Invited Symposium: Perspectives on Behavioural Function of Dopamine in the Nucleus Accumbens
The thesis of the present review will be that there are two central features of the neural integrative activities of the nucleus accumbens, which are subserved by the two recently defined subterritories of the nucleus accumbens, the core and shell (Alheid & Heimer, 1988; Zahm & Brog, 1992). These two functions, which will be elaborated in detail below, constitute the learning of adaptive motor responses and the control of brain feeding circuits (see also Kelley, 1999). Both of these proposed functions have their conceptual and historical roots in a number of theories that attempted to explain motivated behavior and learning. Perhaps the most important of these for the present hypotheses is Thorndike’s Law of Effect, which stated that behavioral acts followed by “satisfaction” to the organism would tend to be repeated in the future, while behavioral acts followed by negative consequences would diminish in their occurrence (Thorndike, 1911). In other words, the Law of Effect states that learning consists of the reinforcing of a connection between a response and a stimulus situation, and this strengthening is dependent on the response being followed by a positive event that is presumably beneficial to the animal in some way. Clark Hull’s contribution to learning theory (Hull, 1943), integrating the concept of drive or biological need with reinforcement and the strengthening of behavior, is also closely related to many current ideas about the nucleus accumbens more than fifty years later. He proposed that deprivation state, such as food or water deprivation, energized behavior nonspecifically. This activation increased the probability that an adaptive response would occur; let us imagine, for example, a very hungry, exploratory rat accidentally bumping into a lever that provides a food pellet (reinforcement). The reduction of drive (and, in Hull’s later writings, “drive-stimulus reduction”, or reduction of cravings) that results with the reinforcement causes the animal to repeat the response and engage in learning. In Hull’s scheme he called the stimulus-response connection “habit”, and postulated that drive and habit multiply together to determine the strength of behavior. Hull noted that “Habit strength increases when receptor and effector activities occur in close temporal contiguity, provided their approximately contiguous occurrence is associated with primary or secondary reinforcement.” (Hull, 1943), pg. 178. The concept of habit is important, because it has contributed substantially to current thinking about the basal ganglia and learning. As expounded below, this notion may provide a conceptual basis for the neuromolecular events within accumbens associated with response learning.
Another set of historical developments that pertains to the current hypotheses concerning the nucleus accumbens grew out of classical studies on the physiology of motivation. Curt Richter conceived of the idea that motivated behaviors served to maintain the internal homeostatic environment, in coordination with more automatic mechanisms (Richter, 1942-1943). Thus, motivated behaviors, such as feeding, drinking, nest-building, or temperature-regulating behaviors were self-regulatory and highly sensitive to fluctuating internal conditions of the organism. A further significant contribution was the work of Eliot Stellar, who was among the first to develop a truly integrative theory of motivation based on brain-behavior relationships. In his classic papers, he synthesized significant theoretical constructs, such as drive, goal-directed behavior, instinct, sensation, and learning with the current empirical data, forming a broad conceptual framework (Stellar, 1954; Stellar, 1960). Although his major focus was on the hypothalamus, Stellar also suggested that “...central neural structures outside of the hypothalamus also contribute excitatory and inhibitory influences to the control of motivation...” Recent work on the nucleus accumbens, as described below, demonstrates a important role in this regard, with significant functional connections to the hypothalamus.
