Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine

Integral field spectroscopy of 2.0 < z < 2.7 submillimetre galaxies : gas morphologies and kinematics

We present 2D, integral field spectroscopy covering the rest-frame wavelengths of strong optical emission lines in nine submillimetre luminous galaxies (SMGs) at 2.0 < z < 2.7. The Gemini-North/Near-Infrared Integral Field Spectrograph (NIFS) and Very Large Telescope (VLT) Spectrograph for INtegral Field Observations in the Near Infrared (SINFONI) imaging spectroscopy allow the mapping of the gas morphologies and dynamics within the sources, and we measure an average Hα velocity dispersion of 〈σ〉 = 220 ± 80 km s−1 and an average half-light radius of 〈r1/2〉 = 3.7 ± 0.8 kpc. The dynamical measure, 〈Vobs/2σ〉 = 0.9 ± 0.1, for the SMGs is higher than in more quiescent star-forming galaxies at the same redshift, highlighting a difference in the dynamics of the two populations. The far-infrared star formation rates (SFRs) of the SMGs, measured using Herschel-SPIRE† far-infrared photometry, are on average 370 ± 90 M⊙ yr−1, which is ∼2 times higher than the extinction-corrected SFRs of the more quiescent star-forming galaxies. Six of the SMGs in our sample show strong evidence for kinematically distinct multiple components with average velocity offsets of 200 ± 100 km s−1 and average projected spatial offsets of 8 ± 2 kpc, which we attribute to systems in the early stages of major mergers. Indeed, all SMGs are classified as mergers from a kinemetry analysis of the velocity and dispersion field asymmetry. We bring together our sample with the seven other SMGs with integral field unit observations to describe the ionized gas morphologies and kinematics in a sample of 16 SMGs. By comparing the velocity and spatial offsets of the SMG Hα components with subhalo offsets in the Millennium Simulation data base, we infer an average halo mass for SMGs in the range of 13 < log (M[h−1 M⊙]) < 14. Finally, we explore the relationship between the velocity dispersion and star formation intensity within the SMGs, finding that the gas motions are consistent with the Kennicutt–Schmidt law and a range of extinction corrections, although they might also be driven by the tidal torques from merging or even the star formation itself

More May Not be Better: Enhanced Spacecraft Shielding May Exacerbate Cognitive Decrements by Increasing Pion Exposures during Deep Space Exploration.

The pervasiveness of deep space radiation remains a confounding factor for the transit of humans through our solar system. Spacecraft shielding both protects astronauts but also contributes to absorbed dose through galactic cosmic ray interactions that produce secondary particles. The resultant biological effects drop to a minimum for aluminum shielding around 20 g/cm2 but increase with additional shielding. The present work evaluates for the first time, the impact of secondary pions on central nervous system functionality. The fractional pion dose emanating from thicker shielded spacecraft regions could contribute up to 10% of the total absorbed radiation dose. New results from the Paul Scherrer Institute have revealed that low dose exposures to 150 MeV positive and negative pions, akin to a Mars mission, result in significant, long-lasting cognitive impairments. These surprising findings emphasize the need to carefully evaluate shielding configurations to optimize safe exposure limits for astronauts during deep space travel

Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.

Ultra-high dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising anti-tumor efficacy compared to conventional dose rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. Cohorts of three-week-old male and female C57Bl/6 mice exposed to hypofractionated (2×10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months post-treatment. Animals were sacrificed 6 months post-irradiation and tissues analyzed for neurological and cerebrovascular decrements. The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin) and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and a preservation of cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlight its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature

Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.

BackgroundUltra-high dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising anti-tumor efficacy compared to conventional dose rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes.MethodsCohorts of three-week-old male and female C57Bl/6 mice exposed to hypofractionated (2×10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months post-treatment. Animals were sacrificed 6 months post-irradiation and tissues analyzed for neurological and cerebrovascular decrements.ResultsThe neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin) and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and a preservation of cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels.ConclusionsHypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlight its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature