Author ORCID Identifier

https://orcid.org/0000-0001-5525-4882?lang=en

Date of Award

Spring 3-21-2023

Document Type

Thesis (Ph.D.)

Department or Program

Integrative Neuroscience

First Advisor

Hermes Yeh

Abstract

Fetal Alcohol Spectrum Disorders are the most common non-genetic cause of neurodevelopmental disability worldwide. Individuals with Fetal Alcohol Spectrum Disorder experience clinical symptoms including differences in physical, cognitive and behavioral development beginning in early childhood, but continue to face challenges into adulthood. There is a critical need to examine the effects of prenatal ethanol exposure across early development, and to establish how the developmental effects of prenatal ethanol exposure may or may not progress in aging individuals. To contribute to these two areas, I asked how a binge-type prenatal ethanol exposure might affect: (1) early postnatal development of striatal neurons and, relate to the development of early motor behaviors over time, and (2) synaptic function in the medial prefrontal cortex, and affect the onset and severity of cognitive deficits in a transgenic mouse model of familial Alzheimer’s disease. I used whole-cell patch clamp electrophysiology to assess the functional and synaptic maturation of two populations of striatal neurons: striatal GABAergic interneurons and spiny striatal projection neurons, and the excitatory-inhibitory balance in deep layer medial prefrontal cortex pyramidal neurons. I found that prenatal ethanol exposure altered the postnatal developmental trajectory of striatal neurons in a sex-dependent manner, that coincided with sex-differences in the development of early motor behaviors, and morphological differences in striatal projection neurons. I also determined that prenatal ethanol exposure resulted in an earlier onset of deficits in GABAergic synaptic activity in cortical pyramidal neurons, that was an associated with a decreased number of parvalbumin expressing GABAergic interneurons, and an increase in intraneuronal APP/β-amyloid. These findings highlight the dynamic effects of prenatal ethanol exposure on synaptic function and behavioral outcomes during early development, and the lasting effects of prenatal ethanol exposure on neural circuits, modifying the aging process.

Original Citation

Tousley, A.R., Yeh, P.W.L., Yeh, H.H., 2022. Precocious emergence of cognitive and synaptic dysfunction in 3xTg-AD mice exposed prenatally to ethanol. Alcohol S0741-8329(22)00073–8. https://doi.org/10.1016/j.alcohol.2022.08.003

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