Neuron heterogeneity and network dynamic control of synaptic responses in the external globus pallidus

点击翻译按钮获取中文摘要

Project Summary/Abstract The external globus pallidus (GPe) is traditionally viewed as a homogenous relay nucleus in the movement- suppressing indirect pathway but is now known to be more complex. Indirect pathway striatopallidal neurons provide transient inhibition to GPe neurons expressing Parvalbumin (PV), but direct pathway striatal neurons also inhibit the GPe, targeting primarily Npas1 neurons. PV and Npas1 neurons have different downstream targets and are interconnected by a network of local axon collaterals. In addition, both cell groups exhibit intrinsic oscillations and fire rapidly, even in brain slices. In healthy animals, GPe neurons exhibit little to no spike-time correlations, which emerge in Parkinsonian states and could be attributed to local connectivity or common striatopallidal input. The goal of this proposal is to investigate the mechanisms by which the local collateral network in the GPe (1) shapes the spontaneous pattern of GPe neuron firing in the absence of striatal input, and (2) controls the spiking responses of GPe neurons to synaptic input from direct and indirect pathway striato-pallidal neurons. To address these questions, this proposal is divided into two aims. (Aim 1) Determine how the GPe network forms its own pattern of firing. Synaptic potentials from local axon collaterals and their effect on the firing patterns of PV and Npas1 neurons will be measured in slice preparations using perforated patch-clamp recordings before and after blocking synaptic transmission in local collaterals with GABA receptor antagonists. The spiking dynamics of PV and Npas1 neurons can be summarized in the dynamics of their oscillation phase. Using a phase resetting model, the effect of simulated local IPSP barrages on the phase dynamics of PV and Npas1 neurons will be determined, providing a mechanism for their influence on firing patterns. (Aim 2) Determine how the GPe networks shape spiking responses to striato-pallidal inputs. Indirect pathway signals will be mimicked using a brief Archaerhodopsin (Arch) activation in PV neurons, and Arch activation in Npas1 neurons will be used to mimic direct pathway signals. The spiking responses of the same cell type (directly inhibited by Arch and indirectly disinhibited by the local network) and the other cell type (disinhibited by the network only) will be measured. The effect of the local network on the spiking responses of cells to direct inhibition by Arch will be isolated by subtracting the measurements repeated in the presence of GABA antagonists. The phase resetting model will be used to provide a mechanism for how the GPe network shapes spiking responses to striato-pallidal signals. Under this fellowship, the applicant will continue his training in slice electrophysiology and coding, honing his skills as an experimentalist and his quantitative approach to research. The applicant will develop a strong mathematical framework by training under his sponsor and a supporting group of computationally oriented neuroscientists. The applicant will also develop skills as a mentor by training undergraduate students.