Xiao_2015_J.Neurosci_35_3734

The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either alpha4beta2 or alpha7 nAChRs. STN neurons containing alpha4beta2 nAChRs (alpha4beta2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing alpha7 nAChRs (alpha7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of alpha4beta2 neurons but exerted strong inhibition in 58% of alpha7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects alpha4beta2 nAChRs in STN: this treatment increased the number of alpha4beta2 neurons, upregulated alpha4-containing nAChR number and sensitivity, and enhanced the basal firing rate of alpha4beta2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving alpha4beta2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons.