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.

Simultaneous Cellular Imaging, Electrical Recording and Stimulation of Hippocampal Activity in Freely Behaving Mice

“…Previous studies have combined single-photon microendoscope with deep brain stimulation [37] or silicon probe recordings [38].…”

Therapeutic Deep Brain Stimulation Disrupts Subthalamic Nucleus Activity Dynamics in Parkinsonian Mice

“…In this study, we used calcium imaging with GCaMP6s to examine how neural activity changes during STN DBS. A recent study demonstrated technical feasibility of using in vivo calcium imaging with electrical STN DBS (Trevathan et al, 2020), but ours is the first to use this approach to link DBS-mediated physiological changes to behavior in freely moving parkinsonian animals. Moreover, our study is one of the first to use fiber photometry in deep basal ganglia nuclei, and to compare these signals with in vivo singleunit electrophysiology.…”

Current approaches to characterize micro- and macroscale circuit mechanisms of Parkinson’s disease in rodent models

“…These results further illustrate pathologic iSPN activity change following a chronic lack of dopamine ( Parker et al, 2018 ). In addition, the combination of electrical STN stimulation and single photon microendoscopy, neural activity of ipsilateral SPNs in anesthetized and freely moving mice in a PD model could be recorded ( Trevathan et al, 2020a , 2020b ). Although this is a single study, it demonstrates the feasibility of this approach to better understand the effects of DBS.…”

“…The proposed mechanisms of DBS range from local changes in single cell firing, alterations of synaptic plasticity, to modulation of pathological oscillatory activity on the network level ( Ashkan et al, 2017 ). The complex interaction of DBS mechanisms between the micro- and macroscale and its potential clinical use in a range of neuropsychiatric disorders makes this therapy particularly interesting for circuit neuroscience and its techniques ( Gittis and Yttri, 2018 ; Trevathan et al, 2020a , 2020b ). In this review, we will highlight studies that use electrophysiological and optogenetic methods to study DBS mechanisms and how these approaches could be used to optimize current DBS therapies and open new avenues of DBS for treatment of other brain diseases ( Creed et al, 2015 ).…”