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Published on: July 13, 2014
Neuropathological consequences of prenatal cocaine exposure in the mouse
Jia-Qian Ren1, C J Malanga, Eddy Tabit
1Laboratory of Molecular and Developmental Neuroscience, Department of Neurology, Massachusetts General Hospital, Room 2508, 149 13th Street, Charlestown, MA 02129, USA.
Insights
Prenatal cocaine exposure in mice leads to a significant loss of neurons in the primary somatosensory cortex by postnatal day 50. This neuronal loss, specifically in deeper cortical layers, may explain persistent brain structure and function alterations observed in affected children.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Prenatal cocaine exposure is linked to persistent neurodevelopmental deficits in children.
- Clinical data correlates higher prenatal cocaine exposure with greater prenatal and postnatal brain growth impairments.
- Previous research indicates cocaine disrupts corticogenesis and cortical lamination development.
Purpose of the Study:
- To investigate the mechanisms underlying persistent brain structural and functional alterations following prenatal cocaine exposure.
- To identify the postnatal developmental trajectory of structural changes in the primary somatosensory (S1) cortex in a mouse model.
- To determine if observed changes are specific to cocaine exposure or a general effect of prenatal stress.
Main Methods:
- Developed an animal model using Swiss Webster mice with prenatal cocaine exposure.
- Conducted morphometric comparisons of brain structures at postnatal days 9 and 50.
- Utilized vehicle and malnutrition control groups to isolate cocaine's effects.
Main Results:
- A significant decrease in the relative number of cortical neurons in the S1 cortex was observed on postnatal day 50 in cocaine-exposed mice compared to controls.
- This neuronal loss was restricted to the infragranular compartment (layers V and VI) of the S1 cortex.
- No significant changes in neuronal number or density were observed in malnourished control animals, suggesting cocaine-specific effects.
Conclusions:
- Prenatal cocaine exposure causes alterations in S1 cortical cytoarchitectonics, partly due to reduced postnatal survival of infragranular cortical neurons.
- The loss of these neurons occurs between postnatal days 9 and 50.
- Further clinical brain imaging studies are warranted to investigate similar processes in humans exposed to cocaine in utero and their potential impact on neurodevelopment.
Abstract:
We have developed an animal model in Swiss Webster mice to identify mechanisms by which prenatal exposure to cocaine results in persistent alterations in brain structure and function. Clinical data suggests that children who demonstrate the largest impairments in prenatal brain growth, which are positively correlated with the highest level of prenatal cocaine exposure, are more likely to demonstrate selective impairment in postnatal brain growth, as well as postnatal impairments in motor function, attention and language skills. We conducted neuroanatomic studies to identify the postnatal evolution of structural changes in the primary somatosensory (SI) cortex of the developing mouse brain following prenatal exposure to cocaine. Our previous work, and that of others, provides evidence that many of the processes underlying corticogenesis are disrupted by gestational exposure of the developing mouse brain to cocaine, and that from the earliest phases of corticogenesis that there is an imprecision in the development of cortical lamination. We performed morphometric comparisons between the brains of animals prenatally exposed to varying amounts of cocaine with vehicle and malnutrition controls on postnatal (P) days P9 and P50. We found that on P50, but not P9, the relative number of cortical neurons in S1 is significantly less in cocaine exposed animals as compared with controls. The significant decrease in the number of cells in cocaine exposed animals on P50 is evident as a decreased density of cells restricted to the infragranular compartment (layers V and VI). Those changes are not seen in malnourished animals. Taken together our findings support the conclusion that cocaine-induced alterations in SI cortical cytoarchitectonics are in part a consequence of altered postnatal survival of infragranular cortical neurons, which are lost during the interval between P9 and P50. Determining whether a similar process is evident in a subset of humans following in utero cocaine exposure is a high priority for future clinical brain imaging studies, because analogous structural changes could impact the brain function and behavioral repertoire of infants and children following significant prenatal exposures.
