The Interface Between Dopamine Neurons and the Amygdala: Implications for Schizophrenia

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1 The Interface Between Dopamine Neurons and the Amygdala: Implications for Schizophrenia by Suzanne N. Haber and Julie L. Fudge Abstract A substantial amount of research has focused on the midbrain dopamine system and its role in emotional and motivational behaviors. In diseases in which dopamine function is compromised, patients exhibit a constellation of symptoms, suggesting that the dopamine system plays an important role in the integration of several functions. Subgroups of dopamine neurons receive information from limbic and association areas and project widely throughout cortex and striatum, including motor areas. A dorsal tier of dopamine neurons receive input from the ventral (limbic-related) striatum and from the amygdala and project widely throughout cortex. A more ventrally located group of dopamine cells receives input from both the limbic and association areas of striatum and projects widely throughout the striatum, including the sensorimotor regions. Through these projections, the limbic system has an enormous influence on dopamine output and can therefore affect the emotional and motivational "coloring" of a wide range of behaviors. Schizophrenia Bulletin, 23(3):471^*82,1997. The idea that dopamine transmission plays a role in the pathogenesis of the major psychoses began with the empirical discovery that the phenothiazines, which were used initially as antimicrobials, had potent antipsychotic effects and were superior to barbiturate sedation. Delay et al. (1952) first reported successful use of chlorpromazine as a single agent for psychosis. Subsequently, studies in rodents revealed that neuroleptic drugs were associated with selective increases in dopamine metabolites and in dopamine neuron firing rates. Both of these changes were viewed as compensatory to the proposed blockade of postsynaptic dopamine transmission in the forebrain. Neuroleptic drugs block both stereotyped behavioral responses and specific neuroendocrine responses induced by dopamine and dopamine agonists. Qinically, the syndrome of extrapyramidal side effects that accompanies neuroleptic administration and the amelioration of these side effects with anticholinergic medications provided further evidence that neuroleptics blocked dopamine transmission. Thus, as clinical and laboratory evidence accumulated (Baldessarini 1985), the idea that increased dopamine transmission is directly related to the etiology of schizophrenia evolved into the dopamine hypothesis of schizophrenia. Generally, its focus has been on the dopamine neurons of the ventral tegmental area (VTA) and their projection to the nucleus accumbens. These two structures, the VTA and the nucleus accumbens, have long been associated with the limbic system, both anatomically and behaviorally. The amygdaloid complex is a prominent component of the limbic system and is involved in controlling or mediating behaviors associated with emotion and visceral reactions (Kaada 1972), including autonomic functions, and in memory formation and cognitive functions. These functions of the amygdala are associated with its interconnections with the limbic-related structures (Potter and Nauta 1979; Aggleton et al. 1980; Turner et al. 1980; Mufson et al. 1981; Porrino et al. 1981; Amaral and Price 1984; Friedman et al. 1986). The amygdala's important role in emotional functioning has long been recognized. In the Kluver-Bucy syndrome, first described in the 1930s (Kluver and Bucy 1939), monkeys with lesions of the anterior temporal lobes exhibited several behavioral abnormalities, including unresponsiveness to stimuli that normally provoke fear. Later, studies of localized lesions to the amygdaloid complex also noted a decrease in responses to previously aversive stimuli (Weiskrantz 1956). On the basis of bilat- Reprint requests should be sent to Dr. S.N. Haber, Dept. of Neurobiology and Anatomy, University of Rochester School of Medicine, 601 Elmwood Ave., Rochester, NY

2 Schizophrenia Bulletin, Vol. 23, No. 3, 1997 S.N. Haber and J.L. Fudge eral amygdalectomy in monkeys, Gaffan and Harrison (1987) argued that the amygdala is especially important in mediating the control over behavior by conditioned reinforcers. Studies on humans undergoing surgical ablation of the amygdala provide limited information due to uncontrolled samples, but tend to show a decrease in aggression and an inability to respond to normally fearful stimuli (AggJeton 1992). A recent article by Adolphs et al. (1994) reported a rare patient with focal bilateral lesions of the amygdala who had interesting deficits in the ability to recognize emotions, particularly fear. Physiological studies in normal monkeys have demonstrated that some neurons in the amygdala respond to the reward (or punishment) contingencies of sensory stimuli (Nishijo et al. 1988). Stimulation studies performed in humans have evoked intense affective experiences (Chapman et al. 1954; Heath et al. 1954; Halgren et al. 1978; Gloor et al. 1982), as well as perceptual disturbances, complex hallucinations, ddja vu, and somatosensory experiences. Patients with temporal lobe epilepsy may develop a schizophrenia-like psychosis, but the exact site of abnormal firing may be difficult to localize. The amygdala, along with the hippocampus, has also been implicated in sustaining the learning of emotionally charged material (Murray and Mishikin 1985; Gaffan and Harrison 1987, 1989; Gaffan and Murray 1990; LeDoux et al. 1990). Despite the obvious link between the amygdala and emotions, surprisingly little has been written on the role of the amygdala in psychosis or schizophrenia. There are several reasons for this gap in the literature. First, despite the high resolution of magnetic resonance imaging (MRI), the amygdala remains difficult to visualize because of its close apposition to the hippocampus. The boundary between the caudal amygdala and rostral hippocampus is poorly resolved with magnetic resonance imaging. Thus, volumetric studies of the amygdala are forced to rely on external landmarks to make approximate measurements (Breier et al. 1992; Bogerts et al. 1993). Second, there is a paucity of patients with confined lesions of the amygdala. Studies of amygdalectomy provide some information, but are largely uncontrolled and vary greatly in the size of the surgical lesion. In general, data from patients with "deficit lesions" of the amygdala show that they are less aggressive and have a lack of response to fear-provoking environmental stimuli (Aggleton 1992). Finally, the amygdala is not a homogeneous structure, but instead comprises several nuclear groups with a vast array of interconnections among cortex, basal ganglia, thalamus, brainstem, and hypothalamus. The circuitry of the amygdala, particularly in the primate, continues to be elucidated (Amaral et al. 1992; Kuo and Chang 1992). This article reviews the connections of the primate midbrain dopamine system with the limbic system, with a particular focus on the primate dopamine system relationship with the amygdala. Based on these connections, we hypothesize that the amygdala may play a key role in the regulation of dopamine output. Overstimulation of the amygdalonigral projection may result in excessive dopamine cell firing in the midbrain, affecting the integration of limbic, cognitive, and motor functions. Organization of the Midbrain Dopamine Neurons On the basis of cytoarchitectonic features, Olszewski and Baxter (1954) divided the substantia nigra pars compacta (SNc) into three groups: (1) a dorsal group (the y group), also referred to as the pars dorsalis (Poirier et al. 1983); (2) the main, densocellular region (the ($ group); and (3) a ventral group (the a group) (figure 1). The SNc is closely associated, and almost imperceptibly merges, with the immediately adjacent dopamine cell groups of the VTA, the most prominent of which in primates are the parabrachial pigmented nucleus and the paranigral nucleus. The dorsal group of the SNc comprises loosely arranged cells, extending dorsolaterally to circumvent the ventral and lateral aspects of the superior cerebellar peduncle and the red nucleus. These dorsal neurons are oriented horizontally, just dorsal to a dense cluster of neurons referred to as the densocellular region (the p group), and form a continuous band with the VTA. The dendrites of this dorsal group stretch in a mediolateral direction and do not extend into the ventral parts of the pars compacta or into the pars reticulata. In contrast, the dendritic arborizations of the densocellular region are oriented ventrally and occupy the major portion of the pars reticulata in primates. The ventral group forms cell columns that penetrate deep into the pars reticulata. Figure 1. Organization of dopamine cells in the ventral midbrain RcdNudcui Dosal tier -r-iuadsnc <A8) y"-vta (AI0) Ventral Her <A9) If -columnt (A9) SNc = substantia nigra, pars compacta; SNr = substantia nigra, pare reticulata; VTA = ventral tegmental area. 472

3 Interface Between Dopamine Neurons and the Amygdala Schizophrenia Bulletin, Vol. 23, No. 3, 1997 Calbindin, a calcium-binding protein (CaBP), is found in the dorsal group of cells and in the VTA, although both the densocellular group and the ventral cell groups are calbindin negative (Lavoie and Parent 1991; Haber et al. 1995b; McRitchie and Halliday 1995). This feature in both the dorsal group and VTA is an important phenotypical similarity between these groups and contributes to the continuity of the mediodorsal cell groups (Haber et al. 1995b). The densocellular and ventral regions of the primate midbrain dopamine neurons, in contrast, have higher levels of messenger ribonucleic acid (mrna) expression for dopamine transporter (DAT) and D 2 receptor mrnas than the dorsal group and the VTA (Haber et al. 1995b). Thus, based on the phenotypical characteristics, the midbrain dopamine neurons can be divided into two tiers: a dorsal tier and