The anatomical organization of the nucleus accumbens is well-suited to its hypothetical role as a limbic-motor integrator. Within this area there is a convergence of afferents conveying information related to affective and motivational states, arising from limbic structures such as amygdala, hippocampus, prefrontal cortex, midbrain monoamine systems, and brainstem autonomic centers (Beckstead, 1979; Brog, Salyapongse, Deutch, & Zahm, 1993; Kelley & Domesick, 1982; Kelley, Domesick, & Nauta, 1982; McDonald, 1991). Further, it has extensive connections to skeletal motor and visceral motor output systems (Groenewegen & Russchen, 1984; Heimer, Zahm, Churchill, Kalivas, & Wohltmann, 1991; Nauta, Smith, Faull, & Domesick, 1978). Although the nucleus accumbens has long been considered a ventral striatal territory with prominent similarities to the overlying caudate-putamen, in recent years there has been a major anatomical re-conceptualization of this structure based on refined anatomical analysis. Analysis of connectivity as well as its histochemical profile indicates that the nucleus accumbens is composed of three major subterritories, which have been termed the core, shell, and rostral pole. The core and shell subregions, which have been most extensively studied, show striking differences in their afferent input and efferent projections (Heimer et al., 1991; Zahm & Brog, 1992). For example, although both core and shell receive input from hippocampus, the ventral subiculum projects exclusively to the shell while the dorsa l subiculum projects to the core. Different regions of prefrontal cortex project to different zones; the prelimbic area projects to core, while the infralimbic and piriform cortices project to shell (Brog et al., 1993). Specific subcompartments of the amygdala also reach distinct subregions within accumbens core and shell (Wright, Beijer, & Groenewegen, 1996). In terms of outputs, the core subregion connects extensively to classic basal ganglia output structures, such as the ventral pallidum, subthalamic nucleus, and substantia nigra. The shell subregion, in contrast, projects preferentially to subcortical limbic regions, such as the lateral hypothalamus, ventral tegmental area, ventromedial ventral pallidum, and brainstem autonomic centers.
On the basis of these distinctive anatomical profiles, it has been proposed that there may be significant functional specializations of these two subregions and their associated circuitry (Deutch & Cameron, 1992; Heimer et al., 1991; Zahm & Brog, 1992). The general notion is that the accumbens core has similarities to the overlying caudate-putamen and may be more allied with voluntary motor functions, whereas the shell has close ties to the “extended amygdala” (Alheid & Heimer, 1988) and its functions are more in the domain of visceral or motivational mechanisms. Evidence is presented in support of this general hypothesis in this paper. Moreover, the hypothesis is further extended to state that the core of accumbens, and particularly NMDA receptors, are critical for instrumental learning, whereas the shell of accumbens, particularly GABAergic and AMPA receptors, are specifically involved in the control of feeding.
Nucleus accumbens core, NMDA receptors and plasticity
Given the long association of the nucleus accumbens with motivation and reward, it is not surprising that many studies have focused on the role of this structure in learning and memory. Earlier studies particularly focused on the role of ventral striatal dopamine in reward-related learning (Beninger, 1983) , and a number of experiments utilizing 6-OHDA lesions or pharmacological manipulations suggested that blockade of DA disrupted learning (Beninger & Phillips, 1980; Taylor & Robbins, 1986) and enhancement of DA facilitated learning (Robbins, 1978; Taylor & Robbins, 1984). However, it is often difficult to clearly interpret DA manipulations since they nearly always affect response output or performance. Work with electrolytic or selective excitotoxic has also indicated a role for the nucleus accumbens in learning; for example, such lesions impair acquisition of learning in the Morris water maze (Sutherland & Rodriguez, 1989), spatial discrimination in a T-maze (Annett, McGregor, & Robbins, 1989), and a visual stimulus-response task (Reading, Dunnett, & Robbins, 1991). Several recent studies employing lidocaine-induced inactivation of accumbens have provided further evidence for this structure mediating certain aspects of spatial learning and performance (Floresco, Seamans, & Phillips, 1996; Floresco, Seamans, & Phillips, 1997). A summary of experiments pertaining to the role of the nucleus accumbens in learning and memory, with particulary emphasis on hippocampal input, is provided in a recent review (Setlow, 1997).
