic dendrite. Double immunolabeling with NiDAB/ DAB. Arrowheads show subsynaptic dense bodies. In all micrographs large arrows point to the postsynaptic side of the synapse, asterisks label the immunostained (ChAT) profile. Bar scale for all micrographs: 1 µm.

Fig. 15.  A: PHA-L labeled terminal varicosities in close apposition to a proximal dendrite of a cholinergic neuron. The grid simulates the proportions of the ocular reticle used to screen sections from high magnification (63x) light microscopic analysis. One division of grid = 16 µm. B-F: Composite maps illustrating putative zones of contact between afferent fibers and cholinergic neuronal elements following PHA-L injections into the (B) locus coeruleus, (D) far-lateral hypothalamus, (E) mid-lateral hypothalamus, (F) medial hypothalamus. C: shows the distribution of putative contact sites from a material stained for DBH/ChAT. Cholinergic neurons are represented by dots. Zones of putative contacts between cholinergic elements and terminal varicosities are depicted as solid squares (corresponding to 80x80 µm areas in the section).