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Gottfried JA, editor. Neurobiology of Sensation and Reward. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Chapter 11Neuroanatomy of Reward: A View from the Ventral Striatum



A key component to rational decision-making and appropriate goal-directed behaviors is the ability to evaluate reward value, predictability, and risk accurately. The reward circuit, central to mediating this information and to assessing the likely outcomes from different choices effectively, is a complex neural network. While the hypothalamus and other subcortical structures are involved in processing information about basic, or primary, rewards, higher-order cortical and subcortical forebrain structures are engaged when complex choices about these fundamental needs are required. Moreover, choices often involve secondary rewards, such as money, power, or challenge, that are more abstract (compared to primary needs). Although cells that respond to different aspects of reward such as anticipation, value, etc., are found throughout the brain, at the center of this network is the cortico-ventral basal ganglia (BG) circuit. This includes the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), the ventral striatum (VS), the ventral pallidum (VP), and the midbrain dopamine (DA) neurons. Overall, the BG works in concert with cortex to execute motivated, well-planned behaviors. The reward circuit is embedded within this system and is a key driving force for the development and monitoring of these behaviors (Figure 11.1). Other BG circuits, those associated with cognition and motor control, work in tandem with elements of the reward system to develop appropriate goal-directed actions.

FIGURE 11.1. (See Color Insert) Schematic illustrating key structures and pathways of the reward circuit, with a focus on the connections of the ventral striatum.


(See Color Insert) Schematic illustrating key structures and pathways of the reward circuit, with a focus on the connections of the ventral striatum. Red arrow = striatal input from the vmPFC; dark orange arrow = striatal input from the OFC; light orange (more...)

An essential element in motivating drive is the interaction between sensory information and the reward pathways. The idea that goal-directed behavior relies on the combined interplay of sensory inputs, emotional information, and memories of prior outcomes is sometimes lost in the details of reward system circuitry and function. Given the fundamental role that the BG plays in reward processing, it is fair to ask: how do sensory inputs—namely, all of those conditioned stimuli eliciting goal-directed responses—make contact with the BG? While the BG does not receive direct sensory inputs, it does receive processed sensory information. The main input structure of the BG is the striatum and its main input is derived from cortex. Most of cortex projects to the striatum, including sensory cortices. The VS is the striatal region most closely associated with reward. It receives its primary input from the orbital prefrontal cortex, insular cortex, and cingulate cortex. These cortical areas, particularly orbital and insular cortex, receive sensory information from all modalities. Moreover, the ventral striatal region receives a dense innervation from the amygdala, which is also tightly linked to sensory processing. In addition, recent evidence has shown that sensory-processing nuclei in the brainstem, particularly the superior colliculus, have a direct BG connection through an input to the substantia nigra. Finally, afferent projections from the olfactory bulb into the olfactory tubercle likely represent a rich source of direct olfactory input to the BG. Together these regions provide the main sensory input to the BG.

The ability to predict and evaluate reward value, and use that information to develop and execute an action plan efficiently, requires: first, integration of incoming sensory information with reward value, expectation, and memory; second, the incorporation of that information with cognition to develop the plan; and finally, the motor control to execute it. However, the BG are traditionally considered to process information in parallel and segregated functional streams consisting of reward (limbic), associative (cognitive), and motor control circuits (Alexander and Crutcher 1990). Moreover, microcircuits within each region are thought to mediate different aspects of each function (Middleton and Strick 2002). Nonetheless, expressed behaviors are the result of a combination of complex information processing that involves all of frontal cortex. Indeed, appropriate responses to environmental stimuli require continual updating and learning to adjust behaviors according to new data. This requires coordination between sensory, limbic, cognitive, and motor systems. While the anatomical pathways are generally topographic from cortex through BG circuits, a large body of growing evidence supports a dual processing system. Thus, information is not only processed in parallel streams, but also through integrative mechanisms through which information can be transferred between functional circuits (Bar-Gad et al. 2000; Belin and Everitt 2008; Bevan, Clarke, and Bolam 1997; Draganski et al. 2008; Haber et al. 2006; Haber, Fudge, and McFarland 2000; Kolomiets et al. 2001; McFarland and Haber 2002b; Mena-Segovia et al. 2005; Percheron and Filion 1991). This chapter will first discuss the place of the reward circuit in the BG; second, how the sensory systems interface within this circuit; and third, the anatomical basis for integrating the reward circuit with cognition and motor control systems.


Specific regions within the frontal-BG network play a unique role in different aspects of reward processing and evaluation of outcomes, including reward value, anticipation, predictability, and risk. The ACC and OFC prefrontal areas mediate different aspects of reward-based behaviors, error prediction, value, and the choice between short- and long-term gains (cf. other chapters in the Reward section of this volume). Cells in the VS and VP respond to anticipation of reward and reward detection. Reward prediction and error detection signals are generated, in part, from the midbrain dopamine cells. While the VS and the ventral tegmental area (VTA) dopamine neurons are the BG areas most commonly associated with reward, reward-responsive activation is not restricted to these, but found throughout the striatum and substantia nigra, pars compacta (SNc). Together, the frontal regions that mediate reward, motivation, and affect regulation project primarily to the rostral striatum, including the nucleus accumbens, the medial caudate nucleus, and the medial and ventral rostral putamen, collectively referred to as the VS. The area occupies over 20% of the striatum (Haber et al. 2006). This striatal region is also involved in various aspects of reward evaluation and incentive-based learning (Corlett et al. 2004; Elliott et al. 2003; Knutson et al. 2001; Schultz Tremblay, and Hollerman 2000; Tanaka et al. 2004), and is associated with pathological risk-taking and addictive behaviors (Kuhnen and Knutson 2005; Volkow et al. 2005). The VS projects to the VP and substantia nigra. From there information is transferred to the ACC and OFC via the mediodorsal nucleus of thalamus (MD) nucleus of the thalamus. While this ventral circuit is similar to the dorsal associative and motor circuits, there are also important differences (see Section

The next section (Section 11.2.1) introduces the principal areas in prefrontal cortex that provide the bulk of afferent input into the VS. This overview will set the stage for an in-depth discussion of the anatomy and connectivity of the VS, which is the main focus of Section 11.2.2. Subsequent sections will consider other key components of the fronto-basal ganglia reward circuit (Sections 11.2.3 and 11.2.4) and how all of these elements are unified anatomically and functionally into an integrated reward circuit (Section 11.2.5 and 11.2.6).

11.2.1. Orbital Prefrontal Cortex and Anterior Cingulate Cortex

Frontal cortex is organized in a hierarchical manner and can be divided into functional regions (Fuster 2001): the orbital (OFC) and anterior cingulate (ACC) prefrontal cortex are involved in reward, emotion, and motivation; the dorsal prefrontal cortex (DPFC) is involved in higher cognitive processes or “executive” functions; and the premotor and motor areas are involved in motor planning and the execution of those plans. Although cells throughout frontal cortex fire in response to various aspects of reward processing, the main components of evaluating reward value and outcome are the ACC and OFC. Each of these regions is comprised of several specific cortical areas: the ACC is divided into areas 24, 25, and 32; the orbital cortex is divided into areas 11, 12, 13, 14 and caudal regions referred to as either parts of insular cortex or periallo- and proiso-cortical areas (Barbas 1992; Carmichael and Price 1994). Based on specific roles for mediating different aspects of reward processing and emotional regulation, these regions can be functionally grouped into: (1) the dorsal ACC (dACC), which includes parts of areas 24 and 32; (2) the ventral, medial prefrontal cortex (vmPFC), which includes areas 25, 14, and subgenual area 32; and (3) the OFC, which includes areas 11, 13, and 12.

