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Biology subjects

Kroenke, C. D.

Publications and source records attributed to Kroenke, C. D..

3 recordsLinked to original sources

Measurement of residual stress in the brain

Mechanical stress in brain tissue is an important feature of the brain, likely to play key roles in brain development and brain injury. Here, we characterize residual stresses in grey matter and white matter from the deformed shape of tissue cylinders extracted from the brain using a biopsy needle and imaged with high-resolution magnetic resonance imaging (MRI). We use finite element simulations to reconstruct the stress state of tissue sections in the intact brain from images of corresponding sections of the deformed excised tissue. In both adult mouse and Yucatan minipig brains, cortical grey matter exhibited predominantly compressive stresses, while white matter exhibited strongly anisotropic tensile stresses. The direction of maximum tension in white matter generally aligns with axon orientation as observed with diffusion MRI in the minipig. These stress patterns (compressive in cortical grey matter, tensile along axons) are consistent with constrained cortical expansion and tension-induced axonal growth during brain development. These findings offer new insights into the biomechanical factors underlying brain morphogenesis, with implications for understanding neurodevelopmental disorders, brain injuries, and neurosurgical interventions.

bioengineering↗

A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with progressive motor and cognitive decline

We created a new nonhuman primate model of the genetic neurodegenerative disorder, Huntingtons disease (HD), by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This novel modeling strategy results in robust expression of mutant huntingtin protein (mHTT) in the injected brain regions, as well as dozens of other cortical and subcortical brain regions that are also affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 20-months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed progressive working memory decline and motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. This novel model will aid in the development of disease biomarkers and therapeutic strategies for this devastating disorder.

neuroscience↗

Maternal Circulating MicroRNAs Control the Placental Response to Alcohol

Prenatal Alcohol exposure (PAE), like other pregnancy complications, can result in placental insufficiency and fetal growth restriction, though the linking causal mechanisms are unclear. We previously identified 11 gestationally-elevated maternal circulating miRNAs that predicted infant growth deficits following PAE. Here, we investigated whether these HEamiRNAs contribute to the pathology of PAE, by inhibiting trophoblast epithelial-mesenchymal transition (EMT), a pathway critical for placental development. We now report for the first time, that PAE inhibits expression of placental pro-EMT pathway members in both rodents and primates, and that HEamiRNAs collectively, but not individually, mediate placental EMT inhibition. HEamiRNAs collectively, but not individually, also inhibited cell proliferation and the EMT pathway in cultured trophoblasts, while inducing cell stress, and following trophoblast syncytialization, aberrant endocrine maturation. Moreover, a single intra-vascular administration of the pooled murine-expressed HEamiRNAs, to pregnant mice, decreased placental and fetal growth and inhibited expression of pro-EMT transcripts in placenta. Our data suggests that HEamiRNAs collectively interfere with placental development, contributing to the pathology of PAE, and perhaps also, to other causes of fetal growth restriction. SummaryMaternal gestational circulating microRNAs, predictive of adverse infant outcomes including growth deficits, following prenatal alcohol exposure, contribute to placental pathology by impairing the EMT pathway in trophoblasts.

developmental biology↗