Plasticity and role of cholinergic interneuron-driven striatal microcircuits in basal ganglia pathophysiological functioning – OptoChAT-Park

The hypothesis that drives this project is that the anatomical remodeling of striatal microcircuits involving cholinergic interneurons is critically important for the pathological functioning of the basal ganglia (BG) network and for mediating the major symptoms of Parkinson’s disease (PD). The striatum, the main BG input structure, is composed of two distinct populations of projection neurons, also known as medium spiny neurons (MSNs). MSNs fall into two main classes, the striatonigral and the striatopallidal MSNs, according to their axonal projections. In PD, the reduced dopamine (DA) input to the striatum disrupts the balance between MSNs outflow: striatonigral MSNs become hypoexcitable whereas striatopallidal MSNs become hyperexcitable. As the tuning of these two striatofugal pathways is determinant for the normal execution of motor command, unraveling the mechanisms that lead to imbalanced activity of MSNs when the level of DA falls is a fundamental issue. Both direct DA-mediated and indirect mechanisms are involved, since DA loss induces profound adaptive changes in the striatal network. Striatal cholinergic interneurons, although in small numbers, are good candidates to contribute to MSNs dysfunction: (1) due to their widespread connections primary directed to both types of MSNs, they are potent modulators of their excitability and, (2) the efficacy of anticholinergic agents, one of the earliest therapies for PD not used anymore because of their side-effects, suggests an increased cholinergic tone in this disease. Although consistent with the cornerstone theory of DA/acetylcholine antagonist interplay, data about hypercholinergy are controversial and the relation between acetylcholine and the opposite changes in MSNs activity in PD state remain enigmatic. Using the trans-synaptic spread of rabies virus, we recently showed, for the first time, that striatal microcircuits involving cholinergic interneurons are susceptible of structural remodeling in parkinsonian state that could explain the pathological impact of acetylcholine on striatal output. The objective of this project is to demonstrate the impact of such remodeling on striatal functions and BG-related behaviors. To achieve this goal, we will take advantage of technical tools recently developed in the field of neuroanatomical tract-tracing and genetically encoded photostimulation methods, combined with in vitro and in vivo electrophysiology and behavioral approaches. Using these complementary techniques, we will address the following issues in control and parkinsonian mice: (1) do cholinergic interneurons belong to a same population which controls both the striatopallidal and the striatonigral MSNs or are they segregated according to the type of MSNs they are targeting. By specifically manipulating the cholinergic interneuron network with optogenetic tools, we will then assess (2) whether the anatomical reorganization of the cholinergic network observed in PD condition contributes to the cell type-specific modifications of MSNs activity and (3) the functional consequences of cholinergic activity downstream the striatum on BG output nuclei and on the behaviors mediated by BG.
This project will unravel an unappreciated aspect of cholinergic striatal plasticity, determinant for the imbalanced striatal outflow in parkinsonian state. Its strength relies on the unique combination of multiple levels of analysis, going from micro- to macrocircuits up to integrated behaviors, to determine the specific role of striatal cholinergic microcircuits in normal condition and in PD. This is crucial to develop new mechanistic-based therapies in PD and guide future researches toward a more efficient way to target striatal cholinergic system for restoring MSNs functional balance and, ultimately, motor command.