Calcium imaging in freely-moving mice during electrical stimulation of deep brain structures

Abstract

After decades of study in humans and animal models, there remains a lack of consensus regarding how the action of electrical stimulation on neuronal and non-neuronal elementse.g. neuropil, cell bodies, glial cells, etc.leads to the therapeutic effects of neuromodulation therapies. To further our understanding of neuromodulation therapies, there is a critical need for novel methodological approaches using state-of-the-art neuroscience tools to study neuromodulation therapy in preclinical models of disease. In this manuscript we outline one such approach combining chronic behaving single-photon microendoscope recordings in a pathological mouse model with electrical stimulation of a common deep brain stimulation (DBS) target. We describe in detail the steps necessary to realize this approach, as well as discuss key considerations for extending this experimental paradigm to other DBS targets for different therapeutic indications. Additionally, we make recommendations from our experience on implementing and validating the required combination of procedures that includes: the induction of a pathological model (6-OHDA model of Parkinson's disease) through an injection procedure, the injection of the viral vector to induce GCaMP expression, the implantation of the GRIN lens and stimulation electrode, and the installation of a baseplate for mounting the microendoscope. We proactively identify unique data analysis confounds occurring due to the combination of electrical stimulation and optical recordings and outline an approach to address these confounds. In order to validate the technical feasibility of this unique combination of experimental methods, we present data to demonstrate that 1) despite the complex multifaceted surgical procedures, chronic optical recordings of hundreds of cells combined with stimulation is achievable over week long periods 2) this approach enables measurement of differences in DBS evoked neural activity between anesthetized and awake conditions and 3) this combination of techniques can be used to measure electrical stimulation induced changes in neural activity during behavior in a pathological mouse model. These findings are presented to underscore the feasibility and potential utility of minimally constrained optical recordings to elucidate the mechanisms of DBS therapies in animal models of disease.

Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

“…To characterize the network effect of DBS, Paulk et al mapped the cortical responses evoked by single-pulse electrical stimulation delivered via intracranial electrodes in epilepsy patients and confirmed that DBS evoked broad network responses that were stimulation location and pulse parameter dependent 26 . Finally, using cellular fluorescent calcium imaging techniques, a couple of recent studies in animal models demonstrated that DBS altered the relationship of intracellular calcium dynamics and behavior, supporting a network effect of DBS [27][28][29] .…”

Intracortical microstimulation pulse waveform and frequency recruits distinct spatiotemporal patterns of cortical neuron and neuropil activation

“…However, the connectivity and cellular composition influences the population responses during DBS (83) and these factors differ considerably between deep brain structures and the cortex (84)(85)(86). Therefore, it will be important to experimentally determine how waveform asymmetry modulates activation of neural subtypes in the cortex and deeper brain structures (87) and how their respective activity changes over timescales relevant to symptom relief (88).…”

Bioelectronic medicines: past, present and future. Highlights from The Society for Medicines Research Symposium. London, UK - October 1, 2019

“…Lastly, Dr. Ludwig highlighted the need for understanding the mechanisms by which electrical stimulation interacts with neuronal and non-neuronal elements-e.g., neuropil, cell bodies, glial cells, etc., because there remains a lack of consensus regarding how electrical stimulation leads to the therapeutic effects during neuromodulation therapies such as deep brain stimulation. He gave an example of a novel experimental paradigm combining subthalamic nucleus 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 capable of measuring stimulation-evoked changes in neural activity (25).…”