BackgroundWorldwide, the vast majority of people have been impacted by COVID-19. While millions of individuals have become infected, billions of individuals have been asked or required by local and national governments to change their behavioral patterns. Previous research on epidemics or traumatic events suggest this can lead to profound behavioral and mental health changes, but rarely are researchers able to track these changes with frequent, near real-time sampling or compare these to previous years of data on the same individuals.ObjectivesWe seek to answer two overarching questions by combining mobile phone sensing and self-reported mental health data among college students participating in a longitudinal study for the past two years. First, have behaviors and mental health changed in response to the COVID-19 pandemic as compared to previous time periods within the same participants? Second, did behavior and mental health changes track the relative news coverage of COVID-19 in the US media?MethodsBehaviors were measured using the StudentLife mobile smartphone sensing app. Depression and anxiety were assessed using weekly self-reported Ecological Momentary Assessments (EMAs). Differences in behaviors and self-reported mental health collected during the Winter 2020 term (the term in which the coronavirus pandemic started), as compared to prevous terms in the same cohort, were modeled using mixed linear models.ResultsDuring the initial COVID-19 impacted academic term (Winter 2020), individuals were more sedentary and reported increased anxiety and depression symptoms (P<.001), relative to the previous academic terms and subsequent academic breaks. Interactions between the Winter 2020 term and week of academic term (linear and quadratic) were significant. In a mixed linear model, phone usage, number of locations visited, and week of the term, were strongly associated with increased coronavirus-related news. When mental health metrics (e.g., depression and anxiety) were added to the previous measures (week of term, number of locations visited, and phone usage), both anxiety (P<.001) and depression (P<.05) were significantly associated with coronavirus-related news.ConclusionsCompared with prior academic terms, individuals in Winter 2020 were more sedentary, anxious, and depressed. A wide variety of behaviors, including increased phone usage, decreased physical activity, and fewer locations visited, are associated with fluctuations in COVID-19 news reporting. While this large-scale shift in mental health and behavior is unsurprising, its characterization is particularly important to help guide the development of methods that could reduce the impact of future catastrophic events on the mental health of the population.

The best-known function of the serine protease tissue-type plasminogen activator (tPA) is as a thrombolytic enzyme. However, it is also found in structures of the brain that are highly vulnerable to hypoxia-induced cell death, where its association with neuronal survival is poorly understood. Here, we have demonstrated that hippocampal areas of the mouse brain lacking tPA activity are more vulnerable to neuronal death following an ischemic insult. We found that sublethal hypoxia, which elicits tolerance to subsequent lethal hypoxic/ischemic injury in a natural process known as ischemic preconditioning (IPC), induced a rapid release of neuronal tPA. Treatment of hippocampal neurons with tPA induced tolerance against a lethal hypoxic insult applied either immediately following insult (early IPC) or 24 hours later (delayed IPC). tPA-induced early IPC was independent of the proteolytic activity of tPA and required the engagement of a member of the LDL receptor family. In contrast, tPA-induced delayed IPC required the proteolytic activity of tPA and was mediated by plasmin, the NMDA receptor, and PKB phosphorylation. We also found that IPC in vivo increased tPA activity in the cornu ammonis area 1 (CA1) layer and Akt phosphorylation in the hippocampus, as well as ischemic tolerance in wild-type but not tPA-or plasminogen-deficient mice. These data show that tPA can act as an endogenous neuroprotectant in the murine hippocampus.

The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA (rtPA) promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.

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The release of the serine proteinase tissue-type plasminogen activator (tPA) from cerebral cortical neurons has a neuroprotective effect in the ischemic brain. Because excitotoxicity is a basic mechanism of ischemia-induced cell death here we investigated the effect of tPA on excitotoxin-induced neuronal death. We report that genetic overexpression of neuronal tPA or treatment with recombinant tPA renders neurons resistant to the harmful effects of an excitotoxic injury in vitro and in vivo. We found that at concentrations found in the ischemic brain tPA interacts with synaptic but not extrasynaptic NMDARs. This effect is independent of tPA’s proteolytic properties and leads to a rapid and transient phosphorylation of the extracellular signal regulated kinases 1 / 2 (ERK ½), with ERK ½-mediated activation of the cAMP response element binding protein (CREB) and induction of the neuroprotective CREB-regulated activating transcription factor 3 (Atf3). In line with these observations, Atf3 down-regulation abrogates the protective effect of tPA against excitotoxin-induced neuronal death. Our data indicate that tPA preferentially activates synaptic NMDARs via a plasminogen-independent mechanism turning on a cell signaling pathway that protects neurons from the deleterious effects of excitotoxicity.