The vmPFC plays a role in monitoring correct responses based on previous experience and the internal milieu, and is engaged when previously learned responses are no longer appropriate and need to be suppressed. This region is a key player in the ability to extinguish previous negative associations and is positively correlated with the magnitude of extinction memory (Mayberg 2003; Milad et al. 2007). The OFC plays a central role in evaluation of value, magnitude, and probability of reward. However, responses to reward can transcend specific rewards, such as food or water, and seem also to code for general value (Padoa-Schioppa and Assad 2006; Roesch and Olson 2004; Tremblay and Schultz 2000; Wallis and Miller 2003). It is the OFC and insula that are most closely associated with the sensory systems (see below). The dACC is a unique part of frontal cortex, in that it contains within it a representation of many diverse frontal lobe functions, including motivation (areas 24a and b), cognition (area 24b), and motor control (area 24c). This is a complex area, but the overall role of the ACC appears to be monitoring these functions in conflict situations (Paus 2001; Vogt et al. 2005; Walton et al. 2003).

Anatomical relationships both within and between different PFC regions are complex. As such, several organizational schemes have been proposed based on combinations of cortical architecture and connectivity (Barbas 1992; Carmichael and Price 1994, 1996; Haber et al. 2006; Mesulam and Mufson 1993). In general, cortical areas within each prefrontal group are highly interconnected. However, these connections are quite specific in that a circumscribed region within each area projects to specific regions of other areas, but not throughout. Overall the vmPFC is primarily connected to other medial subgenual regions and to areas 24a and 12, with few connections to the dACC or areas 9 and 46. Area 24b of the dACC is interconnected with the different regions of the dACC areas and is also tightly linked to area 9. Different OFC regions are also highly interconnected and connected to areas 9 and 46.

In addition, both the vmPFC and OFC are connected to the hippocampus and amygdala (Barbas and Blatt 1995; Carmichael and Price 1995a; Ghashghaei and Barbas 2002). The hippocampus projects most densely to the vmPFC and less prominently to the OFC. By contrast, there are few projections to the dorsal and lateral PFC areas (dACC, areas 9 and 46). Amygdala projections to the PFC terminate primarily in different regions of the vmPFC, OFC, and dACC, with a particularly dense projection to the vmPFC and adjacent OFC. Unlike the hippocampal projections, the amygdalo-cortical projections are bidirectional. The primary target of these cortical areas is the basal and lateral nuclear complex. Here, the OFC-amygdalo projections target the intercalated masses, whereas terminals from the vmPFC and dACC are more diffuse. PFC projects to multiple subcortical brain regions, but their largest output is to the thalamus and striatum. Cortical connections to ventral BG output nuclei of the thalamus primarily target the mediodorsal nucleus and are bidirectional (see Section 11.4.3). The second largest subcortical PFC output is to the striatum.

11.2.2. The Ventral Striatum

The link between the BG (specifically, the nucleus accumbens) and reward was first demonstrated as part of the self-stimulation circuit originally described by Olds and Milner (1954). Since then, the nucleus accumbens (and the VS in general) has been a central site for studying reward and drug reinforcement and for the transition between drug use as a reward and as a habit (Kalivas, Volkow, and Seamans 2005; Taha and Fields 2006). The term VS, coined by Heimer, includes the nucleus accumbens and the broad continuity between the caudate nucleus and putamen ventral to the rostral internal capsule, the olfactory tubercle and the rostrolateral portion of the anterior perforated space adjacent to the lateral olfactory tract in primates (Heimer et al. 1999). From a connectional perspective, it also includes the medial caudate nucleus, rostral to the anterior commissure (Haber and McFarland 1999) (Section Human imaging studies demonstrate the involvement of the VS in reward prediction and reward prediction errors (Knutson et al. 2001; O’Doherty et al. 2004; Pagnoni et al. 2002; Tanaka et al. 2004) and, consistent with physiological non-human primate studies, the region is activated during reward anticipation (Schultz 2000). Collectively, these studies demonstrate its key role in the acquisition and development of reward-based behaviors and its involvement in drug addiction and drug-seeking behaviors (Belin and Everitt 2008; Everitt and Robbins 2005; Porrino et al. 2007; Volkow et al. 2006). Special Features of the Ventral Striatum

While the VS is similar to the dorsal striatum in most respects, there are also some unique features. The VS contains a subterritory, the shell,* which plays a particularly important role in the circuitry underlying goal-directed behaviors, behavioral sensitization, and changes in affective states (Carlezon and Wise 1996; Ito, Robbins, and Everitt 2004). The shell has some unique connections compared to the rest of the VS that are indicated below. Several other characteristics are unique to the VS. The dopamine transporter is relatively low throughout the VS. The cellular composition of the VS varies somewhat compared to the dorsal striatum (Bayer 1985; Chronister et al. 1981; Meyer et al. 1989). Of particular importance is the fact that, while both the dorsal and ventral striatum receive input from the cortex, thalamus, and brainstem, the VS alone also receives a dense projection from the amygdala and hippocampus. Collectively, these are important distinguishing features of the VS, but it is important to note that its dorsal and lateral border is continuous with the rest of the striatum, and neither cytoarchitectonic nor histochemical distinctions mark a clear boundary between it and the dorsal striatum. Indeed, the best way to define the VS is by its afferent projections from cortical areas that mediate different aspects of reward processing, the vmPFC, OFC, dACC, and the medial temporal lobe. Connections of the Ventral Striatum (Figure 11.1) Afferent Connections: Cortical Inputs

The VS is the main input structure of the ventral BG. Like the dorsal striatum, afferent projections to the VS are derived from three major sources: a massive, generally topographic input from cerebral cortex (as reviewed in Section 11.2.1); a large input from the thalamus; and a smaller but critical input from the brainstem, primarily from the midbrain dopaminergic cells. Cortico-striatal terminals are organized in two projection patterns: focal projection fields and diffuse projections (Calzavara, Mailly, and Haber 2007; Haber et al. 2006). Focal projection fields consist of dense clusters of terminals forming the well-known dense patches that can be visualized at relatively low magnification. The diffuse projections consist of clusters of terminal fibers that are widely distributed throughout the striatum, both expanding the borders of the focal terminal fields, but also extending widely throughout other regions of the striatum. We will return to the diffuse projections in Section 11.4.1.

It is the general distribution of the focal terminal fields that gives rise to the topography ascribed to the cortico-striatal projections. This organization is the foundation for the concept of parallel and segregated cortico-BG circuits (see Section 11.2.6). Together, these projections terminate primarily in the rostral, medial, and ventral parts of the striatum and define the ventral striatal territory (Haber et al. 1995a, 2006). The large extent of this region is consistent with the findings that diverse striatal areas are activated following reward-related behavioral paradigms (Apicella et al. 1991; Corlett et al. 2004; Delgado et al. 2003; Kuhnen and Knutson 2005; Tanaka et al. 2004). The focal projection field from the vmPFC is the most limited (particularly from area 25) and is concentrated within, and just lateral to, the shell. The innervation of the shell receives the densest input from area 25, although fibers from areas 14, 32, and from agranular insular cortex also terminate here. The vmPFC also projects to the medial wall of the caudate nucleus, adjacent to the ventricle. In contrast, the central and lateral parts of the VS (including the ventral caudate nucleus and putamen) receive inputs from the OFC. These terminals also extend dorsally, along the medial caudate nucleus, but lateral to those from the vmPFC. There is some medial-to-lateral and rostral-to-caudal topographic organization of the OFC terminal field. Projections from the dACC (area 24b) extend from the rostral pole of the striatum to the anterior commissure and are located in both the central caudate nucleus and putamen. They primarily avoid the shell region. These fibers terminate somewhat lateral and dorsal to those from the OFC. Thus, the OFC terminal fields are positioned between the vmPFC and dACC. Afferent Connections: Amygdala and Hippocampal Input