Within the framework initiated by Mogenson (Mogenson, Jon es, & Yim, 1980), much thought has been given over the past decade or so to the role of glutamate-coded inputs to the nucleus accumbens. As in the overlying caudate nucleus, the medium-sized spiny output neurons, which comprise the main cellular component of these structures, receive excitatory input in the form of glutamate (Fonnum, 1984; McGeer, McGeer, Scherer, & Singh, 1977). Moreover, there are high levels of all glutamate receptor subtypes in the striatum (Albin et al., 1992). As noted in the previous section, the area including nucleus accumbens is particularly distinctive in that it receives strikingly convergent inputs from hippocampus, prefrontal cortex, amygdala, midbrain and thalamus, and in turn projects to both somatic and visceral motor output systems. Recently our research has focused on the investigation of functions of the nucleus accumbens and its related circuitry through the study of its glutamatergic innervation. Our first studies showed that blockade of N-methyl-D-aspartate (NMDA) receptors within the core of the accumbens (but not the shell) reduced exploratory locomotion (Maldonado-Irizarry & Kelley, 1994), a result similar to previous work conducted with non-selective glutamate antagonists (Mogenson & Nielsen, 1984). We then conducted several studies utilizing NMDA antagonist infusion into accumbens subregions on learning in several spatial tasks. Local infusion of the selective competitive antagonist AP-5 into the core was found to severely disrupt path learni ng in a spatial food-gathering task (Maldonado-Irizarry & Kelley, 1995). Infusion of the selective AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)/kainate antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione) into the core mildly impaired learning, and both drugs had lesser effects when infused into the shell. In a recent study of the effect of striatal infusion of AP-5 in an 8-arm radial arm maze (with 4 arms baited), blockade of NMDA receptors in the accumbens core, but not the shell, markedly disrupted acquisition of efficient responding (Smith-Roe, Sadeghian, & Kelley, 1998). Once the animals had learned the task, however, AP-5 infusion into core had no effect.
Although it was clear that NMDA receptors were involved in spatial learning, we were curious if other forms of learning would be affected by intra-accumbens NMDA blockade. In one series of experiments, the consequences of intra-accumbens infusion of AP-5 on acquisition of a lever-press task for food were investigated (Kelley, Smith-Roe, & Holahan, 1997b). In this task, hungry animals are exposed in an operant chamber to two levers, one of which provides a food pellet when pressed, for a 15 minute session on a fixed-ratio 2 schedule. Normal rats learn this task quite rapidly over days. Somewhat to our surprise, rats treated with AP-5 in the core showed no learning whatsoever, and only began to learn the task when infusions were no longer given. Equivalent infusions in the accumbens shell had little effect on response learning. Parallel experiments examining the effects of these treatments on general motor behavior and feeding indicated that the impairment could not be attributed to a general motor or motivational deficit. Moreover, AP-5 had no effect once the animals had learned the task, suggesting that like for the spatial learning experiments, NMDA-dependent mechanisms are critical only in the early stages of learning.
These results are among the first demonstrating NMDA-dependent mechanisms in striatal-based learning. Of course, there is much evidence for a major role of basal ganglia structures in motor learning. Several earlier postulates suggested a role for striatal systems in cognitive and affective functions, in addition to their well known motoric functions (Alexander, DeLong, & Strick, 1986; Divac, 1972). A considerable array of empirical data supports the contention that both ventral and dorsal striatal regions are important for certain forms of learning. One prominent theory holds that the striatum is crucial for the acquisition of relatively automatic motor “habits”, or basic stimulus-response associative learning (McDonald & White, 1993; Mishkin & Petri, 1984; Packard & McGaugh, 1992) (in contrast to hippocampus and amygdala, which are generally thought to be more involved in contextual or declarative learning, and stimulus-reward learning). In other words, returning to Thorndike’s law of effect, a neural mechanism must exist whereby a response followed by “satisfaction” becomes strengthened, and the probability of its occurrence becomes greatly facilitated in the appropriate stimulus conditions. We propose that activation of NMDA receptors in the accumbens core, together with concomitant intracellular molecular events, is such a critical mechanism for adaptive response learning. It should be noted, moreover, that other forms of learning may also be mediated by the accumbens core; for example it has recently been shown that excitotoxic lesions of the core (but not the shell) impair the learning of anticipatory approach response governed by a Pavlovian conditioned stimulus (CS) (Parkinson, Olmstead, Burns, Robbins, & Everitt, 1999); we have shown a similar impairment with intra-core AP-5 infusions (Kelley et al., 1997b). Thus the control of CS-UCS (unconditioned stimulus) over learned behavior may also depend on accumbens core neurons.
