Nature communications
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Nature communications · Mar 2016
Computations of uncertainty mediate acute stress responses in humans.
The effects of stress are frequently studied, yet its proximal causes remain unclear. Here we demonstrate that subjective estimates of uncertainty predict the dynamics of subjective and physiological stress responses. Subjects learned a probabilistic mapping between visual stimuli and electric shocks. ⋯ We observed a coupling between emotional and somatic state, with subjective and physiological tuning to uncertainty tightly correlated. Furthermore, the uncertainty tuning of subjective and physiological stress predicted individual task performance, consistent with an adaptive role for stress in learning under uncertain threat. Our finding that stress responses are tuned to environmental uncertainty provides new insight into their generation and likely adaptive function.
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Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca(2+) responses. ⋯ Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.
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Nature communications · Jan 2016
Human brain networks function in connectome-specific harmonic waves.
A key characteristic of human brain activity is coherent, spatially distributed oscillations forming behaviour-dependent brain networks. However, a fundamental principle underlying these networks remains unknown. Here we report that functional networks of the human brain are predicted by harmonic patterns, ubiquitous throughout nature, steered by the anatomy of the human cerebral cortex, the human connectome. ⋯ In this new frequency-specific representation of cortical activity, that we call 'connectome harmonics', oscillatory networks of the human brain at rest match harmonic wave patterns of certain frequencies. We demonstrate a neural mechanism behind the self-organization of connectome harmonics with a continuous neural field model of excitatory-inhibitory interactions on the connectome. Remarkably, the critical relation between the neural field patterns and the delicate excitation-inhibition balance fits the neurophysiological changes observed during the loss and recovery of consciousness.
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Nature communications · Jan 2016
Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice.
Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. ⋯ Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research.
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Nature communications · Dec 2015
Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.
Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. ⋯ In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.