Marcus Stephenson-Jones

Evolution of the basal ganglia: Dual-output pathways conserved throughout vertebrate phylogeny

The basal ganglia, including the striatum, globus pallidus interna and externa (GPe), subthalamic nucleus (STN), and substantia nigra pars compacta, are conserved throughout vertebrate phylogeny and have been suggested to form a common vertebrate mechanism for action selection. In mammals, this circuitry is further elaborated by the presence of a dual‐output nucleus, the substantia nigra pars reticulata (SNr), and the presence of modulatory input from the cholinergic pedunculopontine nucleus (PPN). We sought to determine whether these additional components of the mammalian basal ganglia are also present in one of the phylogenetically oldest vertebrates, the lamprey. We show, by using immunohistochemistry, tract tracing, and whole‐cell recordings, that homologs of the SNr and PPN are present in the lamprey. Thus the SNr receives direct projections from inwardly rectifying γ‐aminobutyric acid (GABA)‐ergic striatal neurons expressing substance P, but it is also influenced by indirect basal ganglia projections from the STN and potentially the GPe. Moreover, GABAergic SNr projection neurons are tonically active and project to the thalamus and brainstem motor areas. The homolog of the PPN contains both cholinergic and GABAergic neurons and is connected with all the nuclei of the basal ganglia, supporting its proposed role as part of an extended basal ganglia. A separate group of cholinergic neurons dorsal to the PPN corresponds to the descending mesencephalic locomotor region. Our results suggest that dual‐output nuclei are part of the ancestral basal ganglia and that the PPN appears to have coevolved as part of a mechanism for action selection common to all vertebrates. J. Comp. Neurol. 520:2957–2973, 2012.

The evolutionary origin of the vertebrate basal ganglia and its role in action selection

Abstract  The group of nuclei within the basal ganglia of the forebrain is central to the control of movement. We present data showing that the structure and function of the basal ganglia have been conserved throughout vertebrate evolution over some 560 million years. The interaction between the different nuclei within the basal ganglia is conserved as well as the cellular and synaptic properties and transmitters. We consider the role of the conserved basal ganglia circuitry for basic patterns of motor behaviour controlled via brainstem circuits. The output of the basal ganglia consists of tonically active GABAergic neurones, which target brainstem motor centres responsible for different patterns of behaviour, such as eye and locomotor movements, posture, and feeding. A prerequisite for activating or releasing a motor programme is that this GABAergic inhibition is temporarily reduced. This can be achieved through activation of GABAergic projection neurons from striatum, the input level of the basal ganglia, given an appropriate synaptic drive from cortex, thalamus and the dopamine system. The tonic inhibition of the motor centres at rest most likely serves to prevent the different motor programmes from becoming active when not intended. Striatal projection neurones are subdivided into one group with dopamine 1 receptors that provides increased excitability of the direct pathway that can initiate movements, while inhibitory dopamine 2 receptors are expressed on neurones that instead inhibit movements and are part of the ‘indirect loop’ in mammals as well as lamprey. We review the evidence showing that all basic features of the basal ganglia have been conserved throughout vertebrate phylogeny, and discuss these findings in relation to the role of the basal ganglia in selection of behaviour.

Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems

The medial (MHb) and lateral (LHb) habenulae are a small group of nuclei that regulate the activity of monoaminergic neurons. Disruptions to these nuclei lead to deficits in a range of cognitive and motor functions from sleep to decision making. Interestingly, the habenular nuclei are present in all vertebrates, suggesting that they provide a common neural mechanism to influence these diverse functions. To unravel conserved habenula circuitry and approach an understanding of their basic function, we investigated the organization of these nuclei in the lamprey, one of the phylogenetically oldest vertebrates. Based on connectivity and molecular expression, we show that the MHb and LHb circuitry is conserved in the lamprey. As in mammals, separate populations of neurons in the LHb homolog project directly or indirectly to dopamine and serotonin neurons through a nucleus homologous to the GABAergic rostromedial mesopontine tegmental nucleus and directly to histamine neurons. The pallidal and hypothalamic inputs to the LHb homolog are also conserved. In contrast to other species, the habenula projecting pallidal nucleus is topographically distinct from the dorsal pallidum, the homolog of the globus pallidus interna. The efferents of the MHb homolog selectively target the interpeduncular nucleus. The MHb afferents arise from sensory (medial olfactory bulb, parapineal, and pretectum) and not limbic areas, as they do in mammals; consequently, the “context” in which this circuitry is recruited may have changed during evolution. Our results indicate that the habenular nuclei provide a common vertebrate circuitry to adapt behavior in response to rewards, stress, and other motivating factors.