Neuronal plasticity in ventral striatum
There is much empirical evidence to support this hypothesis, which has emerged relatively recently. Although classic work on neuronal plasticity in relation to learning and memory has focused primarily on the hippocampus, in recent years data have accrued supporting plasticity within the striatum and accumbens, at both the cellular and molecular level. First, striatal neurons are involved in assessing, learning and responding to stimuli with motivationally significant valence. For example, neurons in the monkey ventral striatum are sensitive to both primary and conditioned rewards (Aosaki, Graybiel, & Kimura, 1994a; Apicella, Scarnati, Ljungberg, & Schultz, 1992; Bowman, Aigner, & Richmond, 1996). Moreover, during acquisition of sensorimotor conditioning in monkeys, in which a cue predicts delivery of juice reward, a progressive increase in the number of tonically active neurons that respond to that cue emerges (Aosaki et al., 1994b). Examples of cellular plasticity such as long-term potentiation and long-term depression have been demonstrated in both dorsal striatum and accumbens (Boeijinga, Mulder, Pennartz, Manshanden, & Lopes da Silva, 1993; Calabresi, Pisani, Mercuri, & Bernardi, 1996; Kombian & Malenka, 1994; Lovinger, Tyler, & Merritt, 1993; Uno & Ozawa, 1991). For example, tetanic stimulation of prefrontal efferents induces NMDA-dependent LTP in t he nucleus accumbens (Pennartz, Ameerun, Groenewegen, & Lopes da Silva, 1993). A recent study reported simultaneous induction of LTP within the accumbens and prefrontal cortex following stimulation of the fornix-fimbria bundle (Mulder, Arts, & Lopes da Silva, 1997), suggesting that the accumbens may be part of a distributed network participating in memory formation. Indeed, several recent neural network models incorporate the hippocampal-accumbens pathway as a mechanism for successful selection or “stamping in” of correct locomotor actions (Brown & Sharp, 1995; Redish & Touretsky, 1997).
It is important to consider what the role of dopamine might be in this model. A current influential theory posits that activity in dopaminergic neurons serves as a predictor of reward or stimulus salience (Schultz, Dayan, & Montague, 1997). Dopamine neurons alter their firing properties during learning; initially they are activated by primary rewards, but if a stimulus consistently predictive of reward is presented over trials (conditioned stimulus), there is a progressive shift in firing pattern such that the activation is observed only in response to presentation of the conditioned stimulus, but no longer to the primary reward (Schultz, Apicella, & Ljungberg, 1993). Thus, midbrain dopamine neurons, which project to widespread cortical and striatal areas, are proposed to “construct and distribute information about rewarding events” (Schultz et al., 1997). In relation to the present hypotheses concerning accumbens NMDA receptors, glutamate-dopamine interactions may initiate a cascade of biochemical even ts that eventually leads to alterations in gene expression, and that would ultimately influence long-term or permanent synaptic changes underlying motor learning. Indeed, several recent theoretical models have been proposed to explain reinforcement learning in corticostriatal systems. These models postulate an interaction of dopaminergic and corticostriatal synapses, and consequent integrated molecular signals, on the dendritic spines of striatal medium-size spiny output neurons (Houk, Adams, & Barto, 1995; Kotter, 1994; Wickens & Kötter, 1995). Dopaminergic and glutamatergic inputs synapse in close proximity on the same dendritic spine (Smith & Bolam, 1990). Activity in spiny neurons is largely dependent on excitatory input from cortex. Influx of calcium via NMDA receptors in association with dopamine-mediated intracellular changes (such as in the cAMP system) is proposed as essential for the cellular basis of reinforcement. The demonstration of long-term enhancement of synaptic strength when cortical striatal excitation and dopaminergic activation are temporally coordinated supports this notion (Wickens, Begg, & Arbuthnott, 1996), and it has also been found that dopamine selectively enhances NMDA-induced excitations in striatal slices (Cepeda, Buchwald, & Levine, 1993). Thus, it is possible that enhanced dopaminergic activity at a site on the dendritic spine would promote or facilitate the NMDA-mediated synaptic changes necessary for learning. Protein phosphorylation may also play an integral role in this process; for example, we have recently fou nd that intra-accumbens infusions of protein kinase A inhibitors impair response-reinforcement learning (Kelley, Holahan, Smith-Roe, & Baldwin, 1997a).
