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.

Untargeted metabolomics analysis on kidney tissues from mice reveals potential hypoxia biomarkers.

Chronic hypoxia may have a huge impact on the cardiovascular and renal systems. Advancements in microscopy, metabolomics, and bioinformatics provide opportunities to identify new biomarkers. In this study, we aimed at elucidating the metabolic alterations in kidney tissues induced by chronic hypoxia using untargeted metabolomic analyses. Reverse phase ultrahigh performance liquid chromatography-mass spectroscopy/mass spectroscopy (RP-UPLC-MS/MS) and hydrophilic interaction liquid chromatography (HILIC)-UPLC-MS/MS methods with positive and negative ion mode electrospray ionization were used for metabolic profiling. The metabolomic profiling revealed an increase in metabolites related to carnitine synthesis and purine metabolism. Additionally, there was a notable increase in bilirubin. Heme, N-acetyl-L-aspartic acid, thyroxine, and 3-beta-Hydroxy-5-cholestenoate were found to be significantly downregulated. 3-beta-Hydroxy-5-cholestenoate was downregulated more significantly in male than female kidneys. Trichome Staining also showed remarkable kidney fibrosis in mice subjected to chronic hypoxia. Our study offers potential intracellular metabolite signatures for hypoxic kidneys.

Reanalysis of primate brain circadian transcriptomics reveals connectivity-related oscillations.

Research shows that brain circuits controlling vital physiological processes are closely linked with endogenous time-keeping systems. In this study, we aimed to examine oscillatory gene expression patterns of well-characterized neuronal circuits by reanalyzing publicly available transcriptomic data from a spatiotemporal gene expression atlas of a non-human primate. Unexpectedly, brain structures known for regulating circadian processes (e.g., hypothalamic nuclei) did not exhibit robust cycling expression. In contrast, basal ganglia nuclei, not typically associated with circadian physiology, displayed the most dynamic cycling behavior of its genes marked by sharp temporally defined expression peaks. Intriguingly, the mammillary bodies, considered hypothalamic nuclei, exhibited gene expression patterns resembling the basal ganglia, prompting reevaluation of their classification. Our results emphasize the potential for high throughput circadian gene expression analysis to deepen our understanding of the functional synchronization across brain structures that influence physiological processes and resulting complex behaviors.

Spatiotemporal Mapping of Brain Cilia Reveals Region-Specific Oscillation of Length and Orientation.

In this study, we conducted high-throughput spatiotemporal analysis of primary cilia length and orientation across 22 mouse brain regions. We developed automated image analysis algorithms, which enabled us to examine over 10 million individual cilia, generating the largest spatiotemporal atlas of cilia. We found that cilia length and orientation display substantial variations across different brain regions and exhibit fluctuations over a 24-hour period, with region-specific peaks during light-dark phases. Our analysis revealed unique orientation patterns of cilia at 45 degree intervals, suggesting that cilia orientation within the brain is not random but follows specific patterns. Using BioCycle, we identified circadian rhythms of cilia length in five brain regions: nucleus accumbens core, somatosensory cortex, and three hypothalamic nuclei. Our findings present novel insights into the complex relationship between cilia dynamics, circadian rhythms, and brain function, highlighting cilia crucial role in the brain's response to environmental changes and regulation of time-dependent physiological processes.

Behavioral and neuro-functional consequences of eliminating the KCNQ3 GABA binding site in mice.

Voltage-gated potassium (Kv) channels formed by α subunits KCNQ2-5 are important in regulating neuronal excitability. We previously found that GABA directly binds to and activates channels containing KCNQ3, challenging the traditional understanding of inhibitory neurotransmission. To investigate the functional significance and behavioral role of this direct interaction, mice with a mutated KCNQ3 GABA binding site (Kcnq3-W266L) were generated and subjected to behavioral studies. Kcnq3-W266L mice exhibited distinctive behavioral phenotypes, of which reduced nociceptive and stress responses were profound and sex-specific. In female Kcnq3-W266L mice, the phenotype was shifted towards more nociceptive effects, while in male Kcnq3-W266L mice, it was shifted towards the stress response. In addition, female Kcnq3-W266L mice exhibited lower motor activity and reduced working spatial memory. The neuronal activity in the lateral habenula and visual cortex was altered in the female Kcnq3-W266L mice, suggesting that GABAergic activation of KCNQ3 in these regions may play a role in the regulation of the responses. Given the known overlap between the nociceptive and stress brain circuits, our data provide new insights into a sex-dependent role of KCNQ3 in regulating neural circuits involved in nociception and stress, via its GABA binding site. These findings identify new targets for effective treatments for neurological and psychiatric conditions such as pain and anxiety.

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.

Aromatic patterns: Tryptophan aromaticity as a catalyst for the emergence of life and rise of consciousness.

