The Development of the Mesoprefrontal Dopaminergic System in Health and Disease

Abstract

Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.

Bi-phasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan

“…The dopamine (DA) system undergoes profound changes across the lifespan, along with concomitant alterations in cognition ( (Bäckman et al, 2010;Islam et al, 2021;Li et al, 2010;Reynolds and Flores, 2021a;Wahlstrom et al, 2010), for reviews). In childhood and adolescence, ongoing maturation of the prefrontal DA system is associated with excessive DA activity (Islam et al, 2021;Reynolds and Flores, 2021a;Wahlstrom et al, 2010Wahlstrom et al, , 2007, constraining the development of executive functions (Diamond, 2009;Diamond et al, 2004;Diamond and Baddeley, 1996;Klune et al, 2021). At older ages, DA losses may result in insufficient DA modulation (Lindenberger et al, 2008;Nagel et al, 2008), and decline in multiple cognitive domains (Bäckman et al, 2000(Bäckman et al, , 2006Karalija et al, 2019;Nyberg et al, 2010;Volkow et al, 1998).…”

Developing Photoaffinity Probes for Dopamine Receptor D2 to Determine Targets of Parkinson’s Disease Drugs

“…DRD2 is a membrane-bound GPCR, and, as mentioned previously, it is known to be exceedingly difficult to study in isolation from its host cell. Further, DRD2 expression levels differ widely according to brain region, layer, and other biochemical variables. − Thus, to validate our approach, we first determined whether we could detect the DRD2 expression using our mutant cell line, which exogenously expresses DRD2. We found that DRD2 protein could indeed be detected via mass spectrometry following photo-cross-linking of probe and biotin–streptavidin pulldown.…”

Associations between Omega-3 Index, Dopaminergic Genetic Variants and Aggressive and Metacognitive Traits: A Study in Adult Male Prisoners

“…Higher-order cognitive and executive functions such as working memory and attention rely on activation of mesocortical dopaminergic pathways, particularly towards the DLPFC [ 50 , 51 ], whereas the dopaminergic neurons in the anterior region of the cingulate cortex (BA25) appear to play a causal role in behavioural changes such as emotion, negative affect and anhedonia [ 52 ]. Dysfunction of dopaminergic neurotransmission in these cerebral areas was associated with impaired social and cognitive functions typically seen in neurodevelopmental disorders such as schizophrenia, autism spectrum disorder and ADHD, as well as in depression, impulsivity and substance abuse disorders [ 53 ]. The strong association between total ADD, attention and DRD2 rs4274224 also confirms findings from a previous study investigating the association of this genetic marker with executive functions in an obesity context [ 54 ] and from meta-analyses reporting significant associations between some DRD2 polymorphisms and ADHD [ 55 , 56 , 57 ].…”