SUMMARY Neuromodulatory input, acting on G-protein coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.

Metaplasticity, the adaptive changes of long-term potentiation (LTP) and long-term depression (LTD) in response to fluctuations in neural activity is well documented in visual cortex, where dark rearing shifts the frequency threshold for the induction of LTP and LTD. Here we studied metaplasticity affecting spike-timing dependent plasticity (STDP), in which the polarity of plasticity is determined not by the stimulation frequency, but by the temporal relationship between near coincidental pre- and post-synaptic firing. We found that in mouse visual cortex the same regime of deprivation that restricts the frequency range for inducing rate-dependent LTD extends the integration window for inducing timing-dependent LTD, enabling LTD induction with random pre-and postsynaptic firing. Notably the underlying mechanism for the changes in both rate-dependent and time –dependent LTD appears to be an increase of NR2b-containing NMDAR at the synapse. Thus, the rules of metaplasticity might manifest in opposite directions depending on the plasticity induction paradigms.

Scope: This study explores the beneficial effects of dietary supplementation of black rice anthocyanin extract (BRAE) on cholesterol metabolism and gut dysbiosis. Methods and results: C57BL/6J mice are grouped into the normal chow diet group (NCD), the high-fat and the cholesterol diet group (HCD), and three treatment groups feeding HCD supplemented with various dosage of BRAE for 12 weeks. Results reveal that BRAE alleviates the increased body weight, serum triglyceride (TG), total cholesterol (TC), non-high-density lipoprotein cholesterol levels (non-HDL-C), and increased fecal sterols excretion and caecal short-chain fatty acids (SCFAs) concentration in HCD-induced hypercholesterolemic mice. Moreover, BRAE decreases hepatic TC content through the fundamental regulation of body energy balance gene, adenosine 5′-monophosphate activated protein kinase (AMPK ). Meanwhile, BRAE improves the genes expression involved in cholesterol uptake and efflux, and preserves CYP7A1, ATP-binding cassette subfamily G member 5/8 mRNA expression, and the relative abundance of gut microbiota. Additionally, the antibiotic treatment experiment indicates that the beneficial effects of BRAE in reducing hypocholesterolemia risk largely depends on the gut microbiota homeostasis. Conclusion: BRAE supplement could be a beneficial treatment option for preventing HCD-induced hypocholesterolemia and related metabolic syndromes.