Using calcium imaging to characterize neural circuit changes induced by deep brain stimulation



I’ve been writing a lot about sleep and circadian rhythms, but one of the best things about SfN is all of the chances it offers you to step outside your comfort zone. A dynamic poster using calcium imaging to characterize the effects of deep-brain stimulation on dopaminergic circuitry provided the perfect opportunity for me to do just that.

Deep-brain stimulation (DBS) is a therapy used to treat disorders ranging from Parkinsons disease (PD) and essential tremor to major depression and epilepsy. Most DBS protocols involve the chronic implantation of stimulating electrodes, typically targeting either the thalamus or striatum, that connect via a subcutaneous wire to a pulse generator implanted in the patient’s chest. A controller can then be used to wirelessly modulate the stimulation provided by the pulse generator, and fine-tuned to provide the patient relief from debilitating symptoms. Despite a long history and widespread use, especially to treat motor symptoms of PD and essential tremor, the neural mechanisms underlying the relief provided by DBS are poorly understood. Improving our understanding of how DBS works could go a long way in optimizing treatment protocols for patients suffering from these devastating diseases.

Anatomical reconstruction of typical electrode placement into the subthalamic nucleus (STN) in human patients. - (via Wikimedia Commons)

Oftentimes, long-standing problems in neuroscience like this one benefit from innovative approaches and imaginative collaborations. While wandering around the poster hall on Monday afternoon, I was excited to come across a perfect example of just this - a dynamic poster describing the first ever use of calcium imaging to study changes in neural activity during DBS.

The researchers, from the Mayo Clinic in Minnesota, used a mouse model of PD in which dopaminergic neurons in the substantia nigra pars compacta (SNc) are lesioned via injection of 6-hydroxydopamine (6-OHDA). As is typical in human patients, DBS electrodes were then implanted in the subthalamic nucleus (STN). The team chose to study how DBS affected the activity of dopaminergic medium spiny neurons (MSNs) in the dorsal striatum, as previous work demonstrated that these cells encode locomotion information in healthy mice, and that this encoding is impaired in 6-OHDA models. To do this, they injected an adeno-associated virus expressing the calcium indicator GCaMP6m into the dorsal striatum. Finally, they implanted a GRIN lens above the striatum to image calcium transients.

Although other teams have had success in combining calcium imaging and optogenetic stimulation, the high potential for noise being introduced into the calcium signal by the electrical stimulation used in DBS posed a unique technical hurdle for the Mayo Clinic team. To devise a solution, the researchers formed a close collaboration with scientists at Inscopix, an industry leader in the development of calcium imaging technologies for systems neuroscience.

Together, the group was able to adapt an Inscopix nVoke system (typically used for simultaneous optogenetic stimulation/inhibition and calcium imaging) to demonstrate for the first time that activity of striatal MSNs could be evoked by electrical stimulation of the STN. They went on to show that in the 6-OHDA mouse model of PD, MSN activity was reduced in response to stimulation in a frequency-dependent manner. These preliminary results represent an important first step in using optical imaging to characterize changes in circuit-level dynamics in a mouse model of DBS in PD. The Mayo Clinic researchers said they plan to use the Inscopix system to further characterize activity changes in different MSN subtypes in an effort to better understand how DBS induces changes in the brain. As an added bonus, the dynamic poster included some beautiful videos of MSNs lighting up during stimulation in freely behaving mice!

This unique and apparently fruitful collaboration piqued my interest in learning more about Inscopix’s tech, so I decided to stop by their booth in the exhibitors area. After giving me a rundown of some of their cool new tech (their nVista system has a web-based data acquisition interface, allowing you to control your experiments from anywhere - perfect for the neuroscientist on the go!), I got to talking with their reps more about how Inscopix views their role in the neuroscience community. They emphasized that they value working closely with labs to enable totally novel, rigorous experimental paradigms by integrating different modalities for interrogating neural circuit function, and hope that as a result they can help to address reproducibility issues in neuroscience.

This experience was a great reminder of how amazing science can come from close collaborations between academia and industry, and that there’s a lot to be gained from taking the time to talk with exhibitors (besides all the free swag of course). If you haven’t already, make sure to check out some dynamic posters and exhibitor’s booths today before SfN 2017 comes to a close!

Poster info:
389.15 / DP06/Y15 - Calcium imaging of striatal activity evoked by subthalamic nucleus deep brain stimulation. J. Trevathan, E. N. Nicolai, A. J. Asp, D. Cheng, M. J. Schachter, J. J. Nassi, S. L. Otte, J. G. Parker, J. Lujan, K. A. Ludwig.