Dept. of Neuroscience & Regenerative Medicine
1120 15th Street, Rm. CA4008
Medical College of Georgia at Augusta University
Augusta, GA 30912
1982-1987 St.-Petersburg (former Leningrad) State University, St.-Petersburg, Russia; M.S. in Biophysics
Graduate and Professional:
1988-1991 St.-Petersburg State University & Pavlov Institute of Physiology, St.-Petersburg, Russia; Ph.D. in Biophysics
1992-1995 Postdoctoral Fellow, NIH, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland
1995-1997 Senior Postdoctoral Fellow, Dept. of Physiology, University of Maryland, School of Medicine, Baltimore, Maryland
1997-1999 Research Associate, Division of Neuroscience, Harvard Medical School, Children’s Hospital, Boston, Massachusetts
My background is in Neuroscience and Biophysics, with specific training in imaging, electrophysiology, and electron microscopy. My Multiphoton Imaging Laboratory studies mechanisms for neural circuit dysfunction in preclinical models of stroke and TBI. We are integrating a variety of classic and state of the art technologies; viral expression, mouse genetics, in vivo 2-photon microscopy coupled with electrophysiology, laser speckle imaging, and functional intrinsic optical signal imaging, as well as ultrastructural studies with serial section transmission electron microscopy. Such array of sophisticated methods provides a dramatic window several hundred microns deep into the cortex to identify and track, in real-time, responses to neurological insult in defined circuits and cells. Our goal is to attenuate mechanisms that initiate and propagate local injury and amplify responses that promote recovery.
Cortical Spreading Depolarization: Emerging pathophysiologic mechanism in the acutely
Recent clinical data indicate that repeated waves of spreading depolarizations are involved in the mechanism of injury in patients with stroke and brain trauma. We are aiming to understand the causality between changes in neurons, astrocytes, synapses, blood flow, and spreading depolarization. The research has obvious clinical implication by pointing to spreading depolarization as an important mechanistic endpoint in treating these neurological disorders.
Molecular mechanisms of cytotoxic edema
Normal brain function invariably depends on water homeostasis. Disturbance of this homeostasis during stroke and TBI leads to a life-threatening state of brain edema. We are aiming to identify the exact molecular pathways of water influx into neurons at the onset of cytotoxic edema to explore strategies for rescue neurons from swelling.
Injury-induced mitochondrial dynamics
Abnormal mitochondrial dynamics and fragmentation of the mitochondrial network into small spherical structures are considered hallmarks of mitochondrial injury. Excessive fragmentation facilitates apoptosis. Until recently live imaging studies of mitochondria dynamics in vivo were not conducted in the intact brain. Using 2-photon microscopy, we were able to overcome this critical barrier and, for the first time, quantified dendritic mitochondrial fragmentation in real-time in vivo immediately after insult and throughout three weeks in response to injury. We are conducting studies to determine how mitochondrial structural rearrangements affect neuronal survival and if therapeutic approaches targeting this organelle can improve neural pathological outcomes.
A protective role of astrocytes against synaptic injury in stroke and brain trauma
Disruption of synaptic networks after stroke or TBI involves the impairment of astrocytes alongside neuronal dysfunction. My research group was among the first to image astroglial responses to ischemia in vivo using 2-photon microscopy. Our studies revealed critical new information about dynamic astroglial responses to interruptions in blood flow and osmotic stress. We are conducting studies on how impaired astroglial metabolism aggravates neuronal injury during stroke and how functioning astrocytes facilitate neuronal recovery after stroke.
Two-photon imaging in the neocortex of a living mouse
Top row: Schematic of intravital imaging showing dendrites (arrows), astrocyte (asterisk) and capillaries (red). Next two images are the 3D reconstruction of dendrites of pyramidal neurons (yellow), dendritic mitochondria (cyan) and blood vessels (red).
Middle row: Intravital images of dendrites with dendritic spines and astrocyte.
Bottom left: Overlay showing two merged images of microglial cell obtained at a 20 min interval revealing frequent extension (green) and retraction (red) of microglial processes. Bottom right: Dendritic segments from sham-operated (left, with tubular mitochondria) and ischemic (right, with fragmented mitochondria) mice reconstructed in three dimensions from serial electron microscopic images superimposed onto a montage showing changes in neuronal mitochondria morphology after stroke. The frame is a two-photon image of CFP-labeled neuronal mitochondria from a sham-operated mouse.
Jeremy Sword, PhD – Postdoctoral Fellow