CNS Spectr. 2007;12(12):887-892
Faculty Affiliations and Disclosures
Dr. Groenewegen is professor of anatomy and head of the Department of Anatomy and Neurosciences at the Research Institute Neurosciences of VU University Medical Center in Amsterdam, the Netherlands. Dr. Trimble is emeritus professor at the Institute of Neurology, Queen Square in London, United Kingdom, and the field editor of the journal.
Disclosures: Drs. Trimble and Groenewegen do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.
Acknowledgment: The author wishes to dedicate this column to Lennart Heimer, MD, who passed away in March 2007. The scientific work of
Dr. Heimer has been and still is of great inspiration.
Submitted for publication: September 3, 2007; Accepted for publication: October 12, 2007.
Please direct all correspondence to: Henk J. Groenewegen, MD, PhD, VU University Medical Center, Department of Anatomy and Neurosciences, MF-G-102, PO Box 7057, 1007 MB Amsterdam, the Netherlands; Tel: 31-20-4448040/4448033, Fax: 31-20-4448054; E-mail: firstname.lastname@example.org.
Over the next 2 years, CNS Spectrums will be publishing a series of articles on neuroanatomy. The purpose of these articles is to broaden knowledge and interest in neuroanatomy, with a special reference to some key brain structures that are important for neuropsychiatry. Interest in nuclear structures and hodology, in connectivity and circuitry between brain regions, and in neurochemical associations has increased in the last 3 decades due to new neuroanatomical staining methods, brain imaging, and new treatments, such as deep brain stimulation. These columns will enliven an understanding of the clinical neuroscience interface but also provide a solid framework of contemporary neuroanatomy for psychiatrists and neurologists.
The first in the series reviews the ventral striatum. Henk J. Groenewegen, MD, PhD, in a column dedicated to the late Lennart Heimer, MD, reveals the importance of this structure and its connectivity for a contemporary understanding of brain-behavior relationships. In earlier conceptions, the basal ganglia were solely related to motor function, uninvolved with emotion or cognition. This conception arose from a misunderstanding of basic neuroanatomy, which has been unravelled by careful neuroanatomical studies in the last 30 years with new tissue staining and tracing techniques. The basal ganglia are the main target structures of the limbic system, hence the motion in emotion.
The Ventral Striatum
The ventral striatum is generally considered that part of the striatum that is connectionally associated with limbic structures, such as the amygdala, hippocampus, midline thalamus, and certain regions of the prefrontal cortex. In addition, the ventral striatum is strongly innervated by dopaminergic fibers from the ventral tegmental area (VTA [A10 cell group]), known as the mesolimbic dopamine system, and has the highest density of serotonergic inputs in the striatum. In its present connotation, the term “ventral striatum” was introduced in 1975 by Heimer and Wilson1 to differentiate it from the dorsal, sensorimotor-related part of the striatum (ie, the caudate-putamen complex). This inclusion of ventrally located striatal tissue in a “unified” striatum, along with the recognition of connectionally associated pallidal elements in the substantia innominata and deep layers of the olfactory tubercle (ie, the ventral pallidum), has had great impact on the functional-anatomical concept of the basal ganglia. Whereas traditionally, the basal ganglia were thought to be primarily involved in sensory-motor functions,1,2 it has now become accepted that the basal ganglia, as a result of their involvement in a set of parallel, functionally segregated basal ganglia-thalamocortical circuits, which primarily entertain the premotor and prefrontal cortical cortices, are also involved in cognitive and “limbic” functions.2 Thus, in line with the characteristics of its inputs, the ventral striatum is functionally strongly associated with emotional and motivational aspects of behavior. Moreover, structural and functional disturbances of ventral striatal areas have been shown to be correlated with various forms of psychopathology, such as schizophrenia, addictive behavior, and obsessive-compulsive disorder.3-7
Dorsal Versus Ventral Striatum
It is important to note that the distinction between a dorsal and ventral striatum on the basis of specific cortical, thalamic, and dopaminergic inputs does not provide sharply defined borders between these striatal areas. To date, no other structural or functional markers uniquely characteristic for either of the two regions have been identified. In the literature, dorsal and ventral striatum have been virtually equalized with the distinction between the caudate-putamen complex and the nucleus accumbens, respectively.8 However, the ventral striatum as defined on the basis of the aforementioned limbic inputs, as well as based on cyto- and chemoarchitectonic characteristics, occupies a more extensive striatal area than the nucleus accumbens alone and extends more dorsally and caudally into the ventral parts of the caudate nucleus and putamen.8,9 Since most of our knowledge of the ventral striatum derives from data obtained in the nucleus accumbens, the remainder of this brief account primarily refers to this part of the ventral striatum. Ventral striatal areas outside the nucleus accumbens certainly deserve more attention in the future.
Characteristics of the Ventral Striatum/Shell and Core of the Nucleus Accumbens
As stipulated above, the cytoarchitectonic and chemoarchitectonic features of the dorsal and ventral striatum are basically similar, justifying the concept of the striatum as a functional-anatomical unit. Yet, the ventral striatum contains a greater diversity of neurotransmitters and neuroactive peptides than the dorsal striatum. The principal neurons of the ventral striatum are medium-sized, densely spiny projection neurons (MSN) that form >95% of the total population. The population of MSN falls largely into two categories: MSN containing γ-aminobutyric acid (GABA) and the neuropeptides substance P and dynorphin, and MSN containing GABA and enkephalin as neurotransmitters/modulators. The remaining population of ventral striatal neurons encompass cholinergic and a variety GABAergic interneurons, the latter co-storing various neuropeptides.10 The differential distribution of neuroactive substances in the nucleus accumbens, along with the organization of afferent and efferent connections, has led to a distinction between the so-called shell and core subregions.11-13 A well-accepted marker for the outer, crescent-shaped shell and the inner core subregion in a variety of species is the calcium-binding protein calbindin D28K, which is dense in the core and virtually absent in the shell.11-14 Using these and other markers, it is clear that the shell and core subregions of the nucleus accumbens have a heterogeneous composition. Whereas the core shows in-homogeneities resembling the patch-matrix patterns in other parts of the striatum,12,15 cytoarchitectonically it is homogeneous. In contrast, the shell subregion exhibits clustering of cells, some of these clusters containing cells with immature characteristics.9,16 Furthermore, strong in-homogeneities exist in the distribution of various neurochemical substances and neurotransmitter receptors, among which μ-opioid (Figure 1) and dopamine (D)1 and D2 receptors, and these in-homogeneities differ from the patch-matrix configurations in the core and dorsal striatum.17,18 Interestingly, the highest concentration of dopamine D3 receptors in the brain is present in the shell of the nucleus accumbens.19,20
Afferent and Efferent Connectivity of Shell and Core of the Nucleus Accumbens
As in the caudate nucleus and putamen, cerebral cortical fibers form the main source of glutamatergic inputs into the nucleus accumbens. These cortical inputs originate mainly in the medial orbitofrontal, anterior cingulate, and medial parahippocampal cortical areas (Figure 2).12,21,22 In addition, the midline and intralaminar thalamic nuclei, the amygdala, and the hippocampal formation supply the accumbens with excitatory fibers (Figure 2). Extrinsic inhibitory GABAergic projections stem from the ventral pallidum.23,24 The dopaminergic input to the nucleus accumbens originates in the VTA and medial part of the substantia nigra pars compacta, its serotonergic input arises from the dorsal raphe nucleus. The output of the nucleus accumbens reaches the ventral pallidum, the medial part of the globus pallidus, and the dorsomedial part of the substantia nigra pars reticulata (Figure 2). Furthermore, accumbens fibers reach areas in the basal forebrain and mesencephalon that cannot be considered “classical” basal ganglia targets, such as the lateral preoptic area, the lateral hypothalamus, and the caudal mesencephalic regions (Figure 2).12,23
Considerable differences exist between the shell and core subregions in their input-output characteristics, although these differences are not absolute. Therefore, the core subregion receives inputs primarily from the dorsal parts of the medial prefrontal cortex (dorsal prelimbic and anterior cingulate areas), the parahippocampal cortex, the caudal midline and rostral intralaminar thalamic nuclei, and the anterior part of the basolateral amygdaloid nucleus (Figure 2). In its outputs, the core parallels the dorsal striatal projection patterns by sending fibers to the dorsal, subcommissural part of the ventral pallidum (evidently a ventral extension of the external segment of the globus pallidus), the medial part of the internal segment of the globus pallidus, and the dorsomedial part of the substantia nigra pars reticulata (Figure 2).25,26 The subcommissural ventral pallidum is in reciprocal connection with the dorsomedial part of the subthalamic nucleus.27 The medial areas of the internal globus pallidus and substantia nigra project to the ventromedial and mediodorsal thalamic nuclei and via this thalamic relay reach the medial and orbital prefrontal areas that project to the core of the nucleus accumbens, closing one of the “limbic” basal ganglia-thalamocortical circuits.2,12,21
