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Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in the Drosophila nociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth.
Learn More >Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of mutants. mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
Learn More >Time pressure to provide a quick fix is commonly cited as a reason why opioids are frequently prescribed in the United States, but there is little evidence of an association between appointment timing and clinical decision-making. As the workday progresses and appointments run behind schedule, physicians may be more likely to prescribe opioids.
Learn More >An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted.
Learn More >High rates of chronic non-cancer pain (CNCP), concerns about adverse effects including dependence among those prescribed potent pain medicines, the recent evidence supporting active rather than passive management strategies and a lack of funding for holistic programme have resulted in challenges around decision making for treatment among clinicians and their patients. Discrete choice experiments (DCEs) are one way of assessing and valuing treatment preferences. Here, we outline a protocol for a study that assesses patient preferences for CNCP treatment.
Learn More >Migraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization. However, the underlying cellular and molecular mechanisms remain unclear.
Learn More >The Centers for Disease Control and Prevention guidelines in 2016 recommended avoiding concurrent use of opioids and benzodiazepines.
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