Sunlight held the key to the origin of life on Earth. The earliest life forms, cyanobacteria, captured the sunlight to generate energy through photosynthesis. Life on Earth evolved in accordance with the circadian rhythms tied to sensitivity to sunlight patterns. A unique feature of cyanobacterial photosynthetic proteins and circadian rhythms' molecules, and later of nearly all photon-sensing molecules throughout evolution, is that the aromatic amino acid tryptophan (Trp) resides at the center of light-harvesting active sites. In this perspective, I review the literature and integrate evidence from different scientific fields to explore the role Trp plays in photon-sensing capabilities of living organisms through its resonance delocalization of π-electrons. The observations presented here are the product of apparently unrelated phenomena throughout evolution, but nevertheless share consistent patterns of photon-sensing by Trp-containing and Trp-derived molecules. I posit the unique capacity to transfer electrons during photosynthesis in the earliest life forms is conferred to Trp due to its aromaticity. I propose this ability evolved to assume more complex functions, serving as a host for mechanisms underlying mental aptitudes - a concept which provides a theoretical basis for defining the neural correlates of consciousness. The argument made here is that Trp aromaticity may have allowed for the inception of the mechanistic building blocks used to fabricate complexity in higher forms of life. More specifically, Trp aromatic non-locality may have acted as a catalyst for the emergence of consciousness by instigating long-range synchronization and stabilizing the large-scale coherence of neural networks, which mediate functional brain activity. The concepts proposed in this perspective provide a conceptual foundation that invites further interdisciplinary dialogue aimed at examining and defining the role of aromaticity (beyond Trp) in the emergence of life and consciousness.

Alzheimer's disease is associated with disruption in thiamin transport physiology: A potential role for neuroinflammation.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid-ß peptide (Aß) containing plaques and cognitive deficits. The pathophysiology of AD also involves neuroinflammation. Vitamin B1 (thiamin) is indispensable for normal cellular energy metabolism. Thiamin homeostasis is altered in AD, and its deficiency is known to aggravate AD pathology. Little, however, is known about possible alterations in level of expression of thiamin transporters-1 and -2 (THTR-1 and -2) in the brain of AD, and whether pro-inflammatory cytokines affect thiamin uptake by brain cells. We addressed these issues using brain tissue samples [prefrontal cortex (PFC) and hippocampus (HIP)] from AD patients and from 5XFAD mouse model of AD, together with cultured human neuroblastoma SH-SY5Y cells as model. Our results revealed a significantly lower expression of both THTR-1 and THTR-2 in the PFC and HIP of AD patients and 5XFAD mouse model of AD compared to appropriate normal controls. Further, we found that exposure of the SH-SY5Y cells to pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) led to a significant inhibition in thiamin uptake. Focusing on IL-1ß, we found the inhibition in thiamin uptake to be time-dependent and reversible; it was also associated with a substantial reduction in expression of THTR-1 (but not THTR-2) protein and mRNA as well as a decrease in promoter activity of the SLC19A2 gene (which encodes THTR-1). Finally, using transcriptomic analysis, we found that thiamin availability in SH-SY5Y cells caused changes in the expression of genes relevant to AD pathways. These studies demonstrate, for the first time, that thiamin transport physiology/molecular biology parameters are negatively impacted in AD brain and that pro-inflammatory cytokines inhibit thiamin uptake by neuroblastoma cells. The results also support a possible role for thiamin in the pathophysiology of AD.

L-methionine enhances neuroinflammation and impairs neurogenesis: Implication for Alzheimer's disease.

The disruption of methionine (L-MET) metabolism has been linked with neurodevelopmental disorders such as autism and schizophrenia and neurodegenerative disorders such as Alzheimer's disorder. We previously showed that repeated administration to adult mice of methionine produced impairments of cognitive deficits. Considering the decreased neurogenesis and increased molecular inflammation hypotheses of cognitive deficits in Alzheimer's, we aimed to explore whether the methionine regimen that produced cognitive deficits is associated with altered neuroinflammation, neurogenesis, or neurodegeneration. We found that repeated administration of L-MET at a dose equivalent to two-fold of daily dietary intake for seven days enhanced the activation of microglia and inflammation in the brain, and decreased neurogenesis in the hippocampus without affecting degeneration. Furthermore, sub-chronic and chronic L-MET treatment of human neuroblastoma (SH-SY5Y) inhibited cell cycle progression, an effect that was reversed by decreasing removing L-MET from the medium. These results support a role for neuroinflammation and neurogenesis in mediating the mechanism through which L-MET induces cognitive deficits. The results also uncover L-MET restriction, neuroinflammation, and neurogenesis as potential preventive and/or therapeutic targets for mental disorders associated with cognitive disorders, including schizophrenia and Alzheimer's disease.

