Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been ...increasingly recognized as an "accomplice." According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination. Astrocytes within brain regions that are implicated in drug addiction exhibit dynamic changes in activity upon exposure to cocaine and subsequently undergo adaptive changes themselves during chronic drug exposure. Recent results have identified several key astrocytic signaling pathways that are involved in cocaine-induced synaptic and circuit adaptations. In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse. We also consider the therapeutic potential of targeting astrocytic substrates to ameliorate drug-induced neuroplasticity for behavioral benefits. While primarily focusing on cocaine-induced astrocytic responses, we also include brief discussion of other drugs of abuse where data are available.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to ...depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.
•A large-scale multi-brain region transcriptomic cohort to probe stress susceptibility•Reveals susceptible and resilient transcriptional networks across brain regions•Identifies many novel hub genes that emerge in susceptible mice•In vivo validation of key regulators at molecular, synaptic, and behavioral levels
Molecular mechanisms of dysregulated circuit function in depression are poorly understood. Employing integrative network analysis of large-scale RNA sequencing data, Bagot et al. identify distinct inter-regional transcriptional networks regulating depression susceptibility versus resilience. In vivo validation of networks suggests novel antidepressant targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we ...focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become "unsilenced" by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent ...about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression.
•LncRNAs are robustly altered in depression in a sex- and brain site-specific manner•LINC00473 is downregulated in cortex of depressed females but not males•LINC00473 expression in mouse cortex promotes stress resilience in females only•LINC00473 regulates gene expression and physiology in a sex-specific manner
Issler et al. demonstrate that long non-coding RNAs are robustly regulated in the brains of postmortem depressed humans in a brain site- and sex-specific manner. LINC00473 is highlighted as key regulator of mood in females only, where it acts in prefrontal cortex by regulating gene expression, neurophysiology, and behavior.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study presents a data-driven approach to identifying anomaly-sensitive parameters through a multiscale, multifaceted analysis of simulated respiratory flows. The anomalies under consideration ...include a pharyngeal model with three levels of constriction (M1, M2, M3) and a flapping uvula with two types of kinematics (K1, K2). Direct numerical simulations (DNS) were implemented to solve the wake flows induced by a flapping uvula; instantaneous vortex images, as well as pressures and velocities at seven probes, were recorded for twelve cycles. Principal component analysis (PCA), wavelet-based multifractal spectrum and scalogram, and Poincaré mapping were implemented to identify anomaly-sensitive parameters. The PCA results demonstrated a reasonable periodicity of instantaneous vortex images in the leading vector space and revealed distinct patterns between models with varying uvula kinematics (K1, K2). At higher PCA ranks, the periodicity gradually decays, eventually transitioning to a random pattern. The multifractal spectra and scalograms of pressures in the pharynx (P6, P7) show high sensitivity to uvula kinematics, with the pitching mode (K2) having a wider spectrum and a left-skewed peak than the heaving mode (K1). Conversely, the Poincaré maps of velocities and pressures in the pharynx (Vel6, Vel7, P6, P7) exhibit high sensitivity to pharyngeal constriction levels (M1–M3), but not to uvula kinematics. The parameter sensitivity to anomaly also differs with the probe site; thus, synergizing measurements from multiple probes with properly extracted anomaly-sensitive parameters holds the potential to localize the source of snoring and estimate the collapsibility of the pharynx.
Interleukin-6 (IL-6) blockers including tocilizumab and sarilumab were approved by the U.S. Food and Drug Administration (FDA) in June 2021 for the treatment of patients with moderate to severe ...COVID-19. The use of sarilumab or tocilizumab in COVID-19 patients has been related to a reduction in mortality compared to standard care. Recent evidence has emerged concerning drug-induced liver injury (DILI) after sarilumab or tocilizumab applications in COVID-19 patients.
The study aimed to estimate DILI associated with sarilumab or tocilizumab in treating moderate to severe patients infected with SARS-Cov-2.
We conducted a retrospective pharmacovigilance study by data mining of the FDA's adverse event reporting systems (FAERS) database from the first quarter of 2004 to the fourth quarter of 2021 in confirmed COVID-19 patients. We analyzed DILI cases associated with tocilizumab or sarilumab in treating COVID-19 patients from the FAERS during this period. Disproportionality analysis and Bayesian analysis of COVID-19 patients were utilized for case analysis, and we also next compared the onset time and fatality rates of DILI following tocilizumab or sarilumab.
A total of 275 cases of TCZ or SAR-related DILI reports were extracted. A total of 192 AEs cases were related to tocilizumab (TCZ), and 83 were related to sarilumab (SAR). In patients treated with TCZ, most were < 75 years old (51.57%), with more male than female (46.35% vs. 13.02%). The correlation between IL-6 receptor antagonists and DILI was stronger in SAR (ROR = 12.94; 95%CI 9.6-17.44) than in TCZ (ROR = 1.33; 95%CI 1.14-1.55). The onset time of DILI was different between TCZ and SAR, and a significant difference was observed in TCZ than SAR (P < 0.0001). A significant difference was observed in the mortality rate of TCZ and SAR (P = 0.0009). DILI associated with COVID-19 patients treated with TCZ appeared to have earlier onset-time (1(0-46) day) VS. SAR (3.5(0-27) day).
This study shows strict monitor ought to be paid for TCZ or SAR when used for COVID-19 patients with poor liver function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The nucleus accumbens (NAc) is a critical brain reward region that mediates the rewarding effects of drugs of abuse, including those of morphine and other opiates. Drugs of abuse induce widespread ...alterations in gene transcription and dendritic spine morphology in medium spiny neurons (MSNs) of the NAc that ultimately influence NAc excitability and hence reward‐related behavioral responses. Growing evidence indicates that within the NAc small GTPases are common intracellular targets of drugs of abuse where these molecules regulate drug‐mediated transcriptional and spine morphogenic effects. The RhoA small GTPase is among the most well‐characterized members of the Ras superfamily of small GTPases, and recent work highlights an important role for hippocampal RhoA in morphine‐facilitated reward behavior. Despite this, it remains unclear how RhoA pathway signaling in the NAc is affected by withdrawal from morphine. To investigate this question, using subcellular fractionation and subsequent protein profiling we examined the expression of key components of the RhoA pathway in NAc nuclear, cytoplasmic, and synaptosomal compartments during multiple withdrawal periods from repeated morphine administration. Furthermore, using in vivo viral‐mediated gene transfer, we determined the consequences of revealed RhoA pathway alterations on NAc MSN dendritic spine morphology. Our findings reveal an important role for RhoA signaling cascades in mediating the effects of long‐term morphine withdrawal on NAc MSN dendritic spine elimination.
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The expression profile of the RhoA network was examined in nuclear, cytosolic, and synaptosomal fractions from nucleus accumbens tissue following multiple withdrawal periods from repeated morphine administration. We found that short‐term morphine withdrawal increases the expression of a key component of the RhoA network in nuclear fractions, and this increase is directed toward specific actin cytoskeleton states. Long‐term morphine withdrawal, on the other hand, increases expression of a component of the RhoA network in synaptosomal fractions. These findings have implications for understanding the mechanisms that contribute to drug‐seeking behavior during opiate withdrawal.
Open Science: This manuscript was awarded with the Open Materials Badge.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Reliability for network-on-chips has been widely researched in last decades not only to support the rapid growing requirement of on-chip communication but also to address the challenge on reliability ...due to aggressive technology scaling. Simulation is the most common method to evaluate the capacity of reliability design but its cost is significant. Therefore, it is necessary to calculate the capacity for reliability of a design with light-weight mathematic models. A model for faults on links is described to calculate the delivery rate of networks based on a Markov chain fault model, fault-tolerant configuration and network traffic. The calculation results show accurate approximation of simulation results.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To achieve high reliability in on-chip networks, it is necessary to test the network as frequently as possible to detect physical failures before they lead to system-level failures. A main obstacle ...is that the circuit under test has to be isolated, resulting in network cuts and packet blockage which limit the testing frequency. To address this issue, we propose a comprehensive network-level approach which could test multiple routers simultaneously at high speed without blocking or dropping packets. We first introduce a reconfigurable router architecture allowing the cores to keep their connections with the network while the routers are under test. A deadlock-free and highly adaptive routing algorithm is proposed to support reconfigurations for testing. In addition, a testing sequence is defined to allow testing multiple routers to avoid dropping of packets. A procedure is proposed to control the behavior of the affected packets during the transition of a router from the normal to the testing mode and vice versa. This approach neither interrupts the execution of applications nor has a significant impact on the execution time. Experiments with the PARSEC benchmarks on an 8x8 NoC-based chip multiprocessors show only 3 percent execution time increase with four routers simultaneously under test.
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