Inflammation is a normal response of the organism to infection, injury, and trauma. In this framework, inflammation can be viewed as a complicated series of local immune responses that serve to deal with a threat to the cellular microenvironment. Such reactions are initiated to neutralize invading pathogens, repair injured tissues, and promote wound healing to restore tissue homeostasis. A Significant contributions from neuroinflammatory responses have been implied in various neurodegenerative diseases such as Parkinsons Disease, Alzheimers Disease, and Huntington Disease, as well as brain injury including trauma and stroke. However, identifying and characterizing the neuroprotective versus the injurious aspects of the response still remains a major illusive question. While neuroinflammation has been considered a mediator of secondary damage, the local immune response also has beneficial effects on the traumatized tissue. Microglia serve as the resident mononuclear phagocytes of the brain and are highly heterogeneous within the healthy CNS. They comprise only 10% of the total cell population of the brain;yet, they have multiple morphological and potential functional profiles depending on their environment. Characterization of functional differences between the various microglia structural phenotypes continues to be a major question in addressing the functional role of these cells. One limitation has been with the lack of a good model system where the brain macrophage response is limited to resident microglia and does not involve infiltrating macrophages. This has also served as a limitation in both understanding the role of a brain macrophage response in neurodegenerative disease and developing successful therapeutic approaches. We have established such a model in the mouse by utilizing a known neurotoxicant, the organometal, trimethyltin (TMT), to create focal sites of injury in the absence of an altered blood brain barrier and infiltration of blood borne cells. Using this model we are able to examine the role of microglia in the cell death and clearance of dentate granule neurons as well as their role in promoting survival of hippocampal pyramidal neurons susceptible to ischemia. The fact that these cells are spared in our TMT model of injury allows us to examine potential critical events occurring in these neurons to promote survival. The identification of such factors would then be beneficial in translating these events to a therapeutic intervention under ischemic conditions such as stroke. A distinction between the source of the insult or injury becomes important in that CA1 neurons are involved in the pathology of Alzheimers disease and in a mouse model of tauopathy in the absence of ischemia. Thus, understanding the endogenous mechanisms utilized by CA1 neurons to survive within an injured environment can lead to therapeutic intervention strategies to minimize cell loss. Using a slice culture model, we have examined the contribution of microglia to the neuronal cell death associated with expression of the mutant Huntingtin gene. In this model we have demonstrated an early neuroprotective effect of microglia and a role for microglia in the clearance of damaged neurites. The elevated number of microglia within the substantia nigra in the normal brain has lead to a speculation associating chronic neuroinflammation and loss of dopamine neurons in Parkinson's Disease. This population of neurons is also sensitive to environmental pesticide exposure. Understanding the impact of chronic neuroinflammation has been limited by the lack of a relevant animal model. To address this question, we utilized the HIV transgenic rat to examine changes in the inflammatory status of distinct brain regions and to correlate this with the morphological phenotype of microglia and any evidence of neuronal death (1).
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