Pushing the Envelope
Research Models
Regina Kelder

Pushing the Envelope

Four imaging experts talk about new innovations in preclinical in vivo modeling

The human brain contains 100 billion neurons—with 100 trillion connections—surrounded by structural support cells closely packed together. Understanding how these networks of neurons process information would enable neuroscientists to better study and model the twisted circuitry of neurological disorders.

But most of the current options for imaging the brain have limitations, noted Jin Lee, who heads an Imaging Research Group at Stanford University. Methods like Diffusion Tensor Imaging (DTI) can be used to trace activity across the entire brain, but identifying relationships between measured neural activities and structural phenotypes only gets us so far, she says. "Even if you have full connectivity in front of you, it's hard to relate that to given behaviors, so you need to understand the dynamics of the brain," said Lee, one of four imaging experts who delivered talks during Charles River's scientific luncheon at the Society of Neuroscience meeting.

Lee, an Assistant Professor of Bioengineering, Neurology and and Neurological Sciences, has been applying optogenetic functional magnetic resonance imaging (ofMRI), to probe brain circuitry at the cellular level.

Optogenetics, the combination of genetics and optics to control well-defined events within cells of living tissue, is a hot topic in neuroscience right now. In the four years since the journal Nature declared it their "method of the year" the field of optogenetics has expanded rapidly. Some of the most well-attended poster presentations at SfN were on applications of this technology, and Nature Communications recently described using a wireless-powered optogenetic designer cell implant to switch on genes using the power of thought. Brainwaves from human participants activated a tiny light which had been implanted in mice, the BBC reported.

Lee's lab is capitalizing on recent advances in ofMRI, which allow for the integration of much faster data acquisition (13 milliseconds rather than 8 seconds) and high signal-to-noise (SNR) ratio to visualize brain activity by modulating genetically, spatially and topologically cell populations in real-time. Some of her recent work has involved stimulating the dorsal and medial temporal regions of the brain (where the hippocampus is located) to induce seizures in mice, and dissecting out different pathways associated with different phenotypes. But her lab is also interested in stem cell integration, Parkinson's disease and Alzheimer's disease.

Yet while the technology could open doors for future studies of neurological disease. Lee acknowledged that it's not an easily translatable technique. Her lab uses recombinant adeno-associated viral viruses to introduce the transgenes into neural cells, and must constantly validate the vector from lot to lot to ensure that the variable results they are seeing in animals are reproducible.

Head Injuries

Advances in neuroimaging are also allowing scientists to study traumatic brain injuries (TBI) with a greater degree of specificity. Because so many factors determine the immediate and long-term consequences of head trauma—from the speed, angle and force at which the skull is struck, to the frequency of the injury, and the time and quality of the medical response—studying TBI in a controlled environment with defined endpoints seems almost counterintuitive to what actually occurs when you hit the windshield of your car, step on a land mine, take a bullet, or suffer repeated blows to the head.

Moreover, the therapeutic window is extremely narrow for intervening in the cascade of secondary complications that a TBI triggers, notably the catastrophic rise in chemically reactive molecules that destroys cellular structures, and leads to brain edema, inflammation, apoptosis and late cell death. Understanding this complex TBI cascade remains a major focus in animal studies.

"Acute changes in the brain trigger a number of different processes that go on for months and leads to different outcomes in patients," says Olli Gröhn, professor in Biological Nuclear Magnetic Resonance at the University of Eastern Finland, who also spoke at CR's scientific luncheon,Pushing the Envelope: MRI Applications in Preclinical In Vivo Modeling. "Imaging methods are not very specific so we are trying to find better ways of detecting these processes."

Those ways include using both microstructural and fMRI to study progressive damage and plasticity after a TBI.

Gröhn says DTI has been useful in studying the microsctructural changes that occur after injury (and which could be responsible for the persistent cognitive and behavioral impairments that often occur after TBI). But because the MRI results lack specificity, labs have turned to high angular resolution diffusion-weighted imaging or HARDI as a next-generation application that is designed to extract more information from the signals being produced by MRI. "We are starting to work with this and we're hoping this kind of technique will give us new information that we can use," says Gröhn.

The two other speakers who rounded out the luncheon event included Dr. Fuqiang Zhao, Senior Imaging Scientist at Merck, who spoke about preclinical fMRI and olfactory responses, and Thomas Mueggler, Principal Scientist and Imaging Expert at Roche, who spoke about fMRI in models of neurodevelopmental disorders.