a ventral tier. The cells of the dorsal tier are CaBP-positive and include both the dorsal SNc and the contiguous VTA. The ventral tier cells, which include both the densocellular and the ventral group, are calbindin-negative and have relatively high levels of expression for DAT and the D 2 receptor. Functional Connections of the Two Groups of Dopamine Neurons Dorsal and Ventral Tier Projections to Functionally Distinct Areas of Striatum. Studies of the primate striatum have recently focused on its organization with respect to inputs from functionally defined cortical regions (Alexander et al. 1986). The primate striatum has been divided into separate domains based on cortical input (figure 2) (Kemp and Powell 1970; Kiinzle 1975, 1978; Jones et al. 1977; Kiinzle and Akert 1977; Poletti and Cresswell 1977; Selemon and Goldman-Rakic 1985; Flaherty and Graybiel 1991; Kunishio and Haber 1994<J, 1994b; Haber et al. 1995a). Classically, the nucleus accumbens, which is part of the ventral striatum, has been associated with limbic function. However, cortical and subcortical inputs that are considered to be related to the limbic system project not only to the nucleus accumbens but also to the ventral caudate nucleus and to the rostral, ventral putamen (Nimmi and Kuwahara 1973; Poletti and Cresswell 1977; Russchen et al. 1985; Gim6nez-Amaya et al. 1995; Haber et al. 1995a). Furthermore, there is no clear cytoarchitectonic boundary between the nucleus accumbens and the caudate nucleus dorsomedially nor between the nucleus accumbens and the putamen laterally. Therefore, the entire rostroventral area that receives input from the limbic system is referred to as the ventral striatum and is considered limbic-related (Heimer et al. 1982; Haber et al. 1990). Figure 2. Schematic representation of functional map of the striatum based on cortical inputs A. Rostral B. Caudal uaroututbcomx Levels of overlap Eire indicated by Intermediate shades of gray. Based on work in rats (Zahm and Brog 1992; Heimer et al. 1994), the nucleus accumbens in primates is further divided into core and shell subterritories (Martin et al. 1991; Lynd-Balta and Haber 1994c; Meredith et al. 1995). The core is continuous with the rest of the striatum, whereas the shell surrounds the core at its medial and ventral borders. The shell is linked most tightly to the limbic system. Although the rest of the ventral striatum receives a mixed input from both limbic and association areas, the shell receives a restricted input from the limbic-related thalamus (Gime'nez-Amaya et al. 1995), cortex (Kunishio and Haber 1994b; Haber et al. 1995a), and the ventral midbrain (Lynd-Balta and Haber 1994c). It is best distinguished from the rest of the ventral striatum by its relative low levels of CaBP-immunoreactivity. The dorsolateral part of the striatum receives inputs from sensorimotor cortex, supplementary motor area, and the frontal eye fields. The large central area of the rostral striatum and much of the caudate nucleus posterior to the commissure receive inputs from a wide range of association cortices. Substantia nigra neurons that project to a given region of striatum (limbic, association, or sensorimotor) are distributed broadly and are found in clusters interrupted by cells that project to other functionally defined areas. Inputs to all functional domains are derived from the entire rostrocaudal extent of the substantia nigra (Smith and Parent 1986; Hedreen and DeLong 1991; Lynd-Balta and Haber 1994a). There are, however, some general principles of nigrostriatal organization as it relates 473

4 Schizophrenia Bulletin, Vol. 23, No. 3, 1997 S.N. Haber and J.L. Fudge to the functional domains of the striatum. The majority of projections to the limbic (ventral) striatum originate from the medial half of the midbrain neurons (Lynd-Balta and Haber 1994c). These projections arise from both the dorsal and ventral tiers. However, it is only the densocellular region of the ventral tier that projects to the limbic (ventral) striatum; the ventral tier cell columns do not (Lynd- Balta and Haber 1994a). There is an important distinction between ascending midbrain projections to the shell region of the nucleus accumbens and those to the rest of the striatum (Lynd-Balta and Haber 1994a, 1994c). Although most of the striatum receives projections from both the dorsal and ventral tier neurons, virtually all of the cells innervating the shell of the nucleus accumbens originate from the dorsal tier of mesencephalic neurons, including the dorsal SNc and the VTA (Lynd-Balta and Haber 1994c). This limited area of the striatum does not receive input from the ventral tier. In contrast, the sensorimotor-related striatum derives its midbrain input from the ventral tier, both the densocellular region and the cell columns. The dorsal tier (the VTA and the dorsal SNc) do not project here (Lynd-Balta and Haber 1994a). Within the densocellular region, groups of cells that project to the sensorimotor striatum are found in the lateral two-thirds