The amygdala is a prominent limbic structure that also plays a key role in emotional coding of environmental stimuli and provides contextual information used for adjusting motivational level. Overall, the main source of amygdala inputs to the VS are the basal nucleus and the magnocellular division of the accessory basal nucleus (Fudge et al. 2002; Russchen et al. 1985). The lateral nucleus has a relatively minor input to the VS. The basal and accessory basal nuclei innervate both the shell and ventromedial striatum outside the shell. The amygdala sends few fibers to the dorsal striatum in primates. In contrast to the amygdala, the hippocampus projects to a more limited region of the VS and is essentially confined to the shell region, where fibers overlap with those from the amygdala (Friedman, Aggleton, and Saunders 2002). Afferent Connections: Thalamic Inputs

The midline and medial intralaminar thalamic nuclei project to medial prefrontal areas, the amygdala, and hippocampus, and, as such, are considered the limbic-related thalamic nuclear groups. The VS receives dense projections from these thalamic nuclei, which are topographically organized (Giménez-Amaya et al. 1995). The shell of the nucleus accumbens receives the most limited projection, almost exclusively midline nuclei and the medial parafascicular nucleus. The medial wall of the caudate nucleus receives projections not only from these nuclei, but also from the central superior lateral nucleus. In contrast, the central and lateral parts of the VS receive their main input from the intralaminar nucleus, with a limited projection from the midline thalamic nuclei. In addition to the midline and intralaminar thalamostriatal projections, in primates there is a large input from the “specific” thalamic BG relay nuclei, the medial dorsalis nucleus (MD), and ventral anterior (VA) and ventral lateral (VL) nuclei (McFarland and Haber 2000, 2001). The VS receives these direct afferent projections primarily from the medial MD nucleus and a limited input from the magnocellular subdivision of the ventral anterior nucleus. Efferent Connections

Efferent projections from the VS, like those from the dorsal striatum, project primarily to the pallidum and substantia nigra/VTA (Haber et al. 1990). Specifically, they terminate topographically in the subcommissural part of the globus pallidus (classically defined as the VP), the rostral pole of the external segment, and the rostromedial portion of the internal segment. The more central and caudal portions of the globus pallidus do not receive this input. VS projections to the substantia nigra are not as confined to a specific region as those to the globus pallidus. Although the densest terminal fields occur in the medial portion, numerous fibers also extend laterally to innervate a wide medio-lateral expanse of the dopamine neurons (see Section 11.2.4). This projection extends throughout the rostral-caudal extent of the substantia nigra. In addition to projections to the typical BG output structures, the VS also projects to non-BG regions. The shell sends fibers caudally and medial into the lateral hypothalamus. Projections from the medial part of the VS also project more caudally, terminating in the pedunculopontine nucleus and to some extent in the medial central gray. Axons from the medial VS (including the shell) travel to and terminate in the bed nucleus of the stria terminalis, and parts of the ventral regions of the VS terminate in the nucleus basalis (Haber et al. 1990). This direct projection to the nucleus basalis in the basal forebrain is of particular interest, since it is the main source of cholinergic fibers to the cerebral cortex and the amygdala. Thus, the VS is in a position to influence cortex directly, without passing through the pallidal, thalamic loop (Beach, Tago, and McGeer 1987; Chang, Penny, and Kitai 1987; Haber 1987; Martinez-Murillo et al. 1988; Zaborszky and Cullinan 1992). Likewise, the projection to the bed nucleus of the stria terminalis indicates direct striatal influence on the extended amygdala.

11.2.3. The Ventral Pallidum

The VP (Figure 11.2) is an important component of the reward circuit. These cells respond during the learning and performance of reward-incentive behaviors and are an area of focus in the study of addictive behaviors (Smith and Berridge 2007; Tindell et al. 2006). While the term VP typically refers to the region below the anterior commissure, in primates it is best defined by its input from the entire reward-related VS (Haber et al. 1990; Heimer 1978). As indicated above, that includes not only the subcommissural regions, but also the rostral pole of the external segment and the medial rostral internal segment of the globus pallidus. Like the dorsal pallidum, the VP contains two parts: a substance-P-positive component and an enkephalin-positive component, which project to thalamus and subthalamic nucleus (STN), respectively (Haber, Wolfe, and Groenewegen 1990; Haber, Lynd-Balta, and Mitchell 1993; Mai et al. 1986; Russchen, Amaral, and Price 1987). Pallidal neurons have a distinct morphology that is useful for determining the boundaries and extent of the VP (DiFiglia, Aronin, and Martin 1982; Fox et al. 1974; Haber and Nauta 1983; Haber and Watson 1985). The VP not only reaches ventrally, but also rostrally to invade the rostral and ventral portions of the VS. In addition to the GABAergic input from the VS, there is a glutamatergic input from the STN and a dopaminergic input from the midbrain (Klitenick et al. 1992; Turner et al. 2001).

FIGURE 11.2. Schematic illustrating the connections of the ventral pallidum.


Schematic illustrating the connections of the ventral pallidum. Same abbreviations as in Figure 11.1. (Reprinted from Haber, S.N., Anatomy and connectivity of the reward circuit, pp. 3–27, in Handbook of Reward and Decision Making, Dreher, J.C. (more...)

Descending efferent projections from the enkephalin-positive VP terminate primarily in the medial subthalamic nucleus, extending into the adjacent lateral hypothalamus (Haber et al. 1985; Haber, Lynd-Balta, and Mitchell 1993; Zahm 1989). The VP also projects to the substantia nigra, terminating medially in the SNc, SN pars reticulata (SNr), and the VTA. Projections from the VP to the subthalamic nucleus and the lateral hypothalamus are topographically arranged. By contrast, terminating fibers from the VP in the substantia nigra overlap extensively, suggesting convergence of terminals from different ventral pallidal regions. VP fibers also innervate the pedunculopontine nucleus. As with the dorsal pallidum, components of the substance P-positive VP project to the thalamus, terminating in the midline nuclei and medial MD. Pallidal fibers entering the thalamus give off several collaterals forming branches that terminate primarily onto the soma and proximal dendrites of thalamic projection cells. In addition, some synaptic contact is also made with local circuit neurons, indicating that, while pallidal projections are primarily inhibitory on thalamic relay cells, they may also function to disinhibit projection cells via the local circuit neurons (Arecchi-Bouchhioua et al. 1997; Ilinsky, Yi, and Kultas-Ilinsky 1997). In addition, the VP also projects to both the internal and external segments of the dorsal pallidum. This is a unique projection, in that the dorsal pallidum does not seem to project ventrally, into the VP.

Parts of the VP (along with the dorsal pallidum) project to the lateral habenular nucleus (LHb). Recent data have supported the role of the LHb in generating a negative reward signal. In particular, it provides the signal that inhibits dopamine activity when an expected reward does not occur (Lecourtier and Kelly 2007; Matsumoto and Hikosaka 2007; Ullsperger and von Cramon 2003). Thus, LHb cells are inhibited by a reward-predicting stimulus, but fire following an unexpected non-reward signal, thus providing a negative reward-related signal to the substantia nigra, pars compacta (SNc). Most pallidal cells that project to the lateral habenula are embedded within accessory medullary laminae that divide the lateral and medial portions of the dorsal internal pallidal segment. In addition, other LHb projecting cells are found circumventing the VP (Haber et al. 1985; Parent and De Bellefeuille 1982). Finally, part of the VP (as with the GPe) also projects to the striatum (Spooren et al. 1996). This pallidostriatal pathway is extensive in the monkey and is organized in a topographic manner preserving a general, but not strict, medial-to-lateral and ventral-to-dorsal organization.

