Kwan Ng

Subventricular zone-derived, newly generated neurons populate several olfactory and limbic forebrain regions.

Neurogenesis persists in several regions of the adult mammalian brain. Although the hippocampus and olfactory bulb are most commonly studied in the context of adult neurogenesis, there is an increasing body of evidence in support of neurogenesis occurring outside of these two regions. The current study expands on previous data by showing newborn neurons with a mature phenotype are located in several olfactory and limbic structures outside of the hippocampus and olfactory bulb, where we previously described doublecortin/bromodeoxyuridine immature neurons. Notably, newborn neurons with a mature neuronal phenotype are found in the olfactory tubercles, anterior olfactory nuclei, tenia tecta, islands of Calleja, amygdala, and lateral entorhinal cortex. The appearance of newborn neurons with a mature phenotype in these regions suggests that these structures are destinations, and that newborn neurons are not simply passing through these structures. In light of the increasing body of evidence for neurogenesis in these and other olfactory, limbic, and striatal structures, we hypothesize that brain regions displaying adult neurogenesis are functionally linked.

Olfactory enrichment enhances the survival of newly born cortical neurons in adult mice.

Neurogenesis persists in the adult rodent olfactory epithelium and olfactory bulbs. Recent studies suggest that neurogenesis might also occur in the adult rodent piriform cortex, the primary cortical projection site of the olfactory bulbs. To determine whether olfactory enrichment influences neurogenesis in the mouse piriform cortex, olfactory enrichment was used in combination with bromodeoxyuridine labeling. Quantification of the number of bromodeoxyuridine-labeled cells in the piriform cortex that double label for either the immature neuronal marker, doublecortin, or the mature neuronal marker, neuronal nuclei or NeuN, showed that olfactory enrichment increases the survival of newborn neurons in the piriform cortex. These results confirm that neurogenesis occurs in the piriform cortex of rodents and suggest that it may play a neuroplastic role there.

Prokineticin 2 Is a Target Gene of Proneural Basic Helix-Loop-Helix Factors for Olfactory Bulb Neurogenesis

Prokineticin 2, a cysteine-rich secreted protein, regulates diverse biological functions including the neurogenesis of olfactory bulb. Here we show that the PK2 gene is a functional target gene of proneural basic helix-loop-helix (bHLH) factors. Neurogenin 1 and MASH1 activate PK2 transcription by binding to E-box motifs on the PK2 promoter with the same set of E-boxes critical for another pair of bHLH factors, CLOCK and BMAL1, in the regulation of circadian clock. Our results establish PK2 as a common functional target gene for different bHLH transcriptional factors in mediating their respective functions.

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke Reopening a Postischemic Sensitive Period

Background and objective. Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity—a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Methods. Mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Results. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. Conclusions. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

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Recent successful endovascular stroke trials have provided unequivocal support for these therapies in selected patients with large-vessel occlusive acute ischemic stroke. In this piece, we briefly review these trials and their utilization of advanced neuroimaging techniques that played a pivotal role in their success through targeted patient selection. In this context, the unique challenges and opportunity for advancement in current stroke networks’ routine delivery of care created by these trials are discussed and recommendations to change current national stroke system guidelines are proposed.

DWI Lesion Patterns Predict Outcome in Stroke Patients with Thrombolysis.

Background: Lesion patterns may predict prognosis after acute ischemic stroke within the middle cerebral artery (MCA) territory; yet it remains unclear whether such imaging prognostic factors are related to patient outcome after intravenous thrombolysis. Aims: The aim of this study is to investigate the clinical outcome after intravenous thrombolysis in acute MCA ischemic strokes with respect to diffusion-weighted imaging (DWI) lesion patterns. Methods: Consecutive acute ischemic stroke cases of the MCA territory treated over a 7-year period were retrospectively analyzed. All acute MCA stroke patients underwent a MRI scan before intravenous thrombolytic therapy was included. DWI lesions were divided into 6 patterns (territorial, other cortical, small superficial, internal border zone, small deep, and other deep infarcts). Lesion volumes were measured by dedicated imaging processing software. Favorable outcome was defined as modified Rankin scale (mRS) of 0-2 at 90 days. Results: Among the 172 patients included in our study, 75 (43.6%) were observed to have territorial infarct patterns or other deep infarct patterns. These patients also had higher baseline NIHSS score (p < 0.001), a higher proportion of large cerebral artery occlusions (p < 0.001) and larger infarct volume (p < 0.001). Favorable outcome (mRS 0-2) was achieved in 89 patients (51.7%). After multivariable analysis, groups with specific lesion patterns, including territorial infarct and other deep infarct pattern, were independently associated with favorable outcome (OR 0.40; 95% CI 0.16-0.99; p = 0.047). Conclusions: Specific lesion patterns predict differential outcome after intravenous thrombolysis therapy in acute MCA stroke patients.

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

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.