Editorial: Dopaminoceptive Forebrain Regions: A Search for Structural and Functional Organization Underlying Normal and Impaired Social Adaptation

Loreta Medina^1*Andras Csillag²

• ¹Medicina Experimental, Universitat de Lleida, Lleida, Spain
• ²Semmelweis Egyetem Altalanos Orvostudomanyi Kar, Budapest, Hungary

This Research Topic explores the structural and functional organization of forebrain dopaminergic (DAergic) systems, encompassing multiple cell groups and pathways involved in reward, motivation, motor control, homeostasis, and social behavior modulation. It comprises six articles spanning various vertebrate species, addressing novel aspects of DAergic cell group evolution, development, and neuromeric organization, along with functions of specific mesocortical and olfactory subsystems and alterations due to gestational valproic acid (VPA) exposure leading to autism-like traits. The ventral tegmental area (VTA) and substantia nigra (SN) are the most studied DAergic groups in mammals and other amniotes for their critical roles in reward and motor control (Smeets and Reiner, 1994; Björklund and Dunnett, 2007). While classically viewed as midbrain structures, developmental research suggests a segmental organization involving both diencephalic and mesencephalic origins (Puelles and Medina, 1994). Ferran et al. (2025) use the updated prosomeric model to examine the segmental origin of VTA and SN DAergic neurons during development across rodents, primates, and humans. By combining tyrosine hydroxylase (TH) immunohistochemistry with gene expression and morphological landmarks, they identify six segments (five in forebrain and one in isthmic r0) giving rise to these neurons. Such multi-neuromeric origin may underlie functional specialization, different connectivity and target patterns, with potential implications for vulnerability to degeneration, hypoxia, or neurodevelopmental disorders. VTA and SN DAergic neurons project to the telencephalon, targeting the striatum and, via mesocortical and mesolimbic pathways, the cortex and extended amygdala (Reiner et al., 1998; Björklund and Dunnett, 2007). Messore et al. (2025) focus on cortical dopamine modulation, manipulating layer 6 neurons in the mouse somatosensory cortex expressing dopamine receptor 1. These cells are considered remnants of the subplate, which is essential for the establishing of thalamocortical connections. Messore et al. (2025) demonstrate that these dopaminoceptive cells also play a critical role in the activation of cortico-thalamo-cortical loops, possibly participating in stimulus representation and sensory processing. While in tetrapods, most DAergic axons targeting striatum and pallium arise from perikarya of VTA and/or SN (Smeets and González, 2000; excepting the olfactory bulb, which contains intrinsic DAergic neurons in all vertebrates), in fishes, at least part of the telencephalic innervation comes from locally-born DAergic neurons (Rodríguez-Moldes et al., 2025). The presence of these cells in the telencephalon was once thought to be specific for fishes, but minor subsets of catecholaminergic (CAergic) cells were also found later in the cerebral cortex/pallium and/or striatum in mammals and birds (Marín et al., 2005; Bupesh et al., 2014; Fujita et al., 2025). Tracing the evolution of dopaminoceptive regions of the telencephalon, Rodríguez-Moldes et al. (2025) studied the development of area superficialis basalis in the catshark (a cartilaginous fish close to ancestral jawed vertebrates), using neuronal phenotypic markers and transcription factors of pallium or subpallium. They show that this area is subpallial with cells derived from striatal and pallidal subdivisions, but it becomes quite complex due to tangential migrations during development. In catsharks, some cells from the pallidal embryonic domain migrate into the striatum, giving rise to an ectopic globus pallidus, resembling the situation in birds. Rodríguez-Moldes et al. (2025) suggest that the area superficialis basalis of Chondrychtians contains precursor cells for the striatum, pallidum, and extended amygdala, which may represent a forerunner of these regions in later tetrapods, opening new venues for exploration. In vertebrates, the medial extended amygdala and several preoptic and hypothalamic centers involved in modulation of social behavior and/or homeostasis also contain subpopulations of CAergic neurons (Bupesh et al., 2014; Vicario et al., 2014; Smeets and González, 2000; Fujita et al., 2025). These cells are morphologically and functionally diverse. Some of them are DAergic (expressing TH and the aromatic amino acid decarboxylase enzyme), while others only express TH (Ahmed et al., 2012; Ugrumov, 2024). The heterogeneity and manifold functions of these CAergic cells reflect that they originate from molecularly distinct progenitors (Romanov et al., 2020), located in different embryonic divisions with precise topological location along the rostrocaudal (neuromeric) and dorsoventral axes of the forebrain (Puelles and Medina, 1994; Bilbao et al., 2022; Ferran et al., 2025). Using Otp-eGFP mice, Morales et al. (2025) show that some subsets of CAergic neurons in the extended amygdala, preoptic area and different nuclei of the hypothalamus derive from cells that express the transcription factor Otp. However, these centers also contain non-Otp CAergic neurons that appear to derive from different progenitors expressing other transcription factors (Romanov et al., 2020; Zhang et al., 2021), raising questions on the function of different Otp and non-Otp CAergic neurons in the modulation of social behavior and homeostasis. In vertebrates, olfactory information reaching directly and indirectly the medial extended amygdala plays a critical role in social behavior. In this Topic, Fujita et al. (2025) show that in chicken the main projection neurons of the olfactory bulb, including the mitral cells, selectively express the dopamine receptor 4 (DRD4), indicating that their activity is modulated by dopamine through this specific receptor. In mammals and birds, DRD4 polymorphisms are associated with animal personality traits, a feature that contributes to shaping social behavior. The findings of Fujita et al. (2025) prompt further investigation into the role of dopaminoceptive mitral cells of the olfactory bulb in relation to personality and social behavior. CAergic systems start to form early in development, and they appear to act as morphogens, modulating axonal growth and the phenotype of target cells (Ugrumov, 2024). The study by Finszter et al. (2025) points out that DAergic projections may determine the formation of synaptic patterns of target regions during development. Following gestational VPA treatment of mice (leading to autistic-like traits), an overall reduction of DA input to ventral striatum (olfactory tubercle, OT; nucleus accumbens, NAc) was observed, together with a decrease in DAergic synaptic contacts with calbindin (in OT) or calretinin (in NAc) expressing interneurons. The findings indicate that the shaping of the social and reward system is affected by prenatal VPA exposure through alteration to DAergic pathways. Future studies are needed for better understanding of the role of other dopaminoceptive regions, including those modulating social behavior, in autism. Overall, the articles presented in this Research Topic promote better understanding of the evolution, development, segmental organization and function of DAergic and dopaminoceptive forebrain centers, and open new venues for future research on DAergic systems.