11.2.4. The Midbrain Dopamine Neurons

Dopamine neurons play a central role in the reward circuit (Schultz 2002; Wise 2002). While behavioral and pharmacological studies of dopamine pathways have led to the association of the mesolimbic pathway and nigrostriatal pathway with reward and motor activity, respectively, more recently both of these cell groups have been associated with reward. The midbrain dopamine neurons project widely throughout the brain. However, studies of the rapid signaling that is associated with incentive learning and habit formation focus on the dopamine striatal pathways. Before turning to its projections, it is important to understand the organization of the midbrain dopamine cells in primates.

The midbrain dopamine neurons are divided into the VTA and the substantia nigra, pars compacta (SNc) (Figure 11.3a). Based on projections and chemical signatures, these cells are also referred to as the dorsal and ventral tier neurons (Haber et al. 1995b). The dorsal tier includes the VTA and the dorsal part of the SNc (also referred to as the retrorubral cell group). The cells of the dorsal tier are calbindin-positive and contain relatively low levels of mRNA for the dopamine transporter and D2 receptor subtype. They project to the VS, cortex, hypothalamus, and amygdala. The ventral tier of dopamine cells are calbindin-negative, have relatively high levels of mRNA for the dopamine transporter and D2 receptor and project primarily to the dorsal striatum. Ventral tier cells (calbindin poor, but DAT and D2 receptor rich) are more vulnerable to degeneration in Parkinson’s disease and to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, while the dorsal tier cells are selectively spared (Lavoie and Parent 1991). As mentioned above, despite these distinctions, both cell groups respond to unexpected rewards.

FIGURE 11.3. Schematic illustrating the organization (a) and connections (b) of the midbrain dopamine cells.


Schematic illustrating the organization (a) and connections (b) of the midbrain dopamine cells. CeA = central nucleus of the amygdala; SC = superior colliculus; SNc = substantia nigra, pars compacta; SNr = substantia nigra, pars reticulate. Other abbreviations (more...) Afferent Connections of the Dopamine Neurons

Input to the midbrain dopamine neurons is primarily from the striatum, both the external segment of the globus pallidus (GPe) and the VP, and the brainstem (Figure 11.3b). In addition, there are projections to the dorsal tier from the bed nucleus of the stria terminalis, the sublenticular substantia innominata, and the central amygdala nucleus (Fudge and Haber 2000, 2001; Haber, Lynd-Balta, and Mitchell 1993; Hedreen and DeLong 1991; Lynd-Balta and Haber 1994a).

As described above, the striatonigral projection is the most massive projection to the SN and terminates in both the VTA/SNc and the SNr (Hedreen and DeLong 1991; Lynd-Balta and Haber 1994a; Szabo 1979). The ventral (like the dorsal) striatonigral connection terminates throughout the rostro-caudal extent of the substantia nigra. There is an inverse ventral/dorsal topography to the striatonigral projections. The ventral striatonigral inputs terminate in the VTA, the dorsal part of the ventral tier, and in the medial and dorsal SNr. Thus the VS projects not only throughout the rostrocaudal extent of the substantia nigra, but also covers a wide mediolateral range. In contrast, the dorsolateral striatonigral inputs are concentrated in the ventrolateral SN. These striatal cells project primarily to the SNr, but also terminate on the cell columns of dopamine neurons that penetrate deep into the SNr (Haber, Fudge, and McFarland 2000).

Both the GPe and the VP project to the substantia nigra. The pallidal projection follows a similar inverse dorsal/ventral organization to the striatonigral projection. Thus, the VP projects dorsally, primarily to the dorsal tier and dorsal SNc. The pedunculopontine nucleus sends a major glutamatergic input to the dopaminergic cell bodies. In addition, there is a serotonergic innervation from the dorsal raphe nucleus, though there is disagreement regarding whether fibers terminate primarily in the pars compacta or pars reticulata. Other brain-stem inputs to the dopamine neurons include those from the superior colliculus, the parabrachial nucleus, and locus coeruleus. These inputs raise the interesting possibility that dopamine cells receive a direct sensory input (see Section 11.3.4). Finally, in primates, there is a small and limited projection from the PFC to the midbrain DA neurons, and to both the VTA and SNc. While considerable attention has been given to this projection, relative to the density of its other inputs, this projection is weak in primates (Frankle, Laruelle, and Haber 2006). Efferent Projections

The midbrain dopamine neurons send their largest output to the striatum (Hedreen and DeLong 1991; Lynd-Balta and Haber 1994b; Szabo 1979). As with the descending striatonigral pathway, there is a mediolateral and an inverse dorsoventral topography arrangement to the projection. The ventral pars compacta neurons project to the dorsal striatum, and the dorsally located dopamine neurons project to the VS. The shell region receives the most limited input, primarily derived from the medial VTA (Lynd-Balta and Haber 1994c). The rest of the VS receives input from the entire dorsal tier. In contrast to the VS, the central striatal area (the region innervated by the DPFC) receives input from a wide region of the SNc. The dorsolateral (motor-related) striatum receives the largest midbrain projection from cells in the ventral tier. In contrast to the dorsolateral region of the striatum, the VS receives the most limited dopamine cell input. Thus, in addition to an inverse topography, there is also a differential ratio of dopamine projections to the different striatal areas (Haber, Fudge, and McFarland 2000).

The dorsal tier cells also project widely throughout the primate cortex and are found not only in granular areas but also in agranular frontal regions, parietal cortex, temporal cortex, and, albeit sparsely, in occipital cortex (Gaspar, Stepneiwska, and Kaas 1992; Lidow et al. 1991). The majority of DA cortical projections are from the parabrachial pigmented nucleus of the VTA and the dorsal part of the SNc. The VTA also projects to the hippocampus, though to a lesser extent than in neocortex. The dopamine cells that project to functionally different cortical regions are intermingled with each other, in that individual neurons send collateral axons to different cortical regions. Thus the nigrocortical projection is a more diffuse system compared to the nigrostriatal system and can modulate cortical activity at several levels. Dopamine fibers are located in superficial layers, including a prominent projection throughout layer I. This input therefore is in a position to modulate the distal apical dendrites. Dopamine fibers are also found in the deep layers in specific cortical areas (Goldman-Rakic et al. 1999; Lewis 1992). Projections to the amygdala arise primarily from the dorsal tier. These terminals form symmetric synapses primarily with spiny cells of specific subpopulations in the amygdala (Brinley-Reed and McDonald 1999). As indicated above, dopamine fibers also project to the VP.

11.2.5. Completing the Cortico-basal Ganglia Reward Circuit

The MD nucleus projects to the PFC and is the final link in the reward circuit (Haber, Lynd-Balta, and Mitchell 1993; McFarland and Haber 2002b; Ray and Price 1993). Projections from the VP terminate primarily in the medial mediodorsal nucleus (MD) and in the adjacent midline nuclei (Haber, Lynd-Balta, and Mitchell 1993) (see Figure 11.1). This projection is also topographic, such that the medial part of the VP, which receives its primary input from the shell, is connected mainly to the midline nuclei. The central parts of the VP that receive input from central regions of the VS project to the medial magnocellular MD, while more lateral regions project more laterally. These different MD thalamic areas are then connected to the vmPFC, OFC, and dACC, respectively (Ray and Price 1993).