Additional evidence for activity-dependent plasticity with the striatum derives from accumulating evidence that drugs of abuse have profound effects on transcription factors and gene expression. Amphetamine, cocaine and morphine rapidly induce expression of the nuclear immediate early genes such as c-fos, c-jun, fosB, junB, Fras, and zif/268 (Graybiel, Moratalla, & Robertson, 1990; Hope, Kosofsky, Hyman, & Nestler, 1992; Wang & McGinty, 1995; Wang, Smith, & McGinty, 1995), and can alter transcription factors such as the expression of phosphorylated CREB (cyclic AMP response element binding protein), AP-1 binding (protein binding to DNA response elements), and peptide gene expression (Hope et al. 1992; Simpson et al. 1995; Wang et al. 1994). It is noteworthy that many of these effects appear to be dependent on either NMDA or dopamine D-1 receptor activation. For example, pretreatment with MK-801, an NMDA antagonist, or the D-1 antagonist SCH-23390 prevents amphetamine induction of c-fos and zif/268 (Konr adi, Leveque, & Hyman, 1996; Wang, Daunais, & McGinty, 1994), and the fos and jun mRNA induction by D-1 agonists or dopamine in dissociated striatal cultures is blocked by both competitive and non-competitive NMDA antagonists (Konradi et al., 1996). Behavioral sensitization to psychostimulants is also prevented by MK-801(Wolf, White, & Hu, 1994). Thus, there is intriguing evidence to suggest that plasticity-related neuroadaptations within the ventral striatum and related circuitry may depend on glutamate-dopamine interactions. Most significantly, these neuroadaptations that are concomitants of learning may also underlie the process of addiction. In other words, the neuromolecular effects of addictive drugs appear to mimic the brain normal mechanisms for ensuring reinforcement learning.
Nucleus accumbens shell:a central integrator of feeding
The first suggestion that the shell might be involved in basic motivational drives arose from the theory that it was part of a forebrain system known as the “extended amygdala”, which included the central and medial amygdala, and bed nucleus of the stria terminalis (Alheid & Heimer, 1988; Heimer, Alheid, & Zahm, 1993), and which has prolific outputs to brainstem autonomic and locomotor areas. Recent studies with very discrete injections of retrograde or anterograde tracers show connections, either monosynaptically or indirectly via the pallidum and hypothalamus, to widespread brainstem circuits involved in autonomic arousal, neuroendocrine regulation, consummatory behaviors, pain modulation and defensive behaviors (e.g central grey, mesopontine tegmentum, nucleus of solitary tract) (Groenewegen, Wright, & Beijer, 1996; Heimer et al., 1991).
In the course of our studies on the role of accumbens glutamate in exploratory and spatial behavior, we noticed animals voraciously feeding when they were put back in their home cages, following blockade of AMPA/kainate receptors in the shell with the drug DNQX (6,7-dinitroquinoxaline-2,3-dione). This effect was systematically examined and we reported that blockade of AMPA/kainate receptors within the shell, but not the core, induced marked and prolonged feeding in satiated rats (Maldonado-Irizarry, Swanson, & Kelley, 1995). This feeding has a short onset latency (20-40 sec. approximately), and is not elicited by infusion of NMDA antagonists. A detailed mapping study of the ventral and dorsal striatum showed an even greater degree of anatomical specificity; feeding was only elicited from the accumbens shell, and the posterior aspects of the shell were more sensitive than the anterior aspects (Kelley & Swanson, 1998). This is an interesting pattern because it suggests that cells within more posterior shel l, which is more strongly connected to viscero-endocrine circuits, are preferentially involved in feeding. A study investigating the behavioral specificity of the DNQX effect found that water intake and wood-chip gnawing were not affected; however, palatable sucrose solution intake was increased by the treatment (Stratford, Swanson, & Kelley, 1998). The feeding response bore remarkable resemblance to electrically-induced feeding from the LH, and we tested the hypothesis that activation of the LH is critical for the feeding effect. Indeed, this effect is blocked by concurrent inactivation of the LH with muscimol, suggesting that the ingestive behavior is mediated through activation of cells within the LH. This was a novel demonstration of a specific behavioral role for the accumbens shell, and suggested an important functional link between two major brain regions involved in reward, the accumbens and lateral hypothalamus.
