Fetal Alcohol Spectrum Disorder (FASD) continues to pose a significant medical and societal problem in the United States and abroad, representing a leading preventable cause of severe intellectual and developmental disability. Neurodevelopmental damage resulting from fetal alcohol exposure causes a severe disruption in prefrontal and hippocampal neuroanatomy and function, and thus causes pervasive cognitive impairments in learning and memory dependent upon these structures. While alcohol-induced disruptions in hippocampal anatomy and function have been extensively explored in both animal models and humans, animal work examining prefrontal mechanisms of impaired cognition after developmental alcohol exposure is sparse. The proposed research seeks to bridge this gap by investigating prefrontal molecular and behavioral mechanisms of impaired cognition of FASD using a rodent model of FASD and a prefrontal-dependent behavioral paradigm. Our lab has demonstrated that a variant of contextual fear conditioning, the Context Preexposure Facilitation Effect (CPFE) is particularly sensitive to the disruption caused by developmental alcohol exposure (across different doses and exposure windows). In the CPFE, learning about the context, acquiring a context-shock association, and retrieving contextual fear are temporally separated across three days (context preexposure, immediate-shock training, and retention). Our lab has recently shown that the CPFE requires the medial prefrontal cortex during all three phases (configural learning/consolidation during context preexposure, consolidation of the context-shock association, and contextual fear expression). The current proposal will examine the downstream molecular mechanisms in the prefrontal cortex, and its interaction with the hippocampus, which may contribute to the cognitive dysfunction observed in the CPFE caused by neonatal alcohol exposure (PD4-9; 5.25g/kg/day) in Long-Evans rats. Using intra-mPFC pharmacological inactivation and quantitative real-time PCR (qPCR), Aim 1 will characterize the functional interaction between the prefrontal cortex and hippocampus in supporting configural learning and context memory formation on the preexposure day of the CPFE.
Aim 2 will determine whether alcohol-induced deficits in the CPFE reflect a disruption of configural/spatial encoding and consolidation (preexposure day) and/or other component processes of the CPFE. Behavioral data from alcohol-exposed animals will be accompanied by measurement of immediate early genes (IEGs) supporting long-term synaptic plasticity in the prefrontal cortex and hippocampus (c-Fos, Arc, BDNF, Egr-1). Finally, Aim 3 will attempt to reverse these neurobehavioral deficits (including disrupted IEG expression) by enhancing cholinergic signaling via systemic administration of physostigmine during the preexposure day of the CPFE. The proposed research will contribute significantly to advancing the current state of basic science on FASD research by characterizing prefrontal mechanisms of impaired cognition in a rodent model of FASD.
This F31 NRSA Predoctoral Fellowship application by Nicholas A. Heroux requests support to study the regional neurobiological and molecular mechanisms underlying impaired neurocognitive development in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). FASD represents an assortment of neurobehavioral deficits resulting from developmental alcohol exposure and is a leading preventable cause of severe intellectual and developmental disability in the United States and abroad. The research in this proposal will advance basic animal model FASD research, with the goal of elucidating neural mechanisms and efficacy of potential interventions in a manner that will inform the human condition.
| Heroux, Nicholas A; Osborne, Brittany F; Miller, Lauren A et al. (2018) Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE). Neurobiol Learn Mem 147:128-138 |
| Robinson-Drummer, P A; Chakraborty, T; Heroux, N A et al. (2018) Age and experience dependent changes in Egr-1 expression during the ontogeny of the context preexposure facilitation effect (CPFE). Neurobiol Learn Mem 150:1-12 |
| Robinson-Drummer, P A; Heroux, N A; Stanton, M E (2017) Antagonism of muscarinic acetylcholine receptors in medial prefrontal cortex disrupts the context preexposure facilitation effect. Neurobiol Learn Mem 143:27-35 |
| Heroux, Nicholas A; Robinson-Drummer, Patrese A; Sanders, Hollie R et al. (2017) Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning. Learn Mem 24:322-330 |