and do not extend to its medial border with the VTA. One way to characterize the organization of the nigrostriatal dopamine projections is to divide them into three groups of neurons the dorsal tier, which projects to the ventral striatum; the densocellular part of the ventral tier, which projects throughout the striatum; and the cell columns, which project primarily to the dorsolateral (sensorimotor) striatum (figure 3). The central part of the densocellular region of the ventral tier projects to both the ventral and dorsal parts of the striatum. Within the center of this midbrain region, there is an intermingling of cells that project to different striatal territories, thereby allowing a large area of the striatum to be modulated by inputs from this midbrain region. Therefore, unlike cortical projections to the striatum there is no simple point-to-point relationship between different groups of substantia nigra neurons and the different functional domains of the striatum. Dopamine Projections to the Cortex. Studies that directly address the topographic organization of midbrain dopamine neurons to cortex in primates have shown that the majority of cells projecting to the cortex arise from both the VTA and the medial half of the SNc throughout its rostrocaudal extent (Porrino and Goldman-Rakic 1982; Gaspar et al. 1992). The parabrachial nucleus of the VTA complex is the most consistently labeled part of the VTA after injections of retrograde tracers are made into various regions of frontal cortex. The dorsal SNc is also well Figure 3. Composite drawing of the midbrain projection to the striatum In two rostrocaudal views dondtior, Inckxlng dona! cat graup ndvta dmocsfciugn><4>(var*njti*f) ceo cdmra (v*ntnj a«r) AC = anterior commissure; C = caudate; IC = internal capsule; P = putamen; SNc = substantia nigra, pars compacta; VP = ventral pallidum; VTA = ventral tegmental area. labeled. The densocellular region and the ventral groups of the substantia nigra do not project to the cortex. Thus, the dorsal but not the ventral tier of midbrain neurons give rise to the dopamine-cortical projection. After injections of different fluorescent dyes into motor, supplementary motor area, and prefrontal regions, Gaspar et al. (1992) found that groups of labeled neurons in the substantia nigra overlapped. Although there was some general mediolateral topography, it was not very precise. Furthermore, some cells were double-labeled, indicating that substantia nigra axons branch and send collaterals to multiple cortical regions. The dorsal tier neurons (the VTA and the dorsal substantia nigra) are the source for the midbrain dopamine cortical projections and the projections to the ventral striatum, particularly the shell region. The ventral tier neurons, for the most part, do not contribute to these projections. However, unlike its projection to the striatum, the dorsal tier projection to the cortex is not organized with respect to function. Cells projecting to functionally different cortical regions are intermingled with each other, many of which send collateral axons to different cortical regions. In contrast, cells in the nigrostriatal projection project primarily to the limbic striatum. The nigrocortical projection, on the other hand, is a diffuse system that can modulate cortical activity at several levels. Dopamine fibers are evident in prefrontal granular areas and also in agranular frontal regions, parietal cortex, temporal cortex, and even, albeit sparsely, in occipital cortex. The densest terminals 474

5 Interface Between Dopamine Neurons and the Amygdala Schizophrenia Bulletin, Vol. 23, No. 3, 1997 are found in a trilaminar arrangement in layers I, Ilia, and V-VI of agranular areas 4 and 6, as well as the supplementary motor area. Prefrontal granular areas, including both dorsal prefrontal cortex and orbitofrontal cortex, parietal regions associated with somatosensory information, and temporal cortical areas also have a relatively high density of dopamine fibers, although less than the agranular frontal cortex. In these cortical regions, the terminal densities are arranged in a bilaminar organization, with layers I and V-VI having particularly dense terminals (Berger et al. 1988; Gaspar et al. 1989, 1992). Terminals in deep layers are in a position to provide a more direct modulation of cortical efferent projections, including corticostriatal and corticothalamic projections. Striatonigral Pathways. The striatum projects massively back to the substantia nigra (Nauta and Mehler 1966; Szabo 1967, 1970; Johnson and Rosvold 1971; Parent et al. 1984; Haber et al. 1990; Selemon and Goldman-Rakic 1990; Hedreen and DeLong 1991; Lynd- Balta and Haber 1994b; Parent and Hazrati 1994). Ventral striatonigral inputs terminate in the medial pars reticulata and much of the densocellular part of the pars compacta, whereas dorsolateral striatonigral inputs are concentrated in the ventrolateral pars reticulata. It is important to note that the ventral striatal fibers terminate throughout