Striatum is composed mostly of GABAergic projection neurons (γ-aminobutyric acid), known as medium spiny neurons, due to the large number of spines in their dendrites. These cells also produce and release some neuropeptides such as enkephalin, substance P, and dynorphin (Fazl and Fleisher, 2018), which amplify GABA’s inhibitory action. In less amount, there are interneurons in the striatum that have as a neurotransmitter GABA, acetylcholine, somatostatin, nitric oxide, neuropeptide Y. Striatal interneurons act mainly by modulating the medium spiny neurons, defining whether or not they will be activated (Kawaguchi, 1997; Assous and Tepper, 2019).

The striatum is the main region for inputs to the basal ganglia, receiving several projections from the cortex, thalamus, and brainstem. The cortico-striatal projections exert the greatest influence on the striatum through glutamatergic synapses, they are mostly excitatory. Another structure that contributes with glutamatergic inputs to the striatum is the thalamus, however, it does not impose the same impact on striatal activity as the cortical afferences. The pedunculopontine nucleus and dorsolateral pontine tegmentum are structures in the brainstem and perform cholinergic projections for both medium spiny neurons and striatal interneurons, nonetheless their functions are not yet fully understood so far. In addition, the midbrain sends large-scale dopaminergic outputs to striatum (Silberberg and Bolam, 2015). Dopaminergic signaling is fundamental for the basal ganglia’s motor circuit. As such, among midbrain dopaminergic nuclei, the SN plays a key role in this pathway, because one of its subdivisions, the SNc, communicates directly with the striatum in a pathway known as nigrostriatal pathway (Rice et al., 2011; Norrara et al., 2018; Rocha et al., 2022).

Once it receives dopaminergic inputs in large amounts, the striatum has high density of dopamine receptors. Dopamine receptors are divided into D₁ and D₂ types, which are metabotropic and exert modulatory effects on neuron activity. Both receptor types are coupled to G proteins (GPCRs) and create responses through a cascade of intracellular signaling. It activates or inhibits key proteins in specific pathways, influencing the neuron depolarization rate (Tritsch and Sabatini, 2012; Steiner and Tseng, 2016).

D₁ like receptors are coupled with the G_αs protein. When D₁ agonists attach, the α subunit displacement from protein G to the enzyme adenylyl cyclase, causing its activation. Then it catalyzes the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). The increased intracellular concentration of cAMP results in kinase A protein (PKA) activation, which phosphorylates other proteins, including some ionic channels, changing their opening kinetics. As a result, PKA promotes the opening of calcium channels (Ca²⁺) L type and the closure of potassium channels (K⁺), leaving the neuron more susceptible to depolarization (Neve, 2009). Besides, stimulation of D₁ receptors leads to a phosphorylation cascade that increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (Xue et al., 2017) and N-methyl-d-aspartate (NMDA) receptors activity (Hallett, 2006) and, therefore, intensifies the excitatory responses of glutamatergic projections from the cortex (Figure 1C).

Conversely, the D₂ receptor when stimulated presents an antagonistic effect to the D₁ receptor. The D₂ receptor works coupled to a G_αi protein, which inhibits adenylyl cyclase activity. For this reason, the cAMP intracellular accumulation is impaired. Consequently, there is no PKA activation, which remains unable to trigger the phosphorylation cascade that makes the neuron more predisposed to depolarization (Neve et al., 2004; Beaulieu and Gainetdinov, 2011). In addition to this pathway, there is a second pathway triggered by G_βγ subunits, where they activate phospholipase C (PLC) which acts by cleaving Phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,2,4 trisphosphate (IP3). DAG acts by activating protein kinase C (PKC), while IP3 acts by releasing Ca²⁺ from the endoplasmic reticulum (Bonci and Hopf, 2005; Juza et al., 2023). Interestingly, in this scenario, the PLC pathway through D2 receptors can activate calcineurin which suppresses the opening of L-type Ca²⁺ channels, thus pushing the membrane potential away from the firing threshold and therefore the medium spiny neuron is less likely to depolarize (Hernández-López et al., 2000). This concept is essential to understand the direct and indirect pathways in the basal ganglia motor circuit (Figure 1D).

By this mechanism the D₂ receptors stimulation suppress excitatory cortical afferences. The main inhibitory projections targets of striatal medium spiny neurons are GPe, GPi and SNr. Those that target the GPe have D₂ receptors, and those that innervate GPi and SNr have D₁ receptors (Lévesque et al., 2003). It is also important to mention the existing collateral connections between the axons of the D₁ medium striatal spiny neurons with their D₂ type homologs, generating feedback inhibition between these two types of striatal neurons (Plenz, 2003).

Substantia nigra pars compacta (SNc) is a nucleus in the midbrain. Its neurons contain much melanin, conferring a dark coloration visible in fresh preparations. Due to this characteristic, it earned its name (Fabbri et al., 2017). Immunohistochemistry studies have shown that this nucleus also expresses the enzyme tyrosine hydroxylase, essential for dopamine synthesis (Cavalcanti et al., 2014, 2016; Rocha et al., 2022). In addition to striatal communications through dopaminergic projections, 3D imaging techniques have shown that SNc maintains connections with various cortical areas (Cacciola et al., 2016). In electrophysiological studies it was observed that the cortico-nigral connections are predominantly glutamatergic, and therefore excitatory (Meltzer et al., 1997). STN is another structure that sends excitatory inputs to the SNc. As seen by Shimo and Wichmann (2009), the STN of primates submitted to lesions presented lower rates of firing and dopamine release by SNc neurons than the control group. On the other hand, the SNr sends GABAergic projections to the adjoined SNc (Tepper and Lee, 2007).