If the theory that removal of an excitatory input caused feeding was correct, we speculated that direct inhibition of the cells would also induce feeding. We found that infusion of muscimol, the GABAA agonist, or baclofen, the GABAB agonist, both caused intense feeding in satiated rats when infused into the accumbens shell (Basso & Kelley, 1999; Stratford & Kelley, 1997b). Like for DNQX, the effect was also completely specific for feeding (water intake was not affected). A mapping study confirmed the posterior shell as most sensitive to feeding, and a pharmacological double dissociation was shown (the GABAA effect was blocked by GABAA antagonists but not by GABAB antagonists, and vice versa). A compound that causes increases in endogenous GABA, gamma-vinyl-GABA, by inhibiting GABA-transaminase, also markedly increased feeding. These findings suggest that the medium spiny neurons within the shell, which contain GABA as their major transmitter, may release GABA to activate normal feeding, which by self-in hibition (through recurrent collaterals) would result in disinhibition of LH or perhaps other downstream cells involved in feeding. We have recent evidence supporting this hypothesis. Utilizing expression of the immediate early gene c-fos as a marker for neuronal activation, we found that intra-shell muscimol markedly activates Fos expression throughout the LH (Stratford & Kelley, 1997a). When LH cells are activated by glutamate agonists, feeding also occurs (Stanley, Willet, Donias, Ha, & Spears, 1993). Also, the GABAB effect is interesting because GABAB receptors are nearly universally presynaptic, and it has been shown that baclofen inhibits glutamate release in the nucleus accumbens (Uchimura and North 1991). Thus, if glutamate terminals have presynaptic GABAB receptors, this could be an additional mechanism by which the glutamate input is attenuated during feeding.
A tentative model regarding the mechanisms underlying the feeding response is proposed as follows. Certain neural inputs may normally exert a tonic excitatory effect on shell neurons, via non-NMDA (AMPA or kainate) receptors. Temporary removal of this excitation with DNQX causes shell neurons to become inactive, thereby disinhibiting intrinsic LH neurons and causing animals to eat. A basic assumption of the model is that neurons arising in the shell exert an inhibitory influence on lateral hypothalamic neurons, via a GABAergic mechanism. Evidence for an inhibitory pathway from medial accumbens to lateral hypothalamus has been demonstrated (Mogenson, Swanson, & Wu, 1983). However, it should be emphasized that that shell-LH interaction may be mediated via an indirect pathway rather than direct. Additionally, mention should be made of opioid modulation of feeding within the ventral striatum, although it is not the primary focus of this review. We have found that mu opioid stimulation of the nucleus accumbens results in considerable enhancement of food intake, particularly highly palatable foods such as fat, sucrose, and salt (Zhang, Gosnell, & Kelley, 1998; Zhang & Kelley, 1997). Interestingly, this effect is not specific to the medial shell and is found throughout the ventral (although not dorsal) striatum, with the lateral shell being the most sensitive part (Zhang, ). Intra-accumbens opioid injection also activates Fos expression in several hypothalamic regions as well the nucleus of the solitary tract (unpublished findings), even without food present, suggesting that this forebrain system has direct effects lower brainstem areas involved in ingestion. These results suggest that opioid peptides within the accumbens shell may play a specific role in palatability, and may also interact with the amino-acid coded systems controlling food intake in this region.