11.2.6. The Place of the Reward Circuit in the Basal Ganglia

Afferent projections to the striatum terminate in a general topographic manner. Different frontal cortical areas have corresponding striatal regions that are involved in various aspects of reward cognition and motor control. As indicated above, the vmPFC, OFC, and dACC project to the ventromedial striatum. The DPFC projects to the head of the caudate nucleus and to the putamen rostral to the anterior commissure. Caudal to the commissure, this projection is confined to the medial, central portion of the head of the caudate nucleus, with few terminals in the central and caudal putamen (Calzavara and Haber 2006; Haber et al. 2006). Physiological, imaging, and lesion studies support the idea that these areas are involved in working memory and strategic planning processes (Battig, Rosvold, and Mishkin 1960; Levy et al. 1997; Pasupathy and Miller 2005). Both caudal and rostral motor areas occupy much of the putamen caudal to the anterior commissure, a region that also receives overlapping projections from somatosensory cortex, resulting in a somatotopically organized sensory-motor area (Aldridge, Anderson, and Murphy 1980; Flaherty and Graybiel 1994; Kimura 1986). In summary, projections from frontal cortex form a functional gradient of inputs from the ventromedial to the dorsolateral striatum, with the medial and orbital prefrontal cortex terminating in the ventromedial part, and the motor cortex terminating in the dorsolateral region. As seen with the cortico-striatal projection, thalamostriatal projections are also organized in a general topographical manner, such that interconnected and functionally associated thalamic and cortical regions terminate in the same general striatal region (McFarland and Haber 2000).

The striatal projections to the pallidal complex and substantia nigra (pars reticulata) are also generally topographically organized, thus maintaining the functional organization of the striatum in these output nuclei (Haber et al. 1990; Hedreen and DeLong 1991; Lynd-Balta and Haber 1994a; Middleton and Strick 2002; Selemon and Goldman-Rakic 1990). The VS terminates in the VP and in the dorsal part of the midbrain. Terminals from the central striatum terminate more centrally in both the pallidum and the pars reticulata, while those from the sensorimotor areas of the striatum innervate the ventrolateral part of each pallidal segment and the ventrolateral SN. Finally, the pallidum and pars reticulata project to the different BG output nuclei of the thalamus, the mediodorsal, ventral anterior, and ventral lateral cell groups, which are connected respectively to limbic, associative, and motor control areas (Ilinsky, Jouandet, and Goldman-Rakic 1985; Kuo and Carpenter 1973; McFarland and Haber 2002a; Middleton and Strick 2002; Strick 1976). Thus, the organization of connections through the cortico-BG–cortical network preserves a general functional topography within each structure, from the cortex through the striatum, from the striatum to the pallidum/pars reticulata, from these output structures to the thalamus, and finally, back to cortex.

This organization has led to the concept that each functionally identified cortical region drives (and is driven by) a specific BG loop or circuit, leading, in turn, to the idea of parallel processing of cortical information through segregated BG circuits (Alexander and Crutcher 1990). This concept focuses on the role of the BG in the selection and implementation of an appropriate motor response, while inhibiting unwanted ones (Mink 1996). The model assumes, however, that the behavior has been learned and the role of the BG is to carry out a coordinated action. We now know that the cortico-BG network is critical in mediating the learning process to adapt and to accommodate past experiences to modify behavioral responses (Cools, Clark, and Robbins 2004; Hikosaka et al. 1998; Muhammad, Wallis, and Miller 2006; Pasupathy and Miller 2005; Wise, Murray, and Gerfen 1996). This requires communication links between circuits. However, before we discuss the integration between the reward circuit and cognitive and motor control circuits, we turn to where the sensory systems enter the cortico-BG reward network.


Sensory systems play a key role in initiating and developing reward responses. While the cortico-BG reward circuit does not receive direct sensory input (with the possible exception of olfactory input), highly processed sensory information does reach the VS indirectly via cortical, amygdala, and midbrain inputs. Moreover, the reward system has access to sensory modulation through its output, albeit limited, to the hypothalamus and brainstem.

11.3.1. Orbital and Insular Prefrontal Cortex

The main cortical sensory input to the VS is through the OFC and adjacent insula. The insula is divided into three cytoarchitectonic areas that are associated with different sensory functions: (1) a rostroventral agranular insula (Ia) that is related to olfactory and autonomic functions; (2) an intermediate dysgranular insula (Id) that is associated with gustatory and some visual and somatosensory functions; and (3) a caudodorsal granular insula (Ig) that is associated with somatosensory, auditory, and visual functions. These three areas are arranged in a radial manner around the piriform olfactory cortex (Friedman et al. 1986; Mesulam and Mufson 1993; Penfield and Faulk 1955; Schneider Friedman, and Mishkin 1993; Showers and Lauer 1961). Taste and visceral information from primary gustatory cortex and olfactory information from piriform cortex overlap in agranular insula. Moreover, direct connections from the visceral nucleus of the thalamus also converge in specific agranular areas (Carmichael and Price 1995b). Anatomical and physiological studies suggest that the anterior Ig and adjacent Id may contribute to tactile object recognition in the hand and mouth associated with feeding behavior (Friedman et al. 1986; Preuss and Goldman-Rakic 1989). The OFC receives input from all of the sensory modalities (Barbas 1993; Carmichael and Price 1995b). Sensory information arrives with different levels of processing, with visual, auditory, and somatosensory systems passing through several cortical areas before reaching the OFC and insula. By contrast, olfaction and gustatory information is derived from direct inputs from primary cortices.

Links between insular cortex, the vmPFC, and OFC are complex. Ia has a tight connection with the vmPFC (Carmichael and Price 1996). Area 13 of orbital cortex receives inputs from olfactory and gustatory areas that overlap with highly processed information from other modalities. Lateral area 12 receives a substantial input from visual association cortex, area TE. In addition, fibers from TE also project to specific regions of area 13. As mentioned above, OFC regions are tightly linked. Thus, the OFC, particularly the caudal regions, receive both primary and multimodal sensory input from high-order association cortical areas. Taken together, through interconnections between the OFC areas 12 and 13 appear to integrate input from multisensory regions (Barbas 1992; Barbas and Pandya 1989; Carmichael and Price 1995b; Morecraft, Geula, and Mesulam 1992).

The VS receives input from both the Ia and Id insular cortex, but not Ig* (Chikama et al. 1997) (Figure 11.4). The densest input from Ia terminates in the shell and the medial wall of the caudate. This ventral striatal region therefore receives convergent input from the olfactory and visceral-associated insula, and input from the vmPFC. The gustatory insular regions in the anterior and central portions of Id (Smith-Swintosky, Plata-Salaman, and Scott 1991; Yaxley, Rolls, and Sienkiewicz 1990) primarily project to the central VS. Moreover, there are additional inputs here from agranular areas associated with olfactory and visceral responses. Finally, the dorsal portion of Id that receives somatosensory information regarding the hand and face (Mesulam and Mufson 1993) also projects partially to VS. Overall, areas 13 and 12 appear to receive the most convergent input from processed multimodal sensory systems. Projections to the striatum from areas 12 and 13 are organized somewhat topographically in that, generally, area 13 projects more centrally and area 12 more laterally. As indicated above, both areas 12 and 13 are involved in multimodal sensory processing and are further divided into somewhat different combinations of sensory input (Carmichael and Price 1995b). However, their projections to the VS do not reflect these subdivisions. It is therefore difficult to match specific sensory modalities to the topographic terminal organization in the striatum. In general the striatal region that receives this input also receives input from the amygdala, Ia, and Id. This combination of inputs that link visual and somatosensory stimuli associated with feeding behaviors provides a wide spectrum of information regarding food acquisition centered in the VS. In addition, although more rostral OFC regions, areas 10 and 11, receive less direct sensory input, here via OFC connections, the above-mentioned modalities are combined with information from auditory areas (Barbas et al. 1999). The VS therefore appears to receive dual sensory inputs from both the OFC and insula. That is, Ia and Id project directly to the shell and the VS, respectively, and also to different OFC regions. OFC also sends inputs to the VS, overlapping with those from the insula.

FIGURE 11.4. Schematic illustrating projections from the insula to the striatum.


Schematic illustrating projections from the insula to the striatum. Ia = agranular insula; Id = dysgranular insula; Ig = granular insula; OFC = orbital prefrontal cortex; vmPFC = ventral medial prefrontal cortex.

