Prenatal heroin exposure alters brain morphology and connectivity in adolescent mice

Abstract

The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on the brain, often identified at school age, manifest as cognitive impairment, attention deficit, and reduced scholastic achievement. The neurobiological basis for these effects is poorly understood. Here, we examine how in utero exposure to heroin affects brain development into early adolescence in a mouse model. Pregnant C57BL/6J mice received escalating doses of heroin twice daily on gestational days 4-18. The brains of offspring were assessed on postnatal day 28 using 9.4 T diffusion MRI of postmortem specimens at 36 μm resolution. Whole-brain volumes and the volumes of 166 bilateral regions were compared between heroin-exposed and control offspring. We identified a reduction in whole-brain volume in heroin-exposed offspring and heroin-associated volume changes in 29 regions after standardizing for whole-brain volume. Regions with bilaterally reduced standardized volumes in heroin-exposed offspring relative to controls include the ectorhinal and insular cortices. Regions with bilaterally increased standardized volumes in heroin-exposed offspring relative to controls include the periaqueductal gray, septal region, striatum, and hypothalamus. Leveraging microscopic resolution diffusion tensor imaging and precise regional parcellation, we generated whole-brain structural MRI diffusion connectomes. Using a dimension reduction approach with multivariate analysis of variance to assess group differences in the connectome, we found that in utero heroin exposure altered structure-based connectivity of the left septal region and the region that acts as a hub for limbic regulatory actions. Consistent with clinical evidence, our findings suggest that prenatal opioid exposure may have effects on brain morphology, connectivity, and, consequently, function that persist into adolescence.

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: a multi-modal magnetic resonance study

“…However, preclinical neuroimaging studies on opioid exposure are rather limited. To the best of our knowledge, there are only six rodent neuroimaging studies to date which have reported no macrostructural changes [7], alterations in major white matter tracts [8], widespread microstructural changes [9, 10] and changes in cerebral metabolites [11, 12]. There is a knowledge gap regarding the cellular mechanisms that may be the driving factor for the microstructural development or the breakdown of regional structural integrity.…”

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: A multi-modal magnetic resonance study

“…However, preclinical neuroimaging studies on opioid exposure are rather limited. To the best of our knowledge, there are only six rodent neuroimaging studies to date which have reported no macrostructural changes [ 6 ], alterations in major white matter tracts [ 13 ], widespread microstructural changes [ 9 , 14 ] and changes in cerebral metabolites [ 15 , 16 ].…”