Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer's Disease.

Research into Alzheimer's Disease (AD) describes a link between AD and the resident immune cells of the brain, the microglia. Further, this suspected link is thought to have underlying sex effects, although the mechanisms of these effects are only just beginning to be understood. Many of these insights are the result of policies put in place by funding agencies such as the National Institutes of Health (NIH) to consider sex as a biological variable (SABV) and the move towards precision medicine due to continued lackluster therapeutic options. The purpose of this review is to provide an updated assessment of the current research that summarizes sex differences and the research pertaining to microglia and their varied responses in AD.

Paranoia and belief updating during the COVID-19 crisis.

The COVID-19 pandemic has made the world seem less predictable. Such crises can lead people to feel that others are a threat. Here, we show that the initial phase of the pandemic in 2020 increased individuals' paranoia and made their belief updating more erratic. A proactive lockdown made people's belief updating less capricious. However, state-mandated mask-wearing increased paranoia and induced more erratic behaviour. This was most evident in states where adherence to mask-wearing rules was poor but where rule following is typically more common. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable. People who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines and the QAnon conspiracy theories. These beliefs were associated with erratic task behaviour and changed priors. Taken together, we found that real-world uncertainty increases paranoia and influences laboratory task behaviour.

Paranoia and belief updating during a crisis.

The 2019 coronavirus (COVID-19) pandemic has made the world seem unpredictable. During such crises we can experience concerns that others might be against us, culminating perhaps in paranoid conspiracy theories. Here, we investigate paranoia and belief updating in an online sample (N=1,010) in the United States of America (U.S.A). We demonstrate the pandemic increased individuals' self-rated paranoia and rendered their task-based belief updating more erratic. Local lockdown and reopening policies, as well as culture more broadly, markedly influenced participants' belief-updating: an early and sustained lockdown rendered people's belief updating less capricious. Masks are clearly an effective public health measure against COVID-19. However, state-mandated mask wearing increased paranoia and induced more erratic behaviour. Remarkably, this was most evident in those states where adherence to mask wearing rules was poor but where rule following is typically more common. This paranoia may explain the lack of compliance with this simple and effective countermeasure. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable, but at the same time predicted more rewards. In a follow-up study we found people who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines - again, mask attitude and conspiratorial beliefs were associated with erratic task behaviour and changed priors. Future public health responses to the pandemic might leverage these observations, mollifying paranoia and increasing adherence by tempering people's expectations of other's behaviour, and the environment more broadly, and reinforcing compliance.

Paranoia as a deficit in non-social belief updating.

Paranoia is the belief that harm is intended by others. It may arise from selective pressures to infer and avoid social threats, particularly in ambiguous or changing circumstances. We propose that uncertainty may be sufficient to elicit learning differences in paranoid individuals, without social threat. We used reversal learning behavior and computational modeling to estimate belief updating across individuals with and without mental illness, online participants, and rats chronically exposed to methamphetamine, an elicitor of paranoia in humans. Paranoia is associated with a stronger prior on volatility, accompanied by elevated sensitivity to perceived changes in the task environment. Methamphetamine exposure in rats recapitulates this impaired uncertainty-driven belief updating and rigid anticipation of a volatile environment. Our work provides evidence of fundamental, domain-general learning differences in paranoid individuals. This paradigm enables further assessment of the interplay between uncertainty and belief-updating across individuals and species.

Everyone has had fleeting concerns that others might be against them at some point in their lives. Sometimes these concerns can escalate into paranoia and become debilitating. Paranoia is a common symptom in serious mental illnesses like schizophrenia. It can cause extreme distress and is linked with an increased risk of violence towards oneself or others. Understanding what happens in the brains of people experiencing paranoia might lead to better ways to treat or manage it. Some experts argue that paranoia is caused by errors in the way people assess social situations. An alternative idea is that paranoia stems from the way the brain forms and updates beliefs about the world. Now, Reed et al. show that both people with paranoia and rats exposed to a paranoia-inducing substance expect the world will change frequently, change their minds often, and have a harder time learning in response to changing circumstances. In the experiments, human volunteers with and without psychiatric disorders played a game where the best choices change. Then, the participants completed a survey to assess their level of paranoia. People with higher levels of paranoia predicted more changes would occur and made less predictable choices. In a second set of experiments, rats were put in a cage with three holes where they sometimes received sugar rewards. Some of the rats received methamphetamine, a drug that causes paranoia in humans. Rats given the drug also expected the location of the sugar reward would change often. The drugged animals had harder time learning and adapting to changing circumstances. The experiments suggest that brain processes found in both rats, which are less social than humans, and humans contribute to paranoia. This suggests paranoia may make it harder to update beliefs. This may help scientists understand what causes paranoia and develop therapies or drugs that can reduce paranoia. This information may also help scientists understand why during societal crises like wars or natural disasters humans are prone to believing conspiracies. This is particularly important now as the world grapples with climate change and a global pandemic. Reed et al. note paranoia may impede the coordination of collaborative solutions to these challenging situations.

The influence of sample distribution on growth model output for a highly-exploited marine fish, the Gulf Corvina (Cynoscion othonopterus).

