Fetal alcohol spectrum disorder (FASD) encompasses a range of developmental disorders that result from in utero exposure to alcohol. The prevalence of FASD varies widely, but may affect 2-5% of children with an economic burden 9 times that for children without FASD. These individuals are at a greater risk for cognitive dysfunction, dementia, and seizures. These risks may be related to impairment in reactivity of cerebral resistance arterioles (small vessel disease of the brain). However, there is an absence of information regarding cerebrovascular function in animal models/humans exposed to alcohol in utero. Our central hypothesis is that in utero exposure to alcohol impairs reactivity of cerebral arterioles, which leads to an increase the susceptibility of the brain to ischemic damage, and contributes to cognitive/memory/behavior dysfunction associated with FASD. We propose three specific aims.
In Aim #1 we will test the hypothesis that in utero exposure to alcohol impairs critical vasodilator pathways, but enhances vasoconstrictor responses, of cerebral arterioles, and thus contributes to small vessel diseases of the brain.
In Aim #2 we will test the hypothesis that in utero exposure to alcohol impairs responses of cerebral resistance arterioles via pathways that lead to an increase in oxidative stress. We propose to examine whether inhibition of pathways that contribute to oxidative stress restores impaired cerebral vascular function and whether this is then related to cognition/memory/behavior.
In Aim #3 we will test the hypothesis that in utero exposure to alcohol potentiates ischemia-induced brain damage in young and adult rats. We have reported a relationship between impaired dilation of cerebral arterioles during disease states and brain damage following cerebral ischemia/reperfusion. Our studies will investigate the novel concept that in utero exposure to alcohol will negatively impact indices of cerebral vascular function in young and adult animals, and thus may contribute to cognitive/memory/behavioral abnormalities observed in children and adults exposed to alcohol in utero. We will utilize state-of-the-art in vivo techniques to examine functional responses of cerebral arterioles, innovative molecular/biochemical techniques to examine cellular pathways critical to cerebral vascular function, and behavioral approaches to identify cognitive/memory/behavior decline to determine the impact of in utero exposure to alcohol on the brain during development. The information gained from these studies will lead to a new dogma regarding how in utero exposure to alcohol contributes to the etiology of cerebral vascular abnormalities in children and adults.
In utero exposure to alcohol remains a leading cause of cognitive, memory and behavioral abnormalities that persist into adulthood. The link between in utero exposure to alcohol and cognitive/memory/behavior dysfunction may relate to the effects of alcohol on the coupling of cerebral blood flow to metabolic demand (neurovascular coupling), which is governed by reactivity of cerebral resistance arterioles. The goal of our studies is to define the consequences of in utero exposure to alcohol on reactivity of cerebral arterioles and the susceptibility of the brain to ischemia-induced brain damage, and to then relate these findings to cognitive/memory/behavior dysfunction produced by in utero exposure to alcohol.
