Ophthalmate is a new regulator of motor functions via CaSR: Implications for movement disorders.

Dopamine's role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms. In mouse models of Parkinson's Disease (PD), we observed that L-DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC). Remarkably, the motor activity response to L-DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 hours, compared to when L-DOPA was administered alone. This suggests an alternative pathway or mechanism, independent of dopamine signaling, mediating the motor functions. We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis. Our results revealed that the peak in motor activity induced by NSD1015/L-DOPA in PD mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (OA, also known as ophthalmate in its anionic form). Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in PD mice in a dose-dependent manner. We investigated the molecular mechanisms underlying ophthalmate's action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR). Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR. The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders.

Humanized dopamine D4.7 receptor male mice display risk-taking behavior and deficits of social recognition and working memory in light/dark-dependent manner.

The dopamine D4 receptor 7-repeat allele (D4.7 R) has been linked with psychiatric disorders such as attention-deficit-hyperactivity disorder, autism, and schizophrenia. However, the highly diverse study populations and often contradictory findings make it difficult to draw reliable conclusions. The D4.7 R has the potential to explain individual differences in behavior. However, there is still a great deal of ambiguity surrounding whether it is causally connected to the etiology of psychiatric disorders. Therefore, humanized D4.7 R mice, with the long third intracellular domain of the human D4.7 R, may provide a valuable tool to examine the relationship between the D4.7 R variant and specific behavioral phenotypes. We report that D4.7 R male mice carrying the humanized D4.7 R variant exhibit distinct behavioral features that are dependent on the light-dark cycle. The behavioral phenotype was characterized by a working memory deficit, delayed decision execution in the light phase, decreased stress and anxiety, and increased risk behavior in the dark phase. Further, D4.7 R mice displayed impaired social recognition memory in both the light and dark phases. These findings provide insight into the potential causal relationship between the human D4.7 R variant and specific behaviors and encourage further consideration of dopamine D4 receptor (DRD4) ligands as novel treatments for psychiatric disorders in which D4.7 R has been implicated.

Cilia in the Striatum Mediate Timing-Dependent Functions.

Almost all brain cells contain cilia, antennae-like microtubule-based organelles. Yet, the significance of cilia, once considered vestigial organelles, in the higher-order brain functions is unknown. Cilia act as a hub that senses and transduces environmental sensory stimuli to generate an appropriate cellular response. Similarly, the striatum, a brain structure enriched in cilia, functions as a hub that receives and integrates various types of environmental information to drive appropriate motor response. To understand cilia's role in the striatum functions, we used loxP/Cre technology to ablate cilia from the dorsal striatum of male mice and monitored the behavioral consequences. Our results revealed an essential role for striatal cilia in the acquisition and brief storage of information, including learning new motor skills, but not in long-term consolidation of information or maintaining habitual/learned motor skills. A fundamental aspect of all disrupted functions was the "time perception/judgment deficit." Furthermore, the observed behavioral deficits form a cluster pertaining to clinical manifestations overlapping across psychiatric disorders that involve the striatum functions and are known to exhibit timing deficits. Thus, striatal cilia may act as a calibrator of the timing functions of the basal ganglia-cortical circuit by maintaining proper timing perception. Our findings suggest that dysfunctional cilia may contribute to the pathophysiology of neuro-psychiatric disorders, as related to deficits in timing perception.

The hidden link between circadian entropy and mental health disorders.

The high overlapping nature of various features across multiple mental health disorders suggests the existence of common psychopathology factor(s) (p-factors) that mediate similar phenotypic presentations across distinct but relatable disorders. In this perspective, we argue that circadian rhythm disruption (CRD) is a common underlying p-factor that bridges across mental health disorders within their age and sex contexts. We present and analyze evidence from the literature for the critical roles circadian rhythmicity plays in regulating mental, emotional, and behavioral functions throughout the lifespan. A review of the literature shows that coarse CRD, such as sleep disruption, is prevalent in all mental health disorders at the level of etiological and pathophysiological mechanisms and clinical phenotypical manifestations. Finally, we discuss the subtle interplay of CRD with sex in relation to these disorders across different stages of life. Our perspective highlights the need to shift investigations towards molecular levels, for instance, by using spatiotemporal circadian "omic" studies in animal models to identify the complex and causal relationships between CRD and mental health disorders.