a wide medial, lateral extent of the densocellular region of the ventral tier (Haber et al. 1990; Hedreen and DeLong 1991). Although at the rostral level of the substantia nigra, ventral striatal fibers terminate medially, more caudally these terminals spread dorsalward and laterally to innervate the region of the densocellular SNc and, just ventral to it, in the substantia nigra pars reticulata (SNr) (Haber et al. 1990). Thus, the ventral striatum not only projects throughout the rostrocaudal extent of the substantia nigra but also covers a wide mediolateral range. In contrast, efferent projections from the dorsolateral (sensorimotor) striatum are confined to a relatively small region of the SNr (Smith and Parent 1986; Lynd-Balta and Haber 1994b). These projections are found in the ventrolateral part of the SNr throughout its rostrocaudal extent. As with the nigrostriatal projections, several topographic arrangements have been proposed that can be understood best with respect to the cortical domains in the striatum. The limbic (ventral) striatum projects primarily to the rostromedial part of the SNr and spreads laterally into the region of the densocellular neurons. The sensorimotor (dorsolateral) striatum projects to the ventrolateral SNr. This gives rise to the inverse dorsolateral projections and to the rostral-to-medial and caudal-to-lateral topography. Functional Modulation and Integration Through Striatonigrostriatal Pathways. Although the dorsolateral striatal inputs are limited to pars reticulata, the nondopaminergic region of the substantia nigra, they terminate in close proximity to a subset of the pars compacta neurons projecting to the dorsolateral striatum (Hedreen and DeLong 1991; Lynd-Balta and Haber 1994b). Columns of dopaminergic neurons in the ventral tier invade the pars reticulata and occupy very ventral regions of the substantia nigra. These neurons are retrogradely labeled after injections of the retrograde tracer, horseradish peroxidase, into the dorsolateral striatum. The dorsolateral striatum innervates the region of the pars reticulata that suirounds these invading columns, and numerous anterogradely labeled fibers are intermingled with labeled cells. At the light microscopic levels, these fibers appear to be in direct contact with cells and their dendrites, indicating that the ventrolateral substantia nigra and the ventral columns of pars compacta neurons in this area are selectively and reciprocally connected with the dorsolateral striatum. The limbic and association areas of the striatum are reciprocally connected to the densocellular neurons (Hedreen and DeLong 1991; Lynd-Balta and Haber 1994b). Indeed, there are terminals that lie in close approximation or just ventral to labeled neurons within the area of their dendritic processes. Support for a direct contact between striatonigral projections and nigrostriatal neurons also comes from immunohistochemical studies showing the close relationship between descending substance P positive fibers and dopaminergic cells (Haber and Groenewegen 1989). The connections of the dorsal tier with the ventral striatum, and of the ventral columns of the ventral tier with the sensorimotor-related striatum, suggest that some separation is maintained in nigral projections to different striatal territories. However, the densocellular zone of the ventral tier is unique in that it contains neurons projecting throughout all regions of the striatum. Moreover, the clusters of cells that project to different striatal regions are intermingled. Although after injections of both retrograde and anterograde tracers into the same striatal region, labeled cell bodies are often found within a region of dense terminal fibers; in several instances, labeled cells are also found isolated from anterogradely labeled fibers (Hedreen and DeLong 1991; Lynd-Balta and Haber 1994b). This was predominantly seen in the densocellular region after injections into the more dorsal aspects of the striatum. These findings suggest that the more medially placed densocellular cells that project to the sensorimotor parts of the striatum receive striatal input from ventral regions and not from the dorsal striatum. Indeed, the densocellular region receives a large afferent projection 475

6 Schizophrenia Bulletin, Vol. 23, No. 3, 1997 S.N. Haber and J.L. Fudge from the ventral striarum (Haber et al. 1990; Lynd-Balta and Haber 1994fc). Furthermore, much of the association striarum terminates in the pars reticulata just ventral to the dopaminergic cells' bodies and within their dendritic arborization. This places the densocellular neurons in a unique position to receive ventral striatal input and modulate the dorsal striarum. These cells are in a pivotal position to receive and integrate information, particularly from the ventral (limbic-related) striarum and, to some extent, the association areas, and to modulate a wide area of striatum (Haber et aj. 1994). The idea that the nucleus accumbens serves as an interface connecting the limbic system