Appetitive/aversive interactions in the accumbens shell
Although our work clearly demonstrates a role for GABAergic accumbens shell neurons in feeding, there nevertheless remain some puzzling facts. For example, the dopamine turnover or activation in the shell is very sensitive to a variety of stress procedures (Deutch & Cameron, 1992; Horger, Elsworth, & Roth, 1995; Kalivas & Duffy, 1995; King & Finlay, 1997; Tidey & Miczek, 1996), and expression of c-fos is most apparent in shell versus core with exposure to conditioned fear (Beck & Fibiger, 1995). However, paradoxically, the shell is very sensitive to reward-related effects as well. We have found in our own material that expression of Fos in the shell is activated by both stressful and reinforcing stimuli (unpublished findings). Drugs of abuse tend to activate dopamine preferentially in the shell compared to the core (Pontieri, Tanda, & Di Chiara, 1995; Pontieri, Tanda, Orzi, & Di Chiara, 1996), and microinjections of D-1 dopamine antagonists into the shell reduce the reinforcing effects of intravenous coca ine (Caine, Heinrichs, Coffin, & Koob, 1995). Certain drugs of abuse are preferentially administered to shell compared with core (Carlezon, Devine, & Wise, 1995; Carlezon & Wise, 1996). The shell, therefore, may have a role in regulating both appetitive and aversively motivated behavior. An important question concerns how these two possible functions interact. One interesting conjecture is that there may be distinct neuronal ensembles within the nucleus accumbens, based on analysis of distinct input-output relationships, that suggest even further specialized compartmentalization beyond simply core and shell (Wright et al., 1996; Wright & Groenewegen, 1996). Combining tracing techniques with immunohistochemical staining, these authors have shown that very specific subregions of the amygdaloid complex reach specific subzones within core and shell of accumbens, and further, that the output of these zones is very distinct and segregated. Thus, it appears that limbic influences representing appetitive or aversive information could affect “sub-ensembles” within the shell. O’Donnell has proposed that functional thalamo-cortical-striatal neuronal ensembles, encoding information via differential distributions of spatial and temporal activity, could convey specific cognitive information to the nucleus accumbens (O'Donnell, 1999). Moreover, neurotransmitter influences may regulate the adaptive expression (or suppression) of reward- or stress-related behaviors. The shell is reported to have a substantial noradrenergic innervation (Berridge, Stratford, Foote, & Kelley, 1997), and CRF and its receptors are also dense in this region (see (Holahan, Kalin, & Kelley, 1997). These two systems or their interaction could signal stress- or danger-related information to the nucleus accumbens.
It is of interest to consider the feeding model with regard to appetitive-aversive interactions, and to pose the following question: why have an accumbens shell if the brain presumably already has several structures that control basic regula tory behaviors (hypothalamus, extended amygdala, brain stem regions, etc.). Gradual increases in endogenous GABA within the shell (perhaps regulated by circulating humoral factors such as insulin or leptin) may be associated with increased motivation for food (along with changes in hypothalamic sensing systems). When a threshold level is met, feeding may be triggered, given that food is available. However, imagine a situation where an animal is extremely hungry, finds food, and commences feeding. If a threat arises in the environment, feeding is immediately arrested and the animal engages in appropriate behavior such as fleeing, freezing, or fighting. Although there may be a considerable energy deficit and the motivation for food is strong, there must exist an immediate and powerful override of neural circuits controlling the feeding behavior. One brain region where such a mechanism could occur is in the accumbens shell. The convergence and rapid processing of glutamate-coded inputs from critical cortical regions processing external stimuli (ventral subiculum, infralimbic prefrontal cortex, amygdala) may be key in this regard. Phasic release of glutamate could reverse the hyperpolarization of the medium spiny neurons induced by GABA, resulting in a major switch in behavioral patterning. The ability to switch between behavioral repertoires has been attributed to the accumbens in other models (e.g. (Evenden & Carli, 1985; van den Bos, Charria Ortiz, & Cools, 1992; Weiner, 1990), and such amino acid-coded integration in the shell may strongly influence behavioral selection in response to changing environmental contingencies. Thus the accumbens shell is unique in that it is influenced by a superimposition of information from both the internal environment and the external world.
