Lack of a sensory input not only alters the cortical circuitry subserving the deprived sense, but also produces compensatory changes in the functionality of other sensory modalities. Here we report that visual deprivation produces opposite changes in synaptic function in primary visual and somatosensory cortices in rats, which are rapidly reversed by visual experience. This type of bidirectional cross-modal plasticity is associated with changes in synaptic AMPA receptor subunit composition.Loss of vision is usually accompanied by the increased functionality of other sensory modalities 1,2 . Systems-level analyses of cross-modal plasticity have revealed anatomical and functional rewiring of cortical circuits 3 . However, little is known about the cellular and molecular mechanisms underlying this type of plasticity. Here we examined whether manipulation of visual experience can induce bidirectional cross-modal plasticity of synaptic function in primary sensory cortices, and investigated the molecular mechanisms underlying this form of plasticity.To study cross-modal changes in synaptic function by visual deprivation, we dark-reared 4-week-old Long-Evans rats for a period of 1 week and then measured AMPA receptor (AMPAR)-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer 2/3 pyramidal neurons in slices from primary visual, somatosensory and auditory cortex (Supplementary Methods online). In visual cortex, dark rearing produced an increase in mESPC amplitude that was reversed by re-exposing the rats to lighted conditions for 2 d Correspondence should be addressed to H.-K.L. (hlee21@umd.edu). 4 Current address: Brain Science Institute, Riken, Wako City, Saitama, Japan. 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. AUTHOR CONTRIBUTIONSA.G. and B.J. conducted the electrophysiology experiments (mEPSC recordings and rectification measurements, respectively) and assisted in writing the manuscript; L.W.X. and L.S. performed the biochemistry experiments; A.K. oversaw the electrophysiology (rectification measurements), contributed to discussions on experimental designs and collaborated on manuscript writing; H.-K.L. designed the studies, oversaw experiments, contributed to the electrophysiology (mEPSC recordings) and biochemistry and wrote the manuscript. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. (normal-reared (NR): 10.7 ± 0.6 pA, n = 8; dark-reared (DR): 12.4 ± 0.4 pA, n = 16; re-exposure to light (L): 10.7 ± 0.4 pA, n = 13; analysis of variance (ANOVA): F 2,34 = 5.968, P < 0.01; Fig. 1a). Notably, we observed the opposite changes in somatosensory cortex, where 1 week of dark rearing decreased the amplitude of mEPSCs and 2 d of light exposure reversed this effect (NR: 13.8 ± 0.8 pA, n = 12; DR: 11.3 ± 0.7 pA, n = 16; L: 14.1 ± 0.9 pA, n = 16; ANOVA: F 2,40 = 3.830, P < 0.04; Fig. 1b). Changes in synaptic transmission by dark rearing seems to be general for pr...

Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca2+-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII− cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.

The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances.

Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.

BackgroundTraumatic Brain Injury (TBI) is disproportionally concentrated in low- and middle-income countries (LMICs), with the odds of dying from TBI in Uganda more than 4 times higher than in high income countries (HICs). The objectives of this study are to describe the processes of care and determine risk factors predictive of poor outcomes for TBI patients presenting to Mulago National Referral Hospital (MNRH), Kampala, Uganda.MethodsWe used a prospective neurosurgical registry based on Research Electronic Data Capture (REDCap) to systematically collect variables spanning 8 categories. Univariate and multivariate analysis were conducted to determine significant predictors of mortality.Results563 TBI patients were enrolled from 1 June– 30 November 2016. 102 patients (18%) received surgery, 29 patients (5.1%) intended for surgery failed to receive it, and 251 patients (45%) received non-operative management. Overall mortality was 9.6%, which ranged from 4.7% for mild and moderate TBI to 55% for severe TBI patients with GCS 3–5. Within each TBI severity category, mortality differed by management pathway. Variables predictive of mortality were TBI severity, more than one intracranial bleed, failure to receive surgery, high dependency unit admission, ventilator support outside of surgery, and hospital arrival delayed by more than 4 hours.ConclusionsThe overall mortality rate of 9.6% in Uganda for TBI is high, and likely underestimates the true TBI mortality. Furthermore, the wide-ranging mortality (3–82%), high ICU fatality, and negative impact of care delays suggest shortcomings with the current triaging practices. Lack of surgical intervention when needed was highly predictive of mortality in TBI patients. Further research into the determinants of surgical interventions, quality of step-up care, and prolonged care delays are needed to better understand the complex interplay of variables that affect patient outcome. These insights guide the development of future interventions and resource allocation to improve patient outcomes.

Delays for mild and moderate TBI patients were associated with mortality, suggesting that quality improvement interventions could target current triage practices. Future research should aim to understand the contributors to delays along the care continuum, opportunities for more effective resource allocation, and the need to improve prehospital logistical referral systems.