Pathological neuronal synchrony is the hallmark of many neurological disorders, including Parkinson's disease (PD), epilepsy, dystonia, tremors, autism and schizophrenia and possibly others, as well. However, standard methodologies using microelectrode recordings to monitor the collective (and possible synchronous) activity of neurons in animal models of these diseases typically do not enable the simultaneous monitoring of more that a handful of neurons. Moreover, even methodologies that push this limit cannot guarantee the specific neuronal types of neurons recorded. This latter constraint is paramount because many neurological disorders are typically characterized by an insult that is selective to specific neuronal types, and therefore it is critical to be able to guarantee that one can study exactly those neurons.
In order to overcome these constraints, we opted to use optical imaging of neurons that we can selectively target (using genetic manipulations) to express calcium indicators in our cell type of interest - which is the cholinergic interneuron of the striatum. The receptors activated by the output of these interneurons are therapeutically important in PD, as they were the target of the first available anticholinergic treatment of PD, prior to the advent of dopamine replacement therapy (DRT). Anticholinergics were very effective and are sometimes still used today particularly on young tremulous PD patients.
Thus, our overall objectives of the action is to image molecularly-identified cholinergic interneurons using endoscopic imaging that enables the monitoring of large assemblies of these cells in awake, freely-moving mice. We are initially focused on healthy control animals and at later stages of this action we sutdied mouse models of Parkinson's disease with an emphasis on levodopa induced dyskinesia (that has recently been shown to be accompanied by dysregulation of cholinergic signaling in the striatum). We believe that understanding the collective dynamics of cholinergic interneurons in healthy and diseased mice will lead to novel insights into the disease mechanisms and could potentially identify additional therapeutic targets.
After overcoming several technical setback (poor expression when using viral transfection, a faulty ChAT-Cre mouse that lead to ectopic expression when crossed with a reporter mouse) we completed the funding period with the data set we planned to attain: recordings from molecularly validated CINs in freely moving mice that perform self initiated and operantly conditioned actions. We also began to collect data from 6-OHDA treated mice before and after LID induction.These data will be analyzed and published in the future.
