Recurrent inhibition, wherein excitatory principal neurons stimulate inhibitory interneurons that feedback on the same principal cells, occurs ubiquitously in the brain. However, the regulation and function of recurrent inhibition are poorly understood in terms of the contributing interneuron subtypes as well as their effect on neural and cognitive outputs. In the Drosophila olfactory system, odorants activate olfactory sensory neurons (OSNs), which stimulate projection neurons (PNs) in the antennal lobe. Both OSNs and PNs activate local inhibitory neurons (LNs) that provide either feedforward or recurrent/feedback inhibition in the lobe. During olfactory habituation, prior exposure to an odorant selectively decreases the animal's subsequent response to the odorant. We show here that habituation occurs in response to feedback from PNs. Output from PNs is necessary for olfactory habituation and, in the absence of odorant, direct PN activation is sufficient to induce the odorant-selective behavioral attenuation characteristic of olfactory habituation. PN-induced habituation occludes further odor-induced habituation and similarly requires GABA A Rs and NMDARs in PNs, as well as VGLUT and cAMP signaling in the multiglomerular inhibitory local interneurons (LN1) type of LN. Thus, PN output is monitored by an LN subtype whose resultant plasticity underlies behavioral habituation. We propose that recurrent inhibitory motifs common in neural circuits may similarly underlie habituation to other complex stimuli.

Inducing beta-cell mass expansion in diabetic patients with the aim to restore glucose homeostasis is a promising therapeutic strategy. Although several in vitro studies have been carried out to identify modulators of beta-cell mass expansion, restoring endogenous beta-cell mass in vivo has yet to be achieved. To identify potential stimulators of beta-cell replication in vivo, we established transgenic zebrafish lines that monitor and allow the quantification of cell proliferation by using the fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. Using these new reagents, we performed an unbiased chemical screen, and identified 20 small molecules that markedly increased beta-cell proliferation in vivo. Importantly, these structurally distinct molecules, which include clinically-approved drugs, modulate three specific signaling pathways: serotonin, retinoic acid and glucocorticoids, showing the high sensitivity and robustness of our screen. Notably, two drug classes, retinoic acid and glucocorticoids, also promoted beta-cell regeneration after beta-cell ablation. Thus, this study establishes a proof of principle for a high-throughput small molecule-screen for beta-cell proliferation in vivo, and identified compounds that stimulate beta-cell proliferation and regeneration.

Multiple Sclerosis is associated with deficient serum 25 hydroxyvitamin D (25 (OH)D) level and cognitive impairment. The aim of this study is to evaluate cognitive performance in MS patients with deficient 25 (OH)D (<25 ng/ml) compared to patients with sufficient levels (>35 ng/ml), then to evaluate the change in cognitive performance after 3 months of vitamin D3 oral replacement. Eighty-eight MS patients with relapsing remitting and clinically isolated type of MS, older than 18 years treated with interferon beta were enrolled. Cognitive testing was performed at baseline and at 3 months using the Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities (SDMT) and Brief Visuospatial Memory Test (BVMT-R). Serum 25 (OH)D was measured at baseline and at the end of the study. Vitamin D3 replacement improved the MS patients’ cognitive performance after 3 months on the MoCA and BVMT-Delayed Recall (DR). Sufficient serum 25 (OH)D level predicted better cognitive performance on the BVMT-DR at baseline (β: 1.74, p: <0.008) and 3 months (β: 1.93, p: <0.01) after adjusting for all measured confounding variables. Vitamin D3 replacement could improve cognitive performance in MS patients and make a significant difference in the patient’s quality of life.

Methamphetamine use has emerged as a risk factor for intracerebral hemorrhage (ICH). We aim to investigate the clinical characteristics and outcomes of methamphetamine-associated ICH (Meth-ICH) versus Non-Meth-ICH. Patients with ICH between January 2011 and December 2017 were studied. Meth-ICH and Non-Meth-ICH were defined by history of abuse and urine drug screen (UDS). The clinical features of the 2 groups were explored. Among the 677 consecutive patients, 61 (9.0%) were identified as Meth-ICH and 350 as Non-Meth ICH. Meth-ICH was more common in Hispanics (14.6%) and Whites (10.1%) as compared to Asians (1.2%). Patients with Meth-ICH were more often younger (51.2 vs. 62.2 years, p < 0.001), male (77.0% vs. 61.4.0%, p < 0.05), and smokers (44.3% vs. 13.4%, p < 0.001). Non-Meth-ICH was more likely to have history of hypertension (72.61% v. 59%, p < 0.05) or antithrombotic use (10.9% vs. 1.6%, p < 0.05). There was no significant difference in clinical severity, hospital length of stay (LOS), rate of functional independence (29.5% vs. 25.7%, p = 0.534), or mortality (18.0% vs. 24.6%, p = 0.267) between the 2 groups. Methamphetamine use was not an independent predictor of poor outcome. Despite difference in demographics, Meth-ICH is similar to Non-Meth ICH in hospital course and outcome. MethodsThis is a retrospective observational study. It was approved by the University of California Irvine Institutional Review Board (IRB) and the Ethics Committee. Informed consents were waived as part of the IRB approval. All methods in the study were performed in accordance with the relevant guidelines and regulations.Consecutive patients with spontaneous ICH at the University of California Irvine Comprehensive Stroke Center between January 1, 2011 and December 31, 2017 were identified by searching electronic medical records and the prospectively maintained American Heart Association (AHA)-Get With The Guidelines (GWTG)-Stroke Registry. ICH from cerebral aneurysm, arteriovenous malformation, brain tumors, coagulopathy, or trauma were excluded. Patients with Meth-ICH were identified by recorded history of methamphetamine use or a positive urine drug screen (UDS) at the time of admission. The UDS was performed using EMIT II Plus Amphetamines assay (1,000 ng/mL cutoff) with a sensitivity and specificity of 94.3% and 93.3%, respectively 21 . Those with a positive UDS while taking trazodone, Adderall, bupropion, or labetalol within 2 weeks of admission were excluded due to potential false-positive result 22 . Patients with no history of methamphetamine use and a negative UDS were included in Non-Meth-ICH group. Patients who denied history of drug abuse but had no UDS were excluded from the comparison analysis. All ICH patients were initially managed in the dedicated Neuroscience ICU with standard ICH order-set and clinical pathway by board-certified neurointensivists.The following information was abstracted from chart review and the AHA GWTG-Stroke Registry: age, gender, race, past medical history, the highest blood pressure (BP) lev...

Background Methamphetamine use is an emerging risk factor for intracerebral hemorrhage (ICH). The aim of this study was to investigate the use of urine drug screen (UDS) for identifying methamphetamine-associated ICH. Methods This is a retrospective, single-center study of consecutive patients hospitalized with spontaneous ICH from January 2013 to December 2017. Patients were divided into groups based on presence of UDS. The characteristics of patients with and without UDS were compared. Factors associated with getting UDS were explored using multivariable analyses. Results Five hundred ninety-six patients with ICH were included. UDS was performed in 357 (60%), and positive for methamphetamine in 44 (12.3%). In contrast, only 19 of the 357 patients (5.3%) had a documented history of methamphetamine use. Multivariable analysis demonstrated that patients screened with UDS were more likely to be younger than 45 (OR, 2.24; 95% CI, 0.26–0.78; p = 0.004), male (OR, 1.65; 95% CI, 0.44–0.84; p = 0.003), smokers (OR, 1.74; 95% CI, 1.09–2.77; p <  0.001), with history of methamphetamine use (OR, 10.48; 95% CI, 2.48–44.34; p <  0.001), without diabetes (OR 1.47; 95% CI, 0.471–0.975; p = 0.036), not on anticoagulant (OR, 2.20; 95% CI, 0.26–0.78; p = 0.004), with National Institutes of Health Stroke Scale (NIHSS) > 4 (OR, 1.92; 95%CI, 1.34–2.75; p <  0.001), or require external ventricular drain (EVD) (OR, 1.63; 95%CI, 1.07–2.47; p = 0.021. There was no significant difference in race (p = 0.319). Reported history of methamphetamine use was the strongest predictor of obtaining a UDS (OR,10.48). Five percent of patients without UDS admitted history of use. Conclusion UDS identified 12.3% of ICH patients with methamphetamine use as compared to 5.3% per documented history of drug use. There was no racial bias in ordering UDS. However, it was more often ordered in younger, male, smokers, with history of methamphetamine use, without diabetes or anticoagulant use.