MECHANISMS OF BRAIN RESILIENCY AND REPAIR
Unraveling Survival Strategies
Valina L. Dawson, Ph.D.
Dr. Dawson presented research results on preconditioning, a phenomenon in which brief episodes of sublethal insults induce robust protection against the deleterious effects of subsequent prolonged toxic challenges. Through differential screening using DAzLE and microarray analysis, Dr. Dawson and her team identified 31 potential preconditioning neuroprotective genes. Using a retrovirus expression cloning strategy, they identified another 29 confirmed neuroprotective and cytoprotective genes. Importantly, several of these genes are protective in neurons and fibroblasts, suggesting that there exist general survival mechanisms that could be exploited to spare cells at risk in the brain. Several genes among these sets of genes have been previously shown to be protective; roughly half are novel genes of unknown function. The characterization of these gene sets was discussed, along with a novel clone (932) that protects against excitotoxicity and oxidative stress in neurons, and PARP-1-dependent cytotoxicity induced by MNNG and oxidative stress in fibroblasts.
Novel Therapeutic Approaches for Neurodegenerative Disorders: Enhancing Brain Resiliency and Repair
Ole Isacson, M.D.
Dr. Ole Isacson presented his findings related to the search for compounds that can alter the development and health of a neuron. Several neurotrophic factors have shown impressive growth-inducing effects during development and protective effects in animal models of neurodegeneration, including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), transforming growth factor (TGF)-Ŗ, and basic fibroblast growth factor (bFGF). The identification of these factors helped pave the way for the detection and analyses of the effects of other molecules and compounds with specific trophic and tropic effects on subsets of neuronal populations. In Parkinsonís disease (PD), the major degenerative circuitry change resides in the dopaminergic and midbrain to basal ganglia connection and synapses. Dr. Isacson and his research team have demonstrated the molecular signals required for successful differentiation of embryonic stem cells into specific and functional midbrain dopamine (DA) neurons, which in turn can be transplanted in PD models. They found that fluorescence-activated cell sorting or equivalent cell-selection procedures are necessary steps for an adequate and appropriate surgical DA neuronal cell replacement-therapy method. The team also evaluated alternative methods of restoring DA cells to the circuitry by stimulation of the brainís endogenous stem cells by chemical and trophic factors. Future successful clinical trials using cell therapy for PD will require continued rational development, cell formulation, and the sophisticated use of stem cell technology.
Brain Repair and Rehabilitation: Behavioural and Pharmacological Treatments
Bryan Kolb, Ph.D.
Evidence is accumulating that at least partial functional restitution is possible after cortical injury. This functional improvement is associated with both compensatory changes in the remaining, intact neural circuitry, as well as with the generation of new circuitry. Such changes can be influenced by various factors, including experience, psychomotor stimulants, and neurotrophic factors. Recent work suggests that there may be a common mechanism that involves the upregulation of neurotrophic factors, such as FGF-2. Thus, stimulants such as nicotine and amphetamine also enhance recovery and again appear to work, at least in part, via their action on trophic factors. Preinjury administration of these compounds appears to be problematic, however, and may retard functional recovery and/or prevent later plastic changes. Finally, preliminary studies have shown that the mobilization of intrinsic stem cells may also be a way to stimulate functional recovery.
Estrogen Regulates the Structure and Function of Synapses in the Hippocampus
Catherine S. Woolley, Ph.D.
Fluctuating levels of the hormone estrogen produce dramatic plasticity of synaptic connections in the hippocampus, a brain region critical for spatial memory. Dr. Woolley and her laboratory research team have used a combination of anatomical and electrophysiological approaches to define a sequence of synaptic changes in the hippocampus induced by estrogen. They found that estrogen initially and transiently disinhibits hippocampal neurons, as evidenced by a decrease in GABAA receptor-mediated inhibitory postsynaptic currents. The presence of estrogen receptor immunoreactivity at some inhibitory synapses suggests that estrogen may act directly at synapses to regulate synaptic physiology. With longer exposure to estrogen, inhibition is restored to control levels and excitatory synaptic input to hippocampal neurons is enhanced. In addition, dendritic spine and synapse numbers are increased, sensitivity to the NMDA subtype of glutamate receptor-mediated synaptic input is enhanced, and the capacity for long-term potentiation is increased. These estrogen-induced changes in hippocampal synaptic connectivity are paralleled by differences in spatial working memory that may play a role in cognitive functions, which indirectly facilitate reproduction.