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.
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.
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.
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.
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.
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