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/β-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/β-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

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

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

The hidden link between circadian entropy and mental health disorders

Abstract 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