Dopamine, vocalization, and astrocytes

Abstract

Dopamine, the main catecholamine neurotransmitter in the brain, is predominately produced in the basal ganglia and released to various brain regions including the frontal cortex, midbrain and brainstem. Dopamine's effects are widespread and include modulation of a number of voluntary and innate behaviors. Vigilant regulation and modulation of dopamine levels throughout the brain is imperative for proper execution of motor behaviors, in particular speech and other types of vocalizations. While dopamine's role in motor circuitry is widely accepted, its unique function in normal and abnormal speech production is not fully understood. In this perspective, we first review the role of dopaminergic circuits in vocal production. We then discuss and propose the conceivable involvement of astrocytes, the numerous star-shaped glia cells of the brain, in the dopaminergic network modulating normal and abnormal vocal productions.

Keywords: Astrocytes; Basal ganglia; Dopamine; Glia; Speech; Vocalization.

Figure 1 ∣. Basal ganglia and motor control of speech production circuits.

(A) The basal ganglia thalamo-cortical loop that connects the motor circuits of the basal ganglia to the laryngeal motor cortex through a relay station in the thalamus is important for speech production. The higher order brain structures, directly or indirectly [via periaquedutal gray (PAG)], modulate activities of orofacial and laryngeal motor neurons of facial (VII), hypoglossal (XII) nuclei and nucleus ambiguus (NA) located in the brainstem. (B) The laryngeal motor cortex (LMC) is located towards the ventro-lateral portion of primary motor cortex, and divided into dorsal (dLMC) and ventral (vLMC) regions. Both portions of LMC are involved in the vocal production circuits. Neurons in the preLMC sends direct connections to dLMC and vLMC as well as to the anterior striatum. dLMC and vLMC neurons send projections to PAG and NA . (C) The Basal ganglia region includes the striatum (caudate and putamen), globus pallidus [external (GPe) and internal (GPi)], subthalamic nucleus (STN) and substantial nigra (SN). The intricate connectivity between these regions allows for proper execution of motor behaviors. Information from motor cortex is inputted to the striatum which in conjunction with dopaminergic inputs from the SN, sends information to two parallel pathways in the basal ganglia. In the first pathway (red arrows), the GPe received inhibitory signals from the striatum and relays inhibitory signals to the subthalamic nucleus. The subthalamic nucleus then send an excitatory signal to the GPi which in turn sends an output signal to the thalamus. In the second, parallel pathway (blue arrows), the striatum ends a direct inhibitory signal to the GPi which directly sends an output signal to the thalamus. By integrating inhibitory and excitatory signals, these two pathways can delicately modulate motor behaviors control, including speech production. Abbreviations: Cd – caudate, dLMC – dorsal laryngeal motor cortex, GPe – globus pallidus external, GPi – globus pallidus internal, NA – nucleus ambiguus, PAG – periaqueductal gray, preLMC – premotor laryngeal motor cortex, Pt – putamen, SN – Substantia Nigra, STN – sub thalamic nucleus, vLMC – ventral laryngeal motor cortex, VII – facial nucleus, XII – hypoglossal nucleus.

Figure 2 ∣. Astrocytes in dopaminergic circuits of basal ganglia.

(A) (left) Presynaptic dopaminergic neuron releases dopamine (DA) into synaptic cleft, in which, DA binds to the postsynaptic DA receptor (such as D2R) and is also recycled back into the presynaptic neuron by DAT. However, some dopamine transmitter may also be recycled back through astrocytes potentially through DAT and/or COMT to recycle or break down dopamine, respectively. (right) Following the release of dopamine from the presynaptic terminal, dopamine may also bind to the D2R on astrocytes and lead to an increase in the levels of intracellular calcium ([Ca²⁺]_i), which in turn facilitates the release of gliotransmitters (such as ATP/adenosine and others). The released gliotransmitters affect neurons in the region. (B) (left) Dopaminergic neuronal synapse in a Parkinson’s diseased brain where DA degeneration is prominent and less DA is released into the synapse. In addition to release of DA is release of aggregate alpha-synculein (α-syn). DA and aggregated alpha-synculein are taken up by astrocytes, which causes a dysregulation of [Ca²⁺]_i and an increased release of adenosine. (right) Presynaptic dopamine release increases in the case of developmental stuttering disorder which accumulates in the synapse where it can bind to the postsynaptic receptors, be taken back up by the presynaptic neuron or by the nearby astrocyte. In the proposed model, this increase in DA causes a decrease in [Ca²⁺]_i activity and a reduction in release of gliotransmitters. Abbreviations: [Ca²⁺]_i – intracellular calcium concentrations, COMT - catechol-O-methyltransferase, D2R – dopamine receptor D2, D3R – dopamine receptor D3, DA - dopamine, DAT – dopamine transporter, MAO - monoamine oxidase.