Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this ...study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress.
Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.
The embryos of echinoids (sea urchins and sand dollars) serve as excellent models for studying cilia differentiation and stages of the cilia life cycle including ciliogenic initiation, growth, ...maintenance, and retraction. Early in echinoid development, uniform motile cilia form on all cells simultaneously but then rapidly differentiate into multiple cilia types that differ in morphology, motility, and signaling sensitivity. Metal ion treatments that shift germ layer boundaries and thereby "animalize" or "vegetalize" embryos can be used to enrich for low-abundance cilia types rendering those specialized cilia and the differentiation processes they exhibit much easier to study. The experimental advantages of having robust cilia growth and differentiation is tempered by the challenge of restraining ciliated embryos well enough to view the process of ciliogenesis live. We have developed four observation chambers as modifications of the Kiehart chamber for long-term light microscopic imaging of ciliated echinoid embryos. One of these systems employs paramagnetic beads to render ciliated larvae magnetic so they can be gently and reversibly trapped directly under the objective lens. With this magnetic trapping system, the larva can be positioned and repositioned until they achieve the orientation with the clearest view of any cilia of interest. These methods of gentle embryo restraint allow normal embryo development and the normal ciliogenic cycle and ciliary differentiation processes to continue in direct view. Sequential image series can then be collected and analyzed to quantitatively study the wide spectrum of cilia behaviors and properties that arise in developing echinoid embryos.
During rugby game, or intensive rugby training there are many high intensity explosive exercises and eccentric muscle contractions, therefore adequate recovery is very important to rugby players. In ...the present study we have tested the effects of cold water immersion (CWI) after game-simulated (80 min.) rugby training on muscle power recovery and blood markers of muscle damage. Twenty well-trained collegiate male rugby players (age: 20.3 ± 0.6 years old, body height: 1.74 ± 0.05 m, body weight: 85.4 ± 2.0 kg, body fat: 18.2 ± 1.4 %) volunteered for this study. This study was conducted as a cross-over design; i.e., the subjects were randomly assigned either to CWI (n = 10) or passive rest condition (n = 10) for the 1(st) trial and 1 week later the subjects were switched conditions for the 2(nd) trial. After the simulated rugby training, including tackles and body contacts, muscle functional ability and blood markers of muscle damage were tested immediately, after CWI or passive rest, and again 24 hours later. Statistical analysis of all muscle functional tests (10 m dash, counter movement jump, reaction time, side steps) except for 10 seconds maximal pedaling power and blood makers of muscle damage (aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatinine) revealed significant main effects for time (p < 0.05). However, no statistically significant interactions were found in any of the muscle functional tests and blood markers between groups and time courses. Our results suggest that a rugby game induces muscle damage and reduces muscle function. However, CWI has no significant restorative effect after an 80-minute rugby game in terms of muscle damage. Key PointsCold water immersion study for the recovery of rugby playersMuscle strength and muscle power were mainly evaluated as well as muscle enzymes of muscle break downSubjects were highly trained rugby players with control group.
Executive function (EF) has been presumed to be mediated by the dopaminergic system in the prefrontal cortex. However, little is known about the early development of this function and the roles ...dopamine plays in it. Tetrahydrobiopterin (BH4) deficiencies are genetic disorders affecting catecholamine and serotonin biosynthesis which, if untreated, result in motor and cognitive symptoms including impairment of EF. A comprehensive neuropsychological test battery was administered to six participants with BH4 deficiency (four males, two females, mean Full‐scale intelligence quotient FIQ 63.8 SD 14.7); all were on replacement therapy with L‐dopa and BH4, but time of initiation of treatment varied. Age range (median) was 28 days to 41 years (2y 6mo) at initiation of treatment and 10 to 47 years (19y) at follow‐up. On non‐EF tests, performance agreed with those of IQ‐matched controls (four males, two females; mean age 16y 6mo SD 6mo; mean FIQ 62.3 SD 13.4). On EF tests those who initiated treatment after 2 years 6 months of age performed poorly. In patients with BH4 deficiency, replacement therapy should be started in the first weeks or months of life. Patients diagnosed before the age of 2 years 6 months obtain normal EF, which suggests dopamine may play a critical role in ensuring stable development of EF in early life.
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