Dopamine in the shell does not appear to be directly participate in triggering feeding. Although some feeding can be observed following dopaminergic stimulation of this region (Evans & Vaccarino, 1990; Swanson, Heath, Stratford, & Kell ey, 1997), these small increases in intake are not comparable to that induced by GABAergic agonists or AMPA antagonists. It is generally agreed that dopamine depletion or antagonism in the accumbens does not affect primary motivation for food. However, in several studies it has been clearly demonstrated that extracellular accumbens dopamine is increased in hungry animals or rises with feeding (Bassareo, 1997; Hernandez & Hoebel, 1988; Kiyatkin & Gratton, 1994; Wilson, Nomikos, Collu, & Fibiger, 1995). What then could be the role for dopamine in feeding? In accordance with the general hypothesis that dopamine signals availability of salient, appetitive cues or rewards in the environment, it is likely that availability of food or contexts associated with food stimulates dopamine, which consequently may have a general activating effect on appetitively motivated behavior. In other words, dopamine is not specifically involved with controlling feeding circuits, but rather is facilitory, as proposed in many general theories of dopaminergic function (Robbins & Everitt, 1996; Robinson & Berridge, 1993; Wise & Rompré, 1989). Support for this notion is provided by a recent study reporting that extracellular dopamine increases in the shell of the accumbens when free-feeding animals are presented with a novel, highly palatable food; when the food is not novel, the dopamine response habituates (Bassareo, 1997). It is not yet clear whether dopamine has distinctive functions with regard to core and shell, and this question has not yet been adequately studied. However, a working hypothesis can be put forward based on the general dissociation of functions expounded in this paper. Since the caudate nucleus and accumbens core are the structures most clearly implicated in response learning, release of DA in these areas may facilitate NMDA-receptor-mediated learning. Concurrent release of DA in the accumbens shell is not involved in learning per se, but rather in signalling incentive salience and promoting motor responses that bring the animal in contact with a potentially rewarding stimulus. In a recent study, we found that the shell was generally much more sensitive to the locomotor stimulating effects of DA agonists than the core. Therefore DA in the shell may be involved in increasing the initial output of motor responses (that could potentially lead the organism to a rewarding stimulus), whereas DA in the core participates in the “stamping in” of those responses that led to a satisfactory outcome. In a recent study excitotoxic shell lesions (but not those of the core) abolished the reward-enhancing and locomotor effects of amphetamine (Parkinson et al., 1999). This hypothesis does not exclude the possibility that dopaminergic stimulation of both the shell and core is reinforcing by definition. In other words, it may be that rats would self-administer DA or dopaminergic agonists to both core and shell regions; this experiment has not been carried out to our knowledge.
Conclusions and references
Recent detailed anatomical findings have provided convincing evidence for the original major theory concerning the accumbens: that it acts as an integrator of internal and external sensory and motivationally relevant information with effector mechanisms, in order to ensure adaptive motor behavior. New research has allowed refinement of this theory. Our recent work and that of others has supported the general hypothesis that the core region is preferentially aligned with basal ganglia motor functions, while the role of the shell lies more in the domain of viscero-endocrine functions. More specifically, it is proposed that the core, and specifically NMDA receptors, mediates response-reinforcement learning. It is proposed that the shell is not involved in motor or response learning per se, but is responsible for integrating basic drives and viscero-endocrine effector mechanisms with cortical and subcortical information processing. This dichotomy leads to a further fundamental questions: how are these major fun ctions integrated and coordinated?
There is ample evidence provided through detailed analysis of circuitry, particularly with regard to patch-matrix configurations and microcompartmentalizations, that the subregions within accumbens have extensive cross-talk both locally and through “open” and feed-forward loops (Groenewegen et al., 1996; Pennartz, Groenewegen, & Lopes da Silva, 1994). Joel and Weiner (Joel & Weiner, 1994) have suggested the idea of “split” loops with basal ganglia-thalamocortical circuitry, such that information from striatal subregions (limbic, associative, motor) can be integrated in the prefrontal cortex via overlapping projections to substantia nigra, pars reticulata. The shell, which could be considered a “striatal visceral” area, has access to converging input from corticothalamic circuits, and additionally has close access to response-learning mechanisms via the core and prefrontal output systems. Verification of these hypotheses awaits further experimentation utilizing integrated and multiple approaches; however, it can be said with certainty that in the two decades that have passed since Mogenson’s hypothesis, encouraging progress has been made in understanding the pivotal role of the nucleus accumbens in learning and motivation.
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