ABSTRACT
Environmental fitness is an essential component of animal survival. Fitness is achieved through responsive physiological plasticity of tissues across the entire body, and particularly in the nervous system. At the molecular level, neural plasticity is mediated via gene-environmental interactions whereby developmental cues and experience dependent input adapt neuronal function to ever changing demands. To this end, neuronal gene regulation must be coupled to changes in neural activity. Seminal discoveries of the 20th century demonstrated neural activity modifies gene expression through calcium-dependent gene transcription. Building on this model, recent work over the last two decades shows that mRNA products of transcriptional programming continue to be regulated in the neuron through the activity-dependent post-transcriptional action of microRNAs (miRNAs). miRNAs are special post-transcriptional regulators that can tune gene expression within the spatial and temporal requirements of synaptic compartments. This mode of gene regulation has proven to be essential for synaptic function and plasticity as miRNA loss of function is highly associated with neural disease. In this review we will discuss current perspective on the link between presynaptic plasticity and miRNA biogenesis in the neuron.
Subject(s)
MicroRNAs/genetics , Neurodegenerative Diseases/genetics , Neuronal Plasticity/genetics , Neurons/metabolism , RNA, Messenger/genetics , Adaptation, Physiological/genetics , Animals , Calcium/metabolism , Calcium Signaling , Gene Expression Regulation , Gene-Environment Interaction , Genetic Fitness/physiology , Humans , MicroRNAs/metabolism , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurons/cytology , RNA, Messenger/metabolism , Stress, Physiological/genetics , Synapses/metabolism , Synaptic TransmissionABSTRACT
BACKGROUND: We previously reported the generation of a reporter line of human embryonic stem cells (hESCs) with enhanced green fluorescent protein (eGFP) expression driven by the α-myosin heavy chain (αMHC) promoter. The GFP+/αMHC+ cells derived from this cell line behave as multipotent, human myocardial precursors (hMPs) in vitro. In this study, we evaluated the therapeutic effects of GFP+/αMHC+ cells isolated from the reporter line in a mouse model of myocardial infarction (MI). METHODS: MI was generated in immunodeficient mice. hMPs were injected into murine infarcted hearts under ultrasound guidance at 3 days post-MI. Human fetal skin fibroblasts (hFFs) were injected as control. Cardiac function was evaluated by echocardiography. Infarct size, angiogenesis, apoptosis, cell fate, and teratoma formation were analyzed by immunohistochemical staining. RESULTS: Compared with control, hMPs resulted in improvement of cardiac function post-MI with smaller infarct size, induced endogenous angiogenesis, and reduced apoptosis of host cardiomyocytes at the peri-infarct zone at 28 days post-MI. CONCLUSION: Intramyocardial injection of hMPs improved cardiac function post-MI. The engraftment rate of these cells in the myocardium post-MI was low, suggesting that the majority of effect occurs via paracrine mechanisms.
Subject(s)
Cell- and Tissue-Based Therapy/methods , Embryonic Stem Cells/transplantation , Multipotent Stem Cells/transplantation , Myocardial Infarction/therapy , Myocytes, Cardiac/cytology , Animals , Apoptosis/physiology , Cells, Cultured , Echocardiography , Female , Green Fluorescent Proteins/genetics , Heart/physiopathology , Heart Function Tests , Humans , Mice , Mice, SCID , Neovascularization, PhysiologicABSTRACT
Infectious bovine keratoconjunctivitis (IBK) is a common corneal disease of calves that adversely affects animal welfare by causing pain and weight loss. Identifying behavioral indicators of pain and sickness in calves with IBK is necessary for designing studies that aim to identify effective means of pain mitigation. Consistent with principles of the 3Rs for animal use in research, data from a randomized blinded challenge study was used to identify and describe variation of behaviors that could serve as reliable indicators of pain and sickness in calves with corneal injuries. Behavioral observations were collected from 29 Holstein calves 8 to 12 weeks of age randomly allocated to one of three treatments: (1) corneal scarification only, (2) corneal scarification with inoculation with Moraxella bovoculi and (3) corneal scarification with inoculation with Moraxella bovis. Behavior was continuously observed between time 1230 - 1730 h on day -1 (baseline time period) and day 0 (scarification time period). Corneal scarification and inoculation occurred between 0800 - 1000 h on day 0. Frequency of head-directed behaviors (head shaking, head rubbing, head scratching) and durations of head rubbing, feeding, standing with head lifted, lying with head lifted and sleeping were compared between study days and groups. Following scarification, the frequency of head-directed behavior significantly increased (p = 0.0001), as did duration of head rubbing (p=0.02). There was no significant effect of trial, trial day, treatment or treatment-day interaction on other behaviors studied. Our study demonstrated that head-directed behavior, such as head shaking, rubbing and scratching, was associated with scarification of eyes using an IBK challenge model, but sickness behavior was not observed.
