Subthalamic nucleus (STN) deep brain stimulation (DBS) is a common surgical treatment for Parkinson?s disease (PD). Despite over 20 years of clinical success, the therapeutic mechanisms of STN DBS remain elusive. However, it has become clear that DBS acts at the molecular, cellular, and systems levels in complex and sometimes contradictory ways. Current techniques such as electrophysiology, electrochemistry, and functional imaging commonly used to study pieces of this puzzle are limited in either resolution or behavioral paradigms these can be applied to, and have thus not provided all the information needed to parse out the complicated relationships between stimulation and evoked effects. Here, we propose the use of fluorescence calcium microscopy in GCaMP6f-expressing rats using a head-mounted miniature single photon system as a novel tool to bridge the gap between cellular and system level understanding of DBS in awake behaving animal models of PD. To this end, we will analyze neural activity changes in motor cortex evoked by stimulation of the STN during open field, stepping, cylinder tests, and apomorphine-induced rotations, all of which are stereotypical tests that have shown predictive validity for evaluation of movement and therapeutic efficacy in parkinsonian animals. The techniques proposed here provide a unique approach for answering questions about DBS mechanisms such as whether DBS-induced activation or pharmacologic inhibition of excitatory STN glutamatergic neuronal projections to the globus pallidus internus / substantia nigra reticulata produces detectable changes in motor cortex activity associated with changes in behavioral outcomes (e.g., open field, kinematic assessment of stepping, cylinder, and apomorphine-induced rotation tests).
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective surgical treatment for Parkinson's disease (PD), however despite this success, the mechanisms of action underlying therapeutic DBS are poorly understood. We propose the use of a miniature head mounted microscope with the capability to directly image the activity from hundreds of neurons with high spatial and temporal resolution to study changes in neural activity during movement in nave, parkinsonian, and DBS treated parkinsonian animals. We establish proof of principle of the proposed techniques by analyzing contributions of STN projections, previously implicated in DBS responses, to neural activity and behavior.
