Abstract
Over decades of study in humans and animal models, our understanding of mechanisms by which electrical stimulation interacts with neuronal and non-neuronal elements – e.g. neuropil, cell bodies, glial cells, etc. – has steadily improved. However, there remains a lack of consensus regarding how electrical stimulation leads to the therapeutic effects during deep brain stimulation (DBS) and other neuromodulation therapies. This discord stems in part from technical limitations of commonly used non-invasive imaging and invasive electrophysiological techniques, namely, the inability to perform stable recordings of activity from many neuronal and non-neuronal cells with high spatial and temporal resolution in freely-moving animals. Single-photon, head-mounted, miniature microscopy of neurons expressing the genetically encoded calcium sensor GCaMP overcomes many of these limitations, providing a unique opportunity for studying the mechanisms of neuromodulation therapies during pathological behaviors in relevant disease models.
Herein, we describe a novel experimental paradigm combining subthalamic nucleus (STN) electrical stimulation with single-photon calcium imaging of the dorsal striatum via a head-mounted miniature microscope in healthy and 6-hydroxydopamine lesioned parkinsonian mice during minimally constrained behavior. We demonstrate the capabilities of this technique for measuring stimulation-evoked changes in neural activity and describe the challenges associated with surgical procedures, behavioral evaluation, and data analysis. Data collected using this methodology suggest that neuromodulation produces behavior dependent cellular responses and that individual striatal cells respond differently under the same electrical stimulation paradigm. These findings stress the need for a framework that allows for the study of neuromodulation techniques such as DBS during relevant pathological behavior.