The GPe, with GPi and putamen make up a structure known as lentiform nucleus. Although the lentiform nucleus subdivisions are topographically close and are composed of GABAergic projection neurons, they present communications with different areas, both afferent and efferent. Therefore, only the GPe is part of the intrinsic nuclei, since it receives projections from striatal medium spiny neurons and sends outputs to STN, GPi, SNr (Herrero et al., 2002), frontal cortex (Saunders et al., 2015), and also to striatal medium spiny neurons in a pathway known as arkypallidal pathway (Dunovan and Verstynen, 2016).

The STN also receives cholinergic projections from the peduncle pontine nucleus and glutamatergic ones from the cortex. The latter, in the basal ganglia motor circuit, is known as the hyperdirect pathway. The STN main synaptic targets are GPi, SNc and SNr. Since the STN is composed of neurons that predominantly use glutamate as a neurotransmitter, it acts by exciting these targets (Benarroch, 2008).

The SNr and GPi have similar characteristics. Both are composed of GABAergic neurons that projects to the anterior ventral and lateral ventral nuclei of the thalamus, inhibiting its activity. In addition, both efferent nuclei receive inputs from the same regions: striatum, GPe and STN. However, the SNr maintains additional efferent connections with the superior colliculus and the SNc (Zhou and Lee, 2011). An important fact about the GPi is the different afferences according to their neuron’s location. While neurons at the center of the nucleus receive inhibitory synapses from the striatum and GPe, while neurons in peripheral regions receive inputs from STN (Purves et al., 2017).

The basal ganglia role in motor control has been observed for a long time, especially in the studies of Marsden (1982), who first published the hypothesis that the basal ganglia are responsible for the execution of learned motor planning. Differently from what was thought when the classical models on the circuits of the basal ganglia were postulated, in which the direct and indirect pathways acted in an antagonistic manner, today it is known that these two pathways work in a synergistic and complementary manner (Jin and Costa, 2015; Klaus et al., 2019). As described by Cui et al. (2013), using electrophysiological records, it was observed that when mice started voluntary movement, both pathways were activated. Thus, being direct pathway neurons could select the desired motor program while indirect pathway neurons inhibit competing motor programs (Jin et al., 2014; Tecuapetla et al., 2014).

Pathological conditions such as Huntington’s and hemiballismus exemplify hyperkinetic disorders. Huntington’s disease is characterized by signs that include involuntary movements and motor impairments (Ross et al., 2014). This hyperkinesia originates from an autosomal dominant mutation in chromosome 4 as a pathological increase of the trinucleotide nucleotides cytosine, adenine and guanine (CAG) repetition (Bordelon, 2013). One of the repercussions is loss of striatal cells involved in the indirect pathway (Starr et al., 2008), thus favoring the direct pathway. Differently, in hemiballismus, a hyperkinetic disorder of intermittent, sudden and violent involuntary movements of the ipsilateral leg and arm, the causes are contralateral dysfunctions of the central nervous system (Grandas, 2011), such as STN injury (Nambu et al., 2002). In general, injuries in important regions of the indirect pathway or the direct pathway hyperactivity induces hyperkinesia.

On the other hand, lesions and disorders in important structures of the direct pathway cause hypokinesia, as seen in Parkinson’s disease, where the dopaminergic neuronal degeneration hinders the entire activation cascade for the direct pathway (Wichmann and DeLong, 1996; Höglinger et al., 2004). Therefore, the classic treatment is the administration of levodopa, a dopamine prodrug (Parkinson Study Group, 2004). Besides, it is possible to use deep brain stimulation of the STN, which seems to have an inhibitory effect on this nucleus (Milosevic et al., 2018), since the STN is an active component of the indirect pathway.

In addition, the basal ganglia and the cerebellum are reciprocally interconnected. As observed by Bostan and Strick (2010), in a paper using a viral tracer, the dentate nucleus of the cerebellum communicates with the ventral lateral (VL) nucleus of the thalamus, which in turn relays this information to the striatum. Secondly, STN neurons project into the pontine nuclei, and these into the cerebellar cortex. Together, basal ganglia and cerebellum are essential for the movement general circuit, as they modulate the activity of the premotor cortex, supplementary motor area and primary motor area, through a connection with the thalamus, which relays the information to the cortical areas (Thobois et al., 2000; Figure 2C).

A considerable part of patients with Parkinson’s disease suffers from resting tremor (Fishman, 2008). This condition can be explained by disorders in the interaction between basal ganglia and cerebellum. In this neuropathology, the STN presents over excitation due to the constant indirect pathway activation (Georgiades et al., 2019). And given that the STN influences the cerebellum activity (Bostan et al., 2010), it also becomes hyperactive (Yu et al., 2007). Taking into account that the GPi and dentate nucleus projections to the VL nucleus of the thalamus are related to movement control (Hintzen et al., 2018), the resting tremor occurs due to the cerebellum compensatory mechanisms, in order to counteract changes in the basal ganglia activity, which occurs in Parkinson’s disease, maintains the VL nucleus of the thalamus under strong inhibition (Wu and Hallett, 2013).