Fetal Alcohol Spectrum Disorder (FASD) is the leading cause of non-heritable mental disability. Global prevalence ranges from 1% to 7% of live births, with no available treatment. After gestational exposure to ethanol (EtOH), FASD patients struggle throughout life with many cognitive functions, including learning, memory, visual processing, attention, planning, language, and motor skills. This broad range of deficits suggests that EtOH may disrupt neural networks throughout the brain via a common mechanism. The acutely toxic effects of EtOH on developing neurons have been a primary focus of FASD research. Less is understood about effects on glia, particularly how glial interactions with surviving neurons may remain perturbed long-term after early-life EtOH exposure. Microglia, resident immune cells found throughout the brain, are the first responders to environmental insult, infection, or injury, and thus may be exquisitely sensitive to EtOH. Outside of pathology, microglia also have physiological roles that are critical for the maintenance and plasticity of neuronal networks throughout life. In the healthy brain, highly motile microglial processes frequently interact with neurons at synapses, influencing the physical remodeling and turnover of excitatory postsynaptic sites called dendritic spines. I will test the hypothesis that developmental EtOH exposure has long-term effects on the physiological functions of microglia, impairing microglial interactions with neurons, thus leading to deficits in neural network plasticity. I will examine this hypothesis in a mouse model of human third trimester high binge EtOH exposure, targeting the brain growth spurt (BGS). The BGS is period of intense synaptogenesis and initial formation of neuronal networks during which the developing brain may be particularly vulnerable to EtOH. Using monocular deprivation (MD) in adolescence to induce ocular dominance plasticity (ODP), I will measure shifts in neuronal responses from the deprived eye toward the non-deprived eye (Aim 1). Preliminary data show that the induction of ODP is impaired after BGS EtOH, indicating that early-life EtOH exposure causes a long-term deficit in activity-dependent synaptic plasticity. To explore mechanisms that underlie this deficit, I will investigate the effects of BGS EtOH on the structural dynamics of dendritic spines (Aim 2) as well as the physiological and immune behaviors of microglia (Aim 3). These complementary yet independent aims are designed to assess whether enduring impairments in plasticity during adolescence could stem from 1) alterations in the turnover of specific dendritic spine subpopulations 2) changes in microglial process motility 3) differences in the migratory response of microglia toward focal tissue injury 4) abnormal microglia-synapse interactions. The proposed research will improve our understanding of cognitive dysfunction in FASD, with the potential to inform novel treatment strategies.

Public Health Relevance

Each year in the U.S., alcohol consumption during pregnancy results in an estimated 40,000 new FASD patients who suffer life-long mental disability and have no options for treatment. Our research will use a mouse model to study whether exposure to high binge levels of alcohol during the human third trimester equivalent has long-term effects on neuronal network plasticity. This research will help elucidate mechanisms behind wide-spread cognitive dysfunction in FASD, informing new avenues for treatment development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA024346-02
Application #
9271806
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Powell, Elizabeth
Project Start
2016-05-01
Project End
2017-12-31
Budget Start
2017-05-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Wong, Elissa L; Lutz, Nina M; Hogan, Victoria A et al. (2018) Developmental alcohol exposure impairs synaptic plasticity without overtly altering microglial function in mouse visual cortex. Brain Behav Immun 67:257-278