Prenatal brain ischemia irreversibly destroys developing oligodendrocytes leading to hypomyelination and cognitive dysfunction that can remain through adulthood and so is an immense burden to affected patients, families and society. Enhanced neural activity from environmental enrichment (EE) can mitigate this loss. While the mechanisms for these effects are incompletely defined, recent literature and results from our laboratory indicate that tumor necrosis factor alpha (TNF-a) signaling is involved in both processes. TNF-a and its cell of origin, microglia, can exacerbate oligodendrocyte degeneration. Bacterial endotoxin lipopolysaccharide, which commonly worsens stroke in premature infants is mediated by TNF-a only when astrocytes are present, though again mechanisms for this interactive cellular affect are unknown. In contrast, our data show that low-level TNF-a, which rises with EE, is responsible for the related activitydependent neuroprotection and increased myelin content. This dual pattern of TNF-a behavior is consistent with hormesis (i.e, low-dose stimulation and high-dose inhibition) which takes the form here of acute, high dose toxicity and low-dose adaptive compensatory change via insulin growth factor-1 (IGF-1). Astrocytes are an intrinsic source of IGF-1 that vitalizes oligodendrocytes. Importantly, TNF-a can inhibit IGF-1 signaling. Thus, our general goal is to define the TNF-a/IGF-1 neural signaling involved in oligodendrocyte injury from prenatal brain ischemia and myelin recovery by increased neural activity.
The specific aims are to determine the role of TNF-a/IGF-1 signaling in:
AIM 1 : oligodendrocyte death from prenatal brain ischemia in vitro;
AIM 2 : activity-dependent myelin recovery after prenatal brain ischemia in vitro;
and AIM 3 : characterize the relation between TNF-a/IGF-1 signaling cascades to oligodendrocyte loss from prenatal brain ischemia and subsequent activity-dependent myelin recovery in vivo. PI4 rat hippocampal slice cultures and P7 CD-I mice will be used to model human prenatal ischemic brain injury using endpoints of hippocampal myelin content and "memory" that will be compared to measured, mimicked and modulated TNF-a/IGF-1 signaling cascade variables.
Prenatal stroke can lead to a life-long compromise in cognitive function involving brain cells called that produce the insulation (myelin) of nerve cells, which allows them to work properly. Importantly, environmental enrichment can reverse this loss with both effects due a cytokine, tumor necrosis factor alpha. This project will define how brain acutely and adaptively uses this cytokine to cause these dual effects.
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