Roles of Transcription Factors in the Development and Reprogramming of the Dopaminergic Neurons

The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement neurological disorders, Parkinson’s disease (PD). How these cells die and regenerate are two of the most hotly debated PD research topics. As for the latter, it has been long known that a series of transcription factors (TFs) involves the development of mdDA neurons, specifying cell types and controlling developmental patterns. In vitro and in vivo, TFs regulate the expression of tyrosine hydroxylase, a dopamine transporter, vesicular monoamine transporter 2, and L-aromatic amino acid decarboxylase, all of which are critical for dopamine synthesis and transport in dopaminergic neurons (DA neurons). In this review, we encapsulate the molecular mechanism of TFs underlying embryonic growth and maturation of mdDA neurons and update achievements on dopaminergic cell therapy dependent on knowledge of TFs in mdDA neuronal development. We believe that a deeper understanding of the extrinsic and intrinsic factors that influence DA neurons’ fate and development in the midbrain could lead to a better strategy for PD cell therapy.

Cerebral [18F]-FDOPA Uptake in Autism Spectrum Disorder and Its Association with Autistic Traits

Dopaminergic signaling is believed to be related to autistic traits. We conducted an exploratory 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine positron emission tomography/computed tomography ([18F]-FDOPA PET/CT) study, to examine cerebral [18F]-FDOPA influx constant (kicer min−1), reflecting predominantly striatal dopamine synthesis capacity and a mixed monoaminergic innervation in extrastriatal neurons, in 44 adults diagnosed with autism spectrum disorder (ASD) and 22 controls, aged 18 to 30 years. Autistic traits were assessed with the Autism Spectrum Quotient (AQ). Region-of-interest and voxel-based analyses showed no statistically significant differences in kicer between autistic adults and controls. In autistic adults, striatal kicer was significantly, negatively associated with AQ attention to detail subscale scores, although Bayesian analyses did not support this finding. In conclusion, among autistic adults, specific autistic traits can be associated with reduced striatal dopamine synthesis capacity. However, replication of this finding is necessary.

Age-Dependent Aggregation of α-Synuclein in the Nervous System of Gut-Brain Axis is Associated with Caspase-1 Activation

α-Synuclein (α-Syn) plays a key role in the development of Parkinson’ desease (PD). As aging is acknowledged to be the greatest risk factor for PD, here we investigated α-Syn expression in the ileum, thoracic spinal cord, and midbrain of young (1-month-old), middle-aged (6-, 12-month-old) to old (18-month-old) mice. We demonstrated that both the levels of α-Syn monomers, oligomers and ratios of oligomers to monomers were increased with aging in the ileum, thoracic spinal cord, and midbrain. Whereas, the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, was decreased with aging in the midbrain. We failed to find corresponding α-Syn mRNA increase with aging. However, we found an increased expression of caspase-1 in the ileum, thoracic spinal cord, and midbrain. A specific caspase-1 inhibitor VX765 significantly reduced levels of both the α-Syn monomers and oligomers triggered by the rotenone in vitro. Taken together, the increase in α-Syn aggregation with aging might not occur first in the gut, but simultaneously in the nervous system of gut-brain axis.. The mechanism of the age-dependent aggregation of α-Syn in nervous system is likely triggered by the aging-related caspase-1 activation.

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.

The utility of PET imaging in the diagnosis and management of psychosis: a brief review

