Inducible targeting of CNS astrocytes in Aldh1/1-CreERT2 BAC transgenic mice

Background: Studying astrocytes in higher brain functions has been hampered by the lack of genetic tools for the efficient expression of inducible Cre recombinase throughout the CNS, including the neocortex. Methods: Therefore, we generated BAC transgenic mice, in which CreERT2 is expressed under control of the Aldh1l1 regulatory region. Results: When crossbred to Cre reporter mice, adult Aldh1l1-CreERT2 mice show efficient gene targeting in astrocytes. No such Cre-mediated recombination was detectable in CNS neurons, oligodendrocytes, and microglia. As expected, Aldh1l1-CreERT2 expression was evident in several peripheral organs, including liver and kidney. Conclusions: Taken together, Aldh1l1-CreERT2 mice are a useful tool for studying astrocytes in neurovascular coupling, brain metabolism, synaptic plasticity and other aspects of neuron-glia interactions

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes

Multiscale fluctuations in nuclear response

The nuclear collective response is investigated in the framework of a doorway picture in which the spreading width of the collective motion is described as a coupling to more and more complex configurations. It is shown that this coupling induces fluctuations of the observed strength. In the case of a hierarchy of overlapping decay channels, we observe Ericson fluctuations at different scales. Methods for extracting these scales and the related lifetimes are discussed. Finally, we show that the coupling of different states at one level of complexity to some common decay channels at the next level, may produce interference-like patterns in the nuclear response. This quantum effect leads to a new type of fluctuations with a typical width related to the level spacing.Comment: 34 Latex pages including 6 figures (submitted to Phys. Rev. C

Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2

Nedd4-2 is an E3 ubiquitin ligase, missense mutation of which is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity, and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy

Fine structure of the isoscalar giant quadrupole resonance in 40Ca due to Landau damping?

The fragmentation of the Isoscalar Giant Quadrupole Resonance (ISGQR) in 40Ca has been investigated in high energy-resolution experiments using proton inelastic scattering at E_p = 200 MeV. Fine structure is observed in the region of the ISGQR and its characteristic energy scales are extracted from the experimental data by means of a wavelet analysis. The experimental scales are well described by Random Phase Approximation (RPA) and second-RPA calculations with an effective interaction derived from a realistic nucleon-nucleon interaction by the Unitary Correlation Operator Method (UCOM). In these results characteristic scales are already present at the mean-field level pointing to their origination in Landau damping, in contrast to the findings in heavier nuclei and also to SRPA calculations for 40Ca based on phenomenological effective interactions, where fine structure is explained by the coupling to two-particle two-hole (2p-2h) states.Comment: Phys. Lett. B, in pres

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies