ReviewThe place of dopamine in the cortico-basal ganglia circuit
Introduction
A key component in developing appropriate goal-directed behaviors is the ability to first correctly evaluate different aspects of reward, including value versus risk and predictability, and inhibit maladaptive choices, based on previous experience. These calculations rely on integration of different aspects of motivation and cognition to develop and execute appropriate action plans. The midbrain dopamine (DA) neurons play a central role in these behaviors including reward, cognition, and motor control. Indeed, subpopulations of DA neurons have been associated with these different functions: the mesolimbic, mesocortical, and nigrostriatal pathways, respectively (Wullner et al., 1994, Sawaguchi, 1995, Goldman-Rakic, 1998, Wise, 2004). Recently, all DA cell groups have been associated with the development of reward-based learning, leading to goal-directed behaviors (Schultz, 2002).
The substantia nigra (SN) was first recognized in 1786 with the description of brain neuromelanin distribution (Vicq D’Azyr, 1786). The link to the motor system came much later with its association with Parkinson’s disease (PD) (Brissaud, 1895, Bremer, 1920, Hassler, 1939). Collectively the work of several investigators then demonstrated that the cells contained DA, that DA was a neurotransmitter, and that these cells were depleted in PD (Ehringer and Hornykiewicz, 1960, Hornykiewicz, 1966, Bazelton et al., 1967). Around the same time DA was also linked to psychoses and subsequently addiction, and behavioral disorders, see (Baldessarini, 1985). With the visualization of DA neurons and the advances in connectivity and lesion methods in the 1960s, the subpopulations of DA neurons were associated with reward, cognition, or motor control: the mesolimbic (ventral tegmental area-VTA), mesocortical (VTA-retrorubral), and nigrostriatal (substantia nigra, pars compacta-SNc) pathways, respectively. Collectively these discoveries demonstrated that the DA cells are an integral part of the basal ganglia (BG). The VTA and SNc send a massive output to the striatum, the main input structure of the BG. Moreover, this is a bidirectional pathway, with the DA cells receiving a major input from the striatum.
Overall, the BG was best known for its relevance to motor functions, due to its role in movement control diseases. This concept dramatically changed in the last 35+ years to a more complex set of functions that mediate the full range of goal-directed behaviors, including emotions, motivation, and cognition. In the late 1970s, Heimer discovered that the nucleus accumbens (NAcc), (a basal forebrain region associated with limbic function), and the surrounding area were actually part of the striatum and termed this the ventral striatum (VS). Moreover, he identified the cells that were located ventral to the anterior commissure as pallidal in nature and showed that they received inputs from the VS. These cells are referred to as the ventral pallidum (VP) (Heimer, 1978). Subsequently he and others showed that the VP projected to the medial dorsal (MD) thalamus and back to non-motor cortex, thus identifying a separate functional loop of the BG (Young III et al., 1984, Haber et al., 1985). The concept of several functional, yet separate cortical loops through BG was then expanded in primates (Alexander et al., 1990). While the notion that these circuits are anatomically segregated remains prominent in the field, the idea of a motivation-to-movement interface, rather than separate loops through BG circuits was developed soon after the discovery of the VS/VP circuit. Researchers interested in how motivation impacts learning and the development of habits, recognized that integration between functional circuits was necessary to carry out goal-directed behaviors (Mogenson et al., 1980, Percheron and Filion, 1991, Dickinson and Balleine, 1994, Haber et al., 2000, Belin and Everitt, 2008, Leung and Balleine, 2013). Thus, the BG is now recognized to mediate the full range of behaviors leading to the development and execution of action plans, including the emotions, motivation, and cognition that drive them.
Section snippets
Overview of the BG circuitry
The striatum is the main input structure of the BG. Its afferent projections are derived from three major sources: (1) it receives a massive and topographic input from all of the cerebral cortex; (2) the second largest input is derived from the thalamus; and (3) the third main input is from the brainstem, the largest from the midbrain DA cells. Striatal functional domains are derived from the topography of its cortical inputs. Thus, we briefly review the topography of those inputs here. In
Organization of the midbrain DA cells in primates
The SNc has been divided into three groups: a dorsal (α) group, also referred to as the pars dorsalis; a main, densocellular (β) group; and a ventral (γ) group, or the cell columns (Olszewski and Baxter, 1982, Poirier et al., 1983, Francois et al., 1985, Halliday and Tork, 1986, Haber et al., 1995b). The dorsal group is composed of loosely arranged cells that extend dorsolaterally and circumvent the ventral and lateral superior cerebellar peduncle and the red nucleus. They are oriented
Connections
The main efferent projections of the midbrain DA system are to the striatum and cortex. Other projections include those to the thalamus, amygdala and hippocampus, and globus pallidus. The main afferent projections to the DA cells arise from the striatum and the brainstem pedunculopontine nucleus. Other key afferent projections include those from the lateral habenula (LHb) via the rostromedial tegmental nucleus (RMTg), the globus pallidus, and the superior colliculus. Each of these plays a key
Striato-midbrain-striato connections: the spiral
As indicated above, each functional region differs in its proportional projections that significantly alter their relationship to each other. The VS receives inputs from the areas involved in emotional processing, reward, and motivation. This includes the OFC, ACC, amygdala, and hippocampus. The VS receives a limited midbrain input, primarily from the VTA and dorsal tier. Yet, projections from this limbic area terminate widely in the midbrain, including the dorsal tier and the dorsal part of
Functional considerations
The ability to maintain focus in the execution of specific behaviors and the ability to adapt appropriately to external and internal cues are key deficits in BG diseases that affect these aspects of motor control, cognition, and motivation. Thus, a system that contains separate circuits to mediate various functions to maintain focus in coordinating actions maybe important. However, to have a system that was designed only with parallel and segregated circuits, without interaction between those
Acknowledgment
This work was supported by the NIMH grant MH045573-24.
