ORCID ID

0000-0002-7856-7811

Graduation Date

Spring 5-8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Neuroscience

First Advisor

Sowmya Yelamanchili

Abstract

Prescription opioid abuse during and after pregnancy is a rising public health concern. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. The present work uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different exposure groups.

To understand the direct effects of IUO and PNO exposure on the F1 generation, we employed a systems biology approach encompassing proton magnetic resonance spectroscopy (1H-MRS), electrophysiology RNA-sequencing, and pain assessment to elucidate molecular and behavioral changes in these offspring. 1H-MRS studies revealed significant changes in brain metabolites that were corroborated with changes in synaptic currents. RNA-sequencing of the prefrontal cortex further revealed alterations in the expression of key genes associated with synaptic transmission, neurodevelopment, mood disorders, and addiction. Von Frey testing showed lower pain thresholds in both oxy-exposed groups. Further, because addictive drugs produce significant and persistent changes in the synapse, we investigated the synaptic vesicle (SV) contents of the PNO and IUO groups. To that end, we found that the expression levels of key SV proteins associated with functional pathways and neurological disease were altered in oxy-exposed groups.

While our earlier studies characterized the effects PNO and IUO exposure have on the F1 generation, we next sought to compare the overall development between F1 offspring and their progeny, the F2 generation. We observed significant differences in phenotypic attributes of both generations in each treatment group, and RNA-sequencing of the nucleus accumbens revealed alterations in the expression of key synaptic genes in both generations. Post-validation of these genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits in both treatment groups that persisted into the F2 generation.

Collectively, our studies reveal a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and the intergenerational impact on behavior.

Available for download on Tuesday, October 19, 2021

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