This application for an administrative supplement is in response to NOT-AG-18-008. The objective is to expand my parent grant RO1 AA023410 entitled ?Ethanol Exposure In Utero and Interneuronopathy in the Medial Prefrontal Cortex? toward interrogating the enduring consequences of prenatal alcohol exposure (PAE) as they relate to the propensity for developing Alzheimer?s disease and Alzheimer?s Disease-Related Dementia (AD/ADRD). Indeed, the literature is replete with epidemiologic discussions of alcohol consumption in the adult as a risk factor for AD/ADRD (e.g., https://pubs.niaaa.nih.gov/publications/arh25-4/299-306.htm). However, the consequences and biological underpinnings of PAE are decidedly different from those of adult alcohol consumption, and epidemiologic and preclinical studies have not addressed whether PAE may be a predisposing factor for AD/ADRD. In this light, whereas PAE has been linked to certain brain disorders with neurodevelopmental etiology, such as ADHD, the prospect of PAE as a potential risk factor for developing later- life, adult onset cognitive disorders, including AD/ADRD, has not been explored. The overarching aim is to expand and transition my parent grant toward developing a focus on investigating AD/ADRD. We ask whether PAE predisposes AD/ADRD by precipitating or exacerbating cognitive decline in a 3xTg-AD mouse model of AD (Muoz et al., 2015). My parent grant established a mouse model of maternal alcohol consumption that simulates a binge-type PAE early in gestation. Using this model, we demonstrated impaired behavioral flexibility as well as abnormal mPFC form and GABAergic function that persist in young adult mice (~2 months old) exposed prenatally to alcohol (Skorput et al., 2015; Skorput and Yeh, 2016). Impaired behavioral flexibility is one of the cardinal behavioral hallmarks of AD/ADRD. We propose to subject pregnant 3xTg-AD mice to the PAE paradigm established in my parent grant and assess learning/memory and behavioral flexibility as well as mPFC form and function in the 3xTg-AD progeny without and with PAE at 4 and 6 months of age, leveraging and employing the behavioral, neuroanatomical, electrophysiological assays also established in the parent grant. In so doing, we will accomplish two goals. First, we will determine whether the deficits in spatial learning/memory and behavioral flexibility that we detected in the 3xTg-AD mice as early as 6 months of age (Muoz et al., 2015) manifest themselves even earlier (at 4 months of age) with PAE and, if so, whether they are exacerbated at 6 months of age. Second, we will expand the parent grant by analyzing the long-term adverse behavioral, neuroanatomical and electrophysiological consequences of PAE beyond the young adult (~2 months of age) to include 6-month old male and female mice. Overall, this application will explore an innovative direction in AD research that is highly relevant to both NIA and NIAAA missions. It will yield critical preliminary data to spawn R01-based research programs that will contribute new vistas into the molecular, cellular, behavioral and epigenetic link between PAE and AD/ADRD.
Consumption of ethanol during pregnancy can lead to fetal alcohol spectrum disorders (FASD), hallmarked by varying degrees of life-long neurobehavioral and cognitive abnormalities in the offspring. Prenatal exposure to alcohol, such as occurs with Fetal Alcohol Spectrum Disorders, share many behavioral symptoms seen with Alzheimer?s disease and its related dementias. In this light, this administrative supplement asks if prenatal exposure to alcohol is a risk factor for Alzheimer?s disease and its related cognitive dementia. This is a significant public health and socioeconomic concern, one that has not been, but needs to be, addressed. The exploratory preclinical study proposed is highly significant and innovative. This research aligns perfectly with the NIA vision and with the NIAAA ?Alcohol Across the Lifespan? strategic plan and vision.
| Delatour, Laurie C; Yeh, Pamela W; Yeh, Hermes H (2018) Ethanol Exposure In Utero Disrupts Radial Migration and Pyramidal Cell Development in the Somatosensory Cortex. Cereb Cortex : |
| Skorput, Alexander G J; Yeh, Hermes H (2016) Chronic Gestational Exposure to Ethanol Leads to Enduring Aberrances in Cortical Form and Function in the Medial Prefrontal Cortex. Alcohol Clin Exp Res 40:1479-88 |
| Skorput, Alexander G J; Yeh, Hermes H (2015) Effects of ethanol exposure in utero on Cajal-Retzius cells in the developing cortex. Alcohol Clin Exp Res 39:853-62 |
| Skorput, Alexander G J; Gupta, Vivek P; Yeh, Pamela W L et al. (2015) Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero. J Neurosci 35:10977-88 |
