In 2010, an estimated 6 million individuals in the United States abused prescription pain relievers. This has led to a five-fold increase in prescription drug abuse among expectant mothers over the last decade, giving rise to more than one baby born every hour addicted to prescription pain medications, such as oxycodone. Upon birth, these babies suffer from neonatal abstinence syndrome (NAS). Despite a rapidly growing population of individuals born with NAS, basic research efforts on the effects of prenatal exposure to prescription pain medication are limited. Identifying the effects of prenatal oxycodone exposure on the development of brain circuits will allow for future investigations into the underlying mechanisms. The long-term goal is development of novel and innovative strategies to mitigate the lifelong impact. Behavioral data from adult mice indicates that prenatal exposure to oxycodone results in an anxiolytic-like phenotype that is interpreted as impulsivity and risk-taking. The prefrontal cortex, particularly the anterior cingulate and orbitofrontal cortices, amygdala and striatum are core members of the neural circuit implicated in Impulse Control Disorders, including ADHD, a common diag- nosis in children exposed to opiates prenatally. Thus, our central hypothesis is that prenatal exposure to oxycodone alters the development of both long-range and local neural circuitry involved in the regulation of emotional behaviors. The goal of this project is to determine the impact of this neurodevelopmental insult on long-range and local cortical connectivity. This proposal details an innovative approach that combines behavioral analyses with whole brain mapping of inputs to the prefrontal cortex and amygdala through monosynaptic, retrograde circuit tracing in a rodent model. Preliminary data demonstrates that these methods can be used to uncover subtle alterations in connectivity in mice with behavioral deficits. Upon identification of specific projection(s) that are changed by prenatal oxycodone exposure, the circuit will be more fully characterized by identifying the cell types involved in the brain's disorganization. This will provide substantive functional in- sight that will be further studied in future projects. As a whole, completion of this project is expected to result in several key findings: (1) a framework for future mechanistic studies aimed at mitigating the neurodevelopmental consequences of prenatal oxycodone exposure. (2) A map of critical structures and connectivity shaped by prenatal exposure to prescription pain relievers, with broader applicability to the opiate class of drugs. (3) The potential for discovery of previously unknown brain connectivity in wildtype animals due to the highly sensitive tracing methodology being used.
The proposed research details a preclinical investigation into an immediate and worsening public health issue - the impact of maternal abuse of prescription pain relievers on the brain health of offspring. In order to determine the lifelong effects produce by the neurodevelopmental insult of prenatal exposure to oxycodone, a widely abuse prescription narcotic, this application takes the innovative approach of whole brain input mapping of circuits regulating emotional behaviors.
|Fürth, Daniel; Vaissière, Thomas; Tzortzi, Ourania et al. (2018) An interactive framework for whole-brain maps at cellular resolution. Nat Neurosci 21:139-149|
|Young, E J; Blouin, A M; Briggs, S B et al. (2016) Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use. Mol Psychiatry 21:615-23|
|Aceti, Massimiliano; Creson, Thomas K; Vaissiere, Thomas et al. (2015) Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry 77:805-15|