with the motor system, via its close connections with the limbic system and the basal ganglia, was first proposed based on work in rats (Heimer 1978; Nauta and Domesick 1978; Nauta et al. 1978; Mogenson et al. 1980; Somogyi et al. 1981). Furthermore, Nauta recognized that the ventral striatal projections to the dorsal substantia nigra may allow it to influence a much larger proportion of the dopaminergic neurons than it receives inputs from (Nauta and Domesick 1978, 1984; Nauta et al. 1978). Thus, there are two systems within the substantia nigra: one in which information passes to the thalamus via the pars reticulata and one in which striatal information passes to the dopamine neurons, which in turn modulate the striatum and cortex. A large subset of the dopamine neurons are therefore in a position to modulate the general output of both the striatum and cortex. Connections of the Amygdala. Because of the complexity of the amygdala, various nomenclatures for its nuclear and cortical subdivisions have evolved. Amaral et al. (1992) have reviewed the terminology for regions of the amygdaloid complex and presented a nomenclature for primates. In brief, the amygdaloid complex can be divided into several nuclear groups. There is a deep nuclear group comprising the lateral nucleus, the basal nucleus, the accessory basal nucleus, and the paralaminar nucleus. There is a superficial region containing the anterior cortical nucleus, the medial nucleus, the periamygdaloid cortex, and the posterior cortical nucleus. Other nuclei are the central nucleus, the anterior amygdaloid area, and the amygdalohippocampal area (Amaral et al. 1992). In general, the amygdaloid complex has strong, direct, and reciprocal connections with widespread regions of the limbic-related neocortex, such as the orbital and medial prefrontal cortex and insular, cingulate, and temporal cortices (Whitlock and Nauta 1956; Nauta 1961; Herzog and Van Hoesen 1976; Krettek and Price 1977; Macchi et al. 1978; Aggleton et al. 1980; Turner et al. 1980; Mufson et al. 1981; Porrino et al. 1981; Amaral and Price 1984). For example, the basal nucleus of amygdaloid complex is reciprocally connected to the anterior cingulate cortex, particularly area 25, parts of area 24, the orbitofrontal cortex, and the agranular insular cortex (Llamas et al. 1977; Macchi et al. 1978; Aggleton et al. 1980; Amaral and Price 1984). These cortical regions project to the shell and the medial ventral striatum (Kunishio and Haber 1994a; Haber et al. 1995a). The basal and accessory basal nucleus has direct connections to the same region of the ventral striatum via amygdalostriatal projections. Furthermore, it may also have indirect connections through amygdalo-cortico-striatal projections. The ventral striatum, in particular the shell and the medial ventral striatum that receive amygdaloid input, also receives specific cortical projections from these cortical areas. For example, the rostral part of the anterior cingulate cortex areas 32, 25, 24a, and 24b projects to the medial ventral striatum and to the shell of the nucleus accumbens (Kunishio and Haber 1994a). The orbital and medial prefrontal cortex also projects mainly to the ventral striatum (Haber et al. 1995a). A fiber degeneration study carried out in primates showed that the projections from the amygdala, primarily from the basal and accessory basal nucleus, terminate in the rostral portion of the putamen, the nucleus accumbens, and the olfactory tubercle (Zahm and Brog 1992). Using tritiated amino acids, Russchen et al. (1985) investigated the organization of the amygdalostriatal projection in monkeys and demonstrated that the amygdaloid complex gives rise to a prominent, widespread projection to the nucleus accumbens and adjacent parts of the olfactory tubercle, to a ventral and caudal part of the caudate nucleus including the tail, and to a ventral part of the putamen. These projections arise primarily from the magnocellular and parvicellular subdivisions of the basal nucleus of the amygdala and to some extent from the magnocellular and parvicellular subdivisions of the accessory basal nucleus and the amygdalohippocampal area. They concluded that the parvicellular subdivision of basal nucleus and the amygdalohippocampal area appear to be the major sources of projections to the nucleus accumbens (Russchen et al. 1985). Recent studies indicate that the amygdala projects more densely to the shell and the medial ventral striarum and less densely to the central and lateral part (Kunishio and Haber 1994a). For example, the shell region and the medial ventral striatum receive the densest projections, primarily from the magnocellular and parvicellular subdivisions of the basal nucleus, and from the magnocellular subdivision of the accessory basal nucleus. The central and lateral ventral striatum show fewer labeled cells in the various subdivisions of the amygdala. 476

