NEURONAL AND VASCULAR DEFICITS FOLLOWING CHRONIC ADAPTATION TO HIGH ALTITUDE
The interaction between environmental stressors and the dynamic human genome is a challenging and urgent area of clinical and military research that will aid in alleviating the devastating consequences of operational activity involving battlefield stress in harsh environments. Our lab investigates the mechanisms underlying impaired cognitive performance reported by non-native subjects following prolonged exposure to high altitude (HA).
In our mouse model of HA exposure simulating an altitude of 5000 meters through hypobaric-hypoxia, we have identified HA-triggered deficits in hippocampal learning and memory accompanied by abnormalities in brain MR imaging. HA exposure (1-8 months) induces reduced relative cerebral blood flow and changes in diffusion tensor imaging (DTI) derived parameters in the corpus callosum and hippocampus, as well as an increase in brain ventricular volume. Additionally, neuropathological examination reveals significant demyelination within the corpus callosum, and widespread microglia activation and neurovascular extension. Electrophysiological recordings across the corpus callosum do not reveal changes in action potential conduction velocities of either myelinated or unmyelinated fibers, yet refractory periods are extended and axonal excitabilities increased. Transcriptional signaling pathways identified by whole-genome RNA-sequencing are altered in both the amygdala and hippocampus, detecting epigenetic changes linked to angiogenesis, myelination, and neuroinflammation.
Our findings suggest hypobaric-hypoxia exposure elicits maladaptive responses which induce cognitive deficits. This comprehensive preclinical work, which involved members of Galdzicki lab and members of the Department of Radiology under supervision of Dr. Dardzinski, for the first time implicated brain area specific mechanisms and signaling pathways that may be responsible for the initiation of adverse effects due to HA exposure. Ongoing research combining efforts of Galdzicki’s and Dardzinski’s Laboratories with Neuropathology Laboratory under Dr. Perl with contributions from CMPH and TAGC focuses on epigenetic factors influencing acute and chronic environmental adaptation affecting learning, memory, neuroplasticity and recovery mechanisms to attenuate the neurological consequences of stay at low oxygen and low-pressure environment for military and civilian personnel.
NEUROADAPTATION AND BRAIN PATHOPHYSIOLOGY
The Galdzicki laboratory and collaborators are seeking to provide novel insight into the acute and chronic inflammatory signature of mild traumatic brain injury, adaptation to high altitude, and sleep physiology. Through understanding of the mechanisms underlying microglia facilitated vascular-neuro-repair to mitigate the neurodegenerative impact of injury we aim to assist military and civilian populations to operate in harsh and demanding environments. Our tools and techniques involve whole-genome sequencing, cutting edge imaging, behavior and physiological technologies. We use two-photon imaging aided by machine learning and mathematical modeling approaches to identify interactions between vasculature, neurons and microglia.