References (101)
- et al.
The efferent projections of the rat lateral habenular nucleus revealed by the PHA-L anterograde tracing method
Brain Res
(1988) - et al.
Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum
Neuron
(2008) - et al.
Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction
Behav Brain Res
(2009) - et al.
Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain
Neuroscience
(2010) - et al.
The precise localization of nigral afferents in the rat as determined by a retrograde tracing technique
Brain Res
(1976) - et al.
A histological atlas of the macaque (Macaca mulatta) substantia nigra in ventricular coordinates
Brain Res Bull
(1985) - et al.
Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior
Neuropharmacology
(2010) - et al.
Amygdaloid projections to ventromedial striatal subterritories in the primate
Neuroscience
(2002) The basal ganglia: learning new tricks and loving it
Curr Opin Neurobiol
(2005)- et al.
The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders
Neuron
(2014)
The globus pallidus sends reward-related signals to the lateral habenula
Neuron
The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses
Neuron
The cortico-nigral projection: reduced glutamate content in the substantia nigra following frontal cortex ablation in the rat
Brain Res
Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. An autoradiographic study in Macaca fascicularis
Brain Res
The efferent projections of the medial prefrontal cortex in the squirrel monkey (Saimiri sciureus)
Brain Res
Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H] raclopride, [3H] spiperone and [3H]sch23390
Neuroscience
The organization of midbrain projections to the striatum in the primate: sensorimotor-related striatum versus ventral striatum
Neuroscience
Calbindin D28K-containing neurons are restricted to the medial substantia nigra in humans
Neuroscience
From motivation to action: functional interface between the limbic system and the motor system
Prog Neurobiol
The origin of forebrain afferents to the habenula in rat, cat and monkey
Brain Res Bull
The subcortical afferents to caudate nucleus and putamen in primate: a fluorescence retrograde double labeling study
Neuroscience
Comparative morphology of the substantia nigra and ventral tegmental area in the monkey, cat and rat
Brain Res Bull
The effects of cocaine: a shifting target over the course of addiction
Prog Neuropsychopharmacol Biol Psychiatry
Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient
Biol Psychiatry
Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study
Biol Psychiatry
Getting formal with dopamine and reward
Neuron
Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression
Behav Brain Res
Dopamine terminal loss and onset of motor symptoms in MPTP-treated monkeys: a positron emission tomography study with 11C-CFT
Exp Neurol
Cortico-striate projections in the rhesus monkey: the organization of certain cortico-caudate connections
Brain Res
The cortico-nigral fibre tract. An experimental Fink–Heimer study in cats
J Anat
Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions
Prog Brain Res
Estimates of projection overlap and zones of convergence within frontal-striatal circuits
J Neurosci
Chemotherapy in psychiatry. Principles and practice
Studies on neuromelanin. I. A melanin system in the adult human brainstem
Neurology
Encephalite lethargique avec syndrome Parkinsonien et catatonie
Rev Neurol
A pallidus-habenula-dopamine pathway signals inferred stimulus values
J Neurophysiol
Relationship between the corticostriatal terminals from areas 9 and 46, and those from area 8A, dorsal and rostral premotor cortex and area 24c: an anatomical substrate for cognition to action
Eur J Neurosci
Glutamatergic pathways from the medial pre-frontal cortex to the anterior striatum, nucleus accumbens and substantia nigra
Br J Pharmacol
Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate
J Neurosci
Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat
J Neurosci
Human dorsal striatum encodes prediction errors during observational learning of instrumental actions
J Cogn Neurosci
Motivational control of goal-directed action
Anim Learn Behav
Verteilung von noradrenalin und dopamine (3-hydro-xytyramin) im gehirn des menschen und ihr verhalten bei erkankungen des extrapyramidalen systems
Klin Wochenschr
Monoamine innervation of cerebral cortex and a theory of the role of monoamines in cerebral cortex and basal ganglia
Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection
Neuropsychopharmacology
Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys
J Comp Neurol
The cortical dopamine system: role in memory and cognition
Adv Pharmacol
Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum
J Neurosci
Efferent connections of the ventral pallidum. Evidence of a dual striatopallidofugal pathway
J Comp Neurol
Cited by (249)
Fronto-striatal dynamic connectivity is linked to dopaminergic motor response in Parkinson's disease
2023, Parkinsonism and Related DisordersStress to inflammation and anhedonia: Mechanistic insights from preclinical and clinical models
2023, Neuroscience and Biobehavioral ReviewsFrom Computation to Clinic
2023, Biological Psychiatry Global Open Science