Independent circuits in the basal ganglia for the evaluation and selection of actions

Significance The activity in the dopaminergic reward system of the brain is concerned with the evaluation of actions and is controlled from the lateral habenulae, in all vertebrates investigated, from lamprey to primates. This study considers the mechanisms by which the lateral habenulae is controlled. We show here that a particular group of nerve cells conveys excitatory drive to the lateral habenulae, which, in turn, receive excitatory input from pallium (cortex in mammals) and inhibitory control from a specific compartment (striosomes) in the basal ganglia. This control system is critical for value-based decisions, important in all groups of vertebrates. The basal ganglia are critical for selecting actions and evaluating their outcome. Although the circuitry for selection is well understood, how these nuclei evaluate the outcome of actions is unknown. Here, we show in lamprey that a separate evaluation circuit, which regulates the habenula-projecting globus pallidus (GPh) neurons, exists within the basal ganglia. The GPh neurons are glutamatergic and can drive the activity of the lateral habenula, which, in turn, provides an indirect inhibitory influence on midbrain dopamine neurons. We show that GPh neurons receive inhibitory input from the striosomal compartment of the striatum. The striosomal input can reduce the excitatory drive to the lateral habenula and, consequently, decrease the inhibition onto the dopaminergic system. Dopaminergic neurons, in turn, provide feedback that inhibits the GPh. In addition, GPh neurons receive direct projections from the pallium (cortex in mammals), which can increase the GPh activity to drive the lateral habenula to increase the inhibition of the neuromodulatory systems. This circuitry, thus, differs markedly from the “direct” and “indirect” pathways that regulate the pallidal (e.g., globus pallidus) output nuclei involved in the control of motion. Our results show that a distinct reward–evaluation circuit exists within the basal ganglia, in parallel to the direct and indirect pathways, which select actions. Our results suggest that these circuits are part of the fundamental blueprint that all vertebrates use to select actions and evaluate their outcome.

A basal ganglia circuit for evaluating action outcomes

The basal ganglia, a group of subcortical nuclei, play a crucial role in decision-making by selecting actions and evaluating their outcomes. While much is known about the function of the basal ganglia circuitry in selection, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) in mice are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We find in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision-making task. Moreover, cell-type-specific synaptic manipulations reveal that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies-virus-assisted monosynaptic tracing, we show that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the ‘limbic’ regions of the subthalamic nucleus. Our results provide evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus in which information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.

Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression

The dopaminergic system influences motor behavior, signals reward and novelty, and is an essential component of the basal ganglia in all vertebrates including the lamprey, one of the phylogenetically oldest vertebrates. The intrinsic organization and function of the lamprey basal ganglia is highly conserved. For instance, the direct and indirect pathways are modulated through dopamine D1 and D2 receptors in lamprey and in mammals. The nucleus of the tuberculum posterior, a homologue of the substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) is present in lamprey, but only scarce data exist about its connectivity. Likewise, the D2 receptor is expressed in the striatum, but little is known about its localization in other brain areas. We used in situ hybridization and tracer injections, both in combination with tyrosine hydroxylase immunohistochemistry, to characterize the SNc/VTA efferent and afferent connectivity, and to relate its projection pattern with D2 receptor expression in particular. We show that most features of the dopaminergic system are highly conserved. As in mammals, the direct pallial (cortex in mammals) input and the basal ganglia connectivity with the SNc/VTA are present as part of the evaluation system, as well as input from the tectum as the evolutionary basis for salience/novelty detection. Moreover, the SNc/VTA receives sensory information from the olfactory bulbs, optic tectum, octavolateral area, and dorsal column nucleus, and it innervates, apart from the nigrostriatal pathway, several motor‐related areas. This suggests that the dopaminergic system also contributes to the control of different motor centers at the brainstem level. J. Comp. Neurol. 522:3775–3794, 2014.

Dopamine Differentially Modulates the Excitability of Striatal Neurons of the Direct and Indirect Pathways in Lamprey