11.3.2. Interface between Amygdala and Cortical Inputs to the Ventral Striatum

The three main amygdaloid regions are the basolateral nuclear group (BLNG), the cortico-medial region (including the periamygdaloid cortex [PAC]) and medial nucleus), and the CeA, which are characterized by functional differences based on specific intrinsic and extrinsic connections (Amaral et al. 1992; Carmichael and Price 1995a; Fudge et al. 2002; Jolkkonen and Pitkanen 1998; Pitkanen and Amaral 1998; Saunders, Rosene, and Van Hoesen 1988). The BLNG includes the basal and accessory basal nuclei which process higher-order sensory inputs in all modalities except olfaction. This is the main input to the VS (Iwai and Yukie 1987; Nishijo, Ono, and Nishino 1988a, 1988b; Ono et al. 1989; Pitkanen and Amaral 1998; Turner, Mishkin, and Knapp 1980). The shell receives the most complex amygdala input. This is derived not only from the BLNG, but also from the cortico-medial region and the CeA. The CeA can be viewed as a site where the “drive” value of a stimulus is determined based on its converging inputs from the “external” milieu (via the BLNG) and “internal” milieu (via the lateral hypothalamus and brainstem) (Aggleton 1985; Amaral et al. 1992; Ricardo and Koh 1978; Saper and Loewy 1980). Thus, these inputs directed to the shell add important information about matching a stimulus with the animal’s internal “drive” state, e.g., whether the animal is hungry when a food-associated stimulus is presented. These inputs are further strengthened by projections derived from similar functional regions, the vmPFC and agranular insular cortex. The BLNG is the source of all amygdaloid input to the VS outside of the shell. This projection is concentrated in the central part of the VS, in addition to the shell. However, the lateral VS also receives this input. The central and lateral striatum receive additional projections from multimodal sensory regions of the OFC, particularly areas 13 and 12, thus reinforcing multimodal sensory information derived from the amygdala. Overall, the amygdala has strong bilateral connections with the OFC. However, it is important to note that the connections between cortex and striatum and between amygdala and striatum are not bidirectional. Thus, these afferent projections to the VS from the cortex and amygdala leave the cortico-amygdala interface and enter another system, the BG.

11.3.3. Following the Cortico-Amygdala Sensory Topography through the Reward Circuit

The shell region of the VS is unique as it receives inputs that the rest of the VS does not. In particular this area contains overlapping sensory inputs from the vmPFC, Ia, and the CeA and PAC amygdala nuclei (as indicated in Figure 11.4). This information is then combined with inputs from the hippocampus. In addition, the shell, like the rest of the VS, receives input from the BLNG and the VTA. The shell also has some unique outputs. In addition to its projections to the pallidum and the substantia nigra, unlike the rest of the VS, the shell also projects to the hypothalamus and the bed nucleus of the stria terminalis (see Figure 11.1). This provides direct feedback into systems that monitor the internal milieu. Moreover, its projection terminates in the most medial aspect of the VP. This part of the VP projects not only to the subthalamic nucleus, but also to the adjacent lateral hypothalamus. Finally, this VP region projects primarily to the midline thalamic nuclei, with few terminals in the MD. While these features set the shell and medial VP apart from the rest of the VS/ VP, they contribute to the overall integration of the cortico-BG network through their integrative connectivities with other BG elements (see Section 11.4).

The central VS receives input primarily from the OFC, particularly from multimodal sensory areas, particularly area 13, along with the amygdala. In addition, this region also receives input from the more anterior OFC, including areas 10 and 11. Collectively, these inputs converge with those from the dorsal tier dopamine neurons, including part of the VTA. Projections from the central VS terminate centrally in subcommissural VP, extending dorsal and medial, above the anterior commissure. In turn, this area projects to the medial subthalamic nucleus and to the medial parts of the MD. Few, if any, fibers reach the lateral hypothalamus, either directly from the VS or from the VP. More lateral VS receives similar cortical input to the central VS, with a great proportion of OFC projections derived from area 12. In addition, here there is convergence between inputs from OFC and those from dACC. Projections from the lateral VS mirror those from the central VS, but terminate somewhat more laterally. As will be discussed in Section 11.4.2, terminals from throughout the VS converge extensively in the substantia nigra.

11.3.4. Superior Colliculus Inputs to the Midbrain Dopamine Neurons

There is a direct efferent projection from the superior colliculus (SC) to the midbrain dopamine neurons. The SC projects to both the dorsal and ventral tier midbrain dopamine cells, and to a lesser extent to the substantia nigra, pars reticulata. These inputs terminate in close association with TH-positive cells, particularly within the dorsal tier of DA neurons. The SC-projecting cells are located in the intermediate and deep layers of the SC (May et al. 2009; McHaffie et al. 2006). Several SC cell types project to the dopamine neurons, suggesting a heterogeneous input as indicated by differences in DA cell responses to various categories of visual events, e.g., appearance, disappearance, movement (Wurtz and Albano 1980), and looming (Westby et al. 1990). Few of the tectonigral neurons are located in the exclusively visual, superficial layers of the SC, suggesting that the tectonigral cells are multisensory neurons (May et al. 2009). It has been suggested that these provide the multimodal sensory input that tunes the dopamine cells to the novel and salient stimuli in the environment (Stein and Meredith 1993; Stein and Stanford 2008). These cells may include those that increase the gain of their activity for reward-related responses but do not show motor-related activity (Ikeda and Hikosaka 2003).

The dorsal tier of DA neurons receives the densest tectonigral projection. As indicated above, the dorsal tier cells also receive unique inputs from the amygdala and BNST, along with those from the VS. Moreover, these cells preferentially innervate VS (Haber, Fudge, and McFarland 2000). Thus, the tectonigral projection provides a signal of biologically salient sensory stimuli (via a glutamatergic excitatory input) to elicit phasic DA modulation in the VS system. This could be of importance for reinforcing reward-related learning activity derived from cortical and amygdala inputs to the VS (Gruber et al. 2006).

The well-documented nigrotectal projection, derived from the SNr, mediates gaze-related activity of the SC (Graybiel 1978; Chevalier et al. 1981; Hikosaka and Wurtz 1983; Huerta et al. 1991). This pathway provides an output mechanism of the BG to influence sensory modulation of motor systems. The direct tectal projection to the pars reticulata may modulate the afferent signals it receives from the BG (Comoli et al. 2003). Thus, tectonigral input to SNr may modulate the dis-inhibitory output signals from the BG that gate SC saccade-related outputs (Chevalier and Deniau 1990; Hikosaka et al. 2000).


The cortico-BG is a complex system through which prefrontal cortex exploits the BG for additional processing of reward to effectively modulate learning, leading to the development of goal-directed behaviors and action plans. To develop an appropriate behavioral response to external environmental stimuli, sensory information must be integrated into the reward circuit, to develop a strategy and an action plan for obtaining the goal. Thus action plans developed towards obtaining a goal require a combination of sensory and reward processing, cognition, and motor control. Although theories related to cortico-BG processing have traditionally emphasized the segregation of functions (including different reward circuits), highlighting separate and parallel pathways (Alexander and Crutcher 1990; Middleton and Strick 2002; Price, Carmichael, and Drevets 1996), it is now evident that the reward circuit does not work in isolation. As such, this complex circuitry interfaces with pathways that mediate cognitive function and motor planning. There are regions of integration and convergence linking together areas that are associated with different functional domains, both within and between each of the cortico-BG structures. First, there is convergence between terminals derived from different cortical areas in the striatum that permits cortical information to be integrated across multiple functional regions within the striatum. Second, there are interconnections between structures that have both reciprocal and non-reciprocal connections that link across functional domains. The two major ones are the striato-nigro-striatal pathway and the cortico-thalamo-cortical network. In addition, the VP-VS-VP network also has an important non-reciprocal component. Through these networks, sensory information enters the reward circuit, which then impacts on cognition and motor control through several different interactive routes, allowing information about reward to be channeled through cognitive and motor control circuits to mediate the development of appropriate action plans.