7 Interface Between Dopamine Neurons and the Amygdala Schizophrenia Bulletin, Vol. 23, No. 3, 1997 Mesencephalic dopamine neurons also project to the amygdala. Dopamine fibers in the amygdala are predominantly found in the central, basal, and lateral nuclei (Sadikot and Parent 1990). The densest innervation is in the central and medial part of the central nucleus. Projections to the amygdala arise from both the VTA and the adjoining dorsal pars compacta (Aggleton et al. 1980; Mehler 1980; Norita and Kawamura 1980). After an injection of the retrograde tracer horseradish peroxidase into the medial nucleus of the amygdala, many cells were labeled in both the VTA and the SNc primarily in the medial and dorsal part (Norita and Kawamura 1980). Thus, the dorsal tier neurons give rise to projections not only to the ventral striatum but also to the amygdala. In addition, cells are labeled in the SNc and VTA after injections of retrograde tracer into the sublenticular substantia innominata and the basolateral nucleus of the amygdala (Haber, unpublished observations, 1995). Descending projections from the central nucleus of the amygdala terminate in a wide mediolateral region of dopamine cells (Price and Amaral 1981). These fibers descend in the ventral amygdalofugal pathways and terminate primarily in the dorsal SNc and in the densocellular regions. In addition, there are projections to the VTA and the dorsomedial SNc from the bed nucleus of the stria terminalis and from the sublenticular substantia innominata (Haber, unpublished observations, 1995). These fibers travel together with those from the amygdala. Heimer and others have proposed the idea of the "extended amygdala," noting that the central nucleus and limbic forebrain structures namely, the bed nucleus of the stria terminalis and sublenticular substantia innominata have similarities in cell morphology, connectivities, and histochemistry (Alheid and Heimer 1988; Heimer et al. 1991). It is of interest to note that a major afferent system to a wide range of dopamine neurons is therefore derived from the limbic forebrain. This descending system of the extended amygdala has direct access to striatal and cortical structures. Relationship of the Limbic Connections to the Dorsal and Ventral Tier Neurons. The dorsal tier neurons are tightly linked with the limbic system. The shell region of the nucleus accumbens receives inputs exclusively from the dorsal tier (Lynd-Balta and Haber 1994c). Dorsal tier neurons also innervate the core of the nucleus accumbens, the rostral and ventral putamen, and the ventromedial caudate nucleus. In return, the ventral striatum projects to a large region of the pars compacta, including the area of the dorsal tier. In addition, the dorsal tier receives input from the central nucleus to the amygdala, the bed nucleus of the stria terminalis, and the sublenticular substantia innominata, all parts of the extended amygdala. The entire dorsal tier sends ascending fibers to the amygdala. There is a substantial connection of the VTA and the dorsal cells of the substantia nigra to the extended amygdala. The dorsal tier neurons do not extend their processes into the ventral tier and therefore receive little direct information through descending striatonigral pathways. Thus, the neurons of the dorsal tier are selectively and reciprocally connected with the ventral, limbic striatum and with the amygdala. However, these cells project widely throughout cortex and are in a position to influence more than the limbic system through this cortical innervation. The ventral tier can be divided into two groups: the densocellular region and the ventral group. The densocellular region is also in a unique position in that its cells receive information from both the limbic and association striatum and from the extended amygdala. Unlike the dorsal tier, however, these cells project widely throughout the striatum and thus can have a profound influence on all striatal output, including sensorimotor output. Through the dorsal tier connection to cortex and the densocellular connection to striatum, these two cfell groups can influence a wide range of behaviors. The inputs to these cells are limited in that they are derived from structures closely associated with limbic function. The amygdala has a particularly large influence on these cells, both directly through the amygdalonigral pathway and indirectly through the amygdalostriatonigral pathway (figure 4). Function and Disease Much of the interest in the function of the midbrain dopamine neurons centers around the association with different pathologies. The use of phenothiazines for a number of psychiatric disorders, including schizophrenia and Tourette's syndrome, and the side effects of their use support the important role that dopamine plays in behavioral, emotional, and motoric stability. Electrophysiological studies of primates performing different tasks give some insight into the role of dopamine in carrying out and initiating behaviors. Unlike the neurons in other basal ganglia structures, the dopaminergic neurons of the substantia nigra are unresponsive to active or passive limb manipulations, such as innocuous somatosensory stimulation (DeLong et al. 1983; Schultz and Romo 1987). Schultz et al. (1995) have demonstrated several electrophysiological features of the substantia nigra dopamine neurons in the monkey. Specifically, dopamine neurons are characterized by the long duration and homogeneity of their responsiveness. That is, neurons throughout the midbrain dopamine system respond nonpreferentially to a 477