The functions of the basal ganglia are critically dependent on dopamine. In mammals, dopamine differentially modulates the excitability of the direct and indirect striatal projection neurons, and these populations selectively express dopamine D1 and D2 receptors, respectively. Although the detailed organization of the basal ganglia is conserved throughout the vertebrate phylum, it was unknown whether the differential dopamine modulation of the direct and indirect pathways is present in non-mammalian species. We aim here to determine whether the receptor expression and opposing dopaminergic modulation of the direct and indirect pathways is present in one of the phylogenetically oldest vertebrates, the river lamprey. Using in situ hybridization and patch-clamp recordings, we show that D1 receptors are almost exclusively expressed in the striatal neurons projecting directly to the homolog of the substantia nigra pars reticulata. In addition, the majority of striatal neurons projecting to the homolog of the globus pallidus interna/globus pallidus externa express D1 or D2 receptors. As in mammals, application of dopamine receptor agonists differentially modulates the excitability of these neurons, increasing the excitability of the D1-expressing neurons and decreasing the excitability of D2-expressing neurons. Our results suggest that the segregated expression of the D1 and D2 receptors in the direct and indirect striatal projection neurons has been conserved across the vertebrate phylum. Because dopamine receptor agonists differentially modulate these pathways, increasing the excitability of the direct pathway and decreasing the excitability of the indirect pathway, this organization may be conserved as a mechanism that biases the networks toward action selection.

The lamprey blueprint of the mammalian nervous system

The basic features of the vertebrate nervous system are conserved throughout vertebrate phylogeny to a much higher degree than previously thought. In this mini-review, we show that not only the organization of the different motor programs underlying eye, orienting, locomotor, and respiratory movements are similarly organized, but also that the basic structure of the forebrain engaged in the control of movement is conserved. In the lamprey, which diverged already 560 million years ago from the vertebrate line of evolution leading up to primates, the basic components of the basal ganglia are similar to those of mammals in considerable detail. Moreover, the properties of the synaptic input are similar as well as transmitters/peptides in the direct and indirect pathway throughout the basal ganglia. The membrane properties of the striatal projection neurons with D1 and D2 receptors, respectively, are also similar, as are those of the pallidal output neurons. Our evidence suggests that the basal ganglia can be subdivided into functional modules controlling different motor programs, like locomotion and eye movements. What has happened during evolution is that the number of modules has increased in parallel with a progressively more complex behavioral repertoire. For value-based decisions, the circuitry through the lateral habenulae to the dopaminergic modulator neurons is also conserved, as well as the relay inhibitory interneurons involved. The habenular input is from a pallidal glutamatergic nucleus in lamprey as well as mammals, and this nucleus in turn receives input from the striosomal compartment within striatum and also from pallium (cortex in mammals).

The Dopamine D2 Receptor Gene in Lamprey, Its Expression in the Striatum and Cellular Effects of D2 Receptor Activation

All basal ganglia subnuclei have recently been identified in lampreys, the phylogenetically oldest group of vertebrates. Furthermore, the interconnectivity of these nuclei is similar to mammals and tyrosine hydroxylase-positive (dopaminergic) fibers have been detected within the input layer, the striatum. Striatal processing is critically dependent on the interplay with the dopamine system, and we explore here whether D2 receptors are expressed in the lamprey striatum and their potential role. We have identified a cDNA encoding the dopamine D2 receptor from the lamprey brain and the deduced protein sequence showed close phylogenetic relationship with other vertebrate D2 receptors, and an almost 100% identity within the transmembrane domains containing the amino acids essential for dopamine binding. There was a strong and distinct expression of D2 receptor mRNA in a subpopulation of striatal neurons, and in the same region tyrosine hydroxylase-immunoreactive synaptic terminals were identified at the ultrastructural level. The synaptic incidence of tyrosine hydroxylase-immunoreactive boutons was highest in a region ventrolateral to the compact layer of striatal neurons, a region where most striatal dendrites arborise. Application of a D2 receptor agonist modulates striatal neurons by causing a reduced spike discharge and a diminished post-inhibitory rebound. We conclude that the D2 receptor gene had already evolved in the earliest group of vertebrates, cyclostomes, when they diverged from the main vertebrate line of evolution (560 mya), and that it is expressed in striatum where it exerts similar cellular effects to that in other vertebrates. These results together with our previous published data (Stephenson-Jones et al. 2011, 2012) further emphasize the high degree of conservation of the basal ganglia, also with regard to the indirect loop, and its role as a basic mechanism for action selection in all vertebrates.

Evolutionarily conserved differences in pallial and thalamic short-term synaptic plasticity in striatum

Recent studies have shown that the striatum and the basal ganglia are to a remarkable degree conserved throughout the vertebrate phylum. As the basic organization of the neural machinery for action selection is present in the lamprey, it is essential to understand how the striatum is activated. In this study we characterize the pharmacology and synaptic dynamics from the lateral pallium (LPal; cortex) and thalamus (Th), the main excitatory input to the striatum. We show that, as in mammals, the LPal and Th provide glutamatergic excitation to the striatum, but with completely opposite short‐term synaptic plasticity due to differences in presynaptic properties. These synaptic differences are also characteristic of the mammalian striatum, suggesting that these are fundamental components of the vertebrate mechanisms for action selection.