Long-term dynamics of somatosensory activity in a stroke model of distal middle cerebral artery oclussion

A constant challenge in experimental stroke is the use of appropriate tests to identify signs of recovery and adverse effects linked to a particular therapy. In this study, we used a long-term longitudinal approach to examine the functional brain changes associated with cortical infarction in a mouse model induced by permanent ligation of the middle cerebral artery (MCA). Sensorimotor function and somatosensory cortical activity were evaluated with fault-foot and forelimb asymmetry tests in combination with somatosensory evoked potentials. The stroke mice exhibited both long-term deficits in the functional tests and impaired responses in the infarcted and intact hemispheres after contralateral and ipsilateral forepaw stimulation. In the infarcted hemisphere, reductions in the amplitudes of evoked responses were detected after contralateral and ipsilateral stimulation. In the intact hemisphere, and similar to cortical stroke patients, a gradual hyperexcitability was observed after contralateral stimulation but no parallel evidence of a response was detected after ipsilateral stimulation. Our results suggest the existence of profound and persistent changes in the somatosensory cortex in this specific mouse cortical stroke model. The study of evoked potentials constitutes a feasible and excellent tool for evaluating the fitness of the somatosensory cortex in relation to functional recovery after preclinical therapeutic intervention

MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF over expression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)(+) cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the per'-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.Peer reviewe

Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties

Secret Key Generation from Correlated Sources and Secure Link

In this paper, we study the problem of secret key generation from both correlated sources and a secure channel. We obtain the optimal secret key rate in this problem and show that the optimal scheme is to conduct secret key generation and key distribution jointly, where every bit in the secret channel will yield more than one bit of secret key rate. This joint scheme is better than the separation-based scheme, where the secure channel is used for key distribution, and as a result, every bit in the secure channel can only provide one bit of secret key rate.Comment: 5 pages, 1 figur

Selective ROCK2 inhibition in focal cerebral ischemia

Objective: Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known. Methods: We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective ROCK2 inhibitor KD025 (formerly SLx-2119) in focal cerebral ischemia models in mice. Results: KD025 dose-dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 h from stroke onset, and the efficacy was sustained for at least 4 weeks. KD025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic. KD025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection, KD025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform-nonselective ROCK inhibitors, KD025 did not cause significant hypotension, a dose-limiting side effect in acute ischemic stroke. Interpretation Altogether, these data show that KD025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating ROCK2 as the relevant isoform in acute ischemic stroke. Data suggest that selective ROCK2 inhibition has a favorable safety profile to facilitate clinical translation

Effective macroscopic dynamics of stochastic partial differential equations in perforated domains

An effective macroscopic model for a stochastic microscopic system is derived. The original microscopic system is modeled by a stochastic partial differential equation defined on a domain perforated with small holes or heterogeneities. The homogenized effective model is still a stochastic partial differential equation but defined on a unified domain without holes. The solutions of the microscopic model is shown to converge to those of the effective macroscopic model in probability distribution, as the size of holes diminishes to zero. Moreover, the long time effectivity of the macroscopic system in the sense of \emph{convergence in probability distribution}, and the effectivity of the macroscopic system in the sense of \emph{convergence in energy} are also proved

Regularization of point vortices for the Euler equation in dimension two

In this paper, we construct stationary classical solutions of the incompressible Euler equation approximating singular stationary solutions of this equation. This procedure is carried out by constructing solutions to the following elliptic problem [ -\ep^2 \Delta u=(u-q-\frac{\kappa}{2\pi}\ln\frac{1}{\ep})_+^p, \quad & x\in\Omega, u=0, \quad & x\in\partial\Omega, ] where $p>1$, $\Omega\subset\mathbb{R}^2$ is a bounded domain, $q$ is a harmonic function. We showed that if $\Omega$ is simply-connected smooth domain, then for any given non-degenerate critical point of Kirchhoff-Routh function $\mathcal{W}(x_1,...,x_m)$ with the same strength $\kappa>0$, there is a stationary classical solution approximating stationary $m$ points vortex solution of incompressible Euler equations with vorticity $m\kappa$. Existence and asymptotic behavior of single point non-vanishing vortex solutions were studied by D. Smets and J. Van Schaftingen (2010).Comment: 32page