Objective
In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and ...interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain.
Methods
CSF–ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2–3 months), middle‐aged (10–12 months), and old (18–20 months) wild‐type mice. The relationship between age‐related changes in the expression of the astrocytic water channel aquaporin‐4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence.
Results
Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid‐β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF–ISF exchange.
Interpretation
We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. Ann Neurol 2014;76:845–861
Microglia are involved in synaptic pruning both in development and in the mature CNS. In this study, we investigated whether microglia might further contribute to circuit plasticity by modulating ...neuronal recruitment from the neurogenic subventricular zone (SVZ) of the adult mouse striatum. We found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low expression of purinoceptors and lack of ATP-elicitable chemotaxis. Furthermore, the in vivo depletion of these microglia hampered the survival and migration of newly generated neuroblasts through the RMS to the olfactory bulb. SVZ and RMS microglia thus appear to comprise a functionally distinct class that is selectively adapted to the support and direction of neuronal integration into the olfactory circuitry. Therefore, this unique microglial subpopulation may serve as a novel target with which to modulate cellular addition from endogenous neural stem and progenitor cells of the adult brain.
Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural circuitry sculpture. Here, we addressed microglial functions in the subventricular zone (SVZ), the major postnatal neurogenic niche. Our results depict microglia as a conspicuous component of SVZ and its anterior extension, the rostral migratory stream, a pathway used by neuroblasts during their transit toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal progenitor survival and migration in the mammalian brain.
Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals ...deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.
Neurodegenerative diseases such as Alzheimer's are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a ...brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed.
Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30-180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion.
Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions.
Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.
Experimental advances in the study of neuroglia signaling have been greatly accelerated by the generation of transgenic mouse models. In particular, an elegant manipulation that interferes with ...astrocyte vesicular release of gliotransmitters via overexpression of a dominant-negative domain of vesicular SNARE (dnSNARE) has led to documented astrocytic involvement in processes that were traditionally considered strictly neuronal, including the sleep-wake cycle, LTP, cognition, cortical slow waves, depression, and pain. A key premise leading to these conclusions was that expression of the dnSNARE was specific to astrocytes. Inconsistent with this premise, we report here widespread expression of the dnSNARE transgene in cortical neurons. We further demonstrate that the activity of cortical neurons is reversibly suppressed in dnSNARE mice. These findings highlight the need for independent validation of astrocytic functions identified in dnSNARE mice and thus question critical evidence that astrocytes contribute to neurotransmission through SNARE-dependent vesicular release of gliotransmitters.
Three radiation belt flux dropout events seen by the Relativistic Electron Proton Telescope soon after launch of the Van Allen Probes in 2012 (Baker et al., 2013a) have been simulated using the ...Lyon‐Fedder‐Mobarry MHD code coupled to the Rice Convection Model, driven by measured upstream solar wind parameters. MHD results show inward motion of the magnetopause for each event, along with enhanced ULF wave power affecting radial transport. Test particle simulations of electron response on 8 October, prior to the strong flux enhancement on 9 October, provide evidence for loss due to magnetopause shadowing, both in energy and pitch angle dependence. Severe plasmapause erosion occurred during ~ 14 h of strongly southward interplanetary magnetic field Bz beginning 8 October coincident with the inner boundary of outer zone depletion.
Key Points
Simulations of electron flux 8 Oct 2012 produce dropout into L~5.8Magnetopause compression bounding the September storage ring formation modeledModel shows effects of magnetopause inward motion and ULF waves on electrons
Solar energetic protons (SEPs) have been shown to contribute significantly to the inner zone trapped proton population for energies <100 MeV and L > 1.3 (Selesnick et al., 2007, ...https://doi.org/10.1029/2006sw000275). The Relativistic Electron Proton Telescope (REPT) on the Van Allen Probes launched 30 August 2012 observed a double‐peaked (in L) inner zone population throughout the 7‐year lifetime of the mission. It has been proposed that a strong SEP event accompanied by a CME‐shock in early March 2012 provided the SEP source for the higher L trapped proton population, which then diffused radially inward to be observed by REPT at L ∼ 2. Here, we follow trajectories of SEP protons launched isotropically from a sphere at 7 Re in 15 s cadence fields from an Lyon‐Fedder‐Mobarry coupled to Rice Convection Model global magnetohydrodynamic (MHD) simulation driven by measured upstream solar wind parameters. The timescale of the interplanetary shock arrival is captured, launching a magnetosonic impulse propagating azimuthally along the dawn and dusk flanks inside the magnetosphere, shown previously to produce SEP trapping. The MHD‐test particle simulation uses Geostationary Operational Environmental Satellite (GOES) proton energy spectra to weight the initial radial profile required for the radial diffusion calculation over the following 2 years. GOES proton measurements also provide a dynamic outer boundary condition for radial diffusion. A direct comparison with REPT measurements 20 months following the trapping event in March 2012 supports this novel combination of short‐term and long‐term evolution of the newly trapped protons.
Key Points
Solar energetic proton (SEP) trapping explains double‐peaked inner zone structure observed by Van Allen Probes
Highest flux SEP event of Solar Cycle 24 produces trapping following arrival of a coronal mass ejection shock in March 2012
Magnetohydrodynamic‐test particle simulations followed by radial diffusion produce phase space density consistent with observed value at L ∼ 2
Observations of geomagnetically trapped 27–45 MeV protons following the November 2003 magnetic storm show a gradual intensity rise that is interpreted as a direct measurement of the cosmic ray albedo ...neutron decay (CRAND) source strength. The intensity rise is simulated by combining the detector response function with a model CRAND source, obtained by drift‐averaging neutron intensity from Monte Carlo simulation of cosmic ray interactions in the atmosphere. The simulation, for 2.4<L<2.7, matches the data within statistical uncertainties, verifying the CRAND model. Another simulation includes the effects of solar proton trapping and other known radiation belt processes. It further shows that the CRAND source was predominant, while radial diffusion and magnetic storm losses effected minor corrections in certain L ranges.
Key Points
CRAND proton radiation belt source strength is directly verified
Trapped protons were depleted by a magnetic storm, then steadily increased
Rate of increase agrees with a simulation of neutron albedo and proton trapping
The Van Allen Probes spacecraft have provided detailed observations of the energetic particles and fields environment for coronal mass ejection (CME)‐shock‐driven storms in 2012 to 2013 which have ...now been modeled with MHD test particle simulations. The Van Allen Probes orbital plane longitude moved from the dawn sector in 2012 to near midnight and prenoon for equinoctial storms of 2013, providing particularly good measurements of the inductive electric field response to magnetopause compression for the 8 October 2013 CME‐shock‐driven storm. An abrupt decrease in the outer boundary of outer zone electrons coincided with inward motion of the magnetopause for both 17 March and 8 October 2013 storms, as was the case for storms shortly after launch. Modeling magnetopause dropout events in 2013 with electric field diagnostics that were not available for storms immediately following launch have improved our understanding of the complex role that ULF waves play in radial transport during such events.
Key Points
MHD test particle simulations reproduce magnetopause loss seen by VA Probes
E‐field along satellite path agrees with measured shock impulse for 8 October 2013
Electrons are accelerated by prompt inward radial transport
Measurements of inner radiation belt protons have been made by the Van Allen Probes Relativistic Electron‐Proton Telescopes as a function of kinetic energy (24 to 76 MeV), equatorial pitch angle, and ...magnetic L shell, during late 2013 and early 2014. A probabilistic data analysis method reduces background from contamination by higher‐energy protons. Resulting proton intensities are compared to predictions of a theoretical radiation belt model. Then trapped protons originating both from cosmic ray albedo neutron decay (CRAND) and from trapping of solar protons are evident in the measured distributions. An observed double‐peaked distribution in L is attributed, based on the model comparison, to a gap in the occurrence of solar proton events during the 2007 to 2011 solar minimum. Equatorial pitch angle distributions show that trapped solar protons are confined near the magnetic equator but that CRAND protons can reach low altitudes. Narrow pitch angle distributions near the outer edge of the inner belt are characteristic of proton trapping limits.
Key Points
Radiation belt protons have been measured by Van Allen Probes/REPTHigh‐energy proton contamination is removed by a probabilistic analysis methodPitch angle distributions reveal CRAND and solar origins of trapped protons
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