| 2021 |
Alipio, Jason Bondoc |
F31Activity Code Description:
To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Enduring Effects in Thalamocortical Circuits Ensuing Perinatal Opioid Exposure @ University of Maryland Baltimore
Project Summary/Abstract Illicit use of synthetic opioids, primarily fentanyl, has increased dramatically since the 1990s, leading to what is now recognized as the opioid epidemic. Fentanyl is fifty times more potent than heroin and is now responsible for many opioid-related overdose deaths. Fentanyl use among pregnant women has increased dramatically in the past decade, which severely undermines their child?s neurological development. Longitudinal clinical studies reveal an increased incidence of sensory-related deficits in adolescents who were exposed to opioids prenatally. The thalamus and neocortex are essential for normal sensory function, and share reciprocal connections, forming the thalamocortical (TC) and corticothalamic (CT) circuit. It is possible that the effects fentanyl exerts in this circuit could lead to long-lasting sensory-related deficits. Consistent with this, our data indicate that perinatal fentanyl exposure upregulates the expression of metabotropic glutamate receptor 4 (mGluR4), which is a group III mGluR that suppresses neurotransmitter release. My data suggest that perinatal fentanyl exposure suppresses synaptic inputs to ventroposteromedial (VPM) thalamic and primary somatosensory (S1) cortical neurons in adolescent mice. Consistent with the critical role of these projections in sensory processing, these mice have an impaired ability to adapt to tactile stimulation. I hypothesize that perinatal fentanyl exposure leads to a lasting suppression of synaptic activity by increasing mGluR4 expression in thalamocortical and corticothalamic circuits, resulting in sensory abnormalities. I will test predictions that corroborate this hypothesis with three specific aims. First, I will determine whether perinatal fentanyl exposure suppresses synaptic transmission in TC-CT. Then, I will determine whether this exposure increases functional expression of mGluR4 in this circuit. Finally, I will determine whether this exposure impairs sensory network activity both ex vivo and in vivo. These specific aims and experiments will allow the elucidation of the mechanisms that will explain, in part, the underlying pathophysiology of sensory- related conditions associated with perinatal exposure to fentanyl and will contribute to improving treatment and prevention strategies. I have completed all required coursework in the Program of Neuroscience at the University of Maryland School of Medicine and have passed my qualifying exam. This allows me to devote much of my time to the completion of my proposed experiments under the guidance of my Sponsor, Dr. Asaf Keller, a leading expert in sensory perception and the effects of drugs of abuse on the developing brain. I am also mentored by Dr. Yavin Shaham (NIDA), an expert on the neurodevelopmental impact of drugs of abuse, including opioids, and Dr. Margaret McCarthy (UMSOM), a leading expert on rodent brain development. All together, these planned experiments and the guidance from my research team will provide me with valuable experience, improve my technical skill, and facilitate my progress toward my goal of becoming an independent and well-rounded researcher.
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