Significance Statement Astrocytes are a critical component of the neural network in the suprachiasmatic nucleus (SCN) required for the generation of precise circadian rhythms. We hypothesized that postsynaptic SCN neurons recruit astrocytes via endocannabinoid signaling to modulate presynaptic GABA release. We demonstrate, using a combination of approaches including whole-cell patch-clamp electrophysiology, GCaMP6 calcium imaging in astrocytes, pharmacology, and manipulation of intracellular signaling cascades using designer receptors exclusively activated by designer drug (DREADD) technology, that SCN neurons release cannabinoids that activate astrocyte intracellular Ca 2ϩ signaling pathways to modulate GABA neurotransmission via adenosine. In addition to unraveling this novel signaling cascade in the SCN, we demonstrate that both CB1 receptor activation and adenosine phase advance the molecular circadian clock, suggesting an important role for astrocytes in modulating clock timing.

The retina encodes environmental light intensity to drive innate physiological responses. The synaptic basis of such coding remains obscure. Intrinsically photosensitive retinal ganglion cells (ipRGCs) are the only retinal output neurons stably encoding intensity. They do so even without their melanopsin photopigment, so specializations in their synaptic drive from bipolar cells (BCs) must also contribute. Here, we shed new light on mechanisms responsible for this unique intensity-coding drive. By ultrastructural reconstruction, we show that specific BC types and unusual ribbon synapses carry photoreceptor signals to ipRGCs. By glutamate imaging and electrophysiology, we show that their light responses are unusually persistent. Still, we find that virtually all BCs encode intensity. Intensity coding becomes restricted to ipRGCs primarily because other RGCs filter out steady-state intensity signals postsynaptically. Thus, neural 'pinholes' in global, persistent neural 'masking' allow intensity signals to be encoded by ipRGCs and sent to specific centers of the visual brain.

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The role of neoadjuvant chemoradiotherapy and/or chemotherapy (neoCHT) in patients with pancreatic ductal adenocarcinoma (PDAC) is poorly defined. We hypothesized that patients who underwent neoadjuvant therapy (NAT) would have improved systemic therapy delivery, as well as comparable perioperative complications, compared to patients undergoing upfront resection. This is an IRB-approved retrospective study of potentially resectable PDAC patients treated within an academic quaternary referral center between 2011 and 2018. Data were abstracted from the electronic medical record using an institutional cancer registry and the National Surgical Quality Improvement Program. Three hundred and fourteen patients were eligible for analysis and eighty-one patients received NAT. The median overall survival (OS) was significantly improved in patients who received NAT (28.6 vs. 20.1 months, p = 0.014). Patients receiving neoCHT had an overall increased mean duration of systemic therapy (p < 0.001), and the median OS improved with each month of chemotherapy delivered (HR = 0.81 per month CHT, 95% CI (0.76–0.86), p < 0.001). NAT was not associated with increases in early severe post-operative complications (p = 0.47), late leaks (p = 0.23), or 30–90 day readmissions (p = 0.084). Our results show improved OS in patients who received NAT, driven largely by improved chemotherapy delivery, without an apparent increase in early or late perioperative complications compared to patients undergoing upfront resection.