The shell receives inputs from ventrally located medial prefrontal areas (infralimbic and ventral prelimbic), the midline paraventricular thalamic nucleus, posterior parts of the basolateral amygdaloid nucleus, and the subiculum and CA1 regions of the hippocampal formation (Figure 2). In addition to dopaminergic and serotonergic inputs, the caudomedial shell receives, as the only striatal area, significant numbers of noradrenergic fibers, most likely stemming from noradrenergic cell groups in the caudal brainstem.28 Through its outputs, the shell targets the ventral and medial parts of the ventral pallidum and adjacent lateral preoptic area. Shell fibers reach the lateral hypothalamus, the dopaminergic cell groups in the VTA and dorsal tier of the substantia nigra pars compacta and, more caudally in the mesencephalon, the region of the pedunculopontine nucleus (Figure 2). Via the ventral pallidum, the shell is involved a re-entrant “limbic” basal ganglia-thalamocortical circuit that also entertains the mediodorsal thalamic nucleus and medial prefrontal areas.12 Through the projections to the VTA and adjacent substantia nigra pars compacta, the shell may be in a position to influence the dopaminergic inputs to other parts of the striatum, in this way forming a neuronal substrate for the integration of activity in various parallel, functionally segregated basal ganglia-thalamocortical circuits.29,30 In primates, an elaborate spiraling circuitry of striatonigrostriatal projections has been described.31 Thus, ventral striatal areas project to medially located dopaminergic cell groups that, in addition to projecting back to the same striatal area, project to dorsally adjacent striatal areas. This shift in projections is a repeating pattern, which leads to the involvement of progressively more dorsal striatal areas and successively more laterally located dopaminergic cell groups in the substantia nigra.31
Notes on the Functions of the Ventral Striatum
Based on the character of the afferents of the nucleus accumbens, this part of the ventral striatum may be viewed as a site for integration of signals with emotional content (amygdala); contextual information (hippocampus); motivational significance (dopaminergic inputs); information about the state of arousal (midline thalamus); and executive/cognitive information (prefrontal cortex). The accumbens’ outputs, directly or via ventral pallidal and dopaminergic and non-dopaminergic nigral relays, lead to brain areas involved in basic functions, such as feeding and drinking behavior (lateral hypothalamus); motivational behavior (VTA and nigral dopaminergic neurons); locomotor behavior (caudal mesencephalon); and more complex cognitive and executive functions (via medial thalamic nuclei to the prefrontal cortex). Thus, Mogenson and colleagues’32 original concept of the nucleus accumbens as a functional interface between the limbic and motor systems, in general terms, is still valid. However, current insights are, of course, much more differentiated. In particular, the functional differentiation between the shell and core has received much attention in the past 2 decades. Primarily based on animal experimental work, it may be concluded that the shell stands out from the core and the rest of the striatum through its involvement in the expression of certain innate, unconditioned behaviors, such as feeding or defensive behavior.33-39 The shell and core subregions play important but distinct roles in Pavlovian and instrumental conditioned learning that may be potentiated by psychostimulants.40-48 The core subregion seems to be preferentially involved in response-reinforcement learning, whereas the shell is not involved in motor or response learning, per se, rather, it integrates basic biological “drives” with the viscero-limbic and motor-effector systems. Dopamine in the nucleus accumbens may have a role in enhancing the gain by which conditioned stimuli and contexts exert control over behavior.
The ventral striatum forms an integral part of the striatum based upon cytoarchitectonic and chemoarchitectonic characteristics and the general patterns of afferent and efferent connections. It is a specific region of the striatum in the sense that it forms the crossroad between limbic, cognitive, and motor systems. As previously discussed, experimental animal studies have shown that the ventral striatum plays an important role in several forms of behavioral learning. Shell and core form structural and functional distinct subregions of the nucleus accumbens as the “central” part of the ventral striatum. Information about ventral striatal functioning in the human brain is unfortunately scarce.49 The dysfunction of this part of the striatum has been associated among individuals with schizophrenia,6,7,50,51 obsessive-compulsive disorder,5 depression, and drug addiction.4,52-54 Preliminary positive effects of deep brain stimulation in the region of the nucleus accumbens in cases of otherwise intractable obsessive-compulsive behavior have been reported.49,55 Whether these findings forebode a development in which the ventral striatum becomes a surgical or pharmacologic target for therapeutic interventions in various neuropsychiatric diseases remains to be seen.
