Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1+ subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. Here, we establish that three genetic dopamine subtypes within the substantia nigra pars compacta each have a unique set of responses to rewards, aversive stimuli, accelerations and decelerations, and these signaling patterns are highly-correlated between somas and axons within subtypes. Remarkably, reward responses were not detected in one subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1β and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

In this essay, the authors explored Pinsker’s conception of two pandemics, as reflected in the concerns expressed about the future of women’s sport, prospects for female athletes, and the security of women leaders in sport as they emerged in articles published in national news sources. The purpose of this essay was to capture, in a limited way, how women’s sport concerns surfaced in the media in the aftermath of a forced industry shutdown; to gauge reactions, assess real and perceived threats; and to examine how and whether this crisis inspired positive thoughts about women’s sport opportunities for the future. Our work is based on the tracking of articles published in major news outlets about the impact of the pandemic on women’s sport from March 10, 2020, to May 25, 2020. Readings of the collected articles revealed several themes that fit within the two pandemics framework: reactions to the loss of momentum in women’s sport; fears regarding a reversal in gains made by women’s sport in the marketplace as competition for limited resources escalates; concerns about women’s sport participation decreasing due to cuts and delays in programs; and a focused commitment to gender equity and maintaining momentum, even in the face of significant headwinds.

MYC translocations in association with Epstein-Barr virus (EBV) infection are often observed in B-cell lymphomas. A subset of Burkitt lymphoma (BL) express EBV latent membrane protein 1 and 2A (LMP1 and LMP2A) in addition to the typical restricted EBV latent gene expression. EBV-associated DLBCL typically exhibit latency type II or III and express LMP1. Here, we investigate the role of LMP1 in MYC-driven lymphomagenesis in our murine model. λ-MYC mice develop tumors having a "starry-sky" appearance and have abnormal p53 expression that is also observed in human BL. LMP2A/λ-MYC double-transgenic mice develop tumors significantly faster than mice only expressing MYC. Similar to LMP2A/λ-MYC mice, LMP1/λ-MYC mice also have accelerated MYC-driven lymphomagenesis. As observed in LMP2A/λ-MYC mice, p27kip1 was degraded in LMP1/λ-MYC pretumor and tumor B cells. Coexpression of LMP1 and LMP2A resulted in enhancement of B cell proliferation. In contrast to LMP2A, the inhibition of Syk or CDK4/6 activity did not effectively inhibit LMP1-mediated MYC lymphomagenesis. Also in contrast to LMP2A, LMP1 did not lessen abnormal p53 expression in λ-MYC tumors. To investigate the significance of LMP1 expression in human BL development, we reanalyzed RNA-Seq data of primary human BL from previous studies. Interestingly, p53 mutations were less observed in LMP1-expressing BL although they were not significantly changed by EBV infection, indicating LMP1 may lessen p53 mutations in human primary BL. This suggests LMP1 effects in EBV-associated human BL varies from what we observe in our murine model. Finally our studies suggest a novel pathogenic role of LMP1 in lymphomagenesis.