Lab-In-A-Syringe: A Novel Electrochemical Biosensor for On-Site and Real-Time Monitoring of Dopamine in Freely Behaving Mice.

There is a growing demand for real-time analysis and sampling of biofluids on a single low-cost platform in ultralow fluid volumes with robustness. In this study, a microfluidic sensor was developed, manufactured through an additive manufacturing technique, and used for dopamine (DA) measurements. We implemented a biosensing system using pencil graphites (PGEs) integrated into a three-dimensional (3D) printed microfluidic syringe-type device (µSyringe). The amperometry technique was used to monitor the current changes associated with the electrooxidation of DA. The sensing signal was stable and linear in a concentration range of DA between the limit of quantification (0.1 nM) and the upper limit of linearity (500 nM). The µSyringe sensing device is simple, robust, and stable, making it suitable for real-time measurement of DA in cerebrospinal fluid (CSF) from freely moving mice.

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations.

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.

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.

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions.

G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the roles of GPCRs in the etiology and pathophysiology of psychiatric disorders are not fully understood. Using publically available datasets, we performed a comprehensive analysis of the transcriptomic signatures of G-protein-linked signaling across the major psychiatric disorders: autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). We also used the BrainSpan transcriptomic dataset of the developing human brain to examine whether GPCRs that exhibit chronological age-associated expressions have a higher tendency to be dysregulated in psychiatric disorders than age-independent GPCRs. We found that most GPCR genes were differentially expressed in the four disorders and that the GPCR superfamily as a gene cluster was overrepresented in the four disorders. We also identified a greater amplitude of gene expression changes in GPCRs than other gene families in the four psychiatric disorders. Further, dysregulated GPCRs overlapped across the four psychiatric disorders, with SCZ exhibiting the highest overlap with the three other disorders. Finally, the results revealed a greater tendency of age-associated GPCRs to be dysregulated in ASD than random GPCRs. Our results substantiate the central role of GPCR signaling pathways in the etiology and pathophysiology of psychiatric disorders. Furthermore, our study suggests that common GPCRs' signaling may mediate distinct phenotypic presentations across psychiatric disorders. Consequently, targeting these GPCRs could serve as a common therapeutic strategy to treat specific clinical symptoms across psychiatric disorders.

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan.

Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia's structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/ß-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/ß-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.

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.

Large-scale analysis reveals spatiotemporal circadian patterns of cilia transcriptomes in the primate brain.

Cilia are dynamic subcellular systems, with core structural and functional components operating in a highly coordinated manner. Since many environmental stimuli sensed by cilia are circadian in nature, it is reasonable to speculate that genes encoding cilia structural and functional components follow rhythmic circadian patterns of expression. Using computational methods and the largest spatiotemporal gene expression atlas of primates, we identified and analyzed the circadian rhythmic expression of cilia genes across 22 primate brain areas. We found that around 73% of cilia transcripts exhibited circadian rhythmicity across at least one of 22 brain regions. In 12 brain regions, cilia transcriptomes were significantly enriched with circadian oscillating transcripts, as compared to the rest of the transcriptome. The phase of the cilia circadian transcripts deviated from the phase of the majority of the background circadian transcripts, and transcripts coding for cilia basal body components accounted for the majority of cilia circadian transcripts. In addition, adjacent or functionally connected brain nuclei had large overlapping complements of circadian cilia genes. Most remarkably, cilia circadian transcripts shared across the basal ganglia nuclei and the prefrontal cortex peaked in these structures in sequential fashion that is similar to the sequential order of activation of the basal ganglia-cortical circuitry in connection with movement coordination, albeit on completely different timescales. These findings support a role for the circadian spatiotemporal orchestration of cilia gene expression in the normal physiology of the basal ganglia-cortical circuit and motor control. Studying orchestrated cilia rhythmicity in the basal ganglia-cortical circuits and other brain circuits may help develop better functional models, and shed light on the causal effects cilia functions have on these circuits and on the regulation of movement and other behaviors.

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.

Patterns of cilia gene dysregulations in major psychiatric disorders.

Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the largest and most recent publicly available databases. We found that 42%, 24%, 17%, and 15% of brain-expressed cilia genes were significantly differentially expressed in SCZ, ASD, BP, and MDD, respectively. Several genes exhibited cross-disorder overlap, suggesting that typical cilia signaling pathways' dysfunctions determine susceptibility to more than one psychiatric disorder or may partially underlie their pathophysiology. Our study revealed that genes encoding proteins of almost all sub-cilia structural and functional compartments were dysregulated in the four psychiatric disorders. Strikingly, the genes of 75% of cilia GPCRs and 50% of the transition zone proteins were differentially expressed in SCZ. The present study is the first to draw associations between cilia and major psychiatric disorders, and is the first step toward understanding the role that cilia components play in their pathophysiological processes, which may lead to novel therapeutic targets for these disorders.