11.4.1. Convergence of Cortico-striatal Projections

Despite the general topography described above, focal terminal fields from the vmPFC, OFC, and dACC show a complex interweaving and convergence, providing an anatomical substrate for modulation between circuits within the reward network (Haber et al. 2006). Focal projections from the OFC extend into areas innervated by the dACC and the vmPFC (Figure 11.5a). Indeed, these terminal fields do not occupy completely separate territories in any part of the striatum, but converge most extensively at rostral levels. Regions of convergence between the focal terminal fields of the vmPFC, OFC, and dACC provide an anatomical substrate for integration between sensory inputs, which, along with different reward processing circuits within specific striatal areas, may represent “hot spots” of plasticity for integrating reward value, predictability, and salience. In addition to convergence between vmPFC, dACC, and OFC focal terminal fields, projections from dACC and OFC also converge with inputs from the DPFC, demonstrating that functionally diverse PFC projections also interface in the striatum. At rostral levels, DPFC terminals converge with those from both the dACC and OFC, although each cortical projection also occupies its own territory. Here, projections from all PFC areas occupy a central region, with the different cortical projection extending into non-overlapping zones. The anterior striatum is, therefore, a particularly critical place where sensory, emotional, and cognitive information intermingle. Coordinated activation of DPFC, dACC, and/ or OFC terminals in the striatum could produce a unique combinatorial activation at the specific sites, enabling reward-based incentive drive to impact on long-term strategic planning. Convergence between these areas is less prominent caudally, with almost complete separation of the dense terminals from the DPFC and dACC/OFC just rostral to the anterior commissure.

FIGURE 11.5. Schematic diagrams demonstrating convergence of cortical projections from different reward-related regions and dorsal prefrontal areas.


Schematic diagrams demonstrating convergence of cortical projections from different reward-related regions and dorsal prefrontal areas. (a) Convergence between focal projections from different prefrontal regions. (b) Distribution of diffuse fibers from (more...)

In addition to the focal projections, each cortical region sends a diffuse fiber projection that extends outside of its focal terminal field (Figure 11.5b) (Haber et al. 2006). These axons can travel some distance, invading striatal regions that receive their focal input from other prefrontal cortex areas. For example, the diffuse projection from the OFC extends deep into the dorsal, central caudate and putamen, with extensive convergence with the focal and diffuse projections from both the dACC and the DPFC. Likewise, the diffuse projections from dACC overlap with focal projections from the vmPFC, OFC, and DPFC. Moreover, clusters of fibers are found in the dorsal lateral caudate nucleus and in the caudal ventral putamen, areas that do not receive a focal input from other prefrontal regions. Finally, clusters of DPFC fibers terminate throughout the rostral striatum, including the VS and lateral putamen. Although the focal projections do not reach into the ventromedial region, clusters of labeled fibers are located here.

Significant and extensive diffuse projections from each frontal cortical region are consistent with the demonstration that a single cortico-striatal axon can innervate 14% of the striatum (Zheng and Wilson 2002). However, activation of medium spiny neurons requires a large coordinated glutama-tergic input from many cortical cells (Wilson 2004). Therefore, the invasions of relatively small fiber clusters from other functional regions are not considered to have much relevance for cortico-striatal information processing and, as a result, anatomical studies have focused on the large, dense focal projections (Ferry et al. 2000; Selemon and Goldman-Rakic 1985). While under normal conditions in which a routine behavior is executed these fibers may have little impact, this diffuse projection may serve a separate integrative or modulatory function. Collectively, these projections represent a large population of axons invading each focal projection field and, under certain conditions, if collectively activated, they may provide the recruitment strength necessary to modulate the focal signal. This would serve to broadly disseminate cortical activity to a wide striatal region, thus providing an anatomical substrate for cross-encoding cortical information to influence the future firing of medium spiny neurons (Kasanetz et al. 2008). Taken together, the combination of focal and diffuse projections from frontal cortex occupies the rostral striatum and continues caudally through the caudate nucleus and putamen (Figure 11.5c). The fronto-striatal network, therefore, constitutes a dual system comprising both topographically organized terminal fields, along with subregions that contain convergent pathways derived from functionally discrete cortical areas (Draganski et al. 2008; Haber et al. 2006).

11.4.2. The Striato-Nigro-Striatal Network

While the role of dopamine and reward is well established, the latency between the presentation of the reward stimuli and the activity of the DA cells is too short to reflect higher cortical processing necessary for linking a stimulus with its rewarding properties. The fast, burst-firing activity is likely, therefore, to be generated from other inputs such as brainstem glutamatergic nuclei (see Section 11.3.4) (Dommett et al. 2005). An interesting issue is, then, how do the dopamine cells receive information concerning reward value? The largest forebrain input to the dopamine neurons is from the striatum. However, this is a relatively slow GABAergic inhibitory projection, unlikely to result in the immediate, fast burst-firing activity. Nonetheless, the collective complex network of PFC, amygdala, and hippocampal inputs to the VS integrate information related to reward processing and memory to modulate striatal activity. These striatal cells then impact directly on a subset of medial dopamine neurons, which, through a series of connections described below, can modulate the dorsal striatum.

As mentioned above, projections from the striatum to the midbrain are arranged in an inverse dorsal-ventral topography and there is also an inverse dorsal-ventral topographic organization to the midbrain striatal projection. When considered separately, each limb of the system creates a loose topographic organization: the VTA and medial SN being associated with the limbic system, and the central and ventral SN with the associative and motor striatal regions, respectively. However, each functional region differs in their proportional projections that significantly alter their relationship to each other. The VS receives a limited midbrain input, but projects to a large region. By contrast, the dorsolateral striatum receives a wide input, but projects to a limited region. In other words, the VS influences a wide range of dopamine neurons, but is itself influenced by a relatively limited group of dopamine cells. On the other hand, the dorsolateral striatum influences a limited midbrain region, but is affected by a relatively large midbrain region.

The proportional differences between inputs and outputs of the dopamine neurons, coupled with their topography, result in complex interweaving of functional pathways. For each striatal region, the afferent and efferent striato-nigro-striatal projection system contains three components in the midbrain. There is a reciprocal connection that is flanked by two non-reciprocal connections. The reciprocal component contains cells that project to a specific striatal area. These cells are embedded within terminals from that same striatal area. Dorsal to this region lies a group of cells that project to the same striatal region but do not lie within its reciprocal terminal field. In other words, these cells receive a striatal projection from a region to which they do not project. Finally, ventral to the reciprocal component are efferent terminals. However, there are no cells embedded in these terminals that project to that same specific striatal region. The cells located in this terminal field project to a different striatal area. These three components for each striato-nigro-striatal projection system occupy different positions within the midbrain. The VS system lies dorsomedially, the dorsolateral striatum system lies ventrolaterally, and the central striatal system is positioned between the two. Thus, the size and position of the afferent and efferent connections for each system, together with the arrangement into three components, allow information from the limbic system to reach the motor system through a series of connections (Haber, Fudge, and McFarland 2000) (Figure 11.6). With this arrangement, while the VS receives input from the vmPFC, OFC, dACC, and amygdala, its efferent projection to the midbrain extends beyond the tight VS/dorsal tier dopamine/VS circuit. It terminates also in the ventral tier, to influence the dorsal striatum. Moreover, this part of the ventral tier is reciprocally connected to the central (or associative) striatum. The central striatum also projects to a more ventral region than it receives input from. This region, in turn, projects to the dorsolateral (or motor) striatum. Taken together, the interface between different striatal regions via the midbrain DA cells is organized in an ascending spiral, interconnecting different functional regions of the striatum and creating a feed-forward organization, from reward-related regions of the striatum to cognitive and motor areas (Figure 11.6). Thus, although the short-latency burst-firing activity of dopamine that signals immediate reinforcement is likely to be triggered from brainstem nuclei, the cortico-striato-midbrain pathway is in the position to influence dopamine cells to distinguish rewards and modify responses to incoming salient stimuli over time. This pathway is further reinforced via the nigro-striatal pathway, placing the striato-nigro-striatal pathway in a pivotal position for transferring information from the VS to the dorsal striatum during learning and habit formation. Indeed, cells in the dorsal striatum are progressively recruited during different types of learning, from simple motor tasks to drug self-administration (Everitt and Robbins 2005; Lehericy et al. 2005; Pasupathy and Miller 2005; Porrino et al. 2004; Volkow et al. 2006). Moreover, when the striato-nigro-striatal circuit is interrupted, information transfer from Pavlovian (stimulus-based) to instrumental (action-based) learning does not take place (Belin and Everitt 2008).

FIGURE 11.6. (See Color Insert)Schematic illustrating the complex connections between the striatum and substantia nigra.


(See Color Insert)Schematic illustrating the complex connections between the striatum and substantia nigra. The arrows illustrate how the ventral striatum can influence the dorsal striatum through the midbrain dopamine cells. Colors indicate functional (more...)

11.4.3. The Place of the Thalamus in Basal Ganglia Circuitry

The thalamocortical pathway is the last link in the circuit and is often treated as a simple “one-way relay” back to cortex. However, this pathway does not transfer information passively, but rather plays a key role in regulating cortical ensembles of neurons through its non-reciprocal connections with cortex. This occurs in two ways. First, the thalamus projects to different cortical layers. Therefore, while the thalamus receives input from the deep cortical layers, the thalamic projection to cortex, from the BG relay nuclei, terminates in superficial, middle, and deep layers (layers I/II, III/IV, and V, respectively) (Erickson and Lewis 2004; McFarland and Haber 2002b). Projections that terminate in layer V form both direct thalamo-cortico-thalamic and thalamo-cortico-striatal loops, thus sustaining information processing from the thalamus through each specific cortico-BG circuit. However, projections to the superficial layers play a key role in cortico-cortical processing. These are particularly interesting in that they have a more global recruiting action response affecting wide networks of cortical activity. In contrast to the topographically specific thalamocortical projections to middle layers, the more widespread, diffuse terminals to layer I are in a position to modulate neuronal activity from all cortical layers, with apical dendrites ascending into layer I. Moreover, this projection can provide an important mechanism for cross-communication between BG circuits. Projections to superficial layers also interface with cortico-cortical connections. These cortical regions, in turn, send axons to the striatum, thereby potentially modulating a different loop.

Second, while cortico-thalamic projections to specific relay nuclei are thought to follow a general rule of reciprocity, cortico-thalamic projections to VA/VL and central MD sites, as seen in other thalamocortical systems, are more extensive than thalamocortical projections (Catsman-Berrevoets and Kuypers 1978; Darian-Smith, Tan, and Edwards 1999; Deschenes, Veinante, and Zhang 1998; Hoogland, Welker, and Van der Loos 1987; Jones 1998; McFarland and Haber 2002b; Sherman and Guillery 1996). Furthermore, they are derived from areas not innervated by the same thalamic region, indicating non-reciprocal cortico-thalamic projections to specific BG relay nuclei (McFarland and Haber 2002b). Although each thalamic nucleus completes the cortico-BG segregated circuit, the non-reciprocal component is derived from a functionally distinct frontal cortical area. For example, the central MD has reciprocal connections with the lateral and orbital prefrontal areas and also a non-reciprocal input from medial prefrontal areas; VA has reciprocal connections with dorsal premotor areas and caudal DLPFC, and also a non-reciprocal connection from medial prefrontal areas; and VL has reciprocal connections with caudal motor areas along with a non-reciprocal connection from rostral motor regions. The potential for relaying information between circuits through thalamic connections, therefore, is accomplished both through the organization of projections to different layers and through the non-reciprocal cortico-thalamic pathways. Thus, similar to the striato-nigro-striatal project system, the thalamic relay nuclei from the BG also appear to mediate information flow from higher cortical “association” areas of the prefrontal cortex to rostral motor areas involved in “cognitive” or integrative aspects of motor control to primary motor areas that direct movement execution.


A key component for developing appropriate goal-directed behaviors is the ability to correctly evaluate different aspects of reward and to select an appropriate action based on previous experience. These calculations rely on integration of sensory input with different aspects of reward processing and cognition to develop and execute appropriate action plans. While parallel networks that mediate different functions are critical to maintaining coordinated behaviors, cross talk between functional circuits during learning and adaptation is critical. Indeed, reward, associative, and motor control functions are not clearly and completely separated within the striatum. For example, consistent with human imaging studies, reward-responsive neurons are not restricted to the VS, but rather are found throughout the striatum. Moreover, cells responding in working memory tasks are often found also in the VS (Apicella et al. 1991; Cromwell and Schultz 2003; Delgado et al. 2005; Hassani, Cromwell, and Schultz 2001; Levy et al. 1997; Takikawa, Kawagoe, and Hikosaka 2002; Tanaka et al. 2004; Watanabe, Lauwereyns, and Hikosaka 2003).

As described above, embedded within limbic, associative, and motor-control striatal territories are subregions containing convergent terminals between different reward-processing cortical areas, and between these projections and those from the DPFC. These nodes of converging terminals may represent “hot spots” that may be particularly sensitive to synchronizing information across functional areas to impact on long-term strategic planning and habit formation (Kasanetz et al. 2008). Indeed, cells in the dorsal striatum are progressively recruited during different types of learning, from simple motor tasks to drug self-administration (Lehericy et al. 2005; Pasupathy and Miller 2005; Porrino et al. 2004; Volkow et al. 2006). The existence of convergent fibers from cortex within the VS, taken together with hippocampal and amygdalo-striatal projections, places the VS as a key entry port for the processing of sensory, emotional, and motivational information that, in turn, drives BG-mediated action selection and output. The ventral, reward-based striatal region, and the associative, central striatal region can impact on motor output circuits, not only through convergent terminal fields within the striatum, but also through the striato-nigro-striatal pathways. One can hypothesize that initially the nodal points of interface between the reward and associative circuits, for example, send a coordinated signal to dopamine cells. This pathway is in a pivotal position for temporal “training” of dopamine cells. In turn, these nodal points may be further reinforced through the burst-firing activity of the nigro-striatal pathway, thus transferring that impact back to the striatum. Moreover, through the striato-nigro-striatal system, information is transferred to other functional regions, during learning and habit formation (Belin et al. 2008; Everitt and Robbins 2005; Porrino et al. 2007; Volkow et al. 2006). This signal then enters the parallel system and, via the pallidum and thalamus, carries an integrated signal back to cortex. Indeed, when the striato-nigro-striatal circuit is interrupted, information transfer from Pavlovian to instrumental learning does not take place (Belin and Everitt 2008).


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In rodent models, the term “core” is often used to distinguish the “shell” from the rest of the nucleus accumbens. However, as discussed here, anatomical and physiological data indicate that reward-related processing extends well beyond the confines of nucleus accumbens. Therefore, in this chapter, the term ventral striatum (VS), which encompasses a much larger region, is favored. On the other hand, because VS does not have a clear set of boundaries, it is difficult to define a “core,” so this term is not used here.


The absence of Ig input to VS would be predicted on evolutionary grounds, since anatomical homologues of the basal ganglia and VS exist in non-mammalian vertebrates that lack granular isocortex, as discussed in detail in Chapter 4.

Copyright © 2011 by Taylor and Francis Group, LLC.
Bookshelf ID: NBK92777PMID: 22593898


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