A New Optogenetic Tool to Investigate the Role of Dopamine Signaling in the Basal Ganglia

For millions of years, dopamine has served as a neurotransmitter in the nervous system of both invertebrates and vertebrates. Throughout evolution, this molecule has maintained conserved roles in a myriad of functions such as regulation of movement, learning, motivation, memory formation, reward-seeking, and feeding behavior. Clusters of dopamine-synthesizing neurons are distributed all over the brain; however, the largest population is found in midbrain nuclei that project to the frontal cortex, dorsal striatum, and nucleus accumbens (NAc; Costa and Schoenbaum, 2022). Like other catecholamines, dopamine acts on G-protein–coupled receptors (GPCRs) to modulate intracellular effector protein activity. Dopamine receptors are classified into two main families: D1-like receptors (DRD1), which include D1 and D5 subtypes, and D2-like receptors (DRD2), comprising D2, D3, and D4 subtypes. DRD1 activation triggers a signaling cascade that enhances adenylate cyclase activity, increasing intracellular cAMP and activating cAMP-dependent protein kinase (PKA), which phosphorylates downstream proteins, including the dopamine- and cAMP-regulated phosphoprotein (DARPP-32), ultimately increasing neuronal excitability. Conversely, DRD2 activation inhibits adenylate cyclase and lowers intracellular cAMP levels, reducing neuronal excitability (Tritsch and Sabatini, 2012). The key site where dopamine regulates motor control is the basal ganglia, which comprise the striatum, substantia nigra pars compacta (SNpc), substantia nigra pars reticulata (SNpr), globus pallidus externus (GPe), globus pallidus internus (GPi), and subthalamic nucleus (STN; Calabresi et al., 2014). Phasic dopamine release from the SNpc modulates the activity of spiny projection neurons (SPNs) in the striatum, playing a crucial role in the initiation, transition, and termination of voluntary movements (Klaus et al., 2019). Most SPNs can be categorized into those that express DRD1 and project directly to the main output nuclei of the basal ganglia (GPi and SNpr) and those that express DRD2 and influence the output nuclei via intermediate nuclei (GPe), … Correspondence should be addressed to Gabriel S. Rocha at gabrielsrocha95{at}academico.ufs.br.