Development of the dopaminergic innervation of the rat cerebral cortex. Developmental and age-related changes in D1-dopamine receptors and dopamine content in the rat striatum. Notably, these DAergic changes are only apparent in adult Dcc haploinsufficient mice, with no observable differences in mesocorticolimbic DA structure or function in juveniles, and occur in both males and females (Grant et al., 2009). Axon guidance proteins in neurological disorders, Sexual differentiation of motivation: a novel mechanism, Sex differences in neural mechanisms mediating reward and addiction. While some studies indicate a steady increase in PFC D1-like receptor density until PND 60 in rats (Tarazi et al., 1999; Tarazi and Baldessarini, 2000), others show that D1-like expression in the PFC peaks in adolescence, before being pruned back in adulthood (Leslie et al., 1991; Andersen et al., 2000; Brenhouse et al., 2008). Sesack S. R., Hawrylak V. A., Melchitzky D. S., Lewis D. A. A PET neuroimaging study in 1832-year-old subjects shows that the decline in striatal D2/3 receptor expression also occurs in humans (Larsen et al., 2020), indicating that findings from preclinical studies on DA system development have strong translational implications. Dopamine in motivational control: rewarding, aversive and alerting, Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF and HPA axis. Vetter-OHagen C. S., Spear L. P. (2012). Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Brenhouse H. C., Sonntag K. C., Andersen S. L. (2008). (B) Sagittal view of the mesocorticolimbic DA pathway (black) and the major nuclei, with the STR semi-transparent in the foreground. NE axons are thick, with regularly spaced rounded varicosities; while DA axons are thin and sinuous, with irregularly spaced varicosities (Berger et al., 1974; Miner et al., 2003). It has taken two decades for the dopamine hypothesis to evolve and reach its current state. Incorporating this knowledge in our understanding of DA diversity is particularly important since the DA system is increasingly considered as a plasticity system, whose development can be shaped by positive or negative experiences, allowing organisms to adapt to their surrounding environmental conditions (Barth et al., 2019; Reynolds and Flores, 2021). Dopamine triggers the maturation of striatal spiny projection neuron excitability during a critical period. Brain. This review . While the majority of these studies have been performed only in male rodents, evidence suggests that the adolescent overexpression and pruning of D1 receptors in striatal regions is not seen in female rats (Andersen et al., 1997). The serotonin innervation of the cerebral cortex in the ratan immunohistochemical analysis. (2013). Andersen S. L., Thompson A. P., Krenzel E., Teicher M. H. (2002). Overall, evidence from studies in rats indicates that DA receptor expression in the PFC is dynamic in adolescence, most likely with a period of overexpression followed by pruning (Figure 3A). Catts V. S., Fung S. J., Long L. E., Joshi D., Vercammen A., Allen K. M., et al.. (2013). [Mesolimbic and mesocortical pathways in Parkinson disease] Limbic and cortical DA pathways have been shown to differ in their molecular markers, anatomical organization, and response to stimuli (Roeper, 2013; Lammel et al., 2014; Morales and Margolis, 2017; Poulin et al., 2018; Nguyen et al., 2021). Yetnikoff L., Reichard R. A., Schwartz Z. M., Parsely K. P., Zahm D. S. (2014c). Howes, O., McCutcheon, R., & Stone, J. We comment on how each of these processes may link experiential factors to alterations in DA development. Kalsbeek A., Voorn P., Buijs R. M., Pool C. W., Uylings H. B. Finally, a critical question that remains open is whether and how positive experiences can promote healthy DA system development and improve mental health outcomes in emerging adults. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The mesocortical pathway is a major dopaminergic pathway that connects the ventral tegmentum to the dorsolateral prefrontal cortex. Lammel S., Hetzel A., Hckel O., Jones I., Liss B., Roeper J. Long-term hyperprolactinemia can be associated with osteoporosis. Benes F. M., Taylor J. If When we performed these same intersectional viral injections in adult mice, we observed very few, if any, labeled DA axons in the PFC (Figure 4B), in line with the lack of collaterals observed in previous studies (Fallon, 1981; Fallon and Loughlin, 1982; Lammel et al., 2008; Beier et al., 2015). The brain undergoes exuberant development during this time, with cortical gray matter thickness, notably in the prefrontal cortex (PFC), decreasing before stabilizing at adult levels, and with white matter volume increasing until early adulthood (Blakemore, 2012; Paquola et al., 2019). Glutamate and dopamine in schizophrenia: an update for the 21st century. DA receptors are seven transmembrane G-protein coupled receptors that initiate intracellular cascades by increasing cAMP (D1-type) or decreasing cAMP (D2-type; Seamans and Yang, 2004; Tritsch and Sabatini, 2012). Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The examination of circuitry between visual areas has revealed that the murine dorsal pathway, which sustains spatial perception, is composed of the latero-medial This discovery is the first proof of long-range growth of axons in adolescence and explains why the mesocorticolimbic DA system is particularly vulnerable to adolescent experiences. Glutamate and dopamine in schizophrenia: an update for the 21st century. DA neurons express high levels of DCC receptors across species, including humans (Osborne et al., 2005; Manitt et al., 2010; Reyes et al., 2013). Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms Projects from the VTA to the prefrontal cortex. Four Major Dopaminergic Pathways & Association with Schizophrenia By harnessing an intersectional viral labeling technique (Figure 4), we were able to restrict fluorescent labeling only to DA neurons with axons present in the NAc at PND 21. Bamford N. S., Wightman R. M., Sulzer D. (2018). Learn All about Antipsychotics - Exploring your mind (2016). While the density of DA fibers in the PFC shows a linear increase across adolescence, the trajectory of postsynaptic DA receptor expression is more complex (Figure 3A). Experience-induced regulation of Netrin-1 and/or DCC expression robustly shapes the adolescent brain. Our developmental studies using intersectional viral tracing techniques indeed demonstrate that the fine organization of mesolimbic DA connectivity is much more malleable than previously thought. This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. A light microscopic immunocytochemical study using anti-tyrosine hydroxylase antibodies. Ontogeny of dopamine D1 and D2 receptor subtypes in rat basal ganglia: a quantitative autoradiographic study. Sesack S. R., Snyder C. L., Lewis D. A. This work would eventually allow for preventive and therapeutic interventions precisely targeted in time. Lu X., Churchill L., Kalivas P. W. (1997). in vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study. The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Zhao B., Zhu J., Dai D., Xing J., He J., Fu Z., et al.. (2016). Adolescent food restriction in rats alters prefrontal cortex microglia in an experience-dependent manner, D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Santana N., Mengod G., Artigas F. (2009). In adulthood D1 and D2 receptor populations attain their mature function. Sex differences have been described regarding the structure and function of adult pre- and postsynaptic components of DA circuitries, including differences in structural organization, DA content, and regulation of local DA release (Becker et al., 2001, 2012; Becker, 2009; Gillies et al., 2014; Walker et al., 2017; Becker and Chartoff, 2018; Kokane and Perrotti, 2020; Zachry et al., 2020). However, puberty may drive subtle changes in PFC DA synthesis and release which would still profoundly impact the developing PFC, even without discernible alterations in DA axon architecture. Carr D. B., ODonnell P., Card J. P., Sesack S. R. (1999). Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. Lithium is one of the most effect mood-stabilizing drugs prescribed especially for bipolar disorder. Delevich K., Klinger M., Okada N. J., Wilbrecht L. (2021). For example, macroautophagy has been suggested to play a role in the synaptic pruning occurring in the adolescent striatum (Hernandez et al., 2012; Lieberman et al., 2020). A., Becker J. We further integrate these recent studies into the larger historical framework of anatomical and neurochemical changes occurring during adolescence in the mesocorticolimbic dopamine system. Hyperactivity of the first causes the negative and cognitive symptoms of schizophrenia. Reports that the density of mesocortical DA innervation continues to increase during adolescence were first published in the 1980s, shortly after the introduction of antibodies against tyrosine hydroxylase (TH, the rate-limiting enzyme of dopamine synthesis), which allowed clear detection of DA axons in the PFC (Verney et al., 1982). The striatum represents a major choice point for DA axons: while the large majority of DA axons already innervating the striatum by early adolescence are destined to remain there, mesocortical axons must pass through this densely innervated DA region and continue to grow into the PFC during adolescence (Reynolds et al., 2018). Glutamate and dopamine in schizophrenia: an update for the 21st century. Scientists differentiate between the pathway that goes from the prefrontal dorsolateral cortex and the one that goes from the prefrontal ventromedial cortex. Dopamine, psychosis and schizophrenia: the widening gap - Nature 2009 Jun;6(6):1506-1533. doi: 10.1111/j.1743-6109.2009.01309.x. (1995). Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Interestingly, despite the close proximity of mesolimbic and mesocortical DA axons throughout their trajectory to forebrain regions, there is little or no overlap in the targets they innervate. Pathways of sexual desire - PubMed Two-dimensional representations were adapted from the three-dimensional regions of interest in the Allen brain atlas (Wang et al., 2020). DA axons form synapses onto PFC glutamatergic pyramidal neurons; which represent the primary projection neurons from the PFC to other regions of the brain (Goldman-Rakic and Brown, 1982; Goldman-Rakic et al., 1992; Krimer et al., 1997; Carr et al., 1999; Carr and Sesack, 2000; Lambe et al., 2000), a phenomenon that is conserved in humans, non-human primates, and rodents. Mechanisms contributing to prefrontal cortex maturation during adolescence. Sex differences in striatal DAergic structure and function have recently been suggested to be strain-dependent, with some of the sex-specific characteristics commonly seen in Sprague-Dawley rats not observable in Long-Evans rats (Rivera-Garcia et al., 2020), highlighting the need for the consideration not only of sex but also species and strain in experimental design. Adolescence is a time when organisms undergo dramatic physical, hormonal, and behavioral changes as they transition from juveniles to adults. Antonopoulos J., Dori I., Dinopoulos A., Chiotelli M., Parnavelas J. G. (2002). These differences include structural divergence, fluctuations in DA release, and/or variation in DA-induced modulation of postsynaptic neuron signaling pathways. Before I. Hernandez D., Torres C. A., Setlik W., Cebrin C., Mosharov E. V., Tang G., et al.. (2012). The ventral striatum includes the nucleus accumbens and the olfactory tubercle. Optogenetic examination of prefrontal-amygdala synaptic development. Now, the mechanisms underlying the pathology of schizophrenia are poorly understood, but there seems to be abnormal levels of dopamine, particularly in the mesolimbic and mesocortical pathways. Mesocorticolimbic dopamine system organization. Early autoradiography studies showed increased D2 receptor expression across early postnatal life, reaching adult levels by early adolescence (Pardo et al., 1977; Hartley and Seeman, 1983; Murrin and Wanyun, 1986; Rao et al., 1991; Schambra et al., 1994). Wang Q., Ding S.-L., Li Y., Royall J., Feng D., Lesnar P., et al.. (2020). (1989). In 1966 Rossum and colleagues proposed a state of excess dopaminergic stimulation in patients with schizophrenia (SZ) ( 1 ), substantiated later by the discovery of the D 2 receptor binding profiles of antipsychotics and the psychotogenic effects of DA agonists ( 2 - 4 ). Reynolds L. M., Pokinko M., Torres-Berro A., Cuesta S., Lambert L. C., Pellitero E. D. C., et al.. (2018). Klune C. B., Jin B., DeNardo L. A. Indeed, in vivo electrophysiology experiments indicate that DA neuron firing rates vary across adolescence in male rats (McCutcheon and Marinelli, 2009; McCutcheon et al., 2012). Autoradiography studies in rats using radio-labeled DA receptor ligands ([3H]SCH-23390 for D1-like receptors, [3H]nemonapride (YM-091512) or [3H]-raclopride for D2-like receptors) show discrepant results regarding the patterns of receptor expression across postnatal life. Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence. More evidence is needed to determine whether the sex differences observed in adult DA circuitry result from puberty-dependent or puberty-independent developmental processes. Other regions of the central nervous system that are rich in dopamine receptors, include the chemoreceptor trigger zone, which initiates the vomiting reflex; and the medullary periventricular pathway, which regulates eating behavior. Verney C., Berger B., Adrien J., Vigny A., Gay M. (1982). Arruda-Carvalho M., Wu W.