Surface Plasmon Resonance Identifies High-Affinity Binding of l-DOPA to Siderocalin/Lipocalin-2 through Iron-Siderophore Action: Implications for Parkinson's Disease Treatment.

l-3,4-Dihydroxyphenylalanine (l-DOPA), the dopamine precursor, remains the frontline treatment for Parkinson's disease (PD). With the treatment progress, l-DOPA efficacy decreases, necessitating higher and more frequent doses, with higher risks of dyskinesia. l-DOPA chelates iron through its catechol group, forming the l-DOPA:Fe complex; however, the fate of this complex is unknown. Catechol siderophore-like compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is upregulated in PD patients' substantia nigra and may play a role in PD pathophysiology. Therefore, in this study, we used the surface plasmon resonance (SPR) technique to examine the binding properties of l-DOPA to Scn. We found that l-DOPA formed a stable complex with Scn in the presence of Fe3+. Our analysis of the binding properties of l-DOPA precursors and metabolites indicates that the catechol group is necessary but not sufficient to form a stable complex with Scn. Finally, the affinity constant (Kd) of DOPA:Fe3+ binding with Scn (0.8 µM) was lower than l-DOPA plasma peak concentrations in l-DOPA preparations in the past six decades. Our results speculate a significant role for the l-DOPA-Scn complex in the decreased bioavailability of l-DOPA with the progress of PD.

Age-Related Neurometabolomic Signature of Mouse Brain.

Neurometabolites are the ultimate gene products in the brain and the most precise biomolecular indicators of brain endophenotypes. Metabolomics is the only "omics" that provides a moment-to-moment "snapshot" of brain circuits' biochemical activities in response to external stimuli within the context of specific genetic variations. Although the expression levels of neurometabolites are highly dynamic, the underlying metabolic processes are tightly regulated during brain development, maturation, and aging. Therefore, this study aimed to identify mouse brain metabolic profiles in neonatal and adult stages and reconstruct both the active metabolic network and the metabolic pathway functioning. Using high-throughput metabolomics and bioinformatics analyses, we show that the neonatal mouse brain has its distinct metabolomic signature, which differs from the adult brain. Furthermore, lipid metabolites showed the most profound changes between the neonatal and adult brain, with some lipid species reaching 1000-fold changes. There were trends of age-dependent increases and decreases among lipids and non-lipid metabolites, respectively. A few lipid metabolites such as HexCers and SHexCers were almost absent in neonatal brains, whereas other non-lipid metabolites such as homoarginine were absent in the adult brains. Several molecules that act as neurotransmitters/neuromodulators showed age-dependent levels, with adenosine and GABA exhibiting around 100- and 10-fold increases in the adult compared with the neonatal brain. Of particular interest is the observation that purine and pyrimidines nucleobases exhibited opposite age-dependent changes. Bioinformatics analysis revealed an enrichment of lipid biosynthesis pathways in metabolites, whose levels increased in adult brains. In contrast, pathways involved in the metabolism of amino acids, nucleobases, glucose (glycolysis), tricarboxylic acid cycle (TCA) were enriched in metabolites whose levels were higher in the neonatal brains. Many of these pathways are associated with pathological conditions, which can be predicted as early as the neonatal stage. Our study provides an initial age-related biochemical directory of the mouse brain and warrants further studies to identify temporal brain metabolome across the lifespan, particularly during adolescence and aging. Such neurometabolomic data may provide important insight about the onset and progression of neurological/psychiatric disorders and may ultimately lead to the development of precise diagnostic biomarkers and more effective preventive/therapeutic strategies.

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.

Microfluidic Electrochemical Sensor for Cerebrospinal Fluid and Blood Dopamine Detection in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder involving dopaminergic neurons from the substantia nigra. The loss of dopaminergic neurons results in decreased dopamine (DA) release in the striatum and thus impaired motor functions. DA is one of the key neurotransmitters monitored for the diagnosis and during the progression and treatment of PD. Therefore, sensitive and selective DA detection methods are of high clinical relevance. In this study, a new microfluidic device utilized for electrochemical DA detection is reported. The microfluidic sensing device operates in the range of 0.1-1000 nM DA requiring only ∼2.4 µL sample volume, which corresponds to detectable 240 amol of DA. Using this sensor, we were able to monitor the changes in DA levels in cerebrospinal fluid and plasma of a mouse model of PD and following the treatment of drug l-3,4-dihydroxyphenylalanine.

Electrochemical Micropyramid Array-Based Sensor for In Situ Monitoring of Dopamine Released from Neuroblastoma Cells.

Abnormal dopamine neurotransmission is associated with several neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, attention deficiency and hyperactivity disorder, and addiction. Developing highly sensitive, selective, and fast dopamine monitoring methods is of high importance especially for the early diagnosis of these diseases. Herein, we report a new ultrasensitive electrochemical sensing platform for in situ monitoring of cell-secreted dopamine using Au-coated arrays of micropyramid structures integrated directly into a Petri dish. This approach enables the monitoring of dopamine released from cells in real-time without the need for relocating cultured cells. According to the electrochemical analyses, our dopamine sensing platform exhibits excellent analytical characteristics with a detection limit of 0.50 ± 0.08 nM, a wide linear range of 0.01-500 µM, and a sensitivity of 0.18 ± 0.01 µA/µM. The sensor also has remarkable selectivity toward DA in the presence of different potentially interfering small molecules. The developed electrochemical sensor has great potential for in vitro analysis of neuronal cells as well as early diagnosis of different neurological diseases related to abnormal levels of dopamine.