8 Schizophrenia Bulletin, Vol. 23, No. 3, 1997 S.N. Haber and J.L. Fudge Figure 4. Schematic drawing of the midbraln dopamine projection and its relationship to amygdaloid Inputs SNc = substantia nlgra, pars compacta. ticular stimulus, which suggests that dopamine neurons activate in parallel, rather than in a sequential or differentiated way, to environmental stimuli. These stereotyped responses are related to the novelty of an unexpected stimulus, to primary rewards, and to the conditioned stimulus that is associated with the reward. Significantly, in overtrained animals, there is a loss of responsiveness in dopaminergic cells, which is presumably a result of the environmental stimulus having lost its salience or ability to predict reward. The overtrained animal has already learned the task, and behavior is no longer driven by reward, but rather by habit. Thus, the midbrain dopaminergic system is postulated to be involved in the rewarded learning of new behaviors, in contrast to maintaining previously learned behaviors (Schultz and Romo 1987; Ljungberg et al. 1992; Schultz et al. 1995). This theory is consistent with the proposed function of the midbrain dopamine neurons as signaling rewards and novel, potentially rewarding stimuli in the environment, which shapes behavior. The symptoms of schizophrenia are wide ranging and include thought disorder, as well as disturbances of affect, perception, and psychomotor function. In addition, patients frequently suffer negative symptoms, such as lack of motivation or anhedonia, which suggest dysfunction of reward circuitry. This broad range of deficits is consistent with both the parallel firing of dopamine cells in response to reward stimuli and the proposed integrative role of the substantia nigra. Excessive firing of amygdaloid neurons projecting to the substantia nigra and VTA would disrupt 478 dopamine levels not only in the so-called mesolimbic circuit the amygdala, nucleus accumbens, and olfactory tubercle but also throughout widespread areas of striatum and cortex. The dorsal tier cells and the densocellular group receive a major input from the amygdala and project widely throughout cortex and striatum, respectively. They are in a position therefore to use information about reward and motivation to influence the execution of a wide variety of behaviors, including initiation of movement and cognition. If the amygdaloid projection to the dorsal tier of the mesencephalon is inhibitory, excessive firing of this projection would create inhibition of mesocortical dopamine circuits. The dorsal tier neurons may function as more "tonically firing" dopaminergic cells, providing a baseline level of dopamine modulation to cortical areas. If these neurons are excessively inhibited by input from the amygdala, decreased dopamine levels in prefrontal circuits could result. Support for a more tonic modulatory function of dorsal tier neurons comes from our finding that these cells are relatively devoid of mrna for the D 2 autoreceptor and for the DAT compared with neurons of the ventral tier. Specialized autoregulatory features such as the D 2 presynaptic receptor and DAT may be more consistent with the function of phasically firing cells, which respond to changing environmental stimuli. The densocellular neurons of the ventral tier receive amygdaloid input and project throughout striatum. The dopaminergic cells projecting to striatum fire phasically in response to environmental cues and may be dysregulated in schizophrenia. One model proposed by Grace (1991) is that abnormally enhanced dopamine release during phasic firing results from lowered tonic release of dopamine in this circuit. This model suggests that tonic dopamine release is lowered in the striatum by decreased glutamate from corticostriatal afferents. An alternative hypothesis is that chronic inhibition of densocellular and dorsal tier neurons by amygdaloid input decrease dopamine "tone" in projections to the striatum and prefrontal cortex, respectively. In contrast to the dorsal tier, the densocellular neurons can respond to this lowered tone by decreased synthesis of D 2 autoreceptor and DAT, for example. This would result in increased dopamine available at each firing of the dopamine cells that project throughout striatum. Postmortem studies to compare levels of mrnas for D 2 and DAT autoreceptors in the ventral tier neurons of schizophrenia subjects and controls will be useful in testing this theory. References Adolphs, R.; Tranel, D.; Damasio, H.; and Damasio, A.

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