Purpose Advances in the pathophysiological characterization of psychosis has led to a newfound role of biomarkers in diagnostic and prognostic contexts. Further, advances in the accuracy and sensitivity of nuclear medicine imaging techniques, and specifically positron emission tomography (PET), have improved the ability to diagnose and manage individuals experiencing first-episode psychosis or those at greater risk for developing psychosis. Methods Literature searches were performed in PubMed, Google Scholar, and Web of Science to identify papers related to the use of PET imaging in the diagnosis or management of psychosis. Search terms used included “positron emission tomography”, “PET imaging”, “psychosis”, “disorders of psychosis”, “schizophrenia”, “biomarkers”, “diagnostic biomarkers”, “prognostic biomarker”, “monitoring biomarker”, “outcome biomarker”, and “predictive biomarker.” Results Studies included fell into three categories: those examining microglia, those studying dopamine synthesis capacity, and those examining acetylcholine receptor activity. Microglial imaging has been shown to be ineffective in all patients with psychosis, but some believe it shows promise in a subset of patients with psychosis, although no defining characteristics of said subset have been postulated. Studies of dopamine synthesis capacity suggest that presynaptic dopamine is reliably elevated in patients with psychosis, but levels of dopamine active transporter are not. Further, positron emission tomography (PET) with [18F]fluoro-l-dihydroxyphenylalanine ([18F]FDOPA)-PET has been recently used successfully as a predictive biomarker of dopaminergic treatment response, although more work is needed to validate such findings. Finally, existing studies have also documented lower levels of binding to the α7 nicotinic cholinergic receptor (α7-nAChR) via [18F]-ASEM PET in patients with psychosis, however there is a dearth of prospective, randomized studies evaluating the efficacy of [18F]-ASEM as a diagnostic or monitoring biomarker of any kind. Conclusion Molecular imaging has become a useful tool in the diagnosis and management of psychosis. Further work must be done to improve the comparative prognostic value and diagnostic accuracy of different radiotracers.

On the learning of addictive behavior: Sensation-seeking propensity predicts dopamine turnover in dorsal striatum

We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the sensation-seeking activity. We interpreted the former as a state associated with normal rates of dopamine synthesis, and the latter as a trait of individuals with abnormally high rates of synthesis. We previously determined dopaminergic receptor density in striatum, and we now tested the hypothesis that an elevated dopaminergic condition with increased extracellular dopamine and receptor density follows increased dopamine synthesis capacity in highly sensation-seeking individuals, as measured by positron emission tomography of 18 men with tracer fluorodopa (FDOPA). We detected a site in left caudate nucleus where the volume of distribution of FDOPA-derived metabolites correlated negatively with FDOPA metabolite turnover, consistent with decreased metabolite breakdown in highly sensation-seeking subjects. High rates of sensation-seeking attenuated the dopamine turnover in association with a low rate of dopamine recycling, low dopamine oxidation, and elevated extracellular dopamine and receptors in caudate nucleus. In contrast, low rates of sensation-seeking were associated with rapid dopamine recycling, rapid dopamine oxidation, low extracellular dopamine, and low receptor density. We conclude that the modulation of dopaminergic neurotransmission associated with sensation-seeking is a state of sensation-seeking, rather than a trait of personality following abnormal regulation of dopaminergic neurotransmission.

Striatal dopamine dissociates methylphenidate effects on value-based versus surprise-based reversal learning

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects, and there are concerns about the potential for abuse. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Reward versus punishment learning signals were boosted to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate modulates reward and attention, impacting our understanding of how it can both enhance attention and mitigate reward-related compulsivity.

Dopamine signaling regulates hematopoietic stem and progenitor cell function

Hematopoietic stem and progenitor cell (HSPC) function in bone marrow (BM) is controlled by stroma-derived signals, but the identity and interplay of these signals remain incompletely understood. Here, we show that sympathetic nerve-derived dopamine directly controls HSPC behavior through D2-subfamily dopamine receptors. Blockade of dopamine synthesis as well as pharmacological or genetic inactivation of D2-subfamily dopamine receptors lead to reduced HSPC frequency, inhibition of proliferation and low BM transplantation efficiency. Conversely, treatment with a D2-type receptor agonist increases BM regeneration and transplantation efficiency. Mechanistically, dopamine controls expression of the kinase Lck, which, in turn, regulates mitogen-activated protein kinase-mediated signaling triggered by stem cell factor in HSPCs. Our work reveals critical functional roles of dopamine in HSPCs, which may open up new therapeutic options for improved BM transplantation and other conditions requiring the rapid expansion of HSPCs.