1. Heimer L, Wilson RD. The subcortical projections of the allocortex: similarities in the neural associations of the hippocampus, the piriform cortex, and the neocortex. In: Santini M, ed. Perspectives in Neurobiology. Golgi Centennial Symposium, New York, NY: Raven Press; 1975:177-193.
2. Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res. 1990;85:119-146.
3. Everitt BJ, Parkinson JA, Olmstead MC, Arroyo M, Robledo P, Robbins TW. Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann N Y Acad Sci. 1999;877:412-438.
4. Robbins TW, Everitt BJ. Limbic-striatal memory systems and drug addiction. Neurobiol Learn Mem. 2002;78:625-636.
5. Van den Heuvel OA, Veltman DJ, Groenewegen HJ, et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder and hypochondriasis. Arch Gen Psychiatry. 2005;62:922-933.
6. Grace AA. Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Rev. 2000;31:330-341.
7. Heimer L. Basal forebrain in the context of schizophrenia. Brain Res Rev. 2000;31:205-235.
8. Voorn P, Vanderschuren LJ, Groenewegen HJ, Robbins TW, Pennartz CM. Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 2004;27:468-474.
9. Fudge JL, Haber SN. Defining the caudal ventral striatum in primates: cellular and histochemical features. J Neurosci. 2002;22:1078-1082.
10. Meredith GE. The synaptic framework for chemical signaling in nucleus accumbens. Ann N Y Acad Sci. 1999;877:140-156.
11. Zaborszky L, Alheid GF, Beinfeld MC, Eiden LE, Heimer L, Palkovits M. Cholecystokinin innervation of the ventral striatum: a morphological and radioimmunological study. Neuroscience. 1985;4:427-453.
12. Groenewegen HJ, Wright CI, Beijer AV. The nucleus accumbens: gateway for limbic structures to reach the motor system? Prog Brain Res. 1996;107:485-511.
13. Zahm DS, Brog JS. On the significance of subterritories in the “accumbens”part of the rat ventral striatum. Neuroscience. 1992;50:751-767.
14. Meredith GE, Pattiselanno A, Groenewegen HJ, Haber SN. Shell and core in monkey and human nucleus accumbens identified with antibodies to calbindin-D28k. J Comp Neurol. 1996;365:628-639.
15. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 1990;13:244-254.
16. Heimer L, de Olmos JS, Alheid GF, et al. The human basal forebrain. Part II. In: Bloom FE, Björklund A, Hökfelt T, eds. The Primate Nervous System, Part III (Handbook of Chemical Neuroanatomy, Vol 15). Amsterdam, the Netherlands: Elsevier; 1999:57-226.
17. Voorn P, Brady LS, Berendse HW, Richfield EK. Densitometrical analysis of opioid receptor ligand binding in the human striatum–I. Distribution of mu opioid receptor defines shell and core of the ventral striatum. Neuroscience. 1996;75:777-792.
18. Berendse HW, Richfield EK. Heterogeneous distribution of dopamine D1 and D2 receptors in the human ventral striatum. Neurosci Lett. 1993;150:75-79.
19. Joyce JN, Gurevich EV. D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann N Y Acad Sci. 1999;877:595-613.
20. Schwartz JC, Diaz J, Pilon C, Sokoloff P. Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res Rev. 2000;31:277-287.
21. Ferry AT, Ongur D, An X, Price JL. Prefrontal cortical projections to the striatum in macaque monkeys: evidence for an organization related to prefrontal networks. J Comp Neurol. 2000;425:447-470.
22. Kunishio K, Haber SN. Primate cingulostriatal projection: limbic striatal versus sensorimotor striatal input. J Comp Neurol. 1994;350:337-356.
23. Groenewegen HJ, Berendse HW, Haber SN. Organization of the output of theventral striatopallidal system in the rat: ventral pallidal efferents. Neuroscience. 1993;57:113-142.
24. Bolam JP, Hanley JJ, Booth PA, Bevan MD. Synaptic organisation of the basal ganglia. J Anat. 2000;196:527-542.
25. Haber SN, Wolfe DP, Groenewegen HJ. The relationship between ventral striatal efferent fibers and the distribution of peptide-positive woolly fibers in the forebrain of the rhesus monkey. Neuroscience. 1990;39:323-338.
26. Deniau JM, Menetrey A, Thierry AM. Indirect nucleus accumbens input to the prefrontal cortex via the substantia nigra pars reticulata: a combined anatomical and electrophysiological study in the rat. Neuroscience. 1994;61:533-545.