Estimating the growth of fishes is critical to understanding their life history and conducting fisheries assessments. It is imperative to sufficiently sample each size and age class of fishes to construct models that accurately reflect biological growth patterns, but this may be a challenging endeavor for highly-exploited species in which older fish are rare. Here, we use the Gulf Corvina (Cynoscion othonopterus), a vulnerable marine fish that has been persistently overfished for two decades, as a model species to compare the performance of several growth models. We fit the von Bertalanffy, Gompertz, logistic, Schnute, and Schnute-Richards growth models to length-at-age data by nonlinear least squares regression and used simple indicators to reveal biased data and ensure our results were biologically feasible. We then explored the consequences of selecting a biased growth model with a per-recruit model that estimated female spawning-stock-biomass-per-recruit and yield-per-recruit. Based on statistics alone, we found that the Schnute-Richards model described our data best. However, it was evident that our data were biased by a bimodal distribution of samples and underrepresentation of large, old individuals, and we found the Schnute-Richards model output to be biologically implausible. By simulating an equal distribution of samples across all age classes, we found that sample distribution distinctly influenced model output for all growth models tested. Consequently, we determined that the growth pattern of the Gulf Corvina was best described by the von Bertalanffy growth model, which was the most robust to biased data, comparable across studies, and statistically comparable to the Schnute-Richards model. Growth model selection had important consequences for assessment, as the per-recruit model employing the Schnute-Richards model fit to raw data predicted the stock to be in a much healthier state than per-recruit models employing other growth models. Our results serve as a reminder of the importance of complete sampling of all size and age classes when possible and transparent identification of biased data when complete sampling is not possible.

The CD40-autophagy pathway is needed for host protection despite IFN-Γ-dependent immunity and CD40 induces autophagy via control of P21 levels.

Autophagy degrades pathogens in vitro. The autophagy gene Atg5 has been reported to be required for IFN-γ-dependent host protection in vivo. However, these protective effects occur independently of autophagosome formation. Thus, the in vivo role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of Toxoplasma gondii dependent on the autophagy machinery. Infected CD40(-/-) mice failed to upregulate Beclin 1 in microglia/macrophages in vivo. Autophagy-deficient Beclin 1(+/-) mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40(-/-) mice exhibited impaired killing of T. gondii and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti-T. gondii activity and the generation of anti-T. gondii T cell immunity. CD40 upregulated Beclin 1 and triggered killing of T. gondii by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates in vivo protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.

Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway.

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipids 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (PEIPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine induce endothelial cells to synthesize chemotactic factors, such as interleukin 8 (IL-8). We have shown recently that Ox-PAPC-mediated induction of IL-8 transcription is independent of NF-kappaB activation, a major transcription factor utilized by cytokines and lipopolysaccharide for the induction of IL-8 transcription. In this study, we provide evidence for the role of c-src in Ox-PAPC and, specifically, PEIPC-mediated IL-8 induction. Ox-PAPC and its component phospholipids induced a rapid and transient phosphorylation of c-src Tyr418, a hallmark of c-src activation, in human aortic endothelial cells (HAEC). Ox-PAPC-mediated IL-8 protein synthesis in HAEC was inhibited by Src family kinase inhibitors, PP1 and PP2, but not by an inactive analog, PP3. Transient expression of plasmids containing C-terminal Src kinase or kinase-deficient dominant-negative c-src resulted in a 72 and 50% reduction in Ox-PAPC-induced IL-8 promoter activation in human microvascular endothelial cells, respectively. In contrast, overexpression of v-src kinase resulted in a 4-fold increase in IL-8 promoter activation, without inducing NF-kappaB promoter activation. Furthermore, treatment of HAEC with Ox-PAPC and its component PEIPC induced the activation of STAT3 by phosphorylating Tyr705, a feature of STAT3 activation. STAT3 is a known downstream effector of c-src. Ox-PAPC-induced activation of STAT3 resulted in the translocation of STAT3 from the cytoplasm of HAEC into their nuclear compartment. Transient expression of a dominant-negative STAT3beta construct in HMEC strongly inhibited IL-8 induction by Ox-PAPC. Taken together, these data demonstrate the role of the c-src kinase/STAT3 pathway in Ox-PAPC-mediated IL-8 expression in endothelial cells.

Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells.

The neurofibromatosis type 1 tumor suppressor protein neurofibromin, is a GTPase activating protein for H-, N-, K-, R-Ras and TC21/R-Ras2 proteins. We demonstrate that Schwann cells derived from Nf1-null mice have enhanced chemokinetic and chemotactic migration in comparison to wild-type controls. Surprisingly, this migratory phenotype is not inhibited by a farnesyltransferase inhibitor or dominant-negative (dn) (N17)H-Ras (which inhibits H-, N-, and K-Ras activation). We postulated that increased activity of R-Ras and/or TC21/R-Ras2, due to loss of Nf1, contributes to increased migration. Mouse Schwann cells (MSCs) express R-Ras and TC21/R-Ras2 and their specific guanine exchange factors, C3G and AND-34. Infection of Nf1-null MSCs with a dn(43N)R-Ras adenovirus (to inhibit both R-Ras and TC21/R-Ras2 activation) decreases migration by approximately 50%. Conversely, expression of activated (72L)TC21/R-Ras2, but not activated (38V)R-Ras, increases migration, suggesting a role of TC21/R-Ras2 activation in the migration of neurofibromin-deficient Schwann cells. TC21/R-Ras2 preferentially couples to the phosphatidylinositol 3-kinase (PI3-kinase) and MAP kinase pathways. Treatment with a PI3-kinase or MAP kinase inhibitor reduces Nf1-null Schwann cell migration, implicating these TC21 effectors in Schwann cell migration. These data reveal a key role for neurofibromin regulation of TC21/R-Ras2 in Schwann cells, a cell type critical to NF1 tumor pathogenesis.