The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.

Modeling the neuronal processes underlying short-term working memory remains the focus of many theoretical studies in neuroscience. In this paper, we propose a mathematical model of a spiking neural network (SNN) which simulates the way a fragment of information is maintained as a robust activity pattern for several seconds and the way it completely disappears if no other stimuli are fed to the system. Such short-term memory traces are preserved due to the activation of astrocytes accompanying the SNN. The astrocytes exhibit calcium transients at a time scale of seconds. These transients further modulate the efficiency of synaptic transmission and, hence, the firing rate of neighboring neurons at diverse timescales through gliotransmitter release. We demonstrate how such transients continuously encode frequencies of neuronal discharges and provide robust short-term storage of analogous information. This kind of short-term memory can store relevant information for seconds and then completely forget it to avoid overlapping with forthcoming patterns. The SNN is inter-connected with the astrocytic layer by local inter-cellular diffusive connections. The astrocytes are activated only when the neighboring neurons fire synchronously, e.g., when an information pattern is loaded. For illustration, we took grayscale photographs of people’s faces where the shades of gray correspond to the level of applied current which stimulates the neurons. The astrocyte feedback modulates (facilitates) synaptic transmission by varying the frequency of neuronal firing. We show how arbitrary patterns can be loaded, then stored for a certain interval of time, and retrieved if the appropriate clue pattern is applied to the input.

Ischemic brain injury is a widespread pathological condition, the main components of which are a deficiency of oxygen and energy substrates. In recent years, a number of new forms of cell death, including necroptosis, have been described. In necroptosis, a cascade of interactions between the kinases RIPK1 and RIPK3 and the MLKL protein leads to the formation of a specialized death complex called the necrosome, which triggers MLKL-mediated destruction of the cell membrane and necroptotic cell death. Necroptosis probably plays an important role in the development of ischemia/reperfusion injury and can be considered as a potential target for finding methods to correct the disruption of neural networks in ischemic damage. In the present study, we demonstrated that blockade of RIPK1 kinase by Necrostatin-1 preserved the viability of cells in primary hippocampal cultures in an in vitro model of glucose deprivation. The effect of RIPK1 blockade on the bioelectrical and metabolic calcium activity of neuron-glial networks in vitro using calcium imaging and multi-electrode arrays was assessed for the first time. RIPK1 blockade was shown to partially preserve both calcium and bioelectric activity of neuron-glial networks under ischemic factors. However, it should be noted that RIPK1 blockade does not preserve the network parameters of the collective calcium dynamics of neuron-glial networks, despite the maintenance of network bioelectrical activity (the number of bursts and the number of spikes in the bursts). To confirm the data obtained in vitro, we studied the effect of RIPK1 blockade on the resistance of small laboratory animals to in vivo modeling of hypoxia and cerebral ischemia. The use of Necrostatin-1 increases the survival rate of C57BL mice in modeling both acute hypobaric hypoxia and ischemic brain damage.

Whether and under what conditions astrocytes can mount a collective network response has recently become one of the central questions in neurobiology. Here, we address this problem, investigating astrocytic reactions to different biochemical stimuli and ischemic-like conditions in vitro. Identifying an emergent astrocytic network is based on a novel mathematical approach that extracts calcium activity from time-lapse fluorescence imaging and estimates the connectivity of astrocytes. The developed algorithm represents the astrocytic network as an oriented graph in which the nodes correspond to separate astrocytes, and the edges indicate high dynamical correlations between astrocytic events. We demonstrate that ischemic-like conditions decrease network connectivity in primary cultures in vitro, although calcium events persist. Importantly, we found that stimulation under normal conditions with 10 µM ATP increases the number of long-range connections and the degree of corresponding correlations in calcium activity, apart from the frequency of calcium events. This result indicates that astrocytes can form a large functional network in response to certain stimuli. In the post-ischemic interval, the response to ATP stimulation is not manifested, which suggests a deep lesion in functional astrocytic networks. The blockade of Connexin 43 during ischemic modeling preserves the connectivity of astrocytes in the post-hypoxic period.

There is growing evidence that suggests the importance of astrocytes as elements for neural information processing through the modulation of synaptic transmission. A key aspect of this problem is understanding the impact of astrocytes in the information carried by compound events in neurons across time. In this paper, we investigate how the astrocytes participate in the information integrated by individual neurons in an ensemble through the measurement of “integrated information.” We propose a computational model that considers bidirectional communication between astrocytes and neurons through glutamate-induced calcium signaling. Our model highlights the role of astrocytes in information processing through dynamical coordination. Our findings suggest that the astrocytic feedback promotes synergetic influences in the neural communication, which is maximized when there is a balance between excess correlation and spontaneous spiking activity. The results were further linked with additional measures such as net synergy and mutual information. This result reinforces the idea that astrocytes have integrative properties in communication among neurons.

A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2 target genes and shows no toxicity up to 20 μM, which is more than an order of magnitude higher than its biologically active concentration. Cell viability, functional activity, and network connectivity between the elements of neuronal networks have been studied using a pairwise correlation analysis of the intracellular calcium fluctuations in the individual cells. An immediate treatment with 1 μM and 15 μM neuradapt right at the onset of hypoxia not only protects from the death, but also maintains the spontaneous calcium activity in nervous cells at the level of the intact cultures. A similar neuroprotective effect in the post-treatment scenario is observed for 15 μM, but not for 1 μM neuradapt. Network connectivity is better preserved with immediate treatment using 1 μM neuradapt than with 15 μM, which is still beneficial. Post-treatment with neuradapt did not restore the network connectivity despite the observation that neuradapt significantly increased cell viability at 1 μM and functional activity at 15 μM. The preservation of cell viability and functional activity makes neuradapt promising for further studies in a post-treatment scenario, since it can be combined with other drugs and treatments restoring the network connectivity of functionally competent cells.