Long-term structural brain changes in adult rats after mild ischaemic stroke.

Preclinical studies of remote degeneration have largely focused on brain changes over the first few days or weeks after stroke. Accumulating evidence suggests that neurodegeneration occurs in other brain regions remote to the site of infarction for months and even years following ischaemic stroke. Brain atrophy appears to be driven by both axonal degeneration and widespread brain inflammation.

Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model.

Midbrain dopaminergic (DA) neurons include many subtypes characterized by their location, connectivity and function. Surprisingly, mechanisms underpinning the specification of A9 neurons [responsible for motor function, including within ventral midbrain (VM) grafts for treating Parkinson's disease (PD)] over adjacent A10, remains largely speculated. We assessed the impact of synaptic targeting on survival, integration, and phenotype acquisition of dopaminergic neurons within VM grafts generated from fetal tissue or human pluripotent stem cells (PSCs).

A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells.

Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients.

Hemispheric cortical atrophy and chronic microglial activation following mild focal ischemic stroke in adult male rats.

Animal modeling has played an important role in our understanding of the pathobiology of stroke. The vast majority of this research has focused on the acute phase following severe forms of stroke that result in clear behavioral deficits. Human stroke, however, can vary widely in severity and clinical outcome.

Histological characterization and quantification of newborn cells in the adult rodent brain.

This protocol describes the identification and characterization of newborn cells generated in the rodent brain after injury through birthdating with the thymidine analog 5-bromo-2'-deoxyuridine, followed by immunohistochemical labeling of fixed tissue sections. We also describe a software-assisted approach for automated detection and quantification of cells in large three-dimensional tissue volumes acquired using confocal microscopy. This approach facilitates the identification of low-frequency events that may be difficult to capture using manual counting methods, including stereology based on random sampling.

Longitudinal hippocampal volumetric changes in mice following brain infarction.

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke.

Focal Ischemic Injury to the Early Neonatal Rat Brain Models Cognitive and Motor Deficits with Associated Histopathological Outcomes Relevant to Human Neonatal Brain Injury.

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP.

The ischemic penumbra: From concept to reality.

The discovery that brain tissue could potentially be salvaged from ischaemia due to stroke, has led to major advances in the development of therapies for ischemic stroke. In this review, we detail the advances in the understanding of this area termed the ischaemic penumbra, from its discovery to the evolution of imaging techniques, and finally some of the treatments developed. Evolving from animal studies from the 70s and 80s and translated to clinical practice, the field of ischemic reperfusion therapy has largely been guided by an array of imaging techniques developed to positively identify the ischemic penumbra, including positron emission tomography, computed tomography and magnetic resonance imaging.

Investigation of nerve pathways mediating colorectal dysfunction in Parkinson's disease model produced by lesion of nigrostriatal dopaminergic neurons.

Background: Gastrointestinal (GI) dysfunction, including constipation, is a common non-motor symptom of Parkinson's disease (PD). The toxin 6-hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD-associated constipation caused by central application of 6OHDA remain unknown.

Ischemic Injury Does Not Stimulate Striatal Neuron Replacement Even during Periods of Active Striatal Neurogenesis.

Ischemic damage to the adult rodent forebrain has been widely used as a model system to study injury-induced neurogenesis, resulting in contradictory reports regarding the capacity of the postnatal brain to replace striatal projection neurons. Here we used a software-assisted, confocal approach to survey thousands of cells generated after striatal ischemic injury in rats and showed that injury fails not only to stimulate production of new striatal projection neurons in the adult brain but also to do so in the neonatal brain at early postnatal ages not previously explored. Conceptually this is significant, because it shows that even during periods of active striatal neurogenesis, injury is not a sufficient stimulus to promote replacement of these neurons.

Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease.

Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes.

Long-Term Motor Deficit and Diffuse Cortical Atrophy Following Focal Cortical Ischemia in Athymic Rats.

Development of new stroke therapies requires animal models that recapitulate the pathophysiological and functional consequences of ischemic brain damage over time-frames relevant to the therapeutic intervention. This is particularly relevant for the rapidly developing area of stem cell therapies, where functional replacement of circuitry will require maturation of transplanted human cells over months. An additional challenge is the establishment of models of ischemia with stable behavioral phenotypes in chronically immune-suppressed animals to allow for long-term survival of human cell grafts.

Isolation of LMX1a Ventral Midbrain Progenitors Improves the Safety and Predictability of Human Pluripotent Stem Cell-Derived Neural Transplants in Parkinsonian Disease.

Human pluripotent stem cells (hPSCs) are a promising resource for the replacement of degenerated ventral midbrain dopaminergic (vmDA) neurons in Parkinson's disease. Despite recent advances in protocols for the generation of vmDA neurons, the asynchronous and heterogeneous nature of the differentiations results in transplants of surprisingly low vmDA neuron purity. As the field advances toward the clinic, it will be optimal, if not essential, to remove poorly specified and potentially proliferative cells from donor preparations to ensure safety and predictable efficacy.

Local Injection of Endothelin-1 in the Early Neonatal Rat Brain Models Ischemic Damage Associated with Motor Impairment and Diffuse Loss in Brain Volume.

Cerebral palsy is an irreversible movement disorder resulting from cerebral damage sustained during prenatal or neonatal brain development. As survival outcomes for preterm injury improve, there is increasing need to model ischemic injury at earlier neonatal time-points to better understand the subsequent pathological consequences. Here we demonstrate a novel neonatal ischemic model using focal administration of the potent vasoconstrictor peptide, endothelin-1 (ET-1), in newborn rats.

Modelling the dopamine and noradrenergic cell loss that occurs in Parkinson's disease and the impact on hippocampal neurogenesis.

Key pathological features of Parkinson's Disease (PD) include the progressive degeneration of midbrain dopaminergic (DA) neurons and hindbrain noradrenergic (NA) neurons. The loss of DA neurons has been extensively studied and is the main cause of motor dysfunction. Importantly, however, there are a range of 'non-movement' related features of PD including cognitive dysfunction, sleep disturbances and mood disorders.

Over-Expression of Meteorin Drives Gliogenesis Following Striatal Injury.

A number of studies have shown that damage to brain structures adjacent to neurogenic regions can result in migration of new neurons from neurogenic zones into the damaged tissue. The number of differentiated neurons that survive is low, however, and this has led to the idea that the introduction of extrinsic signaling factors, particularly neurotrophic proteins, may augment the neurogenic response to a level that would be therapeutically relevant. Here we report on the impact of the relatively newly described neurotrophic factor, Meteorin, when over-expressed in the striatum following excitotoxic injury.