Impact of Prenatal Alcohol Exposure on CRF1R Mediated Neural Mechanisms and Social Behavior - PROJECT SUMMARY/ABSTRACT
Fetal Alcohol Spectrum Disorder is a set of diverse conditions caused by prenatal alcohol exposure (PAE) that
can produce a wide variety of physical, behavioral, and intellectual deficits persisting throughout the lifespan.
Importantly, PAE is also associated with deficits in emotional regulation, including increased non-social and
social anxiety. However, the PAE-induced neurobiological changes that underlie this heightened vulnerability
to develop increased social anxiety are not well understood. This gap in knowledge is problematic because a
precise understanding of neuroadaptations resulting from PAE is necessary to develop targeted treatments for
individuals experiencing PAE-related social impairments. Activity of corticotropin-releasing factor (CRF) and its
receptor (CRF1R) in the medial subnucleus of the central amygdala (CeM), has long been known to regulate
anxiety-like behavior, and disruption of the function of the CeM CRF system could contribute to increased
social anxiety-like behavior in individuals exposed to PAE. Our lab has recently demonstrated that moderate
PAE on gestational day (G)12, around the time of neurogenesis in the rat amygdala, increased social anxiety-
like behavior in adult male rats. Additionally, G12 PAE disrupted CRF1R modulated inhibitory
neurotransmission and non-social anxiety-like behavior in male rats, suggesting that moderate G12 PAE
impairs CeM CRF1R regulated synaptic and behavioral function in adult male rats. These deficits could
subsequently alter the function of CeM downstream projection targets, such as the periaqueductal gray, which
is a brain region known to regulate defensive behaviors in response to threats, including social threats. This led
us to the development of our central hypothesis, that moderate G12 PAE increases social anxiety-like behavior
due to decreased function of the CRF1R positive (+) CeM-PAG projection in male rats. To test this, we will use
whole-cell patch clamp electrophysiology to assess differences in neuronal excitability and neurotransmission
in PAG-projecting CRF1R+ cells. Additionally, we will chemogenetically stimulate the CRF1R+ CeM-PAG
projection prior to testing in a modified social interaction test to generate a measure of social anxiety-like
behavior. Finally, we will further explore the possibility that the PAG underlies PAE-induced social impairments
by assessing differences in cellular activation in the PAG following social interaction testing in male and female
rats. The proposed experiments will expand our understanding of PAE-induced alterations in neural
mechanisms, how these alterations relate to social anxiety-like behavior, and provide evidence to inform future
studies designed to investigate the neuroadaptations resulting from moderate PAE. Additionally, successful
completion of the goals outlined in this proposal will provide me with training in cutting-edge techniques,
science communication, and mentoring that will prepare me for a career as an independent scientist.