27. Groenewegen HJ, Berendse HW. Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat. J Comp Neurol. 1990;294:607-622.
28. Berridge CW, Stratford TL, Foote SL, Kelley AE. Distribution of dopamine beta-hydroxylase-like immunoreactive fibers within the shell subregion of the nucleus accumbens. Synapse. 1997;27:230-241
29. Nauta WJ, Smith GP, Faull RL, Domesick VB. Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience. 1978;3:385-401.
30. Groenewegen HJ, Van den Heuvel OA, Cath DC, Voorn P, Veltman DJ. Does an imbalance between the dorsal and ventral striatopallidal systems play a role in Tourette’s Syndrome? A neuronal circuit approach. Brain Dev. 2003;25:S3-S14.
31. Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci. 2000;20:2369-2382.
32. Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol. 1980;14:69-97.
33. Maldonado-Irizarry CS, Kelley AE. Excitotoxic lesions of the core and shell subregions of the nucleus accumbens differentially disrupt body weight regulation and motor activity in rat. Brain Res Bull. 1995;38:551-559.
34. Kelley AE. Neural integrative activities of nucleus accumbens subregions in relation to learning and motivation. Psychobiol. 1999;27:198-213.
35. Kelley AE. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobeh Rev. 2004;27:765-776.
36. Reynolds SM, Berridge KC. Fear and feeding in the nucleus accumbens shell: rostrocaudal segregation of GABA-elicited defensive behavior versus eating behavior. J Neurosci. 2001;21:3261-3270.
37. Reynolds SM, Berridge KC. Positive and negative motivation in nucleus accumbens shell: bivalent rostrocaudal gradients for GABA-elicited eating, taste “liking”/”disliking” reactions, place preference/avoidance, and fear. J Neurosci. 2002;22:7308-7320.
38. Reynolds SM, Berridge KC. Glutamate motivational ensembles in nucleus accumbens: rostrocaudal shell gradients of fear and feeding. Eur J Neurosci. 2003;17:2187-2200.
39. Cardinal RN, Parkinson JA, Hall J, Everitt BJ. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobeh Rev. 2002;26:321-352.
40. Parkinson JA, Olmstead MC, Burns LH, Robbins TW, Everitt BJ. Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. J Neurosci. 1999;19:2401-2411.
41. Bell K, Duffy P, Kalivas PW. Context-specific enhancement of glutamate transmission by cocaine. Neuropsycopharmacology. 2000;23:335-344.
42. Corbit LH, Muir JL, Balleine BW. The role of the nucleus accumbens in instrumental conditioning: evidence of a functional dissociation between accumbens core and shell. J Neurosci. 2001;21:3251-3260.
43. Fenu S, Acquas E, Di Chiara G. Role of striatal acetylcholine on dopamine D1 receptor agonist-induced turning behavior in 6-hydroxydopamine lesioned rats: a microdialysis-behavioral study. Neurol Sci. 2001;22:63-64.
44. Hotsenpiller G, Giorgetti M, Wolf ME. Alterations n behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure. Eur J Neurosci. 2001;14:1843-1855.
45. Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res. 2002;137:75-114.
46. Phillips GD, Setzu E, Vugler A, Hitchcott PK. Immunohistochemical assessment of mesotelencephalic dopamine activity during the acquisition and expression of pavlovian versus instrumental behaviors. Neuroscience. 2003;117:755-767.
47. Ito R, Robbins TW, Everitt BJ. Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci. 2004;7:389-397.
48. Sellings LH, McQuade LE, Clarke PB. Evidence for multiple sites within rat ventral striatum mediating cocaine-conditioned place preference and locomotor activation. J Pharmacol Exp Ther. 2006;317:1178-1187.
49. Van Kuyck K, Gabriëls L, Cosyns P, et al Behavioural and physiological effects of electrical stimulation in the nucleus accumbens: a review. Acta Neurochir Suppl. 2007;97(pt 2):375-391.
50. Pakkenberg B. Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry. 1990;47:1023-1028.
51. Baumann B, Bogerts B. The pathomorphology of schizophrenia and mood disorders: similarities and differences. Schizophr Res. 1999;39:141-148.
52. Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry. 2001;50:71-83.
53. Brody AL. Functional brain imaging of tobacco use and dependence. J Psychiatr Res. 2006;40:404-418.
54. Kalivas PW, Volkow N, Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron. 2005;45:647-650.
55. Sturm V, Lenartz D, Koulousakis A, et al. The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J Chem Neuroanat. 2003;26:293-299.