A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

Abstract

Stroke affecting white matter accounts for up to 25% of clinical stroke presentations, occurs silently at rates that may be 5-10 fold greater, and contributes significantly to the development of vascular dementia. Few models of focal white matter stroke exist and this lack of appropriate models has hampered understanding of the neurobiologic mechanisms involved in injury response and repair after this type of stroke. The main limitation of other subcortical stroke models is that they do not focally restrict the infarct to the white matter or have primarily been validated in non-murine species. This limits the ability to apply the wide variety of murine research tools to study the neurobiology of white matter stroke. Here we present a methodology for the reliable production of a focal stroke in murine white matter using a local injection of an irreversible eNOS inhibitor. We also present several variations on the general protocol including two unique stereotactic variations, retrograde neuronal tracing, as well as fresh tissue labeling and dissection that greatly expand the potential applications of this technique. These variations allow for multiple approaches to analyze the neurobiologic effects of this common and understudied form of stroke. Video LinkThe video component of this article can be found at

Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury

“…Mice were randomly divided into Sham or L‐NIO groups, and WMS was induced as previously described (Appendix S1).…”

“…We therefore surmised that demyelination and axonal damage might give different CAPs profiles relative to the normal CAPs response. In the present study, we aimed to test this hypothesis by performing a comprehensive comparison of the CAPs response in the CC between demyelination induced by cuprizone and white matter stroke (WMS), which causes both demyelination and axonal damage. Evidence garnered from electrophysiological experiments was substantiated with EM and immunohistological analysis.…”

Foreign body responses in central nervous system mimic natural wound responses and alter biomaterial functions

“…Lysine-based DCHK and methioninesulfoxide based DCHMO are both well tolerated in vivo [8,25], but exhibit noticeably different FBRs. For comparison, mild or severe CNS wound responses were induced by injection of innocuous phosphate buffered saline (PBS), or N5-(1-iminoethyl)-l-ornithine (L-NIO) solution that creates a small focal ischemic stroke [27]. PBS, DCHMO, DCHK, or L-NIO were injected into caudate putamen (CP) of mouse forebrain (Fig.…”

Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

“…Subcortical white matter ischemic injury was induced as previously described (Hinman et al, 2013;Nunez et al, 2016). Animals (n = 4/grp) were sacrificed at 7 and 28 days post-stroke and analyzed for tissue outcomes.…”

“…Focal white matter lesions are characterized by dense loss of axons and oligodendrocytes, a robust inflammatory and astroglial response (Nunez et al 2016), with stroke-responsive OPCs invading the lesion and playing a key role in repair and remyelination ).…”