UC Riverside

Prenatal ethanol exposure (PrEE) is a leading cause of preventable birth defects and neurobehavioral disorders; PrEE can lead to Fetal Alcohol Spectrum Disorders (FASD). Clinical profiles of patients with FASD indicate damage to the central nervous system (CNS), including the neocortex, may underlie the varied, cognitive deficits associated with FASD. Recent preclinical evidence has suggested that PrEE may induce epigenetic dysregulation in offspring, producing adverse heritable, transgenerational behavioral effects, however the neurobiological underpinnings remain unclear. Preventive or therapeutic treatments for FASD have not yet been discovered and need to reflect the neurobiological damage inflicted by PrEE as well as the abstinence-resistant population. Additionally, although much research has focused on maternal PrEE, much less is known about the impact of paternal ethanol exposure (PatEE) and how development of the neocortex may be disrupted by preconception alcohol use by fathers. The research presented within this dissertation attempts to fill these gaps in knowledge using three, distinct research designs and multi-level neurobiological and behavioral approaches. First, in Chapter 1, we assessed the full extent of behavioral disruptions that are passed several generations following PrEE and attempted to find novel mechanistic links within the CNS using a transgenerational mouse model of FASD. We found multi-modality behavioral abnormalities that extend several generations and novel CNS anomalies in directly exposed offspring. Second, in Chapter 2, we investigated how co-administration of choline could prevent PrEE-induced neurobehavioral deficits. We found choline has a robust protective effect on several parameters of neocortical development and behaviors that are normally disrupted by PrEE in a mouse model. Lastly, in Chapter 3, we described the impact of preconception ethanol exposure on early postnatal development of the neocortex in an novel PatEE mouse model. We found that PatEE induced several alterations within the developing CNS including altered cortical gene expression as well as patterns of early sensory area connectivity. Overall, the results gleaned from these studies provide key descriptive, mechanistic, and therapeutic information on the still unclear etiology of FASD, as well as novel information on how paternal alcohol use may impact future offspring. Conclusions drawn from this dissertation have clear implications for the substantial impact of alcohol on human health.