-C., Cummings K. A., Clem R. L. (2017). Prolonged myelination in human neocortical evolution. In this review, we provide an overview of preclinical findings regarding the adolescent development of mesocorticolimbic DA pathways, by both situating it within a historical context and by emphasizing novel advances in understanding its cellular and molecular underpinnings. Influences of dopaminergic system dysfunction on late-life depression Summary of maturational changes in DA connectivity in the STR across adolescence. For example, sex differences in PFC TH expression and in PFC neuronal organization emerge after puberty in mice with genetic reduction of the catechol-o-methyltransferase (COMT) enzyme (Sannino et al., 2017). Adolescent morphine exposure induces long-term changes in NAc microglial function in male rats, which are associated with increased conditioned place preference reinstatement to this drug in adulthood (Schwarz and Bilbo, 2013). An official website of the United States government. width: "100%", Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: a molecular, cellular and behavioral analysis. (B) Adolescence (shaded lines) and puberty (darker portions of the lines) timing in female () and male () rodents, adapted from Vetter-OHagen and Spear (2012) and Schneider (2013). Ontogenesis of dopamine receptor binding in the corpus striatum of the rat. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Some evidence . Projections into the ventromedial prefrontal cortex regulate emotions and affect. (B) Early in adolescence DA signaling through D1 receptors is excitatory onto both classes of neurons, with DA signaling through D2 receptors inhibiting pyramidal neurons and weakly inhibiting GABAergic interneurons. (2019). In clinical practice, there can be a disproportionate focus on positive psychotic symptoms. (2019). Seamans J. K., Gorelova N., Durstewitz D., Yang C. R. (2001). Received 2021 Jul 2; Accepted 2021 Aug 17. Conditional reduction of Dcc in DA neurons in adolescence recapitulates completely this ectopic DCC-positive DA axon phenotype in the PFC (Manitt et al., 2013). Weickert C. S., Webster M. J., Gondipalli P., Rothmond D., Fatula R. J., Herman M. M., et al.. (2007). a disorder characterized by hallucination, delusion, cognitive impairment, mood disturbance, and social withdrawal positive symptoms of schizophrenia hyperactive/too much arousal or meaning given to unimportant things As seen in rodents, post-mortem human brain studies have shown changes in DA receptor expression and DA content during adolescence, including a peak in DA D1 receptor expression in the PFC (Weickert et al., 2007; Rothmond et al., 2012), a marked decline in striatal DA receptors (Seeman et al., 1987), and a dramatic increase in striatal DA content (Haycock et al., 2003). The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. dcc haploinsufficiency results in blunted sensitivity to cocaine enhancement of reward seeking. Battum E. Y. V., Brignani S., Pasterkamp R. J. Rothmond D. A., Weickert C. S., Webster M. J. The proportion of MSNs showing their characteristic DA-sensitive inward rectification potassium currents also continues to increase until early adulthood (Tepper et al., 1998; Zhao et al., 2016), and the effect of D2 receptor signaling of MSNs switches from inhibitory to facilitatory (Benoit-Marand and ODonnell, 2008). These results suggest that the release of DA in the PFC evolves during adolescence in parallel to the establishment of mature pre-synaptic connectivity. VanRyzin J. W., Marquardt A. E., Pickett L. A., McCarthy M. M. (2020). Gillies G. E., Virdee K., McArthur S., Dalley J. W. (2014). Our findings of consistent spatial gradients within SN/VTA thus suggest distinct mesolimbic and mesocortical pathways that can be analyzed along ventral-dorsal and medial-lateral axes in humans. Current Concepts on the Physiopathological Relevance of Dopaminergic Recent results from quantitative real-time PCR (qPCR) studies in rats bolster the idea that PFC D1 and D5 receptor subtypes show a peak in mRNA levels during adolescence (Naneix et al., 2012; Zbukvic et al., 2017). The latter symptoms are defined as a diminished Figure 3.4 Distribution and projections of dopaminergic neurons in the human (right) and rat (left) brains. CSDS induces pathway-specific morphological changes in mesolimbic and mesocortical circuits from males and females. Kopec A. M., Smith C. J., Ayre N. R., Sweat S. C., Bilbo S. D. (2018). Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Sex and pubertal status influence dendritic spine density on frontal corticostriatal projection neurons in mice, Ultrastructural evidence for diffuse transmission by monoamine and acetylcholine neurons of the central nervous system. Trantham-Davidson H., Neely L. C., Lavin A., Seamans J. K. (2004). (A) Summary of maturational changes in DA connectivity in the PFC across adolescence. Tarazi F. I., Tomasini E. C., Baldessarini R. (1999). Schafer D. P., Lehrman E. K., Kautzman A. G., Koyama R., Mardinly A. R., Yamasaki R., et al.. (2012). Cuesta S., Restrepo-Lozano J. M., Popescu C., He S., Reynolds L. M., Israel S., et al.. (2019). 2000, Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Paquola C., Bethlehem R. A., Seidlitz J., Wagstyl K., Romero-Garcia R., Whitaker K. J., et al.. (2019). Verney C., Alvarez C., Geffard M., Berger B. One practical advantage of using rodents in developmental research is their compressed lifespan since they are born after about 3 weeks of gestation and reach adulthood at 2 months of age. From: Medical Epigenetics, 2016 View all Topics Add to Mendeley About this page The Generation of Midbrain Dopaminergic Neurons McCutcheon J. E., Conrad K. L., Carr S. B., Ford K. A., McGehee D. S., Marinelli M. (2012). Dr. Sanil Rege is a Consultant Psychiatrist and founder of Psych Scene and Vita Healthcare. Remington, G., Kapur, S., Foussias, G., Agid, O., Mann, S., Borlido, C., & Javaid, N. (2012). Injury during adolescence leads to sex-specific executive function deficits in adulthood in a pre-clinical model of mild traumatic brain injury. Schizophrenia: more dopamine, more D2 receptors. Reynolds L. M., Makowski C. S., Yogendran S. V., Kiessling S., Cermakian N., Flores C. (2015). As work on these topics advances, a major focus should also be placed on unraveling epigenetic mechanisms linking adolescent experiences to changes in DA development, and on discovering non-invasive longitudinal biomarkers for evaluating the state of DA system development. FOIA Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine. The extended postnatal increase in PFC DA fiber density contrasts to other neuromodulatory systems, such as norepinephrine (NE) and serotonin, which reach adult PFC innervation density levels in rodents within the first 23 weeks of life (Levitt and Moore, 1979; Lidov et al., 1980). 8600 Rockville Pike However, less emphasis has been placed on the distinct developmental trajectories of dopamine projections. (2008). The pathway may also mediate aggression. This issue will become clearer as SABV (sex as a biological variable) is increasingly included in study designs (Shansky and Murphy, 2021). (1988). Tirelli E., Laviola G., Adriani W. (2003). It remains to be determined whether the segregation of DA receptors in striatonigral and striatopallidal MSNs is dynamic at other postanal periods, as well as the age when the segregated pattern of MSN DA receptor expression is stabilized. (2008). American Journal of Psychiatry. 1Plasticit du Cerveau CNRS UMR8249, cole suprieure de physique et de chimie industrielles de la Ville de Paris (ESPCI Paris), Paris, France, 2Neuroscience Paris Seine CNRS UMR 8246 INSERM U1130, Institut de Biologie Paris Seine, Sorbonne Universit, Paris, France, 3Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montral, QC, Canada. Mesocortical axon growth in adolescence revealed by an intersectional viral labeling technique. The guidance cue Netrin-1 and its receptor DCC (deleted in colorectal cancer) have emerged as critical players in establishing mesocorticolimbic DA circuitry and are highly linked to psychiatric disorders of adolescent onset (Vosberg et al., 2019; Torres-Berro et al., 2020a). Sex and strain differences in dynamic and static properties of the mesolimbic dopamine system, Dissecting the diversity of midbrain dopamine neurons, Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: a tyrosine hydroxylase immunohistochemical study, Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. Midbrain dopamine function in schizophrenia and depression, 3. Adler A., Vescovo P., Robinson J. K., Kritzer M. F. (1999). The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia. Similar findings using autoradiography have been reported in C57BL/6 mice (Pokinko et al., 2017). Quantitative analysis of the expression of dopamine D1 and D2 receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. The mesocortical pathway also originates in the ventral tegmental area, but projects to the frontal cortex and surrounding structures. Mesocortical Pathway - an overview | ScienceDirect Topics It is possible that the margin of error, even using precise stereological methods, masks potential anatomical differences between ages (Brub-Carrire et al., 2012; Manitt et al., 2013; Reynolds et al., 2015). The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents. (A) Timeline of adolescence (shaded lines) and puberty (darker portions of the lines) in girls () and boys (), adapted from Hollenstein and Lougheed (2013); Sawyer et al. visual pathways that follow a dorsal and a ventral stream in mice, as observed in greater mammals (Mishkin et al., 1982; Glickfeld et al., 2013a). Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Elevated striatal dopamine function linked to prodromal signs of schizophrenia. LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA, 2. Pathways of sexual desire J Sex Med. Maturation of the human striatal dopamine system revealed by PET and quantitative MRI, Subpopulations of cortical GABAergic interneurons differ by their expression of D1 and D2 dopamine receptor subtypes.