Sleep Strengthens Predictive Sequence Coding.

Predictive-coding theories assume that perception and action are based on internal models derived from previous experience. Such internal models require selection and consolidation to be stored over time. Sleep is known to support memory consolidation. We hypothesized that sleep supports both consolidation and abstraction of an internal task model that is subsequently used to predict upcoming stimuli. Human subjects (of either sex) were trained on deterministic visual sequences and tested with interleaved deviant stimuli after retention intervals of sleep or wakefulness. Adopting a predictive-coding approach, we found increased prediction strength after sleep, as expressed by increased error rates to deviant stimuli, but fewer errors for the immediately following standard stimuli. Sleep likewise enhanced the formation of an abstract sequence model, independent of the temporal context during training. Moreover, sleep increased confidence for sequence knowledge, reflecting enhanced metacognitive access to the model. Our results suggest that sleep supports the formation of internal models which can be used to predict upcoming events in different contexts.SIGNIFICANCE STATEMENT To efficiently interact with the ever-changing world, we predict upcoming events based on similar previous experiences. Sleep is known to benefit memory consolidation. However, it is not clear whether sleep specifically supports the transformation of past experience into predictions of future events. Here, we find that, when human subjects sleep after learning a sequence of predictable visual events, they make better predictions about upcoming events compared with subjects who stayed awake for an equivalent period of time. In addition, sleep supports the transfer of such knowledge between different temporal contexts (i.e., when sequences unfold at different speeds). Thus, sleep supports perception and action by enhancing the predictive utility of previous experiences.

Attenuated Chemosensory Responsiveness of the Grueneberg Ganglion in Mouse Pups at Warm Temperatures.

Neurons of the Grueneberg ganglion (GG) in the anterior nasal region of mice respond to a small set of odorous compounds, including given dimethylpyrazines present in mouse urine. Consequently, mouse pups living in murine colonies are presumably commonly exposed to such GG-activating substances. Since stimulation of the GG elicits alarm and stress reactions in mice, the question arises whether such a GG activation potentially inducing stress could be reduced when pups might rather feel secure in the presence of their mother. Being together with their warmth-giving dam, mouse pups experience a nest temperature of ∼35 °C. Therefore, we hypothesized that such a warm temperature may attenuate the responses of GG neurons to dimethylpyrazines. Monitoring the expression of the activity marker c-Fos, GG responses to dimethylpyrazines were significantly lower in pups exposed to these substances at 35 °C compared to exposure at 30 °C. By contrast, dimethylpyrazine-induced responses of neurons in the main olfactory epithelium were not diminished at 35 °C in comparison to 30 °C. The attenuated chemosensory responses of GG neurons at 35 °C coincided with a reduced dimethylpyrazine-evoked activation of the glomeruli in the olfactory bulb innervated by GG neurons. The reduction in dimethylpyrazine-evoked GG responses by warm temperatures was positively correlated with exposure time, suggesting that warm temperatures might enhance desensitization processes in GG neurons. In summary, the findings indicate that warm temperatures similar to those in mouse nests in the presence of the dam attenuate GG activation by colony-derived odorants.

Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration.

Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter--i.e. in non-cancerously transformed cells too--as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.