Krikor Dikranian Research Abstract

1. Neuronal and glial cell degeneration
Blockade of NMDA glutamate receptors and activation of GABA receptors during late fetal or early neonatal life trigger widespread apoptotic neurodegeneration in the developing brain of mammals. Our studies also suggested that glutamate, acting at NMDA receptors, controls neuronal survival. We further clarified the deleterious effect of ethanol (with NMDA receptor antagonist & GABA receptor agonist actions) on the developing brain. We have characterized the robust neuronal apoptotic cell death caused by these agents and were able for the first time to give very detailed electron microscopic description of the stages of programmed cell death in cortical, brainstem and cerebellar neurons. We demonstrated these effects also in primates. Ethanol and select anesthetics such as propofol, isofurane and others promoted programmed cell death in both the neuronal and oligodendrocyte cell population. These findings show that similar acting anesthetics can potentially have impact on human neurodevelopmental disorders involving prenatal (drug-abusing mothers, fetal alcohol syndrome) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors or induce GABA-mediated inhibition during the brain growth spurt.

2. Traumatic brain injury
I have extensively contributed to studies that characterized in detail brain/head trauma induced neurodegeneration in the developing mammalian brain. I analyzed the nature and topographic distribution of acute and chronic cell degeneration. We demonstrated that early post trauma neurodegeneration is excitotoxic in nature and is followed by a wave of apoptotic cell degeneration. For the first time in the experimental traumatic brain literature we presented results on the temporal sequence of axonal degeneration and cell death. We demonstrated that early axonal disruption between communicating brain areas is followed by bilateral apoptotic neuronal cell death in these regions. We also characterized the role of repetitive head injury in the adult brain. Our further studies on the application of diffusion tensor imaging in brain trauma experiments in an animal model of traumatic brain injury revealed that this imaging approach can successfully identify areas of axonal disruption. My current collaborative studies relate to mechanisms via which traumatic brain injury accelerates Alzheimer’s disease related pathologies and concern therapeutics in TBI-related tauopathy. Electron microscopy will be routinely used.

3. Collaborative studies
In my collaborative studies on animal models of Alzheimer's disease, tauopathies and Prion's disease I have studied and characterized the electron microscopic features of the developing brain pathology including cell degeneration, axonopathy and fibrillar and non-fibrillar plaque structures. These studies have helped in clarifying the degree of involvement of axonal and cellular structures in the progression of the disease process in various experimental transgenic animals.

My experience in the morphology of the CNS has also contributed to research related to some aspects of the Human Connectome Project. Studies are ongoing in relation to the trajectory and pattern of distribution of myelinated axons at the white matter/grey matter boundary in primates. Their relevance in studies